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Su, Bor-Chyuan, Giun-Yi Hung, Yun-Chieh Tu, Wei-Chen Yeh, Meng-Chieh Lin, and Jyh-Yih Chen. "Marine Antimicrobial Peptide TP4 Exerts Anticancer Effects on Human Synovial Sarcoma Cells via Calcium Overload, Reactive Oxygen Species Production and Mitochondrial Hyperpolarization." Marine Drugs 19, no. 2 (February 5, 2021): 93. http://dx.doi.org/10.3390/md19020093.
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Synovial sarcoma is a rare but aggressive soft-tissue sarcoma associated with translocation t(X;18). Metastasis occurs in approximately 50% of all patients, and curative outcomes are difficult to achieve in this group. Since the efficacies of current therapeutic approaches for metastatic synovial sarcoma remain limited, new therapeutic agents are urgently needed. Tilapia piscidin 4 (TP4), a marine antimicrobial peptide, is known to exhibit multiple biological functions, including anti-bacterial, wound-healing, immunomodulatory, and anticancer activities. In the present study, we assessed the anticancer activity of TP4 in human synovial sarcoma cells and determined the underlying mechanisms. We first demonstrated that TP4 can induce necrotic cell death in human synovial sarcoma AsKa-SS and SW982 cells lines. In addition, we saw that TP4 initiates reactive oxygen species (ROS) production and downregulates antioxidant proteins, such as uncoupling protein-2, superoxide dismutase (SOD)-1, and SOD-2. Moreover, TP4-induced mitochondrial hyperpolarization is followed by elevation of mitochondrial ROS. Calcium overload is also triggered by TP4, and cell death can be attenuated by a necrosis inhibitor, ROS scavenger or calcium chelator. In our experiments, TP4 displayed strong anticancer activity in human synovial sarcoma cells by disrupting oxidative status, promoting mitochondrial hyperpolarization and causing calcium overload.
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Su, Bor-Chyuan, Chao-Chin Li, Jiun-Lin Horng, and Jyh-Yih Chen. "Calcium-Dependent Calpain Activation-Mediated Mitochondrial Dysfunction and Oxidative Stress Are Required for Cytotoxicity of Epinecidin-1 in Human Synovial Sarcoma SW982 Cells." International Journal of Molecular Sciences 21, no. 6 (March 19, 2020): 2109. http://dx.doi.org/10.3390/ijms21062109.
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Synovial sarcoma is a rare but highly malignant and metastatic disease. Despite its relative sensitivity to chemotherapies, the high recurrence and low 5-year survival rate for this disease suggest that new effective therapeutic agents are urgently needed. Marine antimicrobial peptide epinecidin-1 (epi-1), which was identified from orange-spotted grouper (Epinephelus coioides), exhibits multiple biological effects, including bactericidal, immunomodulatory, and anticancer activities. However, the cytotoxic effects and mechanisms of epi-1 on human synovial sarcoma cells are still unclear. In this study, we report that epi-1 exhibits prominent antisynovial sarcoma activity in vitro and in a human SW982 synovial sarcoma xenograft model. Furthermore, we determined that calcium overload-induced calpain activation and subsequent oxidative stress and mitochondrial dysfunction are required for epi-1-mediated cytotoxicity. Interestingly, reactive oxygen species (ROS)-mediated activation of extracellular signal-regulated kinase (ERK) plays a protective role against epi-1-induced cytotoxicity. Our results provide insight into the molecular mechanisms underlying epi-1-induced cell death in human SW982 cells.
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Delaloge, S., A. Yovine, A. Taamma, M. Riofrio, E. Brain, E. Raymond, P. Cottu, et al. "Ecteinascidin-743: A Marine-Derived Compound in Advanced, Pretreated Sarcoma Patients—Preliminary Evidence of Activity." Journal of Clinical Oncology 19, no. 5 (March 1, 2001): 1248–55. http://dx.doi.org/10.1200/jco.2001.19.5.1248.
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PURPOSE: To report the activity of the chemotherapeutic agent ecteinascidin-743 (ET-743) in advanced pretreated sarcoma patients observed during a phase I study and a named-patient basis, compassionate use program. PATIENTS AND METHODS: Twenty-nine pretreated, advanced soft tissue sarcoma (STS) and bone sarcoma patients consecutively seen in our centers were included, 12 from a phase I trial and 17 from a compassionate use program cohort. Patients were treated every 3 weeks at either 1,200 μg/m2 (six patients), 1,500 μg/m2 (the recommended dose, 22 patients), or 1,800 μg/m2 (the maximum-tolerated dose, one patient), given as a 24-hour infusion every 3 to 4 weeks. RESULTS: Fifteen men and 14 women were treated. The median patient age was 46 years (range, 16 to 71 years), with a median World Health Organization performance status of 1 (range, 0 to 2). Twenty-five patients had STS, three had osteosarcoma, and one had Ewing’s sarcoma, and all had progressive disease at accrual. Fifteen patients had bulky disease, and 14 had clinical resistance to anthracyclines. A total of 136 treatment cycles were administered (median per patient, five cycles; range, one to 12 cycles). Transient grade 3 and 4 transaminitis was reported in 24% and 5% of cycles, respectively, grade 3 to 4 neutropenia occurred in 32% of cycles, with concomitant sporadic grade 3 to 4 thrombocytopenia in 5.1% of cycles. Grade 2 to 3 asthenia occurred in 21% of cycles. There were two partial responses (PRs) in STS patients and two PRs in osteosarcoma patients. Two minor responses and 10 disease stabilizations were seen. Median duration of response was 10.5 months (range, 2.8 to 15 months), and mean duration of stabilization was 5.2 months. CONCLUSION: ET-743 has activity in advanced, highly pretreated STS and osteosarcoma patients and warrants further trials to establish the extent of its activity in this setting.
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Garcia-Carbonero, R., J. G. Supko, J. Manola, M. V. Seiden, D. Harmon, D. P. Ryan, M. T. Quigley, et al. "Phase II and Pharmacokinetic Study of Ecteinascidin 743 in Patients With Progressive Sarcomas of Soft Tissues Refractory to Chemotherapy." Journal of Clinical Oncology 22, no. 8 (April 15, 2004): 1480–90. http://dx.doi.org/10.1200/jco.2004.02.098.
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Purpose To assess the efficacy of the marine-derived alkaloid ecteinascidin 743 (ET-743) in patients with soft tissue sarcomas that progressed despite prior conventional chemotherapy and to characterize the pharmacokinetic profiles of ET-743 in this patient population. Patients and Methods Thirty-six previously treated soft tissue sarcoma patients from three institutions received ET-743 as a 24-hour continuous intravenous (IV) infusion at a dose of 1,500 μg/m2 every 3 weeks. Pharmacokinetic studies were also performed. Patients were restaged every two cycles for response by objective criteria. Results Objective responses were observed in three patients, with one complete response and two partial responses, for an overall response rate of 8% (95% CI, 2% to 23%). Responses were durable for up to 20 months. Two minor responses (43% and 47% tumor reduction) were observed, for an overall clinical benefit rate of 14%. The predominant toxicities were neutropenia and self-limited transaminitis of grade 3 to 4 severity in 34% and 26% of patients, respectively. The estimated 1-year time to progression and overall survival rates were 9% (95% CI, 3% to 27%) and 53% (95% CI, 39% to 73%), respectively. The maximum observed plasma concentration and total plasma clearance of ET-743 (mean ± standard deviation), 1.04 ± 0.48 ng/mL and 35.6 ± 16.2 L/h/m2, respectively, were consistent with previously reported values from phase I studies of the drug given as a 24-hour IV infusion. Conclusion ET-743 is a promising new option for the management of several histologic subtypes of sarcoma. Durable objective responses were obtained in a subset of sarcoma patients with disease progression despite prior chemotherapy. Additionally, the relatively high survival rate noted in this series of previously treated patients further justifies development of this agent.
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Althagbi, Hanan I., Walied M. Alarif, Khalid O. Al-Footy, and Ahmed Abdel-Lateff. "Marine-Derived Macrocyclic Alkaloids (MDMAs): Chemical and Biological Diversity." Marine Drugs 18, no. 7 (July 17, 2020): 368. http://dx.doi.org/10.3390/md18070368.
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The curiosity and attention that researchers have devoted to alkaloids are due to their bioactivities, structural diversity, and intriguing chemistry. Marine-derived macrocyclic alkaloids (MDMAs) are considered to be a potential source of drugs. Trabectedin, a tetrahydroisoquinoline derivative, has been approved for the treatment of metastatic soft tissue sarcoma and ovarian cancers. MDMAs displayed potent activities that enabled them to be used as anticancer, anti-invasion, antimalarial, antiplasmodial, and antimicrobial. This review presents the reported chemical structures, biological activities, and structure–activity relationships of macrocyclic alkaloids from marine organisms that have been published since their discovery until May 2020. This includes 204 compounds that are categorized under eight subclasses: pyrroles, quinolines, bis-quinolizidines, bis-1-oxaquinolizidines, 3-alkylpiperidines, manzamines, 3-alkyl pyridinium salts, and motuporamines.
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Morgan, J. A., A. Le Cesne, S. Chawla, M. von Mehren, S. Schuetze, P. G. Casali, A. Nieto, Y. Elsayed, M. A. Izquierdo, and G. D. Demetri. "Randomized phase II study of trabectedin in patients with liposarcoma and leiomyosarcoma (L-sarcomas) after failure of prior anthracylines (A) and ifosfamide (I)." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 10060. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.10060.
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10060 Background: Trabectedin, a marine-derived antineoplastic agent, binds to the minor groove of DNA and has previously shown activity in L-sarcomas in single-arm trials. This multicenter, randomized study aimed to characterize the anticancer efficacy with two dosing regimens of trabectedin in pts with treatment-refractory L-sarcomas. Methods: Eligible pts had measurable advanced L-sarcoma, progression despite at least prior A and I, PS 0–1 and adequate organ function. Pts were randomized to IV trabectedin, 1.5 mg/m2, 24h every 3 weeks (q3wk-24h) or 0.58 mg/m2, 3h weekly × 3 on a 28-day cycle (qwk-3h). Primary endpoint is time-to-progression (TTP) and secondary endpoints PFS, overall survival, response, and safety. With 217 events, study provided 90% power to detect a 37% risk reduction in TTP (2-sided 5% significance). Results: 270 pts were randomized as of 5/31/06. Baseline characteristics were comparable: median (range) 2 (1–7) metastatic sites and 2 (1–6) prior regimens; 62% had additional prior agents; 67% had bulky (≥5cm) disease. In the q3wk-24h vs qwk-3h arms median n. cycles were 5 (1–37) vs 2 (1–21); 38% vs 19% received ≥7 cycles. In protocol-specified primary analysis, median (95% CI) TTP was 3.7 (2.1–5.4) vs 2.3 (2.0–3.5) mo [HR: 0.734; p=0.0302] favoring the q3wk-24h arm. Median PFS was 3.3 (2.1–4.6) vs 2.3 (2.0–3.4) mo [HR: 0.755; p=0.0418] and median survival (n=175 events) was 13.8 (12.5–17.9) vs. 11.8 (9.9–13.9) mo [HR: 0.823; p=0.1984]. Benefit from the q3wk-24h arm was more pronounced in pts with central pathology confirmed diagnosis of L-sarcomas. More neutropenia, ↑AST/ALT, emesis and fatigue occurred in the q3wk 24-h. Febrile neutropenia was rare (0.8–1.6%). No cumulative toxicities were noted. Conclusions: Trabectedin can provide clinical benefit to pts with L-sarcoma following failure of all conventional treatment options. Significantly better TTP was noted with the q3wk-24h regimen, although this resulted in somewhat more neutropenia and transaminitis without clinical consequences. No cumulative toxicities were apparent in either arm. Although both dosing regimens are efficacious, there appears to superior disease control with the q3wk-24h arm in this population. [Table: see text]
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Jimeno, Jose, Robert G. Maki, Paolo Casali, Glynn Faircloth, Nerea Martinez, Antonio Nieto, Salvador Cañigueral, and Kenneth Rinehart. "Therapeutic impact of ET-743 (Yondelis; trabectidin), a new marine-derived compound, in sarcoma." Current Opinion in Orthopaedics 14, no. 6 (December 2003): 419–28. http://dx.doi.org/10.1097/00001433-200312000-00011.
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Pierce, J. H., and S. A. Aaronson. "Myeloid cell transformation by ras-containing murine sarcoma viruses." Molecular and Cellular Biology 5, no. 4 (April 1985): 667–74. http://dx.doi.org/10.1128/mcb.5.4.667-674.1985.
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BALB and Harvey murine sarcoma viruses contain ras transforming genes capable of altering the proliferation and differentiation of cells within the erythroid and lymphoid lineages (W. D. Hankins and E. M. Scolnick, Cell 26:91-97, 1981; J. H. Pierce and S. A. Aaronson, J. Exp. Med. 156:873-887, 1982; E. M. Scolnick et al., Mol. Cell. Biol. 1:68-74). The present studies demonstrate hematopoietic targets of ras-containing viruses within the myeloid lineage. Diffuse colonies were induced by BALB or Harvey marine sarcoma virus infection of murine bone marrow cells. Generally, these colonies were made up of relatively mature macrophages which exhibited increased self-renewal capacity but eventually underwent terminal differentiation in culture. Cells from one BALB murine sarcoma virus-induced colony displayed phenotypic markers of more immature myelomonocytic cells. This colony, designated BAMC1, readily established as a continuous cell line and was highly malignant in vivo. Exposure of these cells to 12-O-tetradecanoylphorbol-13-acetate led to the induction of a more mature myeloid phenotype, which was associated with decreased growth potential in vitro and in vivo. The effects of the inducing agent were not mediated by an alteration in the level of expression of the ras-coded p21 transforming protein. Our present findings extend the spectrum of targets whose growth is altered by ras-containing retroviruses to cells at several stages of differentiation within each of the major hematopoietic lineages.
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Pierce, J. H., and S. A. Aaronson. "Myeloid cell transformation by ras-containing murine sarcoma viruses." Molecular and Cellular Biology 5, no. 4 (April 1985): 667–74. http://dx.doi.org/10.1128/mcb.5.4.667.
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BALB and Harvey murine sarcoma viruses contain ras transforming genes capable of altering the proliferation and differentiation of cells within the erythroid and lymphoid lineages (W. D. Hankins and E. M. Scolnick, Cell 26:91-97, 1981; J. H. Pierce and S. A. Aaronson, J. Exp. Med. 156:873-887, 1982; E. M. Scolnick et al., Mol. Cell. Biol. 1:68-74). The present studies demonstrate hematopoietic targets of ras-containing viruses within the myeloid lineage. Diffuse colonies were induced by BALB or Harvey marine sarcoma virus infection of murine bone marrow cells. Generally, these colonies were made up of relatively mature macrophages which exhibited increased self-renewal capacity but eventually underwent terminal differentiation in culture. Cells from one BALB murine sarcoma virus-induced colony displayed phenotypic markers of more immature myelomonocytic cells. This colony, designated BAMC1, readily established as a continuous cell line and was highly malignant in vivo. Exposure of these cells to 12-O-tetradecanoylphorbol-13-acetate led to the induction of a more mature myeloid phenotype, which was associated with decreased growth potential in vitro and in vivo. The effects of the inducing agent were not mediated by an alteration in the level of expression of the ras-coded p21 transforming protein. Our present findings extend the spectrum of targets whose growth is altered by ras-containing retroviruses to cells at several stages of differentiation within each of the major hematopoietic lineages.
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Pecoraro, Camilla, Francesca Terrana, Giovanna Panzeca, Barbara Parrino, Stella Cascioferro, Patrizia Diana, Elisa Giovannetti, and Daniela Carbone. "Nortopsentins as Leads from Marine Organisms for Anticancer and Anti-Inflammatory Agent Development." Molecules 28, no. 18 (September 5, 2023): 6450. http://dx.doi.org/10.3390/molecules28186450.
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The marine environment is an excellent source of molecules that have a wide structural diversity and a variety of biological activities. Many marine natural products (MNPs) have been established as leads for anticancer drug discovery. Most of these compounds are alkaloids, including several chemical subclasses. In this review, we focus on the bis-indolyl alkaloid Nortopsentins and their derivatives with antiproliferative properties. Nortopsentins A–C were found to exhibit in vitro cytotoxicity against the P388 murine leukaemia cell line. Their structural manipulation provided a wide range of derivatives with significant anti-tumour activity against human cell lines derived from different cancer types (bladder, colon, gastric, CNS, liver, lung, breast, melanoma, ovarian, pancreatic, prostate, pleural mesothelioma, renal, sarcoma, and uterus). In vivo assays on animal models also proved that Nortopsentins and related bis-indolyl compounds have potent anti-inflammatory activity. These remarks set the foundation for future investigations into the development of new Nortopsentin derivatives as new anticancer and anti-inflammatory agents.
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Shamai, Sivan, and Ofer Merimsky. "Trabectedin for advanced soft tissue sarcoma: Ten-year real-life perspective." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 11060. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.11060.
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11060 Background: Trabectedin is a marine - derived chemotherapy, which lately received FDA approval for use in anthracycline resistant advanced soft tissue sarcoma (STS), especially liposarcoma and leiomyosarcoma (L-sarcomas). Methods: We report our ten-year real-life experience with trabectedin, 1.5mg/m2/d c.i.v. q3w till progression, regarding safety and efficacy in a cohort of 86 patients (24-83y). Liposarcoma was the diagnosis in 46% , leiomyosarcoma in 43%. Results: A total of 703 cycles of Trabectedin were given, with a median of five cycles per patient (range 1-59). Median overall survival (mOS) was 11 months for liposarcoma patients (range 1-63), and 15 months for leiomyosarcoma patients (range 1-35). There was no statistically significant difference in progression free survival (PFS), when stratified according to previous treatment lines given. Trabectedin exhibited a favorable safety profile, with only 22% requiring dose reductions. Grade 3 and more toxicity were noted in 25% of the patients, mostly myelosuppression. There was no treatment related death. Conclusions: In contrast to former trials, our retrospective data represents real life experience with Trabectedin, and includes patients with diverse age, histology, performane status, prior treatments and tumor burden. The group includes 10 patients (11.6%) who received Trabectedin as first line (Either due to congestive heart failure or to rapid progression following adjuvant Doxorubicin and Ifosfamide), 10 patients (11.6%) were above age 70, nine (10.5%) had histologies other than liposarcoma or leiomyosarcoma, and 23 (26.7%) had ECOG PS of 2 or higher. Trabectedin is a safe and effective drug in advanced high grade STS. Further research is needed to identify which patients will benefit most.
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Hayashi, Keita, Peter Walde, Tatsuhiko Miyazaki, Kenshi Sakayama, Atsushi Nakamura, Kenji Kameda, Seizo Masuda, Hiroshi Umakoshi, and Keiichi Kato. "Active Targeting to Osteosarcoma Cells and Apoptotic Cell Death Induction by the Novel Lectin Eucheuma serra Agglutinin Isolated from a Marine Red Alga." Journal of Drug Delivery 2012 (December 27, 2012): 1–11. http://dx.doi.org/10.1155/2012/842785.
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Previously, we demonstrated that the novel lectin Eucheuma serra agglutinin from a marine red alga (ESA) induces apoptotic cell death in carcinoma. We now find that ESA induces apoptosis also in the case of sarcoma cells. First, propidium iodide assays with OST cells and LM8 cells showed a decrease in cell viability after addition of ESA. With 50 μg/ml ESA, the viabilities after 24 hours decreased to 54.7 ± 11.4% in the case of OST cells and to 41.7 ± 12.3% for LM8 cells. Second, using fluorescently labeled ESA and flow cytometric and fluorescence microscopic measurements, it could be shown that ESA does not bind to cells that were treated with glycosidases, indicating importance of the carbohydrate chains on the surface of the cells for efficient ESA-cell interactions. Third, Span 80 vesicles with surface-bound ESA as active targeting ligand were shown to display sarcoma cell binding activity, leading to apoptosis and complete OST cell death after 48 hours at 2 μg/ml ESA. The findings indicate that Span 80 vesicles with surface-bound ESA are a potentially useful drug delivery system not only for the treatment of carcinoma but also for the treatment of osteosarcoma.
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Ponnusamy, Nirmaladevi, Rajasree Odumpatta, Pavithra Damodharan, and Mohanapriya Arumugam. "Computational investigation of marine bioactive compounds reveals frigocyclinone as a potent inhibitor of Kaposi’s Sarcoma Associated Herpesvirus (KSHV) targets." Biomedical & Pharmacology Journal 12, no. 3 (August 21, 2019): 1289–302. http://dx.doi.org/10.13005/bpj/1757.
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In the present study, in silico analysis was employed to identify the action of marine bioactive compounds against KSHV targets. Virulence factor analysis of KSHV from literature review, three proteins LANA1, vIRF3/LANA2 and PF-8 were identified as putative drug targets. The quality of protein structures play a significant role in the experimental structure validation and prediction, where the predicted structures may contain considerable errors was checked by SAVES v5.0 servers. By virtual screening four potential bioactive compounds Ascorbic acid, Salicylihalamide A, Salicylihalamide B and Frigocyclinone were predicted. One of the potential compounds of Frigocyclinone has acting against KSHV proteins. Hence, determined as the good lead molecule against KSHV. Molecular dynamic simulation studies revealed the stability of LANA1- Frigocyclinone complex and it could be a futuristic perspective chemical compound for Kaposi’s sarcoma.
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Gordon, Erlinda Maria, Victoria S. Chua, Ted T. Kim, Neal Shiv Chawla, Don Arlen Brigham, Ishrat Bhuiyan, Mark Agulnik, Warren Allen Chow, and Sant P. Chawla. "A phase 2 study using ipilimumab, nivolumab, and trabectedin for previously untreated metastatic soft tissue sarcoma." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 11562. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.11562.
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11562 Background: Sarcoma cells are most immunogenic earlier in the disease course and before treatment when the immune system can recognize and destroy them. Hypothesis: Immune checkpoint inhibitors would be most effective when given to previously untreated patients with metastatic soft tissue sarcoma. Methods: Eligible patients for this Phase 2 study are previously untreated patients ≥ 18 years of age with unresectable or metastatic soft tissue sarcoma, with measurable disease by RECIST v1.1. Immune checkpoint inhibitors Ipilimumab (I) and Nivolumab (N) were given with Trabectedin (T), a marine derived alkaloid with defined doses of I (1 mg/kg i.v. q 12 weeks), N (3 mg/kg i.v. q 2 weeks), and T (1.2 mg/m2 i.v. q 3 weeks). Primary endpoints: (1) Objective response rate by RECIST v1.1 via CT scan or MRI, (2) Progression-free survival (PFS): from first day of treatment to disease progression or death due to any cause; otherwise, it is censored at the time of last follow-up, and (3) Overall survival: from first day of treatment to death due to any cause; otherwise, it is censored at the time of last follow-up. Results: There were eighty-two evaluable subjects, having completed the first cycle of I, N, and T and have had a CT or MRI scan at the 6-week follow-up period. Best Overall Response by RECIST v1.1 = 7 CR (2 surgical CR), 9 PR, 54 SD, and 12 PD. Disease control rate was 85.4%. The median PFS was >6.4 (range: 0-32) months; 6-month PFS rate: 57.3%. The median OS was >12.0 (0-38) months; 6-month OS rate: 78.8%. Safety analysis: The most common Grade 3 TRAEs include increased ALT (26), anemia (11), increased AST (9), and fatigue (8). Common Grade 4 TRAEs include thrombocytopenia (2), increased AST (2), increased ALT (2), and increased CPK (2). There was one Grade 5 TRAE of rhabdomyolysis (1). Conclusions: Taken together, these results suggest that first-line combinatorial therapy with I, N, and T are (1) synergistic, and (2) may be equal or superior to, and safer than, standard first line therapy for advanced/metastatic soft tissue sarcoma. Clinical trial information: NCT03138161.
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Fares Amer, Nasrin, and Tal Luzzatto Knaan. "Natural Products of Marine Origin for the Treatment of Colorectal and Pancreatic Cancers: Mechanisms and Potential." International Journal of Molecular Sciences 23, no. 14 (July 21, 2022): 8048. http://dx.doi.org/10.3390/ijms23148048.
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Gastrointestinal cancer refers to malignancy of the accessory organs of digestion, and it includes colorectal cancer (CRC) and pancreatic cancer (PC). Worldwide, CRC is the second most common cancer among women and the third most common among men. PC has a poor prognosis and high mortality, with 5-year relative survival of approximately 11.5%. Conventional chemotherapy treatments for these cancers are limited due to severe side effects and the development of drug resistance. Therefore, there is an urgent need to develop new and safe drugs for effective treatment of PC and CRC. Historically, natural sources—plants in particular—have played a dominant role in traditional medicine used to treat a wide spectrum of diseases. In recent decades, marine natural products (MNPs) have shown great potential as drugs, but drug leads for treating various types of cancer, including CRC and PC, are scarce. To date, marine-based drugs have been used against leukemia, metastatic breast cancer, soft tissue sarcoma, and ovarian cancer. In this review, we summarized existing studies describing MNPs that were found to have an effect on CRC and PC, and we discussed the potential mechanisms of action of MNPs as well as future prospects for their use in treating these cancers.
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Saada, Esma, Chahineze Rahal, Isabelle Ray Coquard, Antoine Italiano, Christine Chevreau, Nicolas Isambert, Binh Bui, et al. "Rechallenge with trabectedin in patients with locally advanced or metastatic soft tissue sarcoma following drug holiday: The experience of the French Sarcoma Group (FSG)." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 10062. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.10062.
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10062 Background: Trabectedin (T) is a marine-derived alkaloid used to treat advanced soft tissue sarcomas (STS) after ifosfamide and/or anthracyclins failure. Since then, the FSG evaluated the clinical benefit in re-administrating T after an initial hold, either medically indicated or upon patient’s request. Methods: Following an online request, clinical and histopathological data were collected from six centers of the FSG who declared to have rechallenged patients. Baseline data were collected and analyze will be used. Results: From 1999 to 2011, 49 pts with T drug holiday have been identified (26 male/ 23 female), with a median age of 50 y [23-75]. Most frequent histotypes were: myxoid liposarcoma (18, 36.7%), leiomyosarcomas (13, 26.5 %) and well-differentiated/dedifferentiated liposarcoma (9, 18%). WHO grade were 1 in 14 (29%), 2 in 19 (39%) and 3 in 5 (10%) pts respectively. Patients who had a maximum of 2, 3 or 4 therapeutic sequences (TS) with T (drug-holiday and rechallenge) were 41/49 ,7/49 and 1/49 respectively. Median number of cycles for 1, 2, 3 and 4 TS were 7 [3-21], 6 [2-30], 6 [2-9] and 6. Median total number of cycles was 15 [6-43]. Median duration of drug-holiday for 1, 2 and 3 TS were 11 [3-91], 7 [2-29] and 4 months [1-5]. Grade 3-4 toxicities incidence decreased with the number of TS (occurred in 36%, 29%, 14% and 0% of pts with 1, 2, 3 and 4 TS) as well as mean T dose per cycle (1.3 mg/m², 1.2 mg/m², 1.1 mg/m² and 1.1 mg/m² for TS 1, 2, 3, 4). Efficacy decreased with number of TS (Number of CR/PR/SD/PD were 1 (2%)/15 (31%)/33 (67%)/0 for TS1; 0/4 (8%)/29 (59%)/16 (3%) for TS2; 0/1 (14%)/2 (29%)/4 (57%) for TS3 and 0/0/0/1(100%) for TS4). Median overall survival was 5.0 y [2.7-7.3] since T introduction, and 1.5 y [0.1-4.8], 0.8 y [0.5-1.3] and 0.6 y following 2nd, 3rd and 4th T reintroduction respectively. Objective response after TS2 were seen in 4 cases of grade 1 sarcomas. Conclusions: Due to the lack of cumulative toxicities over time with T, its rechallenging in responding patients to T (no progression under T) have to be considered in advanced STS.
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Grosso, F., G. D. Demetri, J. Y. Blay, I. Judson, A. Le Cesne, C. Spreafico, J. Jimeno, S. Pilotti, M. D’Incalci, and P. G. Casali. "Patterns of tumor response to trabectedin (ET743) in myxoid liposarcomas." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 9511. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.9511.
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9511 Background: Trabectedin (T) is a marine-derived agent found to be active in ovarian cancer and sarcomas. Among sarcomas, activity has been notable in leiomyosarcomas and liposarcomas. Since liposarcomas are a heterogeneous group, including well/de-differentiated, pleomorphic, and myxoid/round cell subtypes, we have noted particularly interesting patterns of responsiveness to T in myxoid liposarcomas, which are associated with t(12;16)(q13;p11) or t(12;22)(q13;q12) chromosomal translocations, resulting in CHOP-TLS or CHOP-EWS fusion products. Methods: 15 cases of myxoid liposarcomas treated with T at the Istituto Nazionale Tumori, Milan, were retrospectively reviewed. In most cases, T was given as a 24-hr continuous infusion every 21 days, at dose levels from 1.0 to 1.5 mg/sqm. 108 courses were delivered, with a median of 5 courses per patient (range 2–20). Observations made in this series were shared with five other institutions having treated myxoid liposarcoma cases with T, all of which also report a significant response rate, for a total of 44 pts. A centralized radiological review of all pts is ongoing. Results: In the Milan series, early tissue alterations in tumors were observed in 14 patients, mainly with a decrease in tumor density on CT scan and/or decrease in contrast enhancement on MRI. These changes were followed by tumor shrinkage amounting to a conventional PR/CR in 8 (pending final review), while 3 others have responses which continue to evolve. Progression followed treatment interruption in one patient, with a minor response occurring at treatment restart. Treatment is continuing in 12 pts (median duration of therapy in excess of 5 months). Further results of the central radiological review from all centres will be reported. Conclusions: Tumor response to T seen in myxoid liposarcoma appears to be marked by early radiological alterations in tumor tissue, often preceding tumor shrinkage, which may be delayed. A selective mechanism of action for this chromosomal translocation-related sarcoma is suggested, and is being actively investigated at the moment. [Table: see text]
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Dileo, P., F. Grosso, M. Casanova, J. Jimeno, S. Marsoni, R. Sanfilippo, M. Podda, S. Ferrari, R. Bertulli, and P. G. Casali. "Trabectedin (T) in metastatic Ewing's family tumors (EFT) patients (pts) progressing after standard chemotherapy." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 10040. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.10040.
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10040 Background: T is a formerly marine-derived agent which is active in human cancers, such as ovarian cancer and adult soft tissue sarcomas (STS). Efficacy of T in pts with unresectable/metastatic pretreated advanced STS was demonstrated in phase II settings. Leiomyosarcoma and liposarcoma were shown to be sensitive, with myxoid liposarcoma being exceedingly responsive. Data are lacking on “small round blue cell” sarcomas, including EFT. In 2000 a phase II study was launched by SENDO in a sarcoma population including EFT. At Istituto Nazionale Tumori, Milano, Italy, some EFT pts were treated after the completion of this study. We analyzed treatment efficacy in EFT pts treated within these two settings. Methods: Overall 15/29 of the pts were female, and age ranged from 15 to 55 years. Pts received T at a starting dose between 1,650 and 1,100 mcg/sqm every 3 weeks as 24-hour or 3-hour infusion. Each pt received at least 2 cycles of treatment, except in case of disease progression or unacceptable toxicity. Tumor response was assessed by RECIST criteria after the first 2 cycles and then every other cycle. Dose reductions were based on the worst toxicity (hematological or non-hematological) in the previous cycle. Results: As of December 2006, 20 pts were treated in the Phase II study, and 9 on a compassionate use basis. Two pts were still on therapy. A total of 79 treatment cycles (2–14 per pt) were administered. Three pts (10.3%) demonstrated a partial response, 3 had a minor response (10.3%), and 4 (13.7%) stable disease. PFS rate at 6 months was 25%. The most common all-causality AEs were acute reversible liver toxicity, fatigue, and myelosuppression. Following the introduction of steroid pre-medication, thrombocytopenia and fatigue were less frequent. Conclusions: In this cohort, T was overall well tolerated and showed antitumor activity in pts with advanced EFT. This calls for further evaluation of this compound, alone or in combination, in pts suffering from EFT. No significant financial relationships to disclose.
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Souid, Soumaya, Dorra Aissaoui, Najet Srairi-Abid, and Khadija Essafi-Benkhadir. "Trabectedin (Yondelis®) as a Therapeutic Option in Gynecological Cancers: A Focus on its Mechanisms of Action, Clinical Activity and Genomic Predictors of Drug Response." Current Drug Targets 21, no. 10 (July 28, 2020): 996–1007. http://dx.doi.org/10.2174/1389450121666200128161733.
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The use of predictive biomarkers provides potential individualized cancer therapeutic options to prevent therapy failure as well as serious toxicities. Several recent studies showed that predictive and prognostic biomarkers are a notable personalized strategy to improve patients’ care in several cancers. Trabectedin (Yondelis®) is a cytotoxic agent, derived from a marine organism, harbouring a significant antitumor activity against several cancers such as soft tissue sarcoma, ovarian, and breast cancers. Recently and with the advent of molecular genetic testing, BRCA mutational status was found as an important predictor of response to this anticancer drug, especially in gynecological cancers. The aim of this updated review is to discuss the mechanisms of action of trabectedin against the wellknown cancer hallmarks described until today. The current advances were also examined related to genomic biomarkers that can be used in the future to predict the efficacy of this potent anticancer natural molecule in various gynecological cancers.
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Sanfilippo, Roberta, Giacomo Giulio Baldi, Elena Fumagalli, Andrea Marrari, Rossella Bertulli, Elena Palassini, Silvia Stacchiotti, Michela Libertini, and Paolo Giovanni Casali. "Safety of trabectedin (T) in elderly patients (pts) with advanced soft tissue sarcoma (STS)." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 10576. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.10576.
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10576 Background: T is a marine-derived cytoxic alkaloid approved in the European Union for further-line chemotherapy of advanced STS. Most common side effects are fatigue, neutropenia and transient transaminitis. Overall the drug is well tolerated with no cumulative toxicity. Studies in elderly pts are lacking. Methods: We retrospectively reviewed all pts ≥65 year-old, with pre-treated advanced STS, who received T at our Institution from January 2002 to January 2013, focusing on tolerability. All patients received premedication with dexamethasone 4 mg p.o. bid 24 hours prior to T administration. Treatment toxicity was graded according to CTCAE (v 4.0). Results: Fourty-two pts were identified (males = 22, females = 20; median age = 69 years, range 65-82; ECOG PS 0 = 1 pt, 1= 38 pts and 2-3= 3 pts; main histotypes = 22 liposarcoma: 12 myxoid-round cell liposarcoma, 10 well/dedifferentiated liposarcoma, 17 leiomyosarcoma, 2 synovial sarcoma, 4 others; disease extent = 34 metastatic and 8 locally advanced; median line of administration of T= 3rd, range 1st-5th; median T dose = 2.2 mg, range = 2.7-1.7 mg). A total of 319 cycles were administered (median 6, range = 1-23). Starting dose was 1.3 mg/mq in 37 pts and 1.1 mg in 5 pts. The most common side effects were: fatigue (all grades: 19% of cycles), reversible myelosuppression, mainly neutropenia (grade 3-4: 50%), transient transaminitis (grade 3-4: 21%). Eighteen pts needed a dose reduction: inter-cycle transient transaminitis (3 pts), neutropenia ( 13 pts), asthenia (2 pts). In 7 patients, cycles needed to be delayed as well. Three pts interrupted T due to toxicity: grade 3 thrombocytopenia in 1 pt and grade 4 neutropenia in 2 pts. Conclusions: This retrospective analysis confirms that T is well tolerated in elderly pts. No major differences were found in the safety profile compared to historical controls, except a higher incidence of myelosuppression, which however was not influential on subsequent T administration.
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Dembitsky, Valery, Tatyana Gloriozova, and Vladimir Poroikov. "Antitumor Profile of Carbon-Bridged Steroids (CBS) and Triterpenoids." Marine Drugs 19, no. 6 (June 3, 2021): 324. http://dx.doi.org/10.3390/md19060324.
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This review focuses on the rare group of carbon-bridged steroids (CBS) and triterpenoids found in various natural sources such as green, yellow-green, and red algae, marine sponges, soft corals, ascidians, starfish, and other marine invertebrates. In addition, this group of rare lipids is found in amoebas, fungi, fungal endophytes, and plants. For convenience, the presented CBS and triterpenoids are divided into four groups, which include: (a) CBS and triterpenoids containing a cyclopropane group; (b) CBS and triterpenoids with cyclopropane ring in the side chain; (c) CBS and triterpenoids containing a cyclobutane group; (d) CBS and triterpenoids containing cyclopentane, cyclohexane or cycloheptane moieties. For the comparative characterization of the antitumor profile, we have added several semi- and synthetic CBS and triterpenoids, with various additional rings, to identify possible promising sources for pharmacologists and the pharmaceutical industry. About 300 CBS and triterpenoids are presented in this review, which demonstrate a wide range of biological activities, but the most pronounced antitumor profile. The review summarizes biological activities both determined experimentally and estimated using the well-known PASS software. According to the data obtained, two-thirds of CBS and triterpenoids show moderate activity levels with a confidence level of 70 to 90%; however, one third of these lipids demonstrate strong antitumor activity with a confidence level exceeding 90%. Several CBS and triterpenoids, from different lipid groups, demonstrate selective action on different types of tumor cells such as renal cancer, sarcoma, pancreatic cancer, prostate cancer, lymphocytic leukemia, myeloid leukemia, liver cancer, and genitourinary cancer with varying degrees of confidence. In addition, the review presents graphical images of the antitumor profile of both individual CBS and triterpenoids groups and individual compounds.
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Martinez-Trufero, Javier, Isabel Pajares, Alba Hernandez Garcia, Ana Cebollero, Lourdes Calera, and Antonio Anton. "Efficacy of trabectedin for advanced soft tissue sarcoma (ASTS): A retrospective single center analysis." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): e21509-e21509. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e21509.
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e21509 Background: Trabectedin (Yondelis) is the first marine-derived antineoplastic drug approved in Europe for the treatment of patients with recurrent ASTS or for patients unsuited to receive anthracyclines and ifosfamide. We retrospectively analyzed patients with ASTS treated with trabectedin from Nov. 2006 to April 2012. Methods: Trabectedin was given at the approved dose of 1.5 mg/m2as a 24-h infusion every 3 weeks. An analysis of response rate, time to progression (TTP) and overall survival (OS) and univariate analyses of prognostic factors were performed. Results: Overall,39 patients (24 men) with mostly high-grade (n=29) ASTS with a median age of 57 years (range 20-81) were analyzed. Most had L-type STS (leiomyosarcoma n=10; liposarcoma n=3), undifferentiated pleomorphic sarcoma (n=11), sarcoma NOS (n=5), or synovial STS (n=2). Eight had one of 6 very rare STS. At baseline patients had metastatic (n=21), bulky (n=4) or metastatic/bulky (n=14) disease and were pretreated with a median of 2 prior chemotherapy lines (range: 0-3; 4 patients received adjuvant chemotherapy only), including anthracycline-based chemotherapy (n=30), gemcitabine plus dacarbazine (GEM-DTIC; n=18), other (n=20). Patients received a median of 4 trabectedin cycles (range 1-34). Among 37 evaluable patients best responses as per RECIST were partial response (PR, n=7), stable disease (SD >3 months, n=9, 5 had SD >6 months) and disease progression (n=19), and 5 patients had a decrease in tumor density. Responses to trabectedin and GEM-DTIC did not exclude responses to the other regimen suggesting the feasibility of sequential treatment. After a median follow-up of 9.37 months, median TTP and OS were 4.4 months (95% CI: 3.5-5.4) and 9.7 months (95% CI: 4.5-14.9), respectively. Univariate analyses identified low/medium-grade STS and growth modulation index >1.13 as favorable prognostic factors for TTP, and retroperitoneal/visceral localization, L-type and rare STS and low/medium-grade STS for OS. Conclusions: The results of this real-life retrospective analysis confirmed the findings of previous trials showing that trabectedin is active drug for ASTS.
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Le Cesne, Axel, Isabelle Ray-Coquard, Florence Duffaud, Christine Chevreau, Nicolas Penel, Binh Bui, Sophie Piperno-Neumann, et al. "A large retrospective analysis of trabectedin in 885 patients with advanced soft tissue sarcoma." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 10563. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.10563.
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10563 Background: Trabectedin (Yondelis) is the first marine-derived antineoplastic drug approved in Europe for the treatment of patients with recurrent ASTS or for patients unsuited to receive anthracyclines and ifosfamide. We retrospectively analyzed the RetrospectYon database with patients’ data treated with trabectedin between Jan 2008 - Dec 2011. Methods: Trabectedin was given at the approved dose of 1.5 mg/m2 as a 24-h infusion every 3 weeks. Patients who achieved partial response (PR) or stable disease (SD) after 6 cycles could receive maintaining trabectedin treatment. Uni- and multivariate analyses of prognostic factors were performed. Results: 885 patients (486 women) from 26 centers in France with ASTS with a median age of 54 years (range 12-84) were included. Most had leiomyosarcoma (36%), liposarcoma (18%) or synovial STS (11%). At baseline, performance status (PS) was 0 in 26%, 1 in 47% and >1 in 27% of patients. A median of 4 trabectedin cycles (range 1-28) was given as a 2nd (41%), 3rd (39%) or ≥4th (20% of patients) treatment line. Toxic death and unscheduled re-hospitalization occurred in 0.5% and 8% of patients, respectively.The objective response rate was 15% (6 complete and 127 PR), and SD rate was 45.5% (n=403). After a median follow-up of 22.6 months (range 0.03-51.2), the patients who received trabectedin as 2nd, 3rd or ≥4th line had the median PFS of 4.3, 4.2 and 3.4 months, respectively, and the median OS of 12.9, 12.3 and 9.5 months. Multivariate analysis identified liposarcoma, leiomyosarcoma, angiosarcoma, undifferentiated pleomorphic sarcoma (UPS) and trabectedin line as independent prognostic factors for PFS, and UPS, angiosarcoma, rhabdomyosarcoma, gender, PS and trabectedin line for OS. After 6 cycles, 205 of the 273 patients with non-progressive disease received trabectedin as maintenance treatment and obtained a superior PFS (median 11 vs. 7.2 months, p=0.0001) and OS (median 25.1 vs. 16.9 months, p<0.0001) that those who stopped trabectedin after 6 cycles. Conclusions: Patients with ASTS treated with trabectedin had PFS and OS comparable or better to those observed in phase II/III trials. Trabectedin maintenance beyond 6 cycles is associated with improved OS and warrants further exploration.
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Kampmann, Eric, Dominique Harnicek, Ana Sofia Cardoso Martins, Berina Eppink, Eike Gallmeier, Lars Lindner, Roland Kanaar, and Rolf D. Issels. "Heat-shock (H-S) and trabectedin efficacy in human soft-tissue sarcoma (STS) cells in vitro." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): e13540-e13540. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e13540.
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e13540 Background: Regional hyperthermia improves response and survival when combined with chemotherapy in patients with high-risk STSs (Issels, R.D. Lancet Oncol 2010). Trabectedin is the first marine-derived antineoplastic drug approved in Europe for the treatment of advanced STS after failure of anthracyclines and ifosfamide, or for patients who are unsuited to receive these drugs. Trabectedin’s cytotoxicity is associated with the induction of lethal DNA double-strand breaks (DSB). The rationale to combine trabectedin with H-S is that heat-exposure sensitizes tumor cells by inhibiting the repair of induced DSBs (Krawczyk, P.M. PNAS 2011). Methods: Combinations of trabectedin and H-S at clinically relevant temperatures were examined in 3 different human cell lines: Osteosarcoma (U2Os), liposarcoma (SW872) and synovial sarcoma (SW982). Cells were treated with trabectedin at the dose of 500-4000 pM for 3 hours. H-S was applied in an incubator at 41.8°C and 43°C for 90 or 150 min before, during or after trabectedin incubation. Cytotoxicity was assessed measuring clonogenic survival of cells. Expression of BRCA2, which recruits homologous recombination repair recombinase Rad 51 to DSBs, was measured by Western Blot (WB). Recruitment of Rad 51 and the amount of gH2AX positive DSB-repair-foci were analysed by immunocytochemistry (ICC). Results: All cell lines showed reduced viability after increasing doses of trabectedin at 37°C. Combined treatment with trabectedin and H-S additionally enhanced cytotoxicity of trabectedin with strongest effects observed after simultaneous administration of both. WB-analysis showed strong heat-dependent reduction of BRCA2 expression. ICC revealed that recruitment of Rad 51 to DSBs was reduced after heat exposure at 41.8°C and abolished after exposure at 43°C. Accordingly, combined treatment significantly increased the amount of cells with severe DNA damage (>50 DSBs). Conclusions: Combined treatment with trabectedin and H-S in vitro resulted in significantly enhanced cytotoxicity that was accompanied by elevated DNA-damage in term of DSB-accumulation. The mechanisms of interaction between trabectedin and H-S concerning DNA repair are under investigation.
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D'Incalci, Maurizio, Carlos Galmarini, Ines de la Riba Alvarez, Nadia Badri, and Patrick Schöffski. "Association between body weight and efficacy outcomes during trabectedin therapy for recurrent advanced soft tissue sarcoma (STS)." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 10047. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.10047.
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10047 Background: Trabectedin is the first marine-derived antineoplastic drug approved in Europe for the treatment of patients with recurrent advanced STS. Different studies have implicated tumor-derived cytokines as mediators of cachexia in cancer patients. Preclinical studies have demonstrated that trabectedin acts on tumor microenvironment particularly reducing IL-6, which is involved in cancer-induced cachexia (Germano et al. 2011, Ligouri et al. 2011). Methods: This exploratory retrospective analysis evaluated the association between body weight increase during treatment with respect to baseline and efficacy outcomes in 319 adult patients with recurrent STS. Patients were treated in four phase II trials with trabectedin at the approved dose of 1.5 mg/m2, given as a 24-hour infusion every 3 weeks. An analysis of the concordance between weight increase and objective response (OR) rate, tumor control (TC) rate (OR+stable disease lasting ≥3 months), progression-free survival (PFS) and overall survival (OS) was performed. Results: Correlation between weight increase and responses was observed: 68% of patients who achieved OR and 70% of patients with TC increased their weight for a median of 1.2 kg. Remarkably, PFS (5.1 vs. 1.9 months; p<0.0001, log rank) and OS (21.0 vs. 8.2 months; p<0.0001, log rank) were significantly prolonged in patients who gained weight during treatment. Six and 12-months Kaplan-Meier PFS estimates and survival rates at 12, 24 and 36 months were also better in those patients. Additionally, in Cycle 1-2, a significant relationship between weight increase and improved median PFS (4.2 vs. 2.2 months; p<0.0001) and OS (19.4 vs. 9.3 months; p=0.0002) was observed. This is in concordance with the tendency to gain weight starting from the first cycle of treatment. Conclusions: This analysis suggests that weight gain is associated with favorable efficacy outcomes when patients are treated with trabectedin. Further research is needed to assess the prognostic value of weight changes as a complementary source of evaluation on the long-term clinical outcomes and impact of trabectedin on tumor microenvironment.
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Wang, Jun, Shihui Chen, Shiqiang Xu, Xing Yu, Dongqing Ma, Xiamin Hu, and Xiaolu Cao. "In Vivo Induction of Apoptosis by Fucoxanthin, a Marine Carotenoid, Associated with Down-Regulating STAT3/EGFR Signaling in Sarcoma 180 (S180) Xenografts-Bearing Mice." Marine Drugs 10, no. 12 (September 20, 2012): 2055–68. http://dx.doi.org/10.3390/md10092055.
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Cioffi, A., A. LeCesne, J. Blay, S. Delaloge, A. Yovine, R. Maki, A. Nieto, J. J. Jiao, and G. D. Demetri. "Trabectedin phase II clinical trials: Pooled analysis of safety in patients with solid tumors." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): e13510-e13510. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e13510.
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e13510 Background: Trabectedin is an originally marine-derived antineoplastic agent. Its unique antitumor properties, attributed to specific binding to the small groove of DNA, have been demonstrated activity against soft-tissue sarcoma (STS), ovarian, breast and prostate cancer. Trabectedin treatment has been authorized by EMEA for STS after failure of standard treatment and shows efficacy in relapsed ovarian cancer in a phase III study. This retrospective report on safety includes single-agent trabectedin phase II studies in patients (pts) with solid tumors. Methods: A total of 1,132 pts were treated with trabectedin in 19 international trials (Feb’99 - Apr’08). Three schedules were analyzed: 24-hour infusion every 3 weeks (wk) (570 pts), 3-h every 3 wk (258 pts), and 3-h for 3 out of 4 wk (304 pts). Safety analyses included pts who received at least part of 1 infusion. MedDRA and NCI-CTC v1.0/2.0 were used to code and grade treatment-emergent adverse events (AEs). Results: Median pt age was 54 years with ECOG 0–1 (>99%). Diagnosis included sarcoma (56%), ovary (26%) and breast (7%) cancer, for which 90% of pts had received chemotherapy, 37.5% radiotherapy, and 96.0% surgery. Trabectedin lasted for a median of 3 cy (9.4 wks) and 28% of pts received ≥ 6 cycles, with a median dose intensity of 0.4 (0.1–0.6) mg/m2/wk. The overall rate of discontinuations due to toxicity was 10.3%, similar between all three dose schedules. Most common trabectedin-related AEs (≥ 20% of pts) were nausea, fatigue and vomiting. Most common lab abnormalities were reversible myelosuppression, mainly neutropenia (37% grade3–4) though G-CSF was given to less than 10% of pts; and transient transaminase increases (grade3–4: ALT, 45%; AST, 30%). Of note, only 3.7% and 5.7% of pts had alopecia or mucositis/stomatitis, respectively. Fifteen drug-related deaths (1.3%) occurred. Conclusions: Single-agent trabectedin was reasonably well tolerated, with low rates of drug-related discontinuations and deaths. Sustained clinical benefit in the absence of relevant cumulative toxicities allows its administration to patients for prolonged periods of time. [Table: see text]
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Chawla, Sant P., Victoria S. Chua-Alcala, Katherine Kim, Nupur Assudani, Ahmad Al-Shihabi, Ania Moradkhani, Doris Quon, et al. "The SAINT: Initial results of a phase I/II study of safety/efficacy using safe amounts of ipilimumab, nivolumab, and trabectedin as first-line treatment of advanced soft tissue sarcoma." Journal of Clinical Oncology 37, no. 8_suppl (March 10, 2019): 22. http://dx.doi.org/10.1200/jco.2019.37.8_suppl.22.
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22 Background: Sarcoma cells are most immunogenic at the onset of cancer. Hypothesis: Immune checkpoint inhibitors would be most effective when given as first line therapy. Objectives: (1) To evaluate the safety of ipilimumab (I), a CTLA4 inhibitor, nivolumab (N), a PD-1 inhibitor, and escalating doses of trabectedin (T), a marine-derived natural alkaloid, in advanced soft tissue sarcomas (STS), (2) To investigate the BORR, DCR, PFS and OS, and (3) to correlate response with immune cell trafficking in the tumor microenvironment. Methods: This is an IRB-approved dose-seeking phase 1/2 study using defined doses of I (1 mg/kg IV q 12 weeks), N (3 mg/kg IV q 2 weeks) and escalating doses of T (1.0, 1.3, 1.5 mg/m2 IV q 3 weeks), employing “cohort of three” design, with a Phase 2 component using the MTD of T. Results: Phase 1 safety analysis: At Dose 1: Grade 3 treatment related adverse events (TRAEs): fatigue (n = 1), increased TSH (n = 1). At Dose 2, Grade 4 TRAEs: thrombocytopenia with bleeding, DLT (n = 1), increased CK (n = 1); Grade 3 TRAEs: anemia (n = 1), myalgia (n = 1), increased TSH (n = 1), decreased TSH (n = 1), increased AST (n = 1). At Phase 2, Grade 4 TRAEs: increased CK (n = 1); Grade 3 TRAEs: increased ALT (n = 4), anemia (n = 3) neutropenia (n = 1), portal cellulitis (n = 1). Efficacy analysis: Phase 1 (n = 9): At Dose 1: DCR 67%, median PFS, 18 weeks; median OS, 50 weeks; At Dose 2: PR (n-1, rhabdomyosarcoma), DCR 60%, median PFS, > 42 weeks; median OS, > 47 weeks. Phase 2 (n = 16): PR (n = 3; 1 liposarcoma, 1 leiomyosarcoma, 1UPS); BORR 18.75%, DCR 87.5%, median PFS, > 19 weeks; median OS, > 26 weeks. Surgical resection was undertaken in 1 patient with SD after 4 cycles. The surgical specimen showed 80% necrosis and greater number (30%) of CD8+ killer T cells, 10% PD-L1+ cells in the TME compared to that of archived pre-treatment tumor. Conclusions: Taken together, these data suggest that the SAINT protocol (1) is safe with manageable adverse events, with no additive toxicity, and (2) may control tumor growth. The phase 2 part of the study is on-going. Clinical trial information: NCT03138161.
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Aljahdali, Mohammed Othman, Mohammad Habibur Rahman Molla, and Foysal Ahammad. "Compounds Identified from Marine Mangrove Plant (Avicennia alba) as Potential Antiviral Drug Candidates against WDSV, an In-Silico Approach." Marine Drugs 19, no. 5 (April 28, 2021): 253. http://dx.doi.org/10.3390/md19050253.
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Walleye dermal sarcoma virus (WDSV) is a type of retrovirus, which affects most of the adult walleye fishes during the spawning time. The virus causes multiple epithelial tumors on the fish’s skin and fins that are liable for more than 50% of the mortality rate of fish around the world. Till now, no effective antiviral drug or vaccine candidates have been developed that can block the progression of the disease caused by the pathogen. It was found that the 582-amino-acid (aa) residues long internal structural gag polyprotein of the virus plays an important role in virus budding and virion maturation outside of the cell. Inhibition of the protein can block the budding and virion maturation process and can be developed as an antiviral drug candidate against the virus. Therefore, the study aimed to identify potential natural antiviral drug candidates from the tropical mangrove marine plant Avicennia alba, which will be able to block the budding and virion maturation process by inhibiting the activity of the gag protein of the virus. Initially, a homology modeling approach was applied to identify the 3D structure, followed by refinement and validation of the protein. The refined protein structures were then utilized for molecular docking simulation. Eleven phytochemical compounds have been isolated from the marine plant and docked against the virus gag polyprotein. Three compounds, namely Friedlein (CID244297), Phytosterols (CID12303662), and 1-Triacontanol (CID68972) have been selected based on their docking score −8.5 kcal/mol, −8.0 kcal/mol and −7.9 kcal/mol, respectively, and were evaluated through ADME (Absorption, Distribution, Metabolism and Excretion), and toxicity properties. Finally, molecular dynamics (MD) simulation was applied to confirm the binding stability of the protein-ligands complex structure. The ADME and toxicity analysis reveal the efficacy and non-toxic properties of the compounds, where MD simulation confirmed the binding stability of the selected three compounds with the targeted protein. This computational study revealed the virtuous value of the selected three compounds against the targeted gag polyprotein and will be effective and promising antiviral candidates against the pathogen in a significant and worthwhile manner. Although in vitro and in vivo study is required for further evaluation of the compounds against the targeted protein.
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Pawłowska, Natalia, Anna Czajkowska, Anna Bielawska, and Krzysztof Bielawski. "Ecteinascidins – new antineoplastic drugs from the depths of the seas." Postępy Higieny i Medycyny Doświadczalnej 72 (December 13, 2018): 1062–72. http://dx.doi.org/10.5604/01.3001.0012.7873.
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Trabectedin, also known as ecteinascidin 743 (Et-743), is a tetrahydroisoquinoline alkaloid that was originally isolated from the Caribbean sea squirt Ecteinascidia turbinata. Trabectedin is one of the first anticancer drugs of marine origin that has been approved in the European Union. The compound is used to treat patients with advanced soft tissue sarcoma in case of failure of conventional anthracyclines and ifosfamide therapy and in the treatment of recurrent platinum-sensitive ovarian cancer in combination with pegylated liposomal doxorubicin. The mechanism of action of trabectedin is based on interaction with the minor groove of DNA double helix. It triggers a cascade of events that interfere with several transcription factors, DNA binding proteins and DNA repair pathways, resulting in G2/M cell cycle arrest and ultimately apoptosis. Moreover, emerging evidence indicates that Et-743 has dual effects. In addition to induce direct growth inhibition, cell death and differentiation of malignant cells it also affects the tumor microenvironment by reducing the production of key inflammatory mediators. A multifaceted mechanism of action may explain positive results when trabectedin is used in the treatment of cancer that exhibits resistance to conventional chemotherapeutics. The widespread use of ecteinascidins in therapy as well as in clinical trials is, however, limited by the high price of these compounds. Therefore, intensive work is being carried out on the search for synthetic analogues of ecteinascidins with equally high activity against tumor cells.
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Gordon, Erlinda M., Nadezhda Omelchenko, Samantha Jeffrey, Vaishali Kumar, Neal S. Chawla, Mahesh Seetharam, Victoria Chua, et al. "Abstract CT287: LINNOVATE: A Phase 1/2 study of safety/efficacy using lurbinectedin, combined with ipilimumab, and nivolumab for advanced soft tissue sarcomas (NCT05876715)." Cancer Research 84, no. 7_Supplement (April 5, 2024): CT287. http://dx.doi.org/10.1158/1538-7445.am2024-ct287.
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Abstract Background: Sarcoma cells are most immunogenic earlier in the course of the disease. Therefore, immune checkpoint inhibitors such as ipilimumab (ipi) and nivolumab (nivo), that promote sustained T-cell activation by suppressing T regs would be most effective when given as first line therapy, together with a tumoricidal agent, such as lurbinectedin, whose plausible mechanism of action is not only to destroy the cancer cells and expose the tumor neoantigens for immune recognition, but also to destroy growth promoting factors in the tumor microenvironment. In the SAINT phase 2 study using ipi, nivo and trabectedin as first line therapy for advanced soft tissue sarcomas (STS; n=79), there were 6 complete responses, 14 partial responses, 49 stable disease, 25.3% best response rate, 87.3% disease control rate; median PFS, 6.7 months, median OS, 24.6 months (Gordon et al, Cancers vol. 15, 906, 2023). Lurbinectedin is a synthetic marine-derived agent and an analog of trabectedin. Therefore, we expect that lurbinectedin will be as effective as trabectedin when used together with ipi and nivo as first line therapy for advanced STS. Methods: Objective 1: Assess MTD of lurbinectedin. Objective 2: Evaluate PFS, OS, incidence and severity of adverse events; Correlative: Correlate response with ctDNA using Signatera. This is an open label, dose-seeking phase 1/2 study. The phase 1 part employs standard “cohort of three” design with a DLT window of 6 weeks. Treatment schedule: Ipi 1 mg/kg IV q 12 weeks; Nivo 3 mg/kg IV q 2 weeks; escalating doses of lurbinectedin from 2.6 mg/m2 to 3.2 mg/m2 IV q 3 weeks. Phase 2 part follows completion of phase 1 part wherein additional 28-34 participants will receive lurbinectedin at the MTD with fixed doses of Ipi and Nivo. Participants may continue treatment until significant disease progression or unacceptable toxicity occurs. Eligible patients are 18 years of age or older, previously treated in phase 1 and previously untreated in phase 2 with confirmed diagnosis of advanced STS, adequate hematologic and organ function, and no history of autoimmune disorder. To date, 6 patients in phase 1 have been dosed. Citation Format: Erlinda M. Gordon, Nadezhda Omelchenko, Samantha Jeffrey, Vaishali Kumar, Neal S. Chawla, Mahesh Seetharam, Victoria Chua, Ania Moradkhani, Doris Quon, Steven Wong, Sant Chawla. LINNOVATE: A Phase 1/2 study of safety/efficacy using lurbinectedin, combined with ipilimumab, and nivolumab for advanced soft tissue sarcomas (NCT05876715) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT287.
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Blay, J., M. von Mehren, B. L. Samuels, M. P. Fanucchi, I. L. Ray-Coquard, B. Buckley, L. Gilles, C. Lebedinsky, Y. A. Elsayed, and A. Le Cesne. "Combination of trabectedin (T) and doxorubicin (D) for the treatment of patients with soft tissue sarcoma (STS): Safety and efficacy analysis." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 10078. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.10078.
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10078 Background: T is a novel marine-derived DNA minor-groove binder that interferes with gene activation, nucleotide excision repair, and induces DNA strand breaks and cell cycle arrest in S and G2. T is active in STS and exhibits preclinical synergy with D. The objective of this study was to determine the combination regimen that is tolerable and associated with manageable neutropenia. Other objectives included safety, clinical activity and pharmacokinetics (PK) Methods: This was a dose escalation phase I study. Eligible patients (pts) had metastatic or recurrent STS, PS 0–1, and adequate organ function. Pts with more than 1 prior chemotherapy, prior anthracyclines or radiation to more than 20% of bone marrow were excluded. On day 1 of each 3-week cycle, pts received D starting at 60 mg/m2 followed by T starting at 0.9 mg/m2. Incremental doses were explored. D was discontinued after 6–8 cycles. Treatment was administered as an outpatient. PK samples were collected. A modified dose escalation and dose modifications were implemented Results: Forty one pts were treated in three sequential cohorts. In cohort 1 (D60 mg/m2 + T0.9 mg/m2), 4/11 pts without G-CSF experienced unmanageable neutropenia and subsequently prophylactic G-CSF was instituted. No unmanageable neutropenia was seen in the subsequent18 evaluable pts in this cohort. 1/13 and 2/6 DLTs were seen in cohort 2(D60 mg/m2 + T1.1 mg/m2) and cohort 3(D60 mg/m2 + T1.3 mg/m2) respectively. The most frequent grade 3/4 AEs were: neutropenia(71%), ALT elevation(46%), thrombocytopenia34%), AST(24%), anemia (22%), Febrile neutropenia (17%). One pt discontinued due to grade 3 asthenia. The MTD and recommended dose is D60 mg/m2 + T1.1 mg/m2. Anti-tumor activity included 17% ORR (1 CR and 6 PR), 80% stable disease (45% SD>6 months). Median PFS is 8.9 months (95% CI 5.6–11.8). 3-month and 6-month PFS are 85.4% and 58.2% respectively. Mature overall survival and PK data will be presented Conclusions: The combination of T and D with G-CSF support is safe, tolerable and active in pts with metastatic or recurrent STS [Table: see text]
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Xiao, Jin-Fen, Marina Broz, Roberta Piras, Kristin Ishaya, Emily Ko, and Jlenia Guarnerio. "Abstract 1364: Profiling tumor microenvironment for therapeutic intervention to soft-tissue sarcomas." Cancer Research 83, no. 7_Supplement (April 4, 2023): 1364. http://dx.doi.org/10.1158/1538-7445.am2023-1364.
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Abstract Soft-tissue sarcomas (STS) are mesenchymal tumors having remarkably diverse histological features. Genomic studies reported that STS have low frequencies of genetic mutation, but often harboring copy number variations (CNVs). For STS, CNVs frequently happen in essential tumor suppressor genes and oncogenic transcriptional genes, neither of which are easily “druggable” targets. Moreover, in concordance with low tumor mutation burden rate, STS show low immunogenicity with less cytotoxic TIL in the TME and is unfortunately linked to a lower responsive rate to PD1/PD-L1 ICB. Using a syngeneic mouse UPS model, we previously found that tumor-associated macrophages (TAM) in the TME are promoting the growth of sarcoma. We further identified specific tumor microenvironmental elements contributing to the pro-tumorigenicity of TAMs, which represent a promising novel clinical target for myeloid-related intervention. Therefore, we hypothesize that exploration of TME is beneficial to identify clinically promising targets for STS. To study the TME in STS, we performed bulk RNA-seq and scRNA-seq on human sarcoma samples which covered different histological subtypes of STS and compare them to normal samples. Our results show that, unlike carcinomas originating from epithelial cells, extracellular matrix (ECM)-related genes are highly upregulated in both cancer-associated fibroblast (CAF) and sarcoma tumor cells. Further analysis show that upregulation of these ECM genes is associated with a worse survival outcome in sarcoma patients. In order to further explore the STS and TME orchestra, we established several syngeneic mouse models according to the genetic aberrations reported in TCGA data. We are currently characterizing these syngeneic mouse models to find out whether they recapitulate human STS samples. Our goal is to utilize these mouse models to study the relationship of ECM-related genes in both CAF and tumor cells, find out the effect of upregulated ECM-related genes on the immune compartment in TME and search for potential therapeutic interventions. Citation Format: Jin-Fen Xiao, Marina Broz, Roberta Piras, Kristin Ishaya, Emily Ko, Jlenia Guarnerio. Profiling tumor microenvironment for therapeutic intervention to soft-tissue sarcomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1364.
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Behra, Biswadeep, S. Vairamuthu, Natesan Pazhanivel, Periyasamy Jalantha, and Ganne Venkata Sudhakar Rao. "Histological and Immunohistochemical Features of Pulmonary Metastatic Oral Melanoma in a Labrador dog." Indian Journal of Veterinary Sciences & Biotechnology 18, no. 5 (November 7, 2022): 119–22. http://dx.doi.org/10.48165/ijvsbt.18.5.24.
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Melanoma is a malignant tumour that originates from melanocytes. It has been reported in human beings as well as in many domesticated animal species (Reddy et al., 1998), and wild terrestrial and marine animals. Melanomas are the most commonly diagnosed malignant tumours in the oral cavity of canines (Goldschmidt, 1985; Faramade et al., 2017). Gingiva is the most common site for canine oral malignant melanoma (OMM) but other parts like palatine, labile or buccal mucosa also act as the sites of origin (Delverdier et al., 1991). It is generally an aggressive tumour, often locally invasive, and frequently metastasizes to regional lymph nodes and lungs but metastasis to other organs like the brain, heart, spleen, and liver is not common (Goldschmidt and Hendrick, 2002). Canine OMM accounts for about 7% of all malignant tumours of canine, 11.5% to 17.1% of all oral tumours (Mikiewicz et al., 2019), and 33% to 35.8% of all malignant oral tumours (Sarowitz et al., 2017). OMM is reported in old age group animals mainly ranging from 7 to 14 years age (Esplin, 2008). Most common breeds affected by OMM include Cocker Spaniels, Golden Retrievers, Dachshunds, mixed-breed dogs (Gillard et al., 2014) but histologically well-differentiated melanocytic neoplasms (HWDMN) also reported in Golden Retrievers, Labrador, Doberman Pinscher, Irish Setters, Cocker Spaniels, Beagles, etc. (Esplin, 2008). The diagnosis of melanoma is difficult mainly in tumors without appreciable melanin. Histological appearance resembles carcinoma, lymphoma, sarcoma, and osteogenic tumours. Therefore, immunohistochemistry with numerous melanoma specific markers is mostly used for confirmatory diagnosis in human and veterinary pathology (Wick, 2008). This case report is on the occurrence of oral melanoma with pulmonary metastasis in a Labrador dog.
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Gradl, Stefan, Sooncheol Lee, Martin Lange, Xiaoyun Wu, Silvia Goldoni, Timothy Lewis, Charlotte Kopitz, et al. "Abstract ND04: BAY 2666605: The first PDE3A-SLFN12 complex inducer for cancer therapy." Cancer Research 82, no. 12_Supplement (June 15, 2022): ND04. http://dx.doi.org/10.1158/1538-7445.am2022-nd04.
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Abstract Velcrin compounds are a class of small molecules that induce complex formation between PDE3A and SLFN12, killing cancer cells that express elevated levels of these two proteins by a mechanism independent of PDE3A enzymatic inhibition. Instead, PDE3A binding stimulates the RNase activity of SLFN12, resulting in cleavage of the specific SLFN12 substrate, tRNA-Leu-TAA. Cleavage of tRNA-Leu-TAA in turn causes ribosomal pausing, inhibition of protein synthesis, and cancer cell death. Unlike traditional targeted therapies that leverage dependencies created in cancer cells by genomic alterations, velcrins instead kill cancer cells by a gain-of-function mechanism dependent on the RNase activity of SLFN12. In a collaboration between the Broad Institute and Bayer Pharmaceuticals, we developed the first velcrin, BAY 2666605, to enter Phase I clinical trials. BAY 2666605 is active in cell line and patient-derived xenografts of several tumor types, specifically where elevated levels of the two biomarkers, PDE3A and SLFN12, are expressed. Biomarker-positive tumors are especially enriched among melanomas, and we have consistently observed tumor regression in biomarker-positive melanoma tumor models in vivo. BAY 2666605 furthermore shows drug-like properties, excellent brain penetration, increased stimulation of SLFN12 RNase activity, and reduced inhibition of PDE3A enzymatic activity compared with most other velcrins and approved PDE3A inhibitors. BAY 2666605 has recently entered a First-in-Human study (NCT04809805) in patients with advanced solid tumors that co-express PDE3A and SLFN12, including melanoma, ovarian cancer, and sarcoma. Citation Format: Stefan Gradl, Sooncheol Lee, Martin Lange, Xiaoyun Wu, Silvia Goldoni, Timothy Lewis, Charlotte Kopitz, Colin Garvie, Philip Lienau, Stephanie Hoyt, Henrik Seidel, Stephan Kaulfuss, Manuel Ellermann, Luc de Waal, Adrian Tersteegen, Sven Golfier, Detlev Suelzle, Christa Hegele-Hartung, James Carr, Frederick Brookfield, Michael Bruening, Melanie Berthold, Thibaud Jourdan, Monica Schenone, Galen Gao, Joseph McGaunn, Antje Wengner, Elisa Aquilanti, Franziska Siegel, Marine Garrido, Annette Walter, Isabelle Genvresse, Andrew Cherniack, Stuart Schreiber, Knut Eis, Ashley Eheim, Matthew Meyerson, Heidi Greulich. BAY 2666605: The first PDE3A-SLFN12 complex inducer for cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr ND04.
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Leone, Francesco, Caterina Peraldo-Neia, Giuliana Cavalloni, Marco Soster, Loretta Gammaitoni, Serena Marchiò, and Massimo Aglietta. "Preclinical evidence of ET-743 as a potential chemotherapy option for the treatment of biliary carcinoma." Journal of Clinical Oncology 31, no. 4_suppl (February 1, 2013): 193. http://dx.doi.org/10.1200/jco.2013.31.4_suppl.193.
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193 Background: The standard chemotherapy for unresectablebiliary tract carcinoma (BTC) is based on gemcitabine and platinum compounds. However, these combinations have not been shown to be effective in improving long-term survival. Thus, there is a real need to find new strategies that would impact in a significant way on clinical outcome. Ecteinascidin-743 (ET-743), a compound isolated from the marine tunicate Ecteinascidia turbinata. ET-743, is approved for the treatment of ovarian cancer and soft tissue sarcoma. Phase II and III clinical trials are ongoing for the treatment of different solid tumors. No preclinical data are available about the efficacy of ET-743 in BTC. In a phase I study, one patient received ET-743 plus capecitabine and experienced a long lasting complete metabolic response. Here, we investigated the antitumor activity of ET-743 in preclinical BTC models. Methods: Four BTC cell lines TFK1, EGI-1, HuH28 and TGBC1 were used to evaluate the effect of ET-743 on proliferation, cell cycle, apoptosis and on the activation of DNA damage proteins. The effect on proliferation was also investigated on a primary cell culture of a gallbladder carcinoma (GBC) resistant to gemcitabine and oxaliplatin. On the same cells, the inhibition of VEGF secretion mediated by ET-743 was analyzed by ELISA. The anti-tumor activity of ET-743 was tested on EGI-1 xenografts in NOD/SCID mice. Results: In vitro, ET-743 is able to markedly reduce cell proliferation of BTC cell lines through cell cycle blockage on G0/G1 phase and to inhibit the growth of primary cell culture derived from GBC patient. Moreover, ET-743 promotes apoptosis by caspase 3 activation, activates proteins involved in DNA damage and reduces VEGF secretion. In the in vivo model, ET-743 is able to slow tumor growth in BTC xenograft. The mechanism of anti-tumor activity involves DNA damage, the induction of hypoxia transcription factor-1, and angiogenesis inhibition. ET-743 has no significant effect on apoptosis in vivo. Conclusions: These data suggest that ET-743 could represent an alternative chemotherapy for BTC treatment and encourage the development of clinical trials of ET-743 in BTC patients.
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Del Campo, J., A. Roszak, T. Ciuleanu, M. Bidzinski, T. Hogberg, M. Wojtukienicz, K. Boman, A. Poveda, A. Westermann, and M. Izquierdo. "Phase II open label randomized study of trabectedin (T) given as two different dosing schedules in women with platinum-sensitive, recurrent ovarian carcinoma: Preliminary results." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 5031. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.5031.
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5031 Background: Trabectedin (Yondelis, ET-743) is a marine derived compound which binds to the minor groove of DNA distorting the DNA structure and induces apoptosis and cell cycle arrest. It has shown clinical activity in soft tissue sarcoma, ovarian, prostate and breast cancer. Methods: Patients (pts) with recurrent platinum sensitive ovarian carcinoma were randomized in a multicenter, open label study to receive T as 1.5 mg/m2 over 24 h infusion (schedule A) or 1.3 mg/m2 over 3 h infusion (schedule B) both every 3 weeks. All pts received dexamethasone premedication. Primary objective is to evaluate the response rate (RECIST) and secondary objectives are response duration, CA-125 response, time to progression and safety. Results: 107 pts were enrolled in 23 centers. Demographic and disease characteristics were well balanced. Toxicity and response data on the first 99 pts are available: median age 57 (25–78) years; ECOG PS=0: 72% and =1: 28%; pts received a median of 4 cycles (range:1–19 in A, 1–13 in B). Relative dose intensity was 84% and 93% respectively. Objective responses due to investigator’s assessment were 29% (8% CR, 21% PR) with 52% SD in A and 28% (11% CR, 17% PR) with 45% SD in B, with 11 pts not yet evaluable for response. CA 125 responses ≥ 50% occurred in 23% in A and 26% in B. TTP data will be presented. Safety: 501cycles were delivered; the most common any grade drug-related AEs per patient were (A and B) fatigue (56% and 47%), nausea (63% and 70%), vomiting (56% and 45%) and constipation (25% and 30%). Consistent with previous experience, alopecia, stomatitis and neurotoxicity were uncommon and mild/moderate. Grade 3/4 fatigue occurred in 15% in A and 4% in B. Grade 3/4 lab abnormalities were non-cumulative neutropenia (50% and 32%) and reversible ALT increase (58% and 53%). G-CSF support was not routinely given. There were 4 deaths <30 days last infusion date (3 in A unrelated to study drug, one in B due to related multiorgan failure). Conclusions: This analysis suggests that both T schedules appear active with manageable toxicity. There was a trend for less neutropenia and fatigue with schedule B. On the basis of these efficacy results, no additional phase III comparisons between these 2 schedules seem warranted [Table: see text]
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Peyraud, Florent, Jean-Philippe Guegan, Christophe Rey, Marina Pulido, Emmanuelle Bompas, Sophie Piperno-Neumann, Christine Chevreau, et al. "Abstract 2578: High regulatory T cells infiltrate within tertiary lymphoid structure restricts response to immune checkpoint blockers in sarcomas." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2578. http://dx.doi.org/10.1158/1538-7445.am2022-2578.
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Abstract Background: While composition of the tumor microenvironment (TME) is a prerequisite for an effective antitumor immunity, infiltration of organized B- and T-cells aggregates called tertiary lymphoid structures (TLS) has been recently demonstrated to predict response to immune checkpoint blockers (ICB) in sarcomas. However, only a minority of patient derive benefit, suggesting the implication of additional key determinants of ICB-mediated response in TLS-positive sarcomas, such as TLS composition. Using high-throughput spatial transcriptomics and multiplex immunofluorescence (IHF), we aimed at investigating the association between TLS composition and clinical outcome to ICB. Methods: In an exploratory cohort, we spatially profiled the expression of more than 18000-protein encoding genes from responders (R) and non-responders (NR) using Nanostring’s GeoMx Digital Spatial Profiler (DSP) Whole Transcriptome Atlas (WTA) assay. A first set of regions of interest (ROI) was selected in the TLS and further segmented in “B-cells” vs “no B-cells” areas according to CD20+ staining; a second set of ROI was selected in the tumor tissue and further segmented into “tumor” vs “stroma” areas according to CD45+ staining. Deconvolution of data was performed using SpatialDecon algorithm to estimate cell population within TLS. We then evaluated the association between immune cell composition and response to ICB in each segment. In a validation cohort, we performed multiplexed-IHF assay enabling detection of T cells (CD8/GzmA/CD4/FoxP3/CD56) and B cells. These panel was applied to whole sections baseline sarcoma samples. We investigated the association between immune cell composition and clinical benefit in term of progression-free survival (PFS) and overall survival (OS). Results: Six patients were selected for the exploratory cohort, including 3 R and 3 NR. Among the top immune cell infiltrate within TLS segment, NR demonstrated higher Treg infiltrate versus R in “no B-cells” compartment (3.4% vs 2.0%, respectively; p=0.010), whereas no association was observed between Treg infiltration and response to ICB in both stromal (p=0.67) or tumor cells (p=0.36) compartments from tumor area. In the validation cohort (N=16), we observed that Treg density within TLS was higher in NR versus R (p=0.0059). Patients with Treg-enriched TLS had shorter PFS (2.6 vs 11.1 months, p=0.042) and OS (9.0 vs 18.3 months, p=0.12) compared to those with Treg-low TLS infiltration. Concordantly, the CTLA-4 key Treg regulator gene was upregulated in the TLS regions from NR. Conclusions: Altogether, our findings suggest that the presence of Treg within TLS may exert a negative influence on the capacity of TLS to generate an effective antitumor immune response in sarcoma patients treated with ICB, providing new insights in understanding role of TLS in antitumor immunotherapy. Citation Format: Florent Peyraud, Jean-Philippe Guegan, Christophe Rey, Marina Pulido, Emmanuelle Bompas, Sophie Piperno-Neumann, Christine Chevreau, Nicolas Penel, François Bertucci, Maud Toulmonde, Carine Bellera, Catherine Sautès-Fridman, Antoine Bougoüin, Coralie Cantarel, Michèle Kind, Mariella Spalato-Ceruso, Bérengère Dadone-Montaudie, Jean-Yves Blay, Wolf Herman Fridman, François Le Loarer, Alban Bessede, Antoine Italiano. High regulatory T cells infiltrate within tertiary lymphoid structure restricts response to immune checkpoint blockers in sarcomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2578.
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Salazar, R., B. Pardo, M. Majem, M. García, A. Montes, C. Cuadra, E. Ciruelos, H. Cortés-Funes, C. Lebedinsky, and L. Paz-Ares. "Phase I clinical and pharmacological trial of trabectedin (T) in 3 hour infusion every 3 weeks (3h/q3w) in patients with advanced cancer and hepatic function disorder." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 2080. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.2080.
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2080 Background: Trabectedin (ET-743) is a marine-derived DNA and transcription interacting agent with activity in pretreated soft tissue sarcoma, breast, prostate and ovarian cancer. T is associated with 2 types of liver function alterations: a frequent acute and reversible elevation of ALT and AST and a less frequent cholestasis, usually reflected by low grade increases in alkaline phosphatase (AP) and bilirubin (B). The main predictors of dose limiting toxicity (DLT) or T-related serious adverse events appear to include elevated baseline or intercycle peaks of AP, B and ALT > 5 × ULN (Gomez J, ASCO 2000). The objectives of this trial are to determine the maximum tolerated dose (MTD) and pharmacokinetics (PK) of T 3h/q3w in patients (pts) with advanced cancer and baseline liver dysfunction. Methods: All pts are stratified according to basal liver function as follows: STRATUM (S) I: ULN < AP ≤ 1.5 × ULN S II: 1.5 × ULN < AP ≤ 2.5 × ULN S III: AP > 2.5 × ULN All pts had to have AST and ALT ≤ 2.5 × ULN, albumin > 2.5 g/dl and B < 2.5 mg/dl. T concentrations in plasma are determined using a validated LC-MS/MS method. PK parameters were calculated by non-compartmental methods. Results: 32 pts were recruited.Median age: 54 years (26–76); PS≤1:28 pts; prior chemotherapy (CT): 31 pts (97%); median number of prior CT: 2 (1–6); B > ULN: 0 pts. In S I, T was administered at 1.1 mg/m2 (3 pts) and 1.3 mg/m2 (13 pts). Two DLTs were reported at 1.3 mg/m2: neutropenia G4 > 5 days with febrile neutropenia and G3 ALT not recovered by day +28. In S II no DLT occurred in 4 pts at T 0.9 mg/m2 nor 3 pts at T 1.1 mg/m2, 1 out of 4 pts at 1.3 mg/m2 suffered DLT: G3 AST not recovered by day +24. In S III one out of 2 pts at 0.9 mg/m2 had DLT: AP increase. Initial PK evaluation from S I and II (8 from each) showed a long half life (geometric mean (GM) S I: 124.6 h, S II: 118.8 h) and wide distribution (GM Vss S I: 2366 l/m2, S II: 3830 l/m2). GM clearance: 18.3 l/(hr*m2) in S I; 26.3 l/(hr*m2) in S II. Clearance is somewhat lower than in normal liver function population (GM under equal dexamethasone treatment 33.8 l/hr*m2) in study ET-B-010. Conclusions: The recommended dose (RD) of T for pts with mild AP elevations (< 1.5 ULN) and B levels < ULN is 1.3 mg/m2 3h/q3w. The study is ongoing to define the RD for S II and III [Table: see text]
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Sinko, J., J. Rajchard, Z. Balounova, and L. Fikotova. " Biologically active substances from water invertebrates: a review." Veterinární Medicína 57, No. 4 (May 18, 2012): 177–84. http://dx.doi.org/10.17221/5914-vetmed.
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Some species of invertebrates especially bryozoans (Bryozoa syn. Ectoprocta) and marine sponges (Porifera) are very important sources of pharmacologically exploitable compounds. These substances are probably produced to protect themselves from fish predators and may be an advantage in competition. The real sources of compounds with these antipredatory effects are probably not marine invertebrates themselves, but microscopic symbionts or food which they feed on. Bryostatins from bryozoan species Bugula neritina are produced by a bacterial symbiont called Candidatus Endobugula sertula. They have significant anti-cancer effects, but also other therapeutic benefits. Compounds with the structure of bryostatins were also discovered in some other invertebrates. Sponges are a source of many compounds, e.g., ara-A (vidarabine), manzamine, lasonolides, spongistatins, peloruside and others with antimicrobial, anti-cancer, immunosuppressive and similar activities. Other important sources of compounds with medical effects are tunicates (Tunicata syn. Urochordata) and some snails (Mollusca). One drug was developed from tunicates – Yondelis against refractory soft-tissue sarcomas. Certain other drugs originate from snails: e.g., prialt, which acts against chronic pain in spinal cord injury.
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Broz, Marina T., Marco DeSimone, Emily Ko, Roberta Piras, and Jlenia Guarnerio. "Abstract A29: Uncovering transcriptional signatures of drug resistant tumor cells: Mechanisms of therapeutic resistance and opportunities for combination therapies." Cancer Immunology Research 10, no. 12_Supplement (December 1, 2022): A29. http://dx.doi.org/10.1158/2326-6074.tumimm22-a29.
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Abstract Soft tissue sarcomas (STS) are tumors of mesenchymal origin and include multiple sub-types such as undifferentiated pleomorphic sarcoma (UPS) which is the most frequent classification of STS. UPS is one of the most aggressive and recurrent sarcomas. The current standard of care for UPS patients remains surgical resection, radiotherapy, and chemotherapy, but many patients still develop recurrent tumors after these interventions. In addition, anti-PD-1 therapy has only been successful in a small fraction of patients with high levels of tumor infiltrating B and T cells, while immune excluded tumors showed poor responses. To understand why these tumors are frequently recurrent, it is essential to understand the characteristics of resistant tumor cells following standard treatment regimens in both immune excluded and immune infiltrated tumor microenvironments. We generated multiple mouse models that reflect the genetic alterations frequently found in patients via overexpression of oncogenes Ccne1 or Vgll3 in p53KO mesenchymal stem cells. Classification of the immune microenvironment of these models revealed that these driver genetics promote an immune excluded or immune infiltrated tumor microenvironment, respectively. We leveraged these two tumor models to understand the mechanisms of therapeutic resistance to common agents doxorubicin or anti-PD-1. We found that despite higher levels of baseline tumor infiltrating lymphocytes in Vgll3 tumors, anti-PD-1 failed to reduce tumor growth. Doxorubicin treatment resulted in a modest reduction of tumor volume in Ccne1 tumors, and more significantly in immune infiltrated Vgll3 tumors. To understand the transcriptional profiles of resistant tumor cells we harnessed single-cell RNA-sequencing (scRNA-seq) to characterize the least responsive model to determine if treatments had an impact on tumor cell expression profiles and which tumor clusters persist after treatment. scRNA-seq analysis revealed that different clusters of tumor cells were differently affected by anti-PD-1 and doxorubicin. While doxorubicin mainly affected tumor cells expressing collagens and matrix associated adhesion proteins, treatment with anti-PD-1 selectively reduced tumor cells enriched in interferon signaling pathways. Interestingly, tumor cells expressing high levels of extracellular matrix (ECM) remodeling genes remained unaffected and, in some cases, were enriched under both treatments. These results may suggest that tumor cells capable of ECM remodeling may shield tumor cells from chemotherapy agents and immune cells from immune checkpoint inhibitors and promote tumor recurrence. Therefore, these results highlight the need for investigation of combination therapies targeting extracellular matrix proteins in addition to immune checkpoint blockade. Citation Format: Marina T Broz, Marco DeSimone, Emily Ko, Roberta Piras, Jlenia Guarnerio. Uncovering transcriptional signatures of drug resistant tumor cells: Mechanisms of therapeutic resistance and opportunities for combination therapies [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A29.
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Banella, Cristina, Laura Zocca, Alessia Boaretto, Gianluca Mattei, Marina Mola, Lara Ballerini, Lorito Nicla, Annalisa Tondo, and Maura Calvani. "Abstract A108: Metabolic oriented treatment: efficacy of sr59230a 𝜷3-adrenergic receptor antagonist, and sr plus buformin® in Ewing sarcoma." Molecular Cancer Therapeutics 22, no. 12_Supplement (December 1, 2023): A108. http://dx.doi.org/10.1158/1535-7163.targ-23-a108.
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Abstract Purpose of study: Metabolic targeted therapies may represent an innovative strategy in Ewing sarcoma (ES). Introduction: Ewing sarcoma (ES) is highly aggressive round cell mesenchymal neoplasm, most often occurring in children and young adults. Metabolic peculiarities of ES cells are indeed involved in tumor growth, survival and resistance to therapy. We have further investigated apoptotic role of 𝜷3-adrenergic receptor (𝜷3-AR) SR59230A (SR) antagonist for its ability to reduce cells viability due increased oxidative stress, now we underline the metabolic role of SR. Materials & Methods: The metabolic profile after SR administration in A673 ES cell model was studied using the Seahorse XF Analyzer. Viability was evaluated with MTS. Changes in gene expression was evaluated with RNA sequencing. Western blot analysis and Immunofluorescence was performed for redox signature and metabolic alteration. Ros production was assessed by flow cytometry. Results: Quantification of transcript abundance using Salmon in A673 after SR treatment showed decrease in response to reactive oxygen species, increase of Thioredoxin Interacting Protein (TXNIP) inhibits the antioxidative function of thioredoxin, moreover reduced glucose uptake, consequently decrease NADPH/NADP resulting in the accumulation of ROS coincident with a decrease of GLUT1, SOD2, TrDX an increase of LC3IIA protein expression. SR enhances A673 pyruvate dependency, and decrease glyco and mito ATP production rate, more over observed under glucose deprivation. To inibite mitochondrial ATP production rate we proposed the metabolic oriented treatment with Buformin® (BUF) an oral antidiabetic drug of the biguanide class. BUF completely shut down mitochondrial respiration acted on complex I of electron transport chain (ETC). Buf combined with SR decrease ATP production and up-regulated ROS production in ES cells. Conclusion: SR antagonist of 𝜷3-AR and combination of SR with BUF could be an innovative therapeutic option to raise awareness ES. Citation Format: Cristina Banella, Laura Zocca, Alessia Boaretto, Gianluca Mattei, Marina Mola, Lara Ballerini, Lorito Nicla, Annalisa Tondo, Maura Calvani. Metabolic oriented treatment: efficacy of sr59230a 𝜷3-adrenergic receptor antagonist, and sr plus buformin® in Ewing sarcoma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A108.
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Banella, Cristina, Francesco Carrozzo, Laura Zocca, Amada Pasha, Gianluca Mattei, Marina Mola, Lara Ballerini, et al. "Abstract 1787: The β3-adrenergic receptor as novel target of metabolic phenotype in Ewing sarcoma." Cancer Research 84, no. 6_Supplement (March 22, 2024): 1787. http://dx.doi.org/10.1158/1538-7445.am2024-1787.
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Abstract Purpose of study: Metabolic targeted therapies may represent an innovative strategy in Ewing sarcoma (ES). Introduction: Ewing sarcoma (ES) is highly aggressive round cell mesenchymal neoplasm, most often occurring in children and young adults. Metabolic peculiarities of ES cells are indeed involved in tumor growth, survival and resistance to therapy. We have further investigated apoptotic role of 𝜷;;3-adrenergic receptor (𝜷;;3-AR) SR59230A (SR) antagonist for its ability to reduce cells viability due increased oxidative stress, now we underline the metabolic role of SR. Materials & Methods: The metabolic profile after SR administration in A673 ES cell model was studied using the Seahorse XF Analyzer. Viability was evaluated with MTS. Changes in gene expression was evaluated with RNA sequencing. Western blot analysis and Immunofluorescence was performed for redox signature and metabolic alteration. Ros production and cell death was assessed by flow cytometry. Results: Metabolic analysis reveals glucose and fatty acid dependency in A673 cells using the Fuel Flex Test of Seahorse XFe Analyzer. Quantification of transcript abundance using Salmon in A673 after SR treatment showed decrease in response to reactive oxygen species, increase of Thioredoxin Interacting Protein (TXNIP) inhibits the antioxidative function of thioredoxin, moreover reduced glucose uptake, consequently, decrease NADPH/NADP resulting in the accumulation of ROS coincident with a decrease of GLUT1, SOD2, TrDX an increase of LC3IIA protein expression. SR enhances A673 pyruvate dependency, and decrease glyco and mito ATP production rate, more over observed under glucose deprivation. Furthermore, apoptotic effect was significantly amplified when cells were under nutrient starvation, revealing a 56% apoptotic rate after 24 hours of SR treatment. Conclusion: SR antagonist of 𝜷;;3-AR and combination of SR with BUF could be an innovative therapeutic option to raise awareness ES. Citation Format: Cristina Banella, Francesco Carrozzo, Laura Zocca, Amada Pasha, Gianluca Mattei, Marina Mola, Lara Ballerini, Nicla Lorito, Annalisa Tondo, Claudio Favre, Maura Calvani. The β3-adrenergic receptor as novel target of metabolic phenotype in Ewing sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1787.
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ZENETOS, A., S. KATSANEVAKIS, D. POURSANIDIS, F. CROCETTA, D. DAMALAS, G. APOSTOLOPOULOS, C. GRAVILI, E. VARDALA-THEODOROU, and M. MALAQUIAS. "Marine alien species in Greek Seas: Additions and amendments by 2010." Mediterranean Marine Science 12, no. 1 (March 11, 2011): 95. http://dx.doi.org/10.12681/mms.55.
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An update of the inventory of alien marine species from the coastal and offshore waters of Greece is presented. Records were compiled based on the existing scientific and grey literature, including the HCMR database of Greek alien species (ELNAIS), technical reports, scientific congresses, academic dissertations, websites, and unpublished/personal observations. 47 species were added to the inventory, including 34 invertebrates, one vertebrate (fish), three plants, eight protozoa, and one cyanobacterium. With the new records, the inventory of alien marine species of Greece now includes a total of 237 species (33 macrophytes, 131 invertebrates, 42 vertebrates, two bacteria and 29 protozoans). Among these, the presence of the gastropodHypselodoris infucata, the bivalvesDendrostrea frons and Septifer forskaliand the chondrichthyan Rhizoprionodon acutus is reported here for the first time. Based on molecular analysis, the occurrence of Bulla arabica in Greek waters is confirmed, and the suggestion that previous records of Bulla ampulla in the Mediterranean should be considered as misidentification of B. arabica is further supported. The acclimitization status of earlier records was revised in the light of new data, and thus the fishEnchelycore anatina, Seriola fasciata andTylerius spinosissimus, the red algaeHypnea cornuta and Sarconema scinaioides, the scyphomedusaCassiopea andromeda, the cephalopodSepioteuthis lessoniana, the nudibranchChromodoris annulata and the bivalvesGastrochaena cymbium andPseudochama corbieri were upgraded from casual records to established populations. The increased rate of introductions of warm water species confirms previous findings, which link the rate of introduction in the eastern Mediterranean to climate change.
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Broz, Marina, Emily Ko, Jinfen Xiao, Marco DeSimone, Roberta Piras, Kristin Ishaya, Xen Ping Hoi, and Jlenia Guarnerio. "Abstract 1255: Glucose dependent CD73+ CAFs enforce a tumor metabolic barrier that promotes T cell exclusion." Cancer Research 83, no. 7_Supplement (April 4, 2023): 1255. http://dx.doi.org/10.1158/1538-7445.am2023-1255.
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Abstract Trafficking of T lymphocytes from the lymph nodes to the tumor microenvironment is a critical process of the tumor immunity cycle to elicit cytotoxic anti-tumor responses driven by CD8+ T cells. However, some tumors termed “immune excluded” recruit lymphocytes to the tumor site, but the lymphocytes are unable to penetrate the tumor parenchyma and localize primarily in the peritumoral region. In soft tissue sarcoma patients, most tumors are poorly infiltrated by T cells, which is associated with a poor response to immunotherapies. It has been described that cancer associated fibroblasts (CAFs) are enriched in immune excluded tumors and may directly block the migration of T cells via the production of dense extracellular matrix or by forging an immunosuppressive niche. We generated two models of undifferentiated pleomorphic sarcoma (UPS) that recapitulate the “immune excluded” and “inflamed” microenvironments observed in sarcoma patients. These syngeneic models rely on p53KO mesenchymal stem cells overexpressing either Ccne1 or Vgll3, which are frequently amplified in UPS patients. These models differ in their overall proportion of infiltrating TILs, and specifically T cells, making them ideal for comparative studies to investigate the mechanisms driving T cell exclusion in the TME. Using single-cell RNA-sequencing, we identified a population of CAFs expressing Nt5e, encoding CD73, which are spatially enriched in the peritumoral region of immune excluded Ccne1 tumors and closely associate with CD8+ T cells located at the tumor margin. Using transwell invasion assays, we show that CD73+ CAFs but not CD73- CAFs are able to block the migration of activated T cells towards tumor cells, even in the presence of CXCL10. Further, we show that Nt5e CAFs are enriched for signatures of glucose metabolism, and hypoxia, thus we hypothesized that CD73+ CAFs may block the migration of T cells into tumors by forging a nutrient poor metabolic barrier around the tumor. To test this, we treated Ccne1 tumors with BAY-876, a GLUT1 inhibitor and observed a significant accumulation of infiltrating CD8+ T cells compared to controls. GLUT1 treated CAFs expressed significantly less Nt5e, indicating that CD73 may play a role in the maintenance of glucose metabolism in CAFs. Furthermore, blockade of CD73 in CD73+ CAFs decreases the expression of the glucose transporter, Glut1. All together, these data suggest that CD73 may serve as a marker of glucose dependent CAFs that alter the metabolic niche to block T cell infiltration into tumors. Citation Format: Marina Broz, Emily Ko, Jinfen Xiao, Marco DeSimone, Roberta Piras, Kristin Ishaya, Xen Ping Hoi, Jlenia Guarnerio. Glucose dependent CD73+ CAFs enforce a tumor metabolic barrier that promotes T cell exclusion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1255.
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Lee, Meng-Chou, Chin-Yi Huang, Chin-Ling Lai, Han-Yang Yeh, Jing Huang, Wei Qing Chloe Lung, Po-Tsang Lee, and Fan-Hua Nan. "Colaconema formosanum, Sarcodia suae, and Nostoc commune as Fermentation Substrates for Bioactive Substance Production." Fermentation 8, no. 7 (July 21, 2022): 343. http://dx.doi.org/10.3390/fermentation8070343.
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Bioactive compounds extracted from natural renewable sources have attracted an increased interest from both industry and academia. Recently, algae have been highlighted as promising sources of bioactive compounds, such as polyphenols, polysaccharides, fatty acids, proteins, and pigments, which can be used as functional ingredients in many industrial applications. Therefore, a simple green extraction and purification methodology capable of recovering biocompounds from algal biomass is of extreme importance in commercial production. In this study, we evaluated the application of three valuable algae (Colaconema formosanum, Sarcodia suae, and Nostoc commune) in combination with Pseudoalteromonas haloplanktis (type strain ATCC 14393) for the production of versatile compounds. The results illustrate that after 6 h of first-stage fermentation, the production of phycobiliproteins in C. formosanum was significantly increased by 156.2%, 188.9%, and 254.17% for PE, PC, and APC, respectively. This indicates that the production of phycobiliproteins from algae can be enhanced by P. haloplanktis. Furthermore, we discovered that after S. suae and N. commune were fermented with P. haloplanktis, mannose was produced. In this study, we describe a feasible biorefinery process for the production of phycobiliproteins and mannose by fermenting marine macroalgae with cyanobacteria. We believe it is worth establishing a scale-up technique by applying this fermentation method to the production of phycobiliproteins and mannose in the future.
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Golozubova, Julia Sergeevna, Lyubov Stepanovna Buzoleva, Elena Aleksandrovna Bogatyrenko, Alexandra Vyacheslavovna Kim, and Alena Igorevna Eskova. "Diversity of cultivated heterotrophic bacteria selected from surface waters of the Vostok Bay of the Japanese Sea." Samara Journal of Science 6, no. 4 (December 1, 2017): 32–35. http://dx.doi.org/10.17816/snv201764106.
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In this article, the taxonomic diversity of cultivated heterotrophic microorganisms of the surface waters of Bay Vostok of Peter the Great Bay of the Japan Sea was considered. In the bay Vostok total number of heterotrophic microorganisms was 2,03-105 КОЕ/ml which can be attributed to mezazoprobnye sea water. Microorganisms isolated from this coastal area are represented by 4 phylums. The cultivated microorganisms were dominated by representatives of the phylum Proteobacteria, which accounted for more than 50% of the total taxonomic diversity of the cultivated bacteria of the Vostok Bay. Phylums of Bacteroidetes, Firmicutes and Actinobacteria were also isolated. The taxonomic diversity of microbial community was represented by 15 genus. Based on the phenotypic characteristics, cultured heterotrophic bacteria was classified into the genera Rhodococcus sp., Micrococcus sp., Actynomycetes sp., Bacillus sp., Sarcina sp., Pseudomonas sp., Acinetobacter sp., Arthrobacter sp., Vibrio sp., Halomonas sp., Flavobacterium sp., Acetobacter sp., and Marinococcus sp., Pseudoalteromonas sp., Aeromonas sp., Staphylococcus sp. Sanitation-indicative bacteria in this bay were not identified, which indicates a slight anthropogenic impact. Thus bay Vostok was really insignificant recreational stress and it was reflected on marine microbial community.
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Atmaca, Harika, Emir Bozkurt, Burcu Cakar, Zeki Gokhan Surmeli, Selim Uzunoglu, Ruchan Uslu, and Burcak Karaca. "Trabectedin to induce mitochondrial membrane potential dissipation and reactive oxygen species generation in breast cancer cells." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): e13580-e13580. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e13580.
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e13580 Background: Trabectedin (Yondelis; ET-743) is a tetrahydroisoquinoline alkaloid that was originally derived from the marine tunicate Ecteinascidia turbinata and is currently prepared synthetically. It ıs currently used for the treatment of soft tissue sarcomas. It has been shown that Trabectedin provides the production of superoxides near the DNA strand, resulting in DNA backbone cleavage and cell apoptosis, however the apoptotic mechanisms of Trabectedin is still very limited. The objective of this study is to investigate the underlying mechanisms of apoptosis Trabectedin in two human breast cancer cell lines (MDA-MB-231 and MDA-MB-453) and one human immortalized non-transformed breast epithelial cell line (MCF-10A), to see if similar oxidation processes take place in breast cancer. Methods: Cytotoxicity was assessed by XTT cell viability assay. Apoptosis was shown by measuring DNA fragmentation, caspase 3/7 activation. Mitochondrial membrane potential (MMP) was evaluated by TMRE dye. Measurement of reactive oxygen species (ROS) was done by using Glutathione S-Transferase (GST) Assay Kit and CM-H2DCFDA dye. Results: Trabectedin induced the cytotoxicity in breast cancer cells in a time and dose dependent manner. Moreover, it increased DNA fragmentation and the MMP dissipation in tested breast cancer cells. The levels of ROS production in parallel with GST enzyme activity were sharply increased by Trabectedin treatment. Conclusions: This is the first study to investigate the role of Trabectedin activity and mechanisms of apoptosis in human breast cancer cells. These preliminary results might show us a way to use Trabectedin alone, or in combination for breast cancer treatment in near future.
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Taamma, A., J. L. Misset, M. Riofrio, C. Guzman, E. Brain, L. Lopez Lazaro, H. Rosing, J. M. Jimeno, and E. Cvitkovic. "Phase I and Pharmacokinetic Study of Ecteinascidin-743, a New Marine Compound, Administered as a 24-hour Continuous Infusion in Patients With Solid Tumors." Journal of Clinical Oncology 19, no. 5 (March 1, 2001): 1256–65. http://dx.doi.org/10.1200/jco.2001.19.5.1256.
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PURPOSE: To define the maximum-tolerated dose (MTD) and the phase II recommended dose (RD) of ecteinascidin-743 (ET-743) given as a 24-hour continuous infusion every 3 weeks to patients with treatment-refractory solid tumors. PATIENTS AND METHODS: Fifty-two patients received a total of 158 cycles of ET-743 at one of nine dose levels (DLs) ranging from 50 to 1,800 μg/m2. RESULTS: The MTD was defined as 1,800 μg/m2 (DL 9), and the phase II RD was 1,500 μg/m2 (DL 8) for moderately pretreated patients with performance status (PS) 0 to 1 and good hepatobiliary function. Neutropenia and thrombocytopenia were the dose-limiting toxicities (DLTs) and were severe at the MTD (1,800 μg/m2) in 94% and 25% of cycles, respectively. At the RD (1,500 μg/m2), neutropenia and thrombocytopenia were present in 33% and 10% of cycles, respectively. Transient acute elevated transaminase levels occurred in almost all cycles and was severe in 38% of cycles. Severe toxicities and DLTs were observed in patients with poor PS or abnormal liver function or who had received a large number of previous chemotherapy regimens. Antitumor activity was observed at the three highest DLs, including three partial responses (breast cancer, osteosarcoma, and liposarcoma), and four patients (all with progressing soft tissue sarcomas) had stable disease lasting ≥ 3 months. Pharmacokinetic studies were performed on all patients for at least the first cycle, giving a linear pharmacokinetic profile; this showed a relationship between area under the curve (AUC) and transaminitis grade and a clear correlation between AUC and severe hematologic toxicity likelihood. CONCLUSION: The RD for a 24-hour continuous intravenous infusion of ET-743 is 1,500 μg/m2, with the most prevalent DLTs being hematologic. Patients with minor baseline hepatobiliary function abnormalities have a higher likelihood of severe hematologic toxicities and AUC-related DLTs, requiring dose adjustments or delays.
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Ganapathi, Shireen S., Emma Wrenn, Nicolas Garcia, Neerja Katiyar, Aya Miyaki, Yuqi Kang, Marina Chan, Taran S. Gujral, and Elizabeth R. Lawlor. "Abstract 150: Transcriptional rewiring of BET inhibitor treated Ewing sarcoma cells augments their dependency on focal adhesion kinase." Cancer Research 84, no. 6_Supplement (March 22, 2024): 150. http://dx.doi.org/10.1158/1538-7445.am2024-150.
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Abstract Outcomes for patients with recurrent and metastatic Ewing sarcoma (EwS) are dismal and novel therapies are needed. As EwS are initiated and maintained by the EWS::FLI1 transcription factor, agents that target aberrant gene transcription are of interest and bromodomain inhibitors (BETi) have shown promise in preclinical models. Nevertheless, despite initial efficacy, BETi tolerance emerges across tumor types, often via transcriptional rewiring. We reasoned that the therapeutic potential of BETi in EwS could be augmented by identifying and targeting mechanisms of drug resistance. To investigate this, we performed transcriptional and phenotypic profiling of BETi-naïve, responsive, and drug-tolerant (DT) EwS cells and used these data to nominate biologically-informed drug combinations. EwS cells (A673, CHLA10, TC32) were exposed for 72 hrs or 20 days to BMS-986158, a clinical grade BETi being tested in a phase I pediatric clinical trial (NCT0393465). A profound cytostatic effect was observed at 72 hrs but in all cell lines proliferation was restored by 20 days. RNA-seq confirmed reversion of the EWS::FLI1-dependent gene signature at 72 hrs and this was maintained at 20 days, demonstrating continued on-target effects despite restored growth of DT cells. Interrogation of differentially expressed genes between drug naïve, cytostatic, and DT cells indicated that that DT cells had been transcriptionally rewired to more mesenchymal states, with notable upregulation of genes involved in integrin signaling. In support of this, DT populations displayed more fibroblastic morphologies, increased F-actin filaments, and enhanced invasion in collagen-rich 3D culture. In parallel, an unbiased kinase inhibitor screen that exploits mathematical modeling revealed that, while BETi-treated cells were overall more resistant than parent cells to kinase inhibitors, their viability depended on focal adhesion kinase (FAK) activity. Western blot confirmed increased phospho-FAK in DT cells. We next tested BMS-986158 and the FAK-inhibitor Defactinib singly or in combination in vitro and in vivo. Defactinib induced cell death in 2D cultures and blocked invasion of 3D spheroids in collagen. Conversely, BMS-986158 enhanced invasive potential in 3D. The combination of Defactinib and BMS-986158 in naïve and DT populations was highly synergistic in 2D assays. In 3D collagen assays, viability and invasion of DT tumor spheroids were significantly reduced by the combination. Finally, ongoing studies show that the combination of FAK and BET inhibition prolongs survival of mice with EwS tumor xenografts. Thus, our studies reveal that exposure of EwS cells to BETi induces transcriptional rewiring that activates integrin and FAK signaling, restoring proliferation. This work supports further investigation of FAKi as agents that could prevent or reverse the BETi tolerant state in EwS. Citation Format: Shireen S. Ganapathi, Emma Wrenn, Nicolas Garcia, Neerja Katiyar, Aya Miyaki, Yuqi Kang, Marina Chan, Taran S. Gujral, Elizabeth R. Lawlor. Transcriptional rewiring of BET inhibitor treated Ewing sarcoma cells augments their dependency on focal adhesion kinase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 150.