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Journal articles on the topic 'Targeted therapy of hematological malignancies'
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1
Kachlany, Scott C., Amy Le, and Benjamin A. Belinka. "Leukotoxin (Leukothera™), a Targeted Therapy for Hematological Malignancies." Blood 116, no. 21 (November 19, 2010): 3284. http://dx.doi.org/10.1182/blood.v116.21.3284.3284.
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Abstract Abstract 3284 Leukotoxin (Leukothera™) is a bacterial protein toxin that naturally targets and kills disease associated white blood cells (WBCs) expressing the activated form of leukocyte function antigen-1 (LFA-1). While leukotoxin has minimal effects on resting and healthy cells, it causes significant death of malignant WBCs associated with leukemias and lymphomas. Leukotoxin is a unique biologic in that it already provides both toxicity and specificity without requiring fusion of the protein to other molecules such as antibody fragments or cytokines. In vivo efficacy was demonstrated in an HL-60 SCID mouse leukemia model previously. In the present work, we compared leukotoxin to the standard chemotherapeutic agents, doxorubicin and cytarabine in a SCID mouse model using THP-1 leukemia cells. Mice (n=14 per group) were injected with THP-1 cells intravenously (i.v.) and then administered either leukotoxin or standard agents i.v. Mice received three doses, once daily, of leukotoxin (1.5 mg/kg) or five doses of doxorubicin (0.5 mg/kg) or cytarabine (10 mg/kg) once daily. Leukemic mice that were treated with leukotoxin maintained and increased body weight more effectively than those which received vehicle alone or the standard agents. The leukotoxin-treated mice showed significantly (p<0.001) higher mean survival than mice treated with vehicle or cytarabine over the 60-day observation period. Necropsy and histopathology of animals after the 60-day period revealed that test animals treated with vehicle or standard agents developed internal tumors on organs such as the thymus and lymph nodes. In contrast, none of the leukotoxin-treated mice developed internal tumors. To determine if leukotoxin could block migration of malignant cells, and thus formation of internal tumors, we performed a cellular migration assay using activated monocytes and human brain endothelial cells. It was found that even a low dose of leukotoxin (10 ng/ml) caused significant suppression (>80%) of monocyte migration across an endothelial barrier. Hence, leukotoxin has the potential to not only deplete malignant WBCs, but may also prevent their spread to other tissues. To test the general safety of leukotoxin, mice were injected with 1 mg/kg for three weeks. None of the mice showed signs of illness or changes in normal behavior and all continued to gain weight throughout the study period. In addition, to determine if a neutralizing antibody response to leukotoxin was generated, we challenged mice with high doses of leukotoxin and assayed monoclonal antibody from ten independent hybridomas. Results showed that antibody was able to bind to and recognize leukotoxin, but did not cause significant neutralization in a bioassay. In conclusion, leukotoxin may represent a highly effective and safe option for patients with hematologic malignancies, especially those with relapsed and refractory disease. Disclosures: Kachlany: Actinobac Biomed, Inc.: Consultancy, Equity Ownership. Belinka:Actinobac Biomed, Inc.: Employment, Equity Ownership.
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Kuriakose, Philip. "Targeted Therapy for Hematologic Malignancies." Cancer Control 12, no. 2 (April 2005): 82–90. http://dx.doi.org/10.1177/107327480501200203.
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Background: The introduction of monoclonal antibodies, either as native molecules or conjugated to radioisotopes or other toxins, has led to new therapeutic options for patients with hematologic malignancies. In addition, the use of small molecules against specific cell surface receptors, enzymes, and proteins has become an important strategy in the treatment of such disorders. Methods: The author reviewed the published clinical trials of monoclonal antibody and other targeted therapies in hematologic malignancies. Results: Results from several trials demonstrate a therapeutic benefit for the use of monoclonal antibodies (either native or conjugated) and other targeted therapies, used alone or in combination with standard cytotoxic chemotherapy. Conclusions: Targeted therapy of hematologic malignancies seems to be an effective and less toxic approach to the treatment of such disorders. Nevertheless, additional studies are needed to determine where and when such management fits into a therapeutic regimen for any given disorder, whether upfront or as salvage therapy, alone or in combination with chemotherapy (concurrent or sequential).
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Joshi, Dolly, Kanjaksha Gosh, and Babu Rao Vundinti. "MicroRNAs in hematological malignancies: a novel approach to targeted therapy." Hematology 17, no. 3 (May 2012): 170–75. http://dx.doi.org/10.1179/102453312x13376952196656.
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Ma, Haiqing, Saradhi Mallampati, Gang An, and Jin Wang. "Targeted Therapy in Hematological Malignancies: From Basic Research to Clinical Practice." BioMed Research International 2015 (2015): 1–2. http://dx.doi.org/10.1155/2015/157570.
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Podhorecka, Monika, Justyna Markowicz, Agnieszka Szymczyk, and Johannes Pawlowski. "Target Therapy in Hematological Malignances: New Monoclonal Antibodies." International Scholarly Research Notices 2014 (October 30, 2014): 1–16. http://dx.doi.org/10.1155/2014/701493.
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Apart from radio- and chemotherapy, monoclonal antibodies (MoAbs) represent a new, more selective tool in the treatment of hematological malignancies. MoAbs bind with the specific antigens of the tumors. This interaction is a basis for targeted therapies which exhibit few side effects and significant antitumor activity. This review provides an overview of the functional characteristics of MoAbs, with some examples of their clinical application. The promising results in the treatment of hematological malignancies have led to the more frequent usage of MoAbs in the therapy. Development of MoAbs is a subject of extensive research. They are a promising method of cancer treatment in the future.
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Leni, Zaira, Geetha Parakkal, and Alexandre Arcaro. "Emerging Metabolic Targets in the Therapy of Hematological Malignancies." BioMed Research International 2013 (2013): 1–12. http://dx.doi.org/10.1155/2013/946206.
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During the last decade, the development of anticancer therapies has focused on targeting neoplastic-related metabolism. Cancer cells display a variety of changes in their metabolism, which enable them to satisfy the high bioenergetic and biosynthetic demands for rapid cell division. One of the crucial alterations is referred to as the “Warburg effect”, which involves a metabolic shift from oxidative phosphorylation towards the less efficient glycolysis, independent of the presence of oxygen. Although there are many examples of solid tumors having altered metabolism with high rates of glucose uptake and glycolysis, it was only recently reported that this phenomenon occurs in hematological malignancies. This review presents evidence that targeting the glycolytic pathway at different levels in hematological malignancies can inhibit cancer cell proliferation by restoring normal metabolic conditions. However, to achieve cancer regression, high concentrations of glycolytic inhibitors are used due to limited solubility and biodistribution, which may result in toxicity. Besides using these inhibitors as monotherapies, combinatorial approaches using standard chemotherapeutic agents could display enhanced efficacy at eradicating malignant cells. The identification of the metabolic enzymes critical for hematological cancer cell proliferation and survival appears to be an interesting new approach for the targeted therapy of hematological malignancies.
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Liang, Xuewu, Hong Liu, and Yingjie Zhang. "Novel-targeted therapy for hematological malignancies with JAK and HDAC dual inhibitors." Future Medicinal Chemistry 11, no. 15 (August 2019): 1849–52. http://dx.doi.org/10.4155/fmc-2019-0168.
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Jurcic, Joseph G. "Targeted Alpha-Particle Therapy for Hematologic Malignancies." Seminars in Nuclear Medicine 50, no. 2 (March 2020): 152–61. http://dx.doi.org/10.1053/j.semnuclmed.2019.09.002.
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Jurcic, Joseph G. "Targeted Alpha-Particle Therapy for Hematologic Malignancies." Journal of Medical Imaging and Radiation Sciences 50, no. 4 (December 2019): S53—S57. http://dx.doi.org/10.1016/j.jmir.2019.05.008.
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Gao, Rili, Yikai Zhang, Chengwu Zeng, and Yangqiu Li. "The role of NFAT in the pathogenesis and targeted therapy of hematological malignancies." European Journal of Pharmacology 921 (April 2022): 174889. http://dx.doi.org/10.1016/j.ejphar.2022.174889.
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Ueda, Takanori. "Update on molecular-targeted therapy in hematologic malignancies." International Journal of Clinical Oncology 12, no. 5 (October 22, 2007): 311–12. http://dx.doi.org/10.1007/s10147-007-0709-3.
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Gabrilove, J. L. "Hematologic Malignancies: An Opportunity for Targeted Drug Therapy." Oncologist 6, no. 90005 (October 1, 2001): 1–3. http://dx.doi.org/10.1634/theoncologist.6-2004-1.
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Gabrilove, Janice L. "Hematologic Malignancies: An Opportunity for Targeted Drug Therapy." Oncologist 6, S5 (October 2001): 1–3. http://dx.doi.org/10.1634/theoncologist.6-suppl_5-1.
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Shakil, Md Salman, Mahruba Sultana Niloy, Kazi Mustafa Mahmud, Mohammad Amjad Kamal, and Md Asiful Islam. "Theranostic Potentials of Gold Nanomaterials in Hematological Malignancies." Cancers 14, no. 13 (June 21, 2022): 3047. http://dx.doi.org/10.3390/cancers14133047.
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Hematological malignancies (HMs) are a heterogeneous group of blood neoplasia generally characterized by abnormal blood-cell production. Detection of HMs-specific molecular biomarkers (e.g., surface antigens, nucleic acid, and proteomic biomarkers) is crucial in determining clinical states and monitoring disease progression. Early diagnosis of HMs, followed by an effective treatment, can remarkably extend overall survival of patients. However, traditional and advanced HMs’ diagnostic strategies still lack selectivity and sensitivity. More importantly, commercially available chemotherapeutic drugs are losing their efficacy due to adverse effects, and many patients develop resistance against these drugs. To overcome these limitations, the development of novel potent and reliable theranostic agents is urgently needed to diagnose and combat HMs at an early stage. Recently, gold nanomaterials (GNMs) have shown promise in the diagnosis and treatment of HMs. Magnetic resonance and the surface-plasmon-resonance properties of GNMs have made them a suitable candidate in the diagnosis of HMs via magnetic-resonance imaging and colorimetric or electrochemical sensing of cancer-specific biomarkers. Furthermore, GNMs-based photodynamic therapy, photothermal therapy, radiation therapy, and targeted drug delivery enhanced the selectivity and efficacy of anticancer drugs or drug candidates. Therefore, surface-tuned GNMs could be used as sensitive, reliable, and accurate early HMs, metastatic HMs, and MRD-detection tools, as well as selective, potent anticancer agents. However, GNMs may induce endothelial leakage to exacerbate cancer metastasis. Studies using clinical patient samples, patient-derived HMs models, or healthy-animal models could give a precise idea about their theranostic potential as well as biocompatibility. The present review will investigate the theranostic potential of vectorized GNMs in HMs and future challenges before clinical theranostic applications in HMs.
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Kim, Miyoung, Jane Snowdon, S. Dilhan Weeraratne, Winnie Felix, Lionel Lim, Irene Dankwa-Mullan, Young Kyung Lee, et al. "Clinical insights for hematological malignancies from an artificial intelligence decision-support tool." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e13023-e13023. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e13023.
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e13023 Background: Next generation sequencing (NGS) in hematological tumors is increasingly shaping clinical treatment decisions at the point of care. While the impact of NGS panels in solid tumors is largely therapeutic, targeted sequencing in hematological tumors can additionally provide diagnostic and prognostic insights. Additional data generated in hematological tumor sequencing makes manual interpretation and annotation of variants tedious and non-scalable. In this study we compared hematological tumor variant interpretation using an artificial intelligence decision-support system, Watsonä for Genomics (WfG), with expert guided manual curation. Methods: Patients with hematological tumors at Hallym University, College of Medicine between December 2017 and December 2018, were sequenced using the 54 gene Illumina TruSight Myeloid Panel. WfG interpreted and annotated all patients’ sequencing results, a subset of which were assessed manually to ascertain concordance. Results: 54 South Korean patients with hematological malignancies were analyzed (23 Acute Myeloid Leukemia, 12 myeloproliferative neoplasm, 5 myelodysplastic syndrome, 5 multiple myeloma and 9 others). Comparison of manual and WfG interpretation of 10 randomly selected cases yielded 90% (9/10) concordance and identification of 9 clinically actionable variants (33%) not found in manual interpretation. In total, WfG identified that 71% (38/54) of all cases had at least one clinically actionable therapeutic alteration (a variant targeted by a US FDA approved drug, off-label drug, or clinical trial). 33% (18/54) of cases had genes that were targeted by a US FDA approved therapy including JAK2, IDH1, IDH2, and FLT3. In cases without therapeutic alterations, WfG identified diagnostic or prognostic insights in an additional 20% (11/54) of patients. 9% (5/54) had no clinically actionable information. Conclusions: WfG variant interpretation correlated well with manually curated expert opinion and identified clinically actionable insights missed by manual interpretation. WfG has obviated the need for labor-intensive manual curation of clinical trials and therapy, enabling our center to exponentially scale our NGS operations.
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Miloudi, Hadjer, Vincent Camus, Antoine Taly, Brigitte Sola, and Fabrice Jardin. "Exportin 1 (or XPO1) abnormalities in hematological malignancies: from the gene to targeted therapy." Hématologie 23, no. 1 (January 2017): 43–56. http://dx.doi.org/10.1684/hma.2017.1208.
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Ahmed, Shah Newaz, and Arun Kumar. "CAR T-cell therapy-transforming treatment of hematological malignancies." Asian Journal of Medical Sciences 14, no. 2 (February 1, 2023): 1–2. http://dx.doi.org/10.3126/ajms.v14i2.50899.
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Hematological malignancies are a significant cause of mortality and morbidity in all age groups. According to the Global Burden of Disease Cancer Collaboration, there were about one million incident cases of hematological malignancies worldwide in 2016. In an analysis of NORDCAN database, it was observed that the 5-year survival rates during the period 1999–2003 for Hodgkin lymphoma, Non-Hodgkin lymphoma, acute leukemia, other leukemia, and multiple myeloma were 80, 50–60, 38–49, 60–73, and 28–41%, respectively. The treatment of these blood cancers has seen rapid advances in modern medicine. However, mortality is still very high and globally, about half a million deaths were attributed to these malignancies in 2016 alone.1 In some cancers, such as the relapsed/refractory B-cell precursor-ALL, the 5-year survival rate is only 10% with conventional treatment. Conventionally, chemotherapy has been the mainstay of treatment supported by radiation therapy, targeted therapy, or stem-cell transplantation resulting in improved outcomes. Novel treatment options that improve outcomes are under research worldwide. The chimeric antigen receptor T-cell therapy (CAR-T) is a promising novel anticancer treatment modality. A CAR-T therapy consists of infusion of engineered T-cells that express a chimeric antigen receptor on their cell membrane. In-vivo, CAR-T cells eliminate tumor cells with precision by interacting with the tumor-associated antigens (TAAs) on tumor cell surface independent of the expression of major histocompatibility complex. CAR is a recombinant immunoreceptor composed of an extracellular binding domain (TAA-reactive antibody derived Single-chain variable fragments), a hinge region, a transmembrane domain, and one or more intracellular signalling domains (CD3ζchain). Second-, third-, and fourth-generations of these receptors have costimulatory domains such as CD28 and/or 4-1BB which enhance auto-proliferation, cytokine secretion, apoptosis resistance, and in-vivo persistence. Fourth generation CARs have additional enzyme secreting properties which degrade extracellular matrix of solid tumours. The first FDA approved therapies, tisagenlecleucel followed by axicabtagene ciloleucel, are third generation anti-CD19 CAR T-cells indicated for treatment of refractory B-cell acute lymphoblastic leukemia (in children and young adults) and refractory diffuse large B-cell lymphoma (in adults), respectively. The approval was based on Phase II trials (ELIANA trial for tisagenlecleucel and ZUMA-1 trial for axicabtagene). An objective response rate of 81 and 82% was observed, respectively. The success of these therapies has rekindled the hope for targeting other malignancies which have been hitherto refractory to treatment. At present, CAR-T cell therapy targeting CD7/CD23/ CD33/CD34/CD38/CD56/CD117/CD123/CD133/ Mucl (for acute myeloid leukemia), CD19/CD20/CD22/ EGFR (for chronic lymphocytic leukemia), CD30 (for Hodgkin lymphoma), and CD38/CD138 (for multiple myeloma) are in various stages of Phase I/II clinical trials (nearly 150). Despite the initial better outcomes, it is too early to predict the final picture. Serious adverse drug reaction (CRS-cytokine release syndrome and NT-neurotoxicity) leading to fatality has already been reported. Moreover, concerns have been expressed about tumor relapse, genotoxicity, and autoimmunity as long-term consequences. In the Phase 2 ELARA trial, tisagenlecleucel was found to be safe and effective in adult relapsed or refractory follicular lymphoma. However, the BELINDA trial (Phase III trial) failed to show superiority to standard salvage therapy. On an optimistic note, ZUMA-7 trial and TRANSFORM trial for axicabtagene in early relapsed or refractory large B-cell lymphoma demonstrated improved survival and response outcomes compared to standard therapy. A handful of Phase 3 trials are underway to test the efficacy and safety of the “revolutionary” drugs in the treatment of hematological malignancies. The acceptability of these “living drugs” in the future will depend on the results of these trials and beyond.
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Xie, Bailu, Zhengdong Li, Jianfeng Zhou, and Wen Wang. "Current Status and Perspectives of Dual-Targeting Chimeric Antigen Receptor T-Cell Therapy for the Treatment of Hematological Malignancies." Cancers 14, no. 13 (June 30, 2022): 3230. http://dx.doi.org/10.3390/cancers14133230.
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Single-targeted chimeric antigen receptor (CAR) T cells tremendously improve outcomes for patients with relapsed/refractory hematological malignancies and are considered a breakthrough therapy. However, over half of treated patients experience relapse or refractory disease, with antigen escape being one of the main contributing mechanisms. Dual-targeting CAR T-cell therapy is being developed to minimize the risk of relapse or refractory disease. Preclinical and clinical data on five categories of dual-targeting CAR T-cell therapies and approximately fifty studies were summarized to offer insights and support the development of dual-targeting CAR T-cell therapy for hematological malignancies. The clinical efficacy (durability and survival) is validated and the safety profiles of dual-targeting CAR T-cell therapy are acceptable, although there is still room for improvement in the bispecific CAR structure. It is one of the best approaches to optimize the bispecific CAR structure by boosting T-cell transduction efficiency and leveraging evidence from preclinical activity and clinical efficacy.
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Ye, Baixin, Creed M. Stary, Qingping Gao, Qiongyu Wang, Zhi Zeng, Zhihong Jian, Lijuan Gu, and Xiaoxing Xiong. "Genetically Modified T-Cell-Based Adoptive Immunotherapy in Hematological Malignancies." Journal of Immunology Research 2017 (2017): 1–13. http://dx.doi.org/10.1155/2017/5210459.
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A significant proportion of hematological malignancies remain limited in treatment options. Immune system modulation serves as a promising therapeutic approach to eliminate malignant cells. Cytotoxic T lymphocytes (CTLs) play a central role in antitumor immunity; unfortunately, nonspecific approaches for targeted recognition of tumor cells by CTLs to mediate tumor immune evasion in hematological malignancies imply multiple mechanisms, which may or may not be clinically relevant. Recently, genetically modified T-cell-based adoptive immunotherapy approaches, including chimeric antigen receptor (CAR) T-cell therapy and engineered T-cell receptor (TCR) T-cell therapy, promise to overcome immune evasion by redirecting the specificity of CTLs to tumor cells. In clinic trials, CAR-T-cell- and TCR-T-cell-based adoptive immunotherapy have produced encouraging clinical outcomes, thereby demonstrating their therapeutic potential in mitigating tumor development. The purpose of the present review is to (1) provide a detailed overview of the multiple mechanisms for immune evasion related with T-cell-based therapies; (2) provide a current summary of the applications of CAR-T-cell- as well as neoantigen-specific TCR-T-cell-based adoptive immunotherapy and routes taken to overcome immune evasion; and (3) evaluate alternative approaches targeting immune evasionviaoptimization of CAR-T and TCR-T-cell immunotherapies.
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Roex, Gils, Tom Feys, Yves Beguin, Tessa Kerre, Xavier Poiré, Philippe Lewalle, Peter Vandenberghe, Dominique Bron, and Sébastien Anguille. "Chimeric Antigen Receptor-T-Cell Therapy for B-Cell Hematological Malignancies: An Update of the Pivotal Clinical Trial Data." Pharmaceutics 12, no. 2 (February 24, 2020): 194. http://dx.doi.org/10.3390/pharmaceutics12020194.
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Chimeric antigen receptor (CAR)-T-cell therapy is an innovative form of adoptive cell therapy that has revolutionized the treatment of certain hematological malignancies, including B-cell non-Hodgkin lymphoma (NHL) and B-cell acute lymphoblastic leukemia (ALL). The treatment is currently also being studied in other B-cell neoplasms, including multiple myeloma (MM) and chronic lymphocytic leukemia (CLL). CD19 and B-cell maturation antigen (BCMA) have been the most popular target antigens for CAR-T-cell immunotherapy of these malignancies. This review will discuss the efficacy and toxicity data from the pivotal clinical studies of CD19- and BCMA-targeted CAR-T-cell therapies in relapsed/refractory B-cell malignancies (NHL, ALL, CLL) and MM, respectively.
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Daraskevicius, Justinas, Vidmantas Petraitis, Linas Davainis, and Andrius Zucenka. "The Feasibility of Ibrexafungerp for the Treatment of Fungal Infections in Patients with Hematological Malignancies." Journal of Fungi 8, no. 5 (April 23, 2022): 440. http://dx.doi.org/10.3390/jof8050440.
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Invasive fungal diseases (IFD) remain a major cause of morbidity and mortality in hematological patients, especially those undergoing hematopoietic stem cell transplantation (HSCT). Despite relatively high incidence, diagnosis and treatment remain a challenge due to non-specific manifestation and limited antifungal armamentarium. A first-in-class triterpenoid antifungal ibrexafungerp that acts by inhibiting the glucan synthase enzyme in the fungal cell wall was recently approved by the USA Food and Drug Administration for the treatment of vaginal yeast infections. Preclinical data show activity against numerous fungi species, including azole- and echinocandin-resistant strains. Preliminary data from ongoing phase 3 studies in IFD have been encouraging, but the role of ibrexafungerp in hematological patients who develop fungal infections has not yet been described. Herein, we discuss the feasibility of oral ibrexafungerp-based antifungal therapy for adult patients with hematological malignancies who have either undergone HSCT or received treatment with a novel targeted therapy agent. We present four clinical cases where ibrexafungerp alone or in combination with other antifungal agents was successfully employed for the management of refractory fungal infection. We describe real-life experiences showing the potential clinical implementation of ibrexafungerp for patients with hematological malignancies for the first time, and provoke future discussion.
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Ueda, Takanori. "Current status of molecular targeted therapy for hematologic malignancies: introduction." International Journal of Clinical Oncology 19, no. 1 (December 20, 2013): 1–2. http://dx.doi.org/10.1007/s10147-013-0652-4.
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Bhalla, Kapil N. "Epigenetic and Chromatin Modifiers As Targeted Therapy of Hematologic Malignancies." Journal of Clinical Oncology 23, no. 17 (June 10, 2005): 3971–93. http://dx.doi.org/10.1200/jco.2005.16.600.
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Epigenetic regulation of gene expression is mediated through alterations in the DNA methylation status, covalent modifications of core nucleosomal histones, rearrangement of histones, and by RNA interference. It is now abundantly clear that deregulation of epigenetic mechanisms cooperates with genetic alterations in the development and progression of cancer and leukemia. Epigenetic deregulation affects several aspects of tumor cell biology, including cell growth, cell cycle control, differentiation, DNA repair, and cell death. This raises the strong possibility that reversing deregulated epigenetic mechanisms may be an effective treatment strategy for leukemia and cancer. This treatment strategy may either be designed to separately or collectively target the specific perturbations in the epigenetic mechanisms found in human hematologic malignancies. The following review describes our current understanding of the important deregulated epigenetic mechanisms and the preclinical and clinical development of epigenetic and chromatin modifiers in the therapy of these disorders.
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Karvonen, Hanna, Wilhelmiina Niininen, Astrid Murumägi, and Daniela Ungureanu. "Targeting ROR1 identifies new treatment strategies in hematological cancers." Biochemical Society Transactions 45, no. 2 (April 13, 2017): 457–64. http://dx.doi.org/10.1042/bst20160272.
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Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a member of the ROR receptor family consisting of two closely related type I transmembrane proteins ROR1 and ROR2. Owing to mutations in their canonical motifs required for proper kinase activity, RORs are classified as pseudokinases lacking detectable catalytic activity. ROR1 stands out for its selective and high expression in numerous blood and solid malignancies compared with a minimal expression in healthy adult tissues, suggesting high potential for this molecule as a drug target for cancer therapy. Current understanding attributes a survival role for ROR1 in cancer cells; however, its oncogenic function is cancer-type-specific and involves various signaling pathways. High interest in ROR1-targeted therapies resulted in the development of ROR1 monoclonal antibodies such as cirmtuzumab, currently in a phase I clinical trial for chronic lymphocytic leukemia. Despite these advances in translational studies, the molecular mechanism employed by ROR1 in different cancers is not yet fully understood; therefore, more insights into the oncogenic role of ROR1 signaling are crucial in order to optimize the use of targeted drugs. Recent studies provided evidence that targeting ROR1 simultaneously with inhibition of B-cell receptor (BCR) signaling is more effective in killing ROR1-positive leukemia cells, suggesting a synergistic correlation between co-targeting ROR1 and BCR pathways. Although this synergy has been previously reported for B-cell acute lymphoblastic leukemia, the molecular mechanism appears rather different. These results provide more insights into ROR1–BCR combinatorial treatment strategies in hematological malignancies, which could benefit in tailoring more effective targeted therapies in other ROR1-positive cancers.
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Garcia, Anita A. "Small Molecules: Big Changes in the Cancer Treatment Paradigm." Journal of Pharmacy Practice 21, no. 1 (February 2008): 17–35. http://dx.doi.org/10.1177/0897190008314779.
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Small molecules, a growing class of targeted therapies, have flourished over the last decade. With increased knowledge on molecular cell signaling, targeted therapy has been refined to targeting molecular targets upstream from the nucleus that are key players in the communication system that regulates cancer cell growth. This article reviews the mechanisms of small molecules with a particular emphasis on tyrosine kinase inhibitors, as well as the literature that supports the current clinical use in the treatment of a variety of solid and hematological malignancies.
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Bethge, Wolfgang A., and Brenda M. Sandmaier. "Targeted Cancer Therapy Using Radiolabeled Monoclonal Antibodies." Technology in Cancer Research & Treatment 4, no. 4 (August 2005): 393–405. http://dx.doi.org/10.1177/153303460500400407.
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Radioimmunotherapy (RIT) combines the advantages of targeted radiation therapy and specific immunotherapy using monoclonal antibodies. RIT can be used either to target tumor cells or to specifically suppress immunocompetent host cells in the setting of allogeneic transplantation. The choice of radionuclide used for RIT depends on its distinct radiation characteristics and the type of malignancy or cells targeted. Beta-emitters with their lower energy and longer path length are more suitable to target bulky, solid tumors whereas α-emitters with their high linear energy transfer and short path length are better suited to target hematopoietic cells (normal or malignant). Different approaches of RIT such as the use of stable radioimmunoconjugates or of pretargeting strategies are available. Encouraging results have been obtained with RIT in patients with hematologic malignancies. The results in solid tumors are somewhat less favorable but new strategies for patients with minimal residual disease using adjuvant and locoregional treatment are evolving. This report outlines basic principles of RIT, gives an overview of available radionuclides and radioimmunoconjugates, and discusses clinical results with special emphasis on their use in hematologic malignancies including use in conditioning regimens for bone marrow transplantation.
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Cronk, Robert J., Joanna Zurko, and Nirav N. Shah. "Bispecific Chimeric Antigen Receptor T Cell Therapy for B Cell Malignancies and Multiple Myeloma." Cancers 12, no. 9 (September 5, 2020): 2523. http://dx.doi.org/10.3390/cancers12092523.
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Chimeric antigen receptor (CAR) modified T cell therapy offers a targeted immunotherapeutic approach to patients with refractory hematological malignancies. This technology is most advanced in B cell malignancies and multiple myeloma and is rapidly evolving as more data become available regarding clinical efficacy and response durability. Despite excellent initial response rates with single antigen targeting CARs, failure to respond to therapy and relapse due to target antigen downregulation remain clinical challenges. To mitigate immunophenotypic selective pressures, simultaneous dual antigen targeting with bispecific CAR T cells or multiple administration of different populations of CAR T cells may prevent relapse by addressing one resistance mechanism attributed to antigenic loss. This article will review recently published data on the use of dual targeting with CAR T cells from early phase clinical trials aimed at treating B cell malignancies and multiple myeloma.
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Zhang, Jianxiang, and Lingyu Wang. "The Emerging World of TCR-T Cell Trials Against Cancer: A Systematic Review." Technology in Cancer Research & Treatment 18 (January 1, 2019): 153303381983106. http://dx.doi.org/10.1177/1533033819831068.
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T-cell receptor–engineered T-cell therapy and chimeric antigen receptor T-cell therapy are 2 types of adoptive T-cell therapy that genetically modify natural T cells to treat cancers. Although chimeric antigen receptor T-cell therapy has yielded remarkable efficacy for hematological malignancies of the B-cell lineages, most solid tumors fail to respond significantly to chimeric antigen receptor T cells. T-cell receptor–engineered T-cell therapy, on the other hand, has shown unprecedented promise in treating solid tumors and has attracted growing interest. In order to create an unbiased, comprehensive, and scientific report for this fast-moving field, we carefully analyzed all 84 clinical trials using T-cell receptor–engineered T-cell therapy and downloaded from ClinicalTrials.gov updated by June 11, 2018. Informative features and trends were observed in these clinical trials. The number of trials initiated each year is increasing as expected, but an interesting pattern is observed. NY-ESO-1, as the most targeted antigen type, is the target of 31 clinical trials; melanoma is the most targeted cancer type and is the target of 33 clinical trials. Novel antigens and underrepresented cancers remain to be targeted in future studies and clinical trials. Unlike chimeric antigen receptor T-cell therapy, only about 16% of the 84 clinical trials target against hematological malignancies, consistent with T-cell receptor–engineered T-cell therapy’s high potential for solid tumors. Six pharma/biotech companies with novel T-cell receptor–engineered T-cell ideas and products were examined in this review. Multiple approaches have been utilized in these companies to increase the T-cell receptor’s affinity and efficiency and to minimize cross-reactivity. The major challenges in the development of the T-cell receptor–engineered T-cell therapy due to tumor microenvironment were also discussed here.
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Wach, Małgorzata, Monika Podhorecka, Maria Cioch, Iwona Hus, Ewa Wąsik-Szczepanek, Bożena Sokołowska, and Marek Hus. "Advances in hematology – research that revolutionized patient care." Polish Journal of Public Health 125, no. 1 (March 1, 2015): 32–35. http://dx.doi.org/10.1515/pjph-2015-0019.
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AbstractIn the last decades, substantial strides have been made in the diagnosis, treatment, and prevention of blood diseases. The new drugs to be used in combination with cytostatic therapy have been developed, based on increased understanding of the biology of neoplasia. The diagnosis of several diseases is based exclusively on cytogenetic and molecular analysis which has become a part of routine diagnostic management. Moreover, molecular definition has allowed the introduction of therapy targeted at molecular change characteristic for a given disease. The introduction of novel agents for the treatment of hematological disorders has resulted in a great improvement in response rate and median survival.The aim of this study is to show advances and possible future directions in the treatment of chosen hematological malignancies during the recent decades.
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Simpson-Haidaris, P. J., S. J. Pollock, S. Ramon, N. Guo, C. F. Woeller, S. E. Feldon, and R. P. Phipps. "Anticancer Role of PPARγAgonists in Hematological Malignancies Found in the Vasculature, Marrow, and Eyes." PPAR Research 2010 (2010): 1–36. http://dx.doi.org/10.1155/2010/814609.
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The use of targeted cancer therapies in combination with conventional chemotherapeutic agents and/or radiation treatment has increased overall survival of cancer patients. However, longer survival is accompanied by increased incidence of comorbidities due, in part, to drug side effects and toxicities. It is well accepted that inflammation and tumorigenesis are linked. Because peroxisome proliferator-activated receptor (PPAR)-γagonists are potent mediators of anti-inflammatory responses, it was a logical extension to examine the role of PPARγagonists in the treatment and prevention of cancer. This paper has two objectives: first to highlight the potential uses for PPARγagonists in anticancer therapy with special emphasis on their role when used as adjuvant or combined therapy in the treatment of hematological malignancies found in the vasculature, marrow, and eyes, and second, to review the potential role PPARγand/or its ligands may have in modulating cancer-associated angiogenesis and tumor-stromal microenvironment crosstalk in bone marrow.
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Koudijs, Marco J., Lennart A. Kester, Jayne Y. Hehir-Kwa, Eugene T. P. Verwiel, Erik Strengman, Marc van Tuil, Douwe van der Leest, et al. "RNA-Sequencing Improves Diagnostics and Treatment of Pediatric Hematological Malignancies." Blood 138, Supplement 1 (November 5, 2021): 107. http://dx.doi.org/10.1182/blood-2021-147692.
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Abstract Background Diagnosis and treatment of hematological malignancies relies increasingly on the detection of underlying genetic abnormalities. Various laboratory techniques, including karyotyping, SNP-array, FISH, MLPA and RT-PCR are typically required to detect the full spectrum of clinically relevant genetic aberrations. These techniques are also hampered in their sensitivity by their targeted approach or lack of resolution. Ideally, an unbiased genome wide approach like RNA sequencing (RNA-seq) as a one-test-fits-all, could save costs and efforts and streamline diagnostic procedures. In the Netherlands, the care for all children with oncological disorders has been concentrated in a single, national center. Within the Laboratory of Childhood Cancer Pathology, we aim for a comprehensive diagnostic pipeline by implementing RNA-seq to aid diagnosis, prognosis and treatment of all children with cancer in the Netherlands. Methods We have established an RNA-seq based diagnostic pipeline, primarily aimed at detecting gene fusion events. Library prep is performed on 50-300 ng total RNA isolated from fresh (frozen) samples, followed by ribo-depletion and subsequent paired-end sequencing (2x150 nt) using the Illumina NovaSeq platform. Data is analyzed using the StarFusion algorithm for gene-fusion detection. We are prospectively comparing the results with routine diagnostic procedures. In addition, we are validating the detection of single nucleotide variants (SNVs) from RNA-seq data and developing a diagnostic classifier, using a nearest neighbor network approach. Results Based on RNA-seq profiling in diagnostics for all patients entering the Princess Maxima Center, there are several use-cases that highlight the value of RNA-seq. 1) In a prospective cohort of 244 patients (pan-cancer, including 97 hematological malignancies) we have shown that the diagnostic yield for detecting gene fusion events increased by approximately 40% compared to classical methods. An example is the TNIP1--PDGFRB gene fusion in a patient with pre B-ALL, making this patient eligible for imatinib treatment, which was not detected by other methods. 2) Variant calling on RNA-seq shows that activating mutations in e.g. KRAS are detected with high sensitivity, stratifying patients for therapeutic MEK intervention. 3) By expression outlier analysis, we were able to detect various promotor exchanges, e.g. IGH-MYC or IGH--DUX4, which are typically hard to detect by molecular techniques since the genomic breakpoint is highly variable and no chimeric transcript is formed. 4) Preliminary results from our diagnostic classifier show its potential to predict subclasses of hematological malignancies, e.g. high-hyperdiploid or bi-phenotypic ALL patients. 5) Fusion gene breakpoints detected by RNA-seq serve as a target for MRD analysis, allowing us to monitor disease progression and therapy response in individual patients. Currently, RNA-seq data is available for more than 1500 pediatric tumor samples. At the upcoming conference we will present an update of our results and some typical cases highlighting the added value of RNA-seq in routine diagnostics. Conclusion We show that RNA-seq on pediatric cancer samples is feasible and of great value for routine diagnostics. It has a higher sensitivity to detect gene fusion events compared to targeted assays. RNA-seq based gene fusion detection, in combination with mutation and expression analysis, is also promising to improve classification of malignancies, prognosis and stratification of patients for targeted therapies. Disclosures No relevant conflicts of interest to declare.
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Rao, Arati V., and Kenneth Schmader. "Monoclonal antibodies as targeted therapy in hematologic malignancies in older adults." American Journal of Geriatric Pharmacotherapy 5, no. 3 (September 2007): 247–62. http://dx.doi.org/10.1016/j.amjopharm.2007.09.002.
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Volkov, Dmitry V., George V. Tetz, Yury P. Rubtsov, Alexey V. Stepanov, and Alexander G. Gabibov. "Neutrophil Extracellular Traps (NETs): Opportunities for Targeted Therapy." Acta Naturae 13, no. 3 (November 15, 2021): 15–23. http://dx.doi.org/10.32607/actanaturae.11503.
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Antitumor therapy, including adoptive immunotherapy, inevitably faces powerful counteraction from advanced cancer. If hematological malignancies are currently amenable to therapy with CAR-T lymphocytes (T-cells modified by the chimeric antigen receptor), solid tumors, unfortunately, show a significantly higher degree of resistance to this type of therapy. As recent studies show, the leading role in the escape of solid tumors from the cytotoxic activity of immune cells belongs to the tumor microenvironment (TME). TME consists of several types of cells, including neutrophils, the most numerous cells of the immune system. Recent studies show that the development of the tumor and its ability to metastasize directly affect the extracellular traps of neutrophils (neutrophil extracellular traps, NETs) formed as a result of the response to tumor stimuli. In addition, the nuclear DNA of neutrophils the main component of NETs erects a spatial barrier to the interaction of CAR-T with tumor cells. Previous studies have demonstrated the promising potential of deoxyribonuclease I (DNase I) in the destruction of NETs. In this regard, the use of eukaryotic deoxyribonuclease I (DNase I) is promising in the effort to increase the efficiency of CAR-T by reducing the NETs influence in TME. We will examine the role of NETs in TME and the various approaches in the effort to reduce the effect of NETs on a tumor.
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Jose, Arun, Hind Rafei, and Jalil Ahari. "Combination targeted pulmonary hypertension therapy in the resolution of Dasatinib-associated pulmonary arterial hypertension." Pulmonary Circulation 7, no. 4 (July 5, 2017): 803–7. http://dx.doi.org/10.1177/2045893217716659.
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Dasatinib is a small-molecule tyrosine kinase inhibitor used in the treatment of hematological malignancies. Pulmonary arterial hypertension (PAH) is a rare but known complication. The mainstay of treatment is cessation of Dasatinib, and while clinical improvement is rapid, complete hemodynamic resolution of pulmonary hypertension (PH) still remains exceedingly uncommon. We present a case of Dasatinib-induced PAH in a woman with chronic myeloid leukemia, who demonstrated rapid and complete clinical and hemodynamic resolution following treatment with combination pulmonary vasodilator therapy using an endothelin receptor antagonist and a phosphodiesterase-5 inhibitor. This case suggests there may be an association between the use of targeted PH medication in combination and the complete resolution of dasatinib-associated PAH, but further investigation is required.
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Saucier, Emilie, Florence Rabian, Hélène Boutroux, Marion Strullu, Karine Morand, Florian Chevillon, Benoit Brethon, Nicolas Boissel, Guy Leverger, and André Baruchel. "Azacitidine in Pediatric Hematologic Myeloid Malignancies: A Retrospective Study." Blood 134, Supplement_1 (November 13, 2019): 5130. http://dx.doi.org/10.1182/blood-2019-131062.
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Purpose: Hypomethylating agents are approved in adults with Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS). By contrast, data in pediatric hematologic malignancies are scarce. Herein, we report the off-label administration of Azacitidine (Aza) in a cohort of children, adolescents and young adults (AYA). Methods: Patients from Robert-Debré, Saint-Louis and Armand-Trousseau University Hospitals (Assistance Publique-Hôpitaux de Paris), 25 year-old or younger at initiation of treatment and who received Aza between 2009 and 2019 were included. Data on indication, efficacy and toxicity of the treatment were retrospectively collected. Results: As 3 patients (pts) were treated twice with Aza at different stages of their disease, 35 treatments in 32 patients were analyzed. Median age at diagnosis was 11.7 y (range 0.1-22.4). Diagnosis were: 16 Acute Myeloid Leukemias (AML), 6 Juvenile Myelomonocytic Leukemias (JMML), 7 Myelodysplastic Syndromes (MDS), 2 Mixed Phenotype Acute Leukemias (MPAL) and 1 Interdigitating Dendritic Cells Sarcoma. Aza was administrated after a median of 2 lines of treatment (range 0-6) and front line in 5 out of 32 pts (16%; MDS = 4, JMML = 1). Concomitant therapy was administrated in 15/35 treatments (43%) (Sorafenib = 6, Gemtuzumab Ozogamicin = 2, donor lymphocyte infusions = 2, other = 5). Fourteen out of 35 treatments (40%) were delivered in patients with a history of hematopoietic stem cell transplantation (HSCT). Aza was administrated either intravenously (n = 11) or subcutaneously (n = 24) at a dose of 75mg/m² for 7 (20/35, 57%) or 5 (6/35, 17%) consecutive days every 28 days, i.e. same daily dose as in adults; at reduced doses (≤ 50mg/m²) in 3/35 patients; at a dosing scheme varying from one cycle to another in 6/35 patients. Patients received a median of 3 cycles of Aza per treatment (range 1-31). A total of 137 cycles was delivered. Aza was well tolerated with only 5/137 cycles delayed due to hematological (n = 3) or non-hematological (n = 2) toxicity. Aza was discontinued due to toxicity in 2/137 cycles (1 rectal bleeding, 1 severe sepsis). Anemia was noted in 68/130 cycles (52%), thrombocytopenia in 68/128 cycles (53%), neutropenia in 84/127 cycles (66%) and febrile neutropenia in 25/131 cycles (19%). Two grade 5 side effects were observed: 1 patient died from cerebral hemorrhage in a context of anti-platelet poly-immunization, another from septic shock in a context of neutropenia. Most common non-hematological side effects included: nausea, vomiting, diarrhea, subcutaneous injections lesions (local inflammation or hematoma) and infections. Responses to Aza are detailed in the attached table. Best responses to Aza included: 2 complete remissions (CR) both after 3 cycles, 3 CR with incomplete hematologic recovery (CRi) after a median of 2 cycles (range 1-2), 2 partial remissions (PR) after 2 and 3 cycles, 6 stable diseases (SD) during a median of 2 cycles (range 2-12) and 2 hematologic improvements. Overall response rate (sum of CR, CRi, PRs), was 19% (6/32) (3 non evaluable responses). Three out of the 6 patients treated with Aza combined with Sorafenib (AML = 4, MPAL = 2) obtained a response (CR: 2, CRi: 1). The association led to HSCT for 2 of them; the third patient had a CR maintained almost 3 years without HSCT, before relapsing on therapy. One patient with MDS had a SD for 12 months after palliative treatment with Aza. Overall, Aza treatment allowed to proceed to HSCT in 8 out of 32 patients (25%), 7 out of 8 proceeding to a first HSCT [CR: 1 patient, CRi: 3 patients, PR: 2 patients, SD: 1 patient, progressive disease: 1 patient]. These 8 pts included: 4 pts with AML, alive in CR after a median follow-up of 29.5 months (2 of them received concomitant targeted therapy); 2 pts with JMML (1 alive in CR after a follow-up of 25 months); 2 pts with MDS (both died, 7 and 30 months after Aza initiation). Finally, 24 out of 32 patients died and overall survival at 5 years was 23% (IC95% [11;48]) with no difference according to diagnosis. Conclusion: In a cohort of pediatric and AYA patients with heavily pretreated myeloid malignancies, Aza was well tolerated, and allowed to bridge 25% of patients to HSCT. Further prospective studies are needed to explore combination of Aza with targeted therapy in pediatric patients. Disclosures Boissel: NOVARTIS: Consultancy.
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Tabe, Yoko, Philip L. Lorenzi, and Marina Konopleva. "Amino acid metabolism in hematologic malignancies and the era of targeted therapy." Blood 134, no. 13 (August 15, 2019): 1014–23. http://dx.doi.org/10.1182/blood.2019001034.
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Almåsbak, Hilde, Tanja Aarvak, and Mohan C. Vemuri. "CAR T Cell Therapy: A Game Changer in Cancer Treatment." Journal of Immunology Research 2016 (2016): 1–10. http://dx.doi.org/10.1155/2016/5474602.
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The development of novel targeted therapies with acceptable safety profiles is critical to successful cancer outcomes with better survival rates. Immunotherapy offers promising opportunities with the potential to induce sustained remissions in patients with refractory disease. Recent dramatic clinical responses in trials with gene modified T cells expressing chimeric antigen receptors (CARs) in B-cell malignancies have generated great enthusiasm. This therapy might pave the way for a potential paradigm shift in the way we treat refractory or relapsed cancers. CARs are genetically engineered receptors that combine the specific binding domains from a tumor targeting antibody with T cell signaling domains to allow specifically targeted antibody redirected T cell activation. Despite current successes in hematological cancers, we are only in the beginning of exploring the powerful potential of CAR redirected T cells in the control and elimination of resistant, metastatic, or recurrent nonhematological cancers. This review discusses the application of the CAR T cell therapy, its challenges, and strategies for successful clinical and commercial translation.
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Mazloom, Anita, Nima Ghalehsari, Victor Gazivoda, Neil Nimkar, Sonal Paul, Peter Gregos, Janice Rateshwar, and Uqba Khan. "Role of Immune Checkpoint Inhibitors in Gastrointestinal Malignancies." Journal of Clinical Medicine 9, no. 8 (August 6, 2020): 2533. http://dx.doi.org/10.3390/jcm9082533.
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Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of several solid and hematological malignancies. ICIs are not only able to produce long and durable responses, but also very well tolerated by patients. There are several approved indications of use of ICIs in treatment of metastatic gastrointestinal malignancies including gastric, esophageal, colorectal and hepatocellular carcinoma. In addition, ICIs can be used in microsatellite instability-high (MSI-H) and high tumor mutational burden (TMB) tumors in chemotherapy-resistant setting. Despite having good efficacy and superior safety profile, ICIs are clinically active in small subset of patients, therefore, there is a huge unmet need to enhance their efficacy and discover new predictive biomarkers. There are several ongoing clinical trials that are exploring the role of ICIs in various gastrointestinal cancers either as single agent or in combination with chemotherapy, radiation therapy, targeted agents or other immunotherapeutic agents. In this review, we discuss the published and ongoing trials for ICIs in gastrointestinal malignancies, including esophageal, gastric cancer, pancreatic, hepatocellular, biliary tract, colorectal and anal cancers. Specifically, we focus on the use of ICIs in each line of therapy and discuss the future directions of these agents in each type of gastrointestinal cancer.
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Matthews, Dana C., Frederick R. Appelbaum, Oliver W. Press, Janet F. Eary, and Irwin D. Bernstein. "Targeted therapy for hematologic malignancies: has its promise been realized? Editorial review." Current Opinion in Hematology 2, no. 4 (1995): 235–39. http://dx.doi.org/10.1097/00062752-199502040-00001.
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Zeidan, Amer M., Tehseen Salimi, and Robert S. Epstein. "Real-world use and outcomes of hypomethylating agent therapy in higher-risk myelodysplastic syndromes: why are we not achieving the promise of clinical trials?" Future Oncology 17, no. 36 (December 2021): 5163–75. http://dx.doi.org/10.2217/fon-2021-0936.
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Myelodysplastic syndromes are hematological malignancies characterized by ineffective hematopoiesis and a high risk of progression to acute myeloid leukemia. Hypomethylating agents (HMAs), azacitidine and decitabine, are standard of care therapy for higher-risk myelodysplastic syndromes. However, outcomes reported for real-world studies fall short of those achieved in clinical trials. We conducted a targeted literature review exploring real-world utilization, persistence and outcomes with intravenous and subcutaneous HMA therapies to better understand barriers to achieving optimal outcomes in clinical practice. The potential benefits of oral HMA therapy were also explored. Underutilization and poor persistence with HMA therapy are associated with suboptimal outcomes, highlighting the need for approaches to improve utilization and persistence, so that patients achieve the optimum benefit from HMA therapy.
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Sorrentino, Vincent G., Srijan Thota, Edward A. Gonzalez, Pranela Rameshwar, Victor T. Chang, and Jean-Pierre Etchegaray. "Hypomethylating Chemotherapeutic Agents as Therapy for Myelodysplastic Syndromes and Prevention of Acute Myeloid Leukemia." Pharmaceuticals 14, no. 7 (July 4, 2021): 641. http://dx.doi.org/10.3390/ph14070641.
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Myelodysplastic Syndromes (MDSs) affect the elderly and can progress to Acute Myeloid Leukemia (AML). Epigenetic alterations including DNA methylation and chromatin modification may contribute to the initiation and progression of these malignancies. DNA hypomethylating agents such as decitabine and azacitidine are used as therapeutic treatments and have shown to promote expression of genes involved in tumor suppression, apoptosis, and immune response. Another anti-cancer drug, the proteasome inhibitor bortezomib, is used as a chemotherapeutic treatment for multiple myeloma (MM). Phase III clinical trials of decitabine and azacitidine used alone and in combination with other chemotherapeutics demonstrated their capacity to treat hematological malignancies and prolong the survival of MDS and AML patients. Although phase III clinical trials examining bortezomib’s role in MDS and AML patients are limited, its underlying mechanisms in MM highlight its potential as a chemotherapeutic for such malignancies. Further research is needed to better understand how the epigenetic mechanisms mediated by these chemotherapeutic agents and their targeted gene networks are associated with the development and progression of MDS into AML. This review discusses the mechanisms by which decitabine, azacitidine, and bortezomib alter epigenetic programs and their results from phase III clinical trials.
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Huang, Chen-Yu, Susanna Guatelli, Bradley M. Oborn, and Barry J. Allen. "Microdosimetry for Targeted Alpha Therapy of Cancer." Computational and Mathematical Methods in Medicine 2012 (2012): 1–6. http://dx.doi.org/10.1155/2012/153212.
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Targeted alpha therapy (TAT) has the advantage of delivering therapeutic doses to individual cancer cells while reducing the dose to normal tissues. TAT applications relate to hematologic malignancies and now extend to solid tumors. Results from several clinical trials have shown efficacy with limited toxicity. However, the dosimetry for the labeled alpha particle is challenging because of the heterogeneous antigen expression among cancer cells and the nature of short-range, high-LET alpha radiation. This paper demonstrates that it is inappropriate to investigate the therapeutic efficacy of TAT by macrodosimetry. The objective of this work is to review the microdosimetry of TAT as a function of the cell geometry, source-target configuration, cell sensitivity, and biological factors. A detailed knowledge of each of these parameters is required for accurate microdosimetric calculations.
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Akbari, Parvin, Elisabeth J. M. Huijbers, Maria Themeli, Arjan W. Griffioen, and Judy R. van Beijnum. "The tumor vasculature an attractive CAR T cell target in solid tumors." Angiogenesis 22, no. 4 (October 18, 2019): 473–75. http://dx.doi.org/10.1007/s10456-019-09687-9.
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Abstract T cells armed with a chimeric antigen receptor, CAR T cells, have shown extraordinary activity against certain B lymphocyte malignancies, when targeted towards the CD19 B cell surface marker. These results have led to the regulatory approval of two CAR T cell approaches. Translation of this result to the solid tumor setting has been problematic until now. A number of differences between liquid and solid tumors are likely to cause this discrepancy. The main ones of these are undoubtedly the uncomplicated availability of the target cell within the blood compartment and the abundant expression of the target molecule on the cancerous cells in the case of hematological malignancies. Targets expressed by solid tumor cells are hard to engage due to the non-adhesive and abnormal vasculature, while conditions in the tumor microenvironment can be extremely immunosuppressive. Targets in the tumor vasculature are readily reachable by CAR T cells and reside outside the immunosuppressive tumor microenvironment. It is therefore hypothesized that targeting CAR T cells towards the tumor vasculature of solid tumors may share the excellent effects of CAR T cell therapy with that against hematological malignancies. A few reports have shown promising results. Suggestions are provided for further improvement.
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Sultana, Tanvira Afroze, Md Abdul Mottalib, Md Sirazul Islam, Mohiuddin Ahmed Khan, and Subhagata Choudhury. "rt-PCR method for diagnosis and follow-up of hematological malignancies: First approach in Bangladesh." Bangladesh Medical Research Council Bulletin 34, no. 1 (September 16, 2008): 1–11. http://dx.doi.org/10.3329/bmrcb.v34i1.1162.
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Nested reverse-transcriptase polymerase chain reaction (rt-PCR) was performed on 58 leukemia patients at BIRDEM Laboratory, as a pioneering work in Bangladesh. Thirty of them were examined for the presence of BCR-ABL being clinically and morphologically diagnosed as chronic myeloid leukemia (CML) and 28 for PML-RARα fusion transcripts being clinically and morphologically diagnosed as acute promyelocytic leukemia (APL/ AML M3). The cases were selected for targeted therapy with imatinib mesylate and all-Trans retinoic acid (ATRA) to treat CML and APL respectively. Samples were received either before commencement or during therapy. In the positive cases, amplified DNA products were visible after gel electrophoresis and were reported accordingly. In case of BCR-ABL, positive results were found for five out of six (83.33%) untreated cases and 11 out of 24 (45.83%) treated cases. Positive results for PML-RARα were found for 12 out of 14 (85.70%) untreated cases and 11 out of 16 (68.75%) treated cases. A strong positive correlation was found between duration of treatment and negativity of PCR results in both the cases. In present times, the detection of minimal residual disease in patients undergoing treatment for hematological malignancies has become an important goal, not only to monitor the effectiveness of therapy but also to detect an impending relapse. This is the first time in Bangladesh that rt-PCR method is being employed to detect or monitor the presence of abnormal fusion genes in hematological malignancies. Keywords: Bangladesh; malignancy; rt-pcrDOI: 10.3329/bmrcb.v34i1.1162Bangladesh Med Res Counc Bull 2008; 34: 1-11
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Parker, Andy. "STP938, a Novel, Potent and Selective Inhibitor of CTP Synthase 1 (CTPS1) Is a Targeted Therapy Specifically Blocking De Novo Nucleotide Synthesis in Lymphomas and Leukemias." Blood 136, Supplement 1 (November 5, 2020): 31. http://dx.doi.org/10.1182/blood-2020-138436.
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Introduction: The ability to reprogram cellular metabolism including enhanced de novo nucleotide synthesis is a hallmark of cancer and essential for tumor progression and survival. The pyrimidine synthesis pathway has been proposed as a metabolic sensitivity for cancer and over the past few decades several inhibitors of enzymes involved in the pathway have been evaluated in clinical trials (e.g. avicin, CPEC, PALA, leflunomide) primarily in solid tumors with limited efficacy and unacceptable toxicity. The final step in the pyrimidine de novo nucleotide synthesis pathway is the conversion of UTP to CTP. This step is unusual in the pathway in having two enzymes which catalyze the same reaction, CTP synthase 1 (CTPS1) and CTPS2, which have the same activity but very different cell type dependencies. CTPS1 has been shown to have an essential and non-redundant role in lymphocyte proliferation with the identification of an ultra-rare human hypomorphic mutation resulting in an 85% reduction in CTPS1 activity which manifests as a profound effect upon lymphoid cells but with no effects on other cell types. This hypomorphic mutation prevents proliferation of T-cells and B-cells following activation, thus selective inhibition of CTPS1 represents a novel targeted approach to inhibit proliferation of lymphocytes in hematological malignancies without inhibiting CTP synthesis in other cell types which utilise CTPS2. We have identified and optimized orally bioavailable selective inhibitors of CTPS1 (exemplified by STP938) and hypothesized that STP938 would demonstrate anti-tumor effects on cells derived from hematological malignancies. Methods: The in vitro anti-tumor activity of selective CTPS1 inhibition was investigated in a 2D monolayer assay in a panel of 200 cancer cell lines. Cell viability was measured with the Cell Titer-Blue Cell Viability Assay after 4 days incubation. Human PBMCs were isolated and T-cells were activated with anti CD3/CD28 antibodies to assess effects of CTPS1 inhibition on intracellular nucleotide levels which were quantified using Liquid Chromatography Mass Spectrometry (LC-MS). Jurkat T-ALL cells and WI38 embryonic fibroblasts were used to assess apoptosis which was quantified using the Caspase-Glo 3/7 Assay. Murine xenograft studies were conducted in NOD.SCID mice implanted with T-ALL cell lines to assess anti-tumor effects of CTPS1 inhibitors. Results: The panel of cancer cell lines consisted of 56 derived from hematological cancers and 141 derived from solid tumors. STP938, a potent and selective inhibitor of CTPS1 specifically blocked cell proliferation of the hematological cancers. 43 (77%) of the hematological cell lines had an IC50 <100nM whereas only 15% of the solid tumor derived cell lines were affected by the CTPS1 inhibitor. The T-cell derived cell lines were extremely sensitive with many IC50 <10nM. Profiling of intracellular nucleotide levels using activated human T-cells exposed to increasing concentrations of STP938 demonstrated the selective depletion of CTP but not ATP or GTP (see Figure). Jurkat T-ALL cells and WI38 fibroblasts were evaluated for markers of apoptosis in the presence of increasing concentrations of STP938. The Jurkat T-ALL cells exhibited a dose dependent increase in caspase 3/7 levels indicative of apoptosis. The WI38-fibroblast cells were unaffected. Murine xenograft studies using NHL T lymphoma and leukemia cell lines were conducted with oral dosing of CTPS1 inhibitor starting at the time of tumor cell inoculation or once tumors were established. In all cases, in a dose-dependent manner, CTPS1 inhibitors reduced or ablated tumor growth meeting NCI criteria for efficacy. Conclusions: Our preliminary results indicate that inhibition of CTPS1 enables cell specific inhibition of de novo pyrimidine nucleotide synthesis with a particular sensitivity displayed by cell lines derived from hematological malignancies. This disruption of de novo nucleotide synthesis by CTPS1 inhibition selectively induces apoptosis in lymphocyte cells but not in other cell types that are able to rely upon CTPS2 for their CTP synthesis. Orally bioavailable small molecule inhibitors of CTPS1 exert an anti-tumor effect in vivo in murine xenograft models and thus inhibition of CTPS1 represents a novel targeted approach to treat hematological malignancies. Figure Disclosures Parker: Step Pharma: Current Employment.
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Ravi, Dashnamoorthy, Afshin Beheshti, Kristine Burgess, Athena Kritharis, Ying Chen, Andrew M. Evens, and Biju Parekkadan. "An Analysis of Transcriptomic Burden Identifies Biological Progression Roadmaps for Hematological Malignancies and Solid Tumors." Biomedicines 10, no. 11 (October 27, 2022): 2720. http://dx.doi.org/10.3390/biomedicines10112720.
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Biological paths of tumor progression are difficult to predict without time-series data. Using median shift and abacus transformation in the analysis of RNA sequencing data sets, natural patient stratifications were found based on their transcriptomic burden (TcB). Using gene-behavior analysis, TcB groups were evaluated further to discover biological courses of tumor progression. We found that solid tumors and hematological malignancies (n = 4179) share conserved biological patterns, and biological network complexity decreases at increasing TcB levels. An analysis of gene expression datasets including pediatric leukemia patients revealed TcB patterns with biological directionality and survival implications. A prospective interventional study with PI3K targeted therapy in canine lymphomas proved that directional biological responses are dynamic. To conclude, TcB-enriched biological mechanisms detected the existence of biological trajectories within tumors. Using this prognostic informative novel informatics method, which can be applied to tumor transcriptomes and progressive diseases inspires the design of progression-specific therapeutic approaches.
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Ana Sami. "Next Generation Stem Cells and their Implications in Cancer Therapy." Journal of the Pakistan Medical Association 73, no. 2 (January 25, 2023): S98—S104. http://dx.doi.org/10.47391/jpma.akus-16.
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Stem cells have been implicated for decades in the treatment of hematological malignancies. These cells when isolated from the bone marrow, adipose tissue, or foetal tissue are deemed as the first generation of stem cells. The turn of the century saw the discovery of the second generation of stem cells such as the human Embryonic Stem Cells (hESCs) and induced Pluripotent Stem Cells (iPSCs). Advances in gene editing technology, in the past decade, have stimulated the rise of next-generation stem cells. Recent studies exploit the tumour tropism, multi-lineage differentiation, and auto-renewal capability of stem cells, and combine it with molecular biology techniques, to create potent anti-cancer therapies. Stem cells have been modified to have low immunogenicity and are thus being used as ‘trojan horses’ for the targeted, intra-tumoral delivery of anti-cancer drugs. continued...
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Alrhmoun, Saleh, and Sergey Sennikov. "The Role of Tumor-Associated Antigen HER2/neu in Tumor Development and the Different Approaches for Using It in Treatment: Many Choices and Future Directions." Cancers 14, no. 24 (December 14, 2022): 6173. http://dx.doi.org/10.3390/cancers14246173.
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The treatment of HER2-positive cancers has changed significantly over the past ten years thanks to a significant number of promising new approaches that have been added to our arsenal in the fight against cancer, including monoclonal antibodies, inhibitors of tyrosine kinase, antibody–drug conjugates, vaccination, and particularly, adoptive-T-cell therapy after its great success in hematological malignancies. Equally important is the new methodology for determining patients eligible for targeted HER2 therapy, which has doubled the number of patients who can benefit from these treatments. However, despite the initial enthusiasm, there are still several problems in this field represented by drug resistance and tumor recurrence that require the further development of new more efficient drugs. In this review, we discuss various approaches for targeting the HER2 molecule in cancer treatment, highlighting their benefits and drawbacks, along with the different mechanisms responsible for resistance to HER2-targeted therapies and how to overcome them.
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Gasic, Vladimir, Teodora Karan-Djurasevic, Djordje Pavlovic, Branka Zukic, Sonja Pavlovic, and Natasa Tosic. "Diagnostic and Therapeutic Implications of Long Non-Coding RNAs in Leukemia." Life 12, no. 11 (November 2, 2022): 1770. http://dx.doi.org/10.3390/life12111770.
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Leukemia is a heterogenous group of hematological malignancies categorized in four main types (acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML) and chronic lymphocytic leukemia (CLL). Several cytogenetic and molecular markers have become a part of routine analysis for leukemia patients. These markers have been used in diagnosis, risk-stratification and targeted therapy application. Recent studies have indicated that numerous regulatory RNAs, such as long non-coding RNAs (lncRNAs), have a role in tumor initiation and progression. When it comes to leukemia, data for lncRNA involvement in its etiology, progression, diagnosis, treatment and prognosis is limited. The aim of this review is to summarize research data on lncRNAs in different types of leukemia, on their expression pattern, their role in leukemic transformation and disease progression. The usefulness of this information in the clinical setting, i.e., for diagnostic and prognostic purposes, will be emphasized. Finally, how particular lncRNAs could be used as potential targets for the application of targeted therapy will be considered.
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Klener Jr, Pavel, Tomas Etrych, and Pavel Klener. "Biological Therapy of Hematologic Malignancies: Toward a Chemotherapy- free Era." Current Medicinal Chemistry 26, no. 6 (May 13, 2019): 1002–18. http://dx.doi.org/10.2174/0929867324666171006144725.
Full textAbstract:
:Less than 70 years ago, the vast majority of hematologic malignancies were untreatable diseases with fatal prognoses. The development of modern chemotherapy agents, which had begun after the Second World War, was markedly accelerated by the discovery of the structure of DNA and its role in cancer biology and tumor cell division. The path travelled from the first temporary remissions observed in children with acute lymphoblastic leukemia treated with single-agent antimetabolites until the first cures achieved by multi-agent chemotherapy regimens was incredibly short. Despite great successes, however, conventional genotoxic cytostatics suffered from an inherently narrow therapeutic index and extensive toxicity, which in many instances limited their clinical utilization. In the last decade of the 20th century, increasing knowledge on the biology of certain malignancies resulted in the conception and development of first molecularly targeted agents designed to inhibit specific druggable molecules involved in the survival of cancer cells. Advances in technology and genetic engineering enabled the production of structurally complex anticancer macromolecules called biologicals, including therapeutic monoclonal antibodies, antibody-drug conjugates and antibody fragments. The development of drug delivery systems (DDSs), in which conventional drugs were attached to various types of carriers including nanoparticles, liposomes or biodegradable polymers, represented an alternative approach to the development of new anticancer agents. Despite the fact that the antitumor activity of drugs attached to DDSs was not fundamentally different, the improved pharmacokinetic profiles, decreased toxic side effects and significantly increased therapeutic indexes resulted in their enhanced antitumor efficacy compared to conventional (unbound) drugs.:Approval of the first immune checkpoint inhibitor for the treatment of cancer in 2011 initiated the era of cancer immunotherapy. Checkpoint inhibitors, bispecific T-cell engagers, adoptive T-cell approaches and cancer vaccines have joined the platform so far, represented mainly by recombinant cytokines, therapeutic monoclonal antibodies and immunomodulatory agents. In specific clinical indications, conventional drugs have already been supplanted by multi-agent, chemotherapy-free regimens comprising diverse immunotherapy and/or targeted agents. The very distinct mechanisms of the anticancer activity of new immunotherapy approaches not only call for novel response criteria, but might also change fundamental treatment paradigms of certain types of hematologic malignancies in the near future.