Статті в журналах: "ONCOTHERAPEUTICS"

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Raja, Junaid, and David C. Madoff. "Oncopharmacology in Interventional Radiology." Seminars in Interventional Radiology 39, no. 04 (August 2022): 411–15. http://dx.doi.org/10.1055/s-0042-1758076.

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AbstractThe broad scope of malignancies treated in interventional oncology is mirrored by the breadth of oncotherapeutics, drugs used to treat cancer. Many of these treatments are administered endovascularly, though a group of therapies can be delivered percutaneously. Perhaps the best taxonomy of oncotherapeutics is based on their biological inactivity or activity and the mechanism by which they interact with treated and targeted tissues. As the fields of interventional oncology and oncotherapeutics continue to grow and expand, this framework may provide a more organized approach in helping distinguish and select the best therapy for patients.

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Ladd, Joseph. "Advancements in oncotherapeutics drive positive outcomes in cancer." Pharmacy Today 23, no. 7 (July 2017): 24–25. http://dx.doi.org/10.1016/j.ptdy.2017.06.019.

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Dailey, Kaitlin M., JuliAnne E. Allgood, Paige R. Johnson, Mackenzie A. Ostlie, Kambri C. Schaner, Benjamin D. Brooks, and Amanda E. Brooks. "The next frontier of oncotherapy: accomplishing clinical translation of oncolytic bacteria through genetic engineering." Future Microbiology 16, no. 5 (March 2021): 341–68. http://dx.doi.org/10.2217/fmb-2020-0245.

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The development of a ‘smart’ drug capable of distinguishing tumor from host cells has been sought for centuries, but the microenvironment of solid tumors continues to confound therapeutics. Solid tumors present several challenges for current oncotherapeutics, including aberrant vascularization, hypoxia, necrosis, abnormally high pH and local immune suppression. While traditional chemotherapeutics are limited by such an environment, oncolytic microbes are drawn to it – having an innate ability to selectively infect, colonize and eradicate solid tumors. Development of an oncolytic species would represent a shift in the cancer therapeutic paradigm, with ramifications reaching from the medical into the socio-economic. Modern genetic engineering techniques could be implemented to customize ‘Frankenstein’ bacteria with advantageous characteristics from several species.

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Kansara, Samarth, Vijay Pandey, Peter E. Lobie, Gautam Sethi, Manoj Garg, and Amit Kumar Pandey. "Mechanistic Involvement of Long Non-Coding RNAs in Oncotherapeutics Resistance in Triple-Negative Breast Cancer." Cells 9, no. 6 (June 21, 2020): 1511. http://dx.doi.org/10.3390/cells9061511.

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Triple-negative breast cancer (TNBC) is one of the most lethal forms of breast cancer (BC), with a significant disease burden worldwide. Chemoresistance and lack of targeted therapeutics are major hindrances to effective treatments in the clinic and are crucial causes of a worse prognosis and high rate of relapse/recurrence in patients diagnosed with TNBC. In the last decade, long non-coding RNAs (lncRNAs) have been found to perform a pivotal role in most cellular functions. The aberrant functional expression of lncRNAs plays an ever-increasing role in the progression of diverse malignancies, including TNBC. Therefore, lncRNAs have been recently studied as predictors and modifiers of chemoresistance. Our review discusses the potential involvement of lncRNAs in drug-resistant mechanisms commonly found in TNBC and highlights various therapeutic strategies to target lncRNAs in this malignancy.

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Raftopoulou, Christina, Fani-Marlen Roumelioti, Eleni Dragona, Stefanie Gimelli, Frédérique Sloan-Béna, Vasilis Gorgoulis, Stylianos E. Antonarakis, and Sarantis Gagos. "Karyotypic Flexibility of the Complex Cancer Genome and the Role of Polyploidization in Maintenance of Structural Integrity of Cancer Chromosomes." Cancers 12, no. 3 (March 5, 2020): 591. http://dx.doi.org/10.3390/cancers12030591.

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Ongoing chromosomal instability in neoplasia (CIN) generates intratumor genomic heterogeneity and limits the efficiency of oncotherapeutics. Neoplastic human cells utilizing the alternative lengthening of telomeres (ALT)-pathway, display extensive structural and numerical CIN. To unravel patterns of genome evolution driven by oncogene-replication stress, telomere dysfunction, or genotoxic therapeutic interventions, we examined by comparative genomic hybridization five karyotypically-diverse outcomes of the ALT osteosarcoma cell line U2-OS. These results demonstrate a high tendency of the complex cancer genome to perpetuate specific genomic imbalances despite the karyotypic evolution, indicating an ongoing process of genome dosage maintenance. Molecular karyotyping in four ALT human cell lines showed that mitotic cells with low levels of random structural CIN display frequent evidence of whole genome doubling (WGD), suggesting that WGD may protect clonal chromosome aberrations from hypermutation. We tested this longstanding hypothesis in ALT cells exposed to gamma irradiation or to inducible DNA replication stress under overexpression of p21. Single-cell cytogenomic analyses revealed that although polyploidization promotes genomic heterogeneity, it also protects the complex cancer genome and hence confers genotoxic therapy resistance by generating identical extra copies of driver chromosomal aberrations, which can be spared in the process of tumor evolution if they undergo unstable or unfit rearrangements.

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Adeniji, Emmanuel A., Fisayo A. Olotu, and Mahmoud E. S. Soliman. "Exploring the Lapse in Druggability: Sequence Analysis, Structural Dynamics and Binding Site Characterization of K-RasG12C Variant, a Feasible Oncotherapeutics Target." Anti-Cancer Agents in Medicinal Chemistry 18, no. 11 (January 28, 2019): 1540–50. http://dx.doi.org/10.2174/1871520618666180718110231.

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Background: The difficulty in druggability of K-Ras variant has presented a challenge in the treatment of cancer diseases associated with its dysfunctionality. Despite the identification of different binding sites, limited information exists in the literature about their characteristics. Therefore, identification, crossvalidation and characterization of its druggable sites would aid the design of chemical compounds that will arrest its dysfunctionality related oncogenesis. Objective: This study entails the identification, cross-validation and characterization of K-Ras G12C variant’s binding sites for potential druggability, coupled with the elucidation of alterations in 3D conformations and dynamics. Method: Molecular dynamics simulation was carried out on the inactive, the active and the hyperactive K-RasG12Cvariant using the amber software package. The SiteMap software was employed in identifying and characterizing the druggable binding sites while the validation of the binding sites was carried out with the SiteHound and MetaPocket servers. Results: Four druggable binding sites were identified, validated and characterized based on physicochemical attributes such as size, volume, degree of enclosure or exposure, degree of contact, hydrophobic/hydrophilic character, hydrophobic/hydrophilic balance and hydrogen-bonding features. Conformational studies also revealed that the K-Ras variant exhibited notable structural instability, increased flexibility and a strongly anticorrelated movement compared to the inactive and active wildtype forms. Conclusion: The attributes of the characterized druggable sites will be useful in designing site-specific K-Ras inhibitors for the treatment of K-Ras variant associated cancer diseases.

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Lantier, Louis, Agathe Poupee-Beauge, Louis Lantier, Céline Ducournau, Anne Di Tommaso, Stéphanie Germon, Nathalie Moiré, Gordon Lee, Antoine Touze, and Isabelle Dimier-Poisson. "846 Neospora caninum – an immunotherapeutic protozoan against solid cancers." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A899. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0846.

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BackgroundImmunotherapy induces, provides, and/or reactivates anti-tumor immune responses. Some microorganisms also can initiate response that lyzes infected tumor and/or stimulates systemic immunity. Attenuated viruses or bacteria are well studied as oncotherapeutics, but not protozoa except Toxoplasma gondii.1 We assessed the effect on tumors of other protozoa that were naturally non-pathogenic to humans. Thus, we discovered the ability to use Neospora caninum (Nc) in a manner and form that demonstrated a synergistic array of pertinent immunotherapeutic characteristics against solid cancers. Our first Article on Neospora as Onco-immunotherapeutic is currently under revision after review by the JITC. We report on the most recent data notably from Nc engineered to secrete human IL-15 within the tumor.MethodsIn vitro, the immunostimulatory properties of Nc strains wildtype and engineered to secrete human IL-15 were studied. In vivo experiments of treatment with of Nc tachyzoites2 administered locally (intra and peri tumoral) or remotely (subcutaneous) in a murine thymoma EG7 tumor and in human Merkel cell carcinoma (MCC).ResultsWe demonstrated that the treatment of thymoma EG7 by Nc strongly inhibited tumor development. Analysis of immune responses and interactions between Nc and tumor cells showed that Nc had the ability to lyze infected cancer cells, reactivated immune competence within the Tumor Microenvironment (TME), and activated the systemic immune system by promoting the recruitment of immune cells to the site of tumor. We also established in a NOD/SCID mouse model that Nc was able to induce a strong regression of human MCC. Recently, to further enhance oncotherapeutic effect, we engineered an Nc strain to secrete human IL-15 (cross reactive with mouse cells), associated with alpha subunit of IL-15 receptor, increasing its stability.3 This strain induced proliferation of human PBMCs and their secretion of IFN-γ. In the EG7 model, human IL-15 secreting Nc showed greater protection against tumor development, confirming enhancement of immunotherapy by engineering Nc to deliver/secrete IL-15.ConclusionsThese results highlight Neospora caninum as a potentially extremely efficient, and non-toxic anti-cancer agent, capable of being engineered to express at its surface or to secrete bio-drugs, like human IL-15 cytokine. Our work has identified the broad clinical possibilities of using N. caninum as an oncolytic protozoan in human medicine capable of vectoring molecular therapy, overcoming TME defenses.ReferencesFox BA, Butler KL, Guevara RB, Bzik DJ. Cancer therapy in a microbial bottle: Uncorking the novel biology of the protozoan Toxoplasma gondii. PLoS Pathog 2017;13(9):e1006523. https://doi.org/10.1371/journal.ppat.1006523Bjerkas I, Jenkins MC, Dubey JP. Identification and characterization of Neospora caninum tachyzoite antigens useful for diagnosis of neosporosis. Clin Diagn Lab Immunol 1994;1(2):214-221.Article for publication in the Journal of Immunotherapy of Cancer, under revision on September 20, 2020.

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AbdRabou, Mervat Ahmed, Ahmed B. M. Mehany, Islam M. Farrag, Amany Belal, Othman F. Abdelzaher, Abdou El-Sharkawy, Asmaa M. Abd El-Azez, Salah M. EL-Sharkawy, and Manal H. Al Badawi. "Therapeutic Effect of Murine Bone Marrow-Derived Mesenchymal Stromal/Stem Cells and Human Placental Extract on Testicular Toxicity Resulting from Doxorubicin in Rats." BioMed Research International 2021 (August 6, 2021): 1–13. http://dx.doi.org/10.1155/2021/9979670.

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Oncotherapeutics like doxorubicin can affect male gonads; as a result, it leads to infertility. This work was conducted to demonstrate the toxic effects of doxorubicin on testes of male albino rats. Fifty male albino rats aged 5-7 weeks were used in this study. The animals were randomly separated into 5 sets (each set containing ten rats). Group I received saline (i.p.) for 4 weeks. Group II was given doxorubicin (DOX), 5 mg/kg BW (i.p.) once/week for 4 weeks. Groups III and IV were treated in the same way as the DOX group, left for one week without medication, and then injected with mesenchymal stromal cells (MSCs) or human placental extract (HPE) therapy in a single dose of 5 × 10 6 in 200 ml PRP/week or 40 μl placental extract for 4 weeks via the caudal vein. Group V rats were treated in the same way as the DOX group also, left for one week without medication, and then injected with MSC+HPE. A significant decrease in serum testosterone, FSH, and LH levels was observed in rats treated with DOX compared to the control group. A significant elevation was recorded in rats treated with DOX+MSC or DOX+HPE when compared with the DOX group only. Rats that were given MSC+HPE after DOX intoxication showed a significant increase in hormone levels when compared to rats treated with either MSC or HPE. Light and electron microscopic examinations revealed that DOX intoxication initiated degenerative and necrotic changes in seminiferous tubules associated with partial or complete cessation of spermatogenesis. These effects were reversed by the effect of MSC or HPE. Coadministration of MSC and HPE even showed further improvement. Finally, we can say that doxorubicin has a deleterious impact on rat testes; however, therapeutic effects can be induced through MSC and/or HPE administration.

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Chhajed, Santosh Subhash, Pramodkumar P. Gupta, Sanjay Kshirsagar, Sakshi Tomar, Debarshi Kar Mahapatra, and Raji Sundararajan. "N-(2-(1H-benzo[d]imidazol-2-yl)Phenyl)-2- (Substituted-styryl)Aniline as Anti-proliferative Agents: Rejuvenating the Importance of Low Molecular Weight Ligands in Oncotherapeutics." Indian Journal of Pharmaceutical Education and Research 54, no. 2 (March 3, 2020): 432–39. http://dx.doi.org/10.5530/ijper.54.2.49.

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Dailey, Kaitlin M., Krysten Vance, Kyle McAndrews, Reed I. Jacobson, Jandro Delgado, Paige R. Johnson, Taylor M. Woolery, et al. "Abstract PO-037: Development of an RGD CRISPR-modified Clostridium novyi NT spores as an intravenous oncotherapy." Cancer Research 81, no. 22_Supplement (November 15, 2021): PO—037—PO—037. http://dx.doi.org/10.1158/1538-7445.panca21-po-037.

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Abstract The efficacy of current oncotherapeutics is largely limited by an inability to access avascular tissues, which is in part responsible for forty years of stagnant pancreatic cancer statistics where the median survival remains a mere six months. Oncolytic bacteria such as Clostridium novyi-NT overcome this challenge with its ultrasensitive, innate affinity for hypoxic/necrotic areas found at the center of solid tumors and their metastases. While preclinical and clinical data from intratumoral injections of C. novyi-NT are promising, many tumors are inaccessible to such injections. Preclinical trials of analogous IV injections have uncovered other obstacles such as rapid clearance of C. novyi-NT by the immune system independent of septic complications. To mitigate rapid clearance, CRISPR/Cas9n was used to genetically modify a non-toxic form of C. novyi-NT to express a tumor targeting RGD peptide on the spore surface. Through this novel, first of its kind, methodology, spores with stronger affinity to a surface coated with the targeted binding partner of RGD, aVb3 integrin, have been generated. Importantly, there was no statistically significant difference in the genetically modified spore’s capacity for sporulation or germination when compared to unmodified C. novyi-NT spores, nor was a difference in lytic capacity observed, suggesting no relevant off-target effects from genomic modification. Biodistribution and efficacy of non-toxic RGD-modified spores was evaluated in an immunocompetent, syngeneic, pancreatic cancer murine model. Ongoing efforts to characterize the biodistribution and efficacy of the intravenously injected RGD-modified C. novyi-NT include the application of multiplex immunofluorescence, laser microdissection, and live, whole animal imaging. Supported as a pilot project by funds from NIH COBRE grant 1P20GM109024, Doctoral Dissertation Funds to KMD from NDSU, and by discretionary funds from investigators at UNMC. Citation Format: Kaitlin M. Dailey, Krysten Vance, Kyle McAndrews, Reed I. Jacobson, Jandro Delgado, Paige R. Johnson, Taylor M. Woolery, Megan Orr, Jiha Kim, Sanku Mallik, Kenneth W. Bayles, Michael A. Hollingsworth, Amanda E. Brooks. Development of an RGD CRISPR-modified Clostridium novyi NT spores as an intravenous oncotherapy [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-037.

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Park, Robin, Fariha Eshrat, Mohammed Al-Jumayli, Azhar Saeed, and Anwaar Saeed. "Immuno-Oncotherapeutic Approaches in Advanced Hepatocellular Carcinoma." Vaccines 8, no. 3 (August 8, 2020): 447. http://dx.doi.org/10.3390/vaccines8030447.

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Advanced hepatocellular carcinoma has limited treatment options, but there has been extensive growth recently with cabozantinib, regorafenib, lenvatinib, nivolumab, atezolizumab, and bevacizumab, which are some of the treatments that have received FDA approval just over the last three years. Because HCC tumor microenvironment is potentially immunogenic and typically characterized by inflammation, immunotherapy has been proposed as a potential novel therapeutic approach, which has prompted studies in advanced HCC patients investigating various immune-therapeutic strategies such as CAR-T cell therapy, checkpoint inhibitors, and onco-vaccines. The anti-PD-1 checkpoint inhibitors nivolumab and pembrolizumab have been FDA approved as a second line treatment in patients who progressed or are intolerant to Sorafenib. To build up on the success of PD-1 monotherapy, combinatorial regimens with PD-1/PD-L1 inhibitors plus VEGF targeted agents have shown positive results in various malignancies including HCC. The combination of atezolizumab plus bevacizumab is the new addition to the HCC treatment armamentarium following a pivotal study that demonstrated an improvement in OS over frontline sorafenib. Other novel immune-based approaches and oncolytic viruses are in the early phases of clinical evaluation. These innovative approaches enhance the intensity of cancer-directed immune responses and will potentially impact the outlook of this aggressive disease.

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O’Reilly, Mary, Anna Linehan, Aleksandar Krstic, Walter Kolch, Kieran Sheahan, Des C. Winter, and Ray Mc Dermott. "Oncotherapeutic Strategies in Early Onset Colorectal Cancer." Cancers 15, no. 2 (January 16, 2023): 552. http://dx.doi.org/10.3390/cancers15020552.

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Early onset colorectal cancer (EOCRC), defined as colorectal cancers in patients aged less than 50 years, is becoming an increasingly common issue, globally. Since 1994, the incidence of this condition has been rising by 2% annually. Approximately one in five patients under 50 years of age diagnosed with colorectal cancer have an underlying genetic predisposition syndrome. The detection of cancer among the other 80% of patients poses a considerable task, as there is no family history to advocate for commencing early screening in this group. Patients with EOCRC have distinct social, spiritual, fertility, and financial needs from their older counterparts that need to be addressed. This review discusses the risk factors associated with the development of EOCRC and current best practice for the management of this disease.

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Singh, Prafull Kumar, Ashok K. Tiwari, R. S. Rajmani, G. Ravi Kumar, Uttara Chaturvedi, Lovleen Saxena, Shikha Saxena, et al. "Apoptin as a Potential Viral Gene Oncotherapeutic Agent." Applied Biochemistry and Biotechnology 176, no. 1 (March 27, 2015): 196–212. http://dx.doi.org/10.1007/s12010-015-1567-5.

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Ye, Johan Z., Finn B. Hansen, Robert W. Mills, and Alicia Lundby. "Oncotherapeutic Protein Kinase Inhibitors Associated With Pro-Arrhythmic Liability." JACC: CardioOncology 3, no. 1 (March 2021): 88–97. http://dx.doi.org/10.1016/j.jaccao.2021.01.009.

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Tsymbal, Sergey, Ge Li, Nikol Agadzhanian, Yuhao Sun, Jiazhennan Zhang, Marina Dukhinova, Viacheslav Fedorov, and Maxim Shevtsov. "Recent Advances in Copper-Based Organic Complexes and Nanoparticles for Tumor Theranostics." Molecules 27, no. 20 (October 19, 2022): 7066. http://dx.doi.org/10.3390/molecules27207066.

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Treatment of drug-resistant forms of cancer requires consideration of their hallmark features, such as abnormal cell death mechanisms or mutations in drug-responding molecular pathways. Malignant cells differ from their normal counterparts in numerous aspects, including copper metabolism. Intracellular copper levels are elevated in various cancer types, and this phenomenon could be employed for the development of novel oncotherapeutic approaches. Copper maintains the cell oxidation levels, regulates the protein activity and metabolism, and is involved in inflammation. Various copper-based compounds, such as nanoparticles or metal-based organic complexes, show specific activity against cancer cells according to preclinical studies. Herein, we summarize the major principles of copper metabolism in cancer cells and its potential in cancer theranostics.

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Jain, Rifika, Mohamed Ali Hussein, Shannon Pierce, Chad Martens, Preksha Shahagadkar, and Gnanasekar Munirathinam. "Oncopreventive and oncotherapeutic potential of licorice triterpenoid compound glycyrrhizin and its derivatives: Molecular insights." Pharmacological Research 178 (April 2022): 106138. http://dx.doi.org/10.1016/j.phrs.2022.106138.

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Kovács, Dávid, Nóra Igaz, Mohana K. Gopisetty, and Mónika Kiricsi. "Cancer Therapy by Silver Nanoparticles: Fiction or Reality?" International Journal of Molecular Sciences 23, no. 2 (January 13, 2022): 839. http://dx.doi.org/10.3390/ijms23020839.

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As an emerging new class, metal nanoparticles and especially silver nanoparticles hold great potential in the field of cancer biology. Due to cancer-specific targeting, the consequently attenuated side-effects and the massive anti-cancer features render nanoparticle therapeutics desirable platforms for clinically relevant drug development. In this review, we highlight those characteristics of silver nanoparticle-based therapeutic concepts that are unique, exploitable, and achievable, as well as those that represent the critical hurdle in their advancement to clinical utilization. The collection of findings presented here will describe the features that distinguish silver nanoparticles from other anti-cancer agents and display the realistic opportunities and implications in oncotherapeutic innovations to find out whether cancer therapy by silver nanoparticles is fiction or reality.

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Alekseenko, I. V., M. B. Kostina, E. O. Serebrovskaia, V. K. Potapov, and E. D. Sverdlov. "Comparative analysis of gene therapy systems expressing two oncotherapeutic genes under control of single promotor." Molecular Genetics Microbiology and Virology (Russian version) 36, no. 1 (2018): 14. http://dx.doi.org/10.18821/0208-0613-2018-36-1-14-18.

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Alekseenko, I. V., M. B. Kostina, E. O. Serebrovskaya, V. K. Potapov, and E. D. Sverdlov. "Comparative Analysis of Gene Therapy Systems Expressing Two Oncotherapeutic Genes under Control of a Single Promotor." Molecular Genetics, Microbiology and Virology 33, no. 1 (January 2018): 15–20. http://dx.doi.org/10.3103/s0891416818010020.

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20

Tuli, Hardeep Singh, Vivek Kumar Garg, Jinit K. Mehta, Ginpreet Kaur, Ranjan K. Mohapatra, Kuldeep Dhama, Katrin Sak, et al. "Licorice (Glycyrrhiza glabra L.)-Derived Phytochemicals Target Multiple Signaling Pathways to Confer Oncopreventive and Oncotherapeutic Effects." OncoTargets and Therapy Volume 15 (November 2022): 1419–48. http://dx.doi.org/10.2147/ott.s366630.

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Pierce, Kyle M., William R. Miklavcic, Kyle P. Cook, Mikayla Sweitzer Hennen, Kenneth W. Bayles, Michael A. Hollingsworth, Amanda E. Brooks, Jessica E. Pullan, and Kaitlin M. Dailey. "The Evolution and Future of Targeted Cancer Therapy: From Nanoparticles, Oncolytic Viruses, and Oncolytic Bacteria to the Treatment of Solid Tumors." Nanomaterials 11, no. 11 (November 10, 2021): 3018. http://dx.doi.org/10.3390/nano11113018.

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While many classes of chemotherapeutic agents exist to treat solid tumors, few can generate a lasting response without substantial off-target toxicity despite significant scientific advancements and investments. In this review, the paths of development for nanoparticles, oncolytic viruses, and oncolytic bacteria over the last 20 years of research towards clinical translation and acceptance as novel cancer therapeutics are compared. Novel nanoparticle, oncolytic virus, and oncolytic bacteria therapies all start with a common goal of accomplishing therapeutic drug activity or delivery to a specific site while avoiding off-target effects, with overlapping methodology between all three modalities. Indeed, the degree of overlap is substantial enough that breakthroughs in one therapeutic could have considerable implications on the progression of the other two. Each oncotherapeutic modality has accomplished clinical translation, successfully overcoming the potential pitfalls promising therapeutics face. However, once studies enter clinical trials, the data all but disappears, leaving pre-clinical researchers largely in the dark. Overall, the creativity, flexibility, and innovation of these modalities for solid tumor treatments are greatly encouraging, and usher in a new age of pharmaceutical development.

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Pan, Lina, Xiyu Liu, Dianfa Fan, Zhangbo Qian, Xinjun Sun, Pan Wu, and Liping Zhong. "Study of Oncolytic Virus Preservation and Formulation." Pharmaceuticals 16, no. 6 (June 5, 2023): 843. http://dx.doi.org/10.3390/ph16060843.

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In recent years, oncolytic viruses (OVs) have emerged as an effective means of treating cancer. OVs have multiple oncotherapeutic functions including specifically infecting and lysing tumor cells, initiating immune cell death, attacking and destroying tumor angiogenesis and triggering a broad bystander effect. Oncolytic viruses have been used in clinical trials and clinical treatment as drugs for cancer therapy, and as a result, oncolytic viruses are required to have long-term storage stability for clinical use. In the clinical application of oncolytic viruses, formulation design plays a decisive role in the stability of the virus. Therefore, this paper reviews the degradation factors and their degradation mechanisms (pH, thermal stress, freeze–thaw damage, surface adsorption, oxidation, etc.) faced by oncolytic viruses during storage, and it discusses how to rationally add excipients for the degradation mechanisms to achieve the purpose of maintaining the long-term stability of oncolytic viral activity. Finally, the formulation strategies for the long-term formulation stability of oncolytic viruses are discussed in terms of buffers, permeation agents, cryoprotectants, surfactants, free radical scavengers, and bulking agent based on virus degradation mechanisms.

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Almeida, Teresa, Maria Elisa Soares, José Cavalheiro, and Maria de Lourdes Bastos. "Silicon and iron levels in tissues of animals treated with a “ferrimagnetic ceramic” with oncotherapeutic potential (anti-tumor) value." Journal of Trace Elements in Medicine and Biology 16, no. 4 (January 2002): 255–59. http://dx.doi.org/10.1016/s0946-672x(02)80054-2.

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Tiwari, Shreya, Rakesh Mehta, Ayush Kushwaha, and Rajnandani Katariya. "A PRELIMINARY SCREENING OF BACTERIAL ISOLATES PRODUCING AN ONCOTHERAPEUTIC ENZYME ASPARAGINASE FROM SOME SEWAGE WATER SAMPLES OF BHOPAL, M.P. INDIA." Asian Journal of Pharmaceutical Education and Research 10, no. 2 (April 10, 2021): 19–26. http://dx.doi.org/10.38164/ajper/10.2.2021.19-26.

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Shen, Yaoyao, Fan Sun, Liu Zhang, Yijia Cheng, Hongrui Zhu, Shu-Ping Wang, Wei-Hua Jiao, Peter F. Leadlay, Yongjun Zhou, and Hou-Wen Lin. "Biosynthesis of depsipeptides with a 3-hydroxybenzoate moiety and selective anticancer activities involves a chorismatase." Journal of Biological Chemistry 295, no. 16 (March 12, 2020): 5509–18. http://dx.doi.org/10.1074/jbc.ra119.010922.

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Neoantimycins are anticancer compounds of 15-membered ring antimycin-type depsipeptides. They are biosynthesized by a hybrid multimodular protein complex of nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS), typically from the starting precursor 3-formamidosalicylate. Examining fermentation extracts of Streptomyces conglobatus, here we discovered four new neoantimycin analogs, unantimycins B–E, in which 3-formamidosalicylates are replaced by an unusual 3-hydroxybenzoate (3-HBA) moiety. Unantimycins B–E exhibited levels of anticancer activities similar to those of the chemotherapeutic drug cisplatin in human lung cancer, colorectal cancer, and melanoma cells. Notably, they mostly displayed no significant toxicity toward noncancerous cells, unlike the serious toxicities generally reported for antimycin-type natural products. Using site-directed mutagenesis and heterologous expression, we found that unantimycin productions are correlated with the activity of a chorismatase homolog, the nat-hyg5 gene, from a type I PKS gene cluster. Biochemical analysis confirmed that the catalytic activity of Nat-hyg5 generates 3-HBA from chorismate. Finally, we achieved selective production of unantimycins B and C by engineering a chassis host. On the basis of these findings, we propose that unantimycin biosynthesis is directed by the neoantimycin-producing NRPS–PKS complex and initiated with the starter unit of 3-HBA. The elucidation of the biosynthetic unantimycin pathway reported here paves the way to improve the yield of these compounds for evaluation in oncotherapeutic applications.

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Trujillo-Nolasco, Maydelid, Pedro Cruz-Nova, Guillermina Ferro-Flores, Brenda Gibbens-Bandala, Enrique Morales-Avila, Liliana Aranda-Lara, Miguel Vargas, and Blanca Ocampo-García. "Development of 177Lu-DN(C19)-CXCR4 Ligand Nanosystem for Combinatorial Therapy in Pancreatic Cancer." Journal of Biomedical Nanotechnology 17, no. 2 (February 28, 2021): 263–78. http://dx.doi.org/10.1166/jbn.2021.3016.

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Pancreatic cancer is highly lethal and has a poor prognosis. The most common alteration during the formation of pancreatic tumors is the activation of KRAS (Kirsten rat sarcoma 2 viral oncogene homolog) oncogene. As a new therapeutic strategy, the C19 molecule ((2S)-N-(2,5-dichlorophenyl)-2-[(3,4-dimethoxyphenyl)-methylamine]propanamide) blocks the KRAS-membrane association in cancer cells. In addition, the chemokine receptor CXCR4 is overexpressed in pancreatic cancer. In this research, a new dendrimer-based nanoradiopharmaceutical (177Lu-DN(C19)-CXCR4L) encapsulating C19 and functionalized to target CXCR4 receptors is proposed as both, a targeted radiotherapy system (lutetium-177) and an oncotherapeutic approach by the stabilization of KRAS4b-PDESδ complex to produce dual-specific therapy in pancreatic cancer. 177The Lu-DN(C19)-CXCR4L was synthesized and characterized, C19 was encapsulated with 81% efficiency, the final nanosystem rendered a particle size of 67 nm and the specific uptake in pancreatic cell lines was demonstrated. The major cytotoxic effect was observed in the KRAS-dependent and radioresistant cell line Mia PaCa-2, which expresses a high density of CXCR4 receptors. The radiation dose of 3 Gy/Bq decreased viability to 7%, and this effect was attributed to the presence of C19. A synergistic effect (radio and chemotherapy) capable of reducing viability in pancreatic cancer cells through apoptotic mechanisms was demonstrated. Thus, 177Lu-DN(C19)-CXCR4L nanoradiopharmaceutical is efficacious in pancreatic cancer cell lines overexpressing the CXCR4 receptor.

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Vay, Christian, Shahrooz Babaei, Sami-Alexander Safi, Levent Dizdar, Alexander Rehders, Lena Haeberle, Christoph Roderburg, et al. "Clinicopathological and Prognostic Value of Survivin Expression in Surgically Resected Pancreatic Ductal Adenocarcinoma." Cancers 14, no. 14 (July 18, 2022): 3494. http://dx.doi.org/10.3390/cancers14143494.

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Background: Survival after surgery for pancreatic ductal adenocarcinoma (PDAC) remains poor. Thus, novel therapeutic concepts focus on the development of targeted therapies. In this context, inhibitor of apoptosis protein (IAP) survivin is regarded as a promising oncotherapeutic target. However, its expression and prognostic value in different tumour compartments of PDAC have not been studied. Methods: Immunohistochemical analysis of survivin in different PDAC tumour compartments from 236 consecutive patients was correlated with clinicopathological variables and survival. Results: In comparison to healthy pancreatic tissue high nuclear (p < 0.001) and high cytoplasmic (p < 0.01) survivin expression became evident in the tumour centre, along the invasion front and in lymph node metastases. Cytoplasmic overexpression of survivin in tumour centres was related to the presence of distant metastasis (p = 0.016) and UICC III/IV stages (p = 0.009), while high cytoplasmic expression at the invasion front grouped with venous infiltration (p = 0.022). Increased nuclear survivin along the invasion front correlated with perineural invasion (p = 0.035). High nuclear survivin in tumour centres represented an independent prognostic factor for overall survival of pancreatic tail carcinomas (HR 13.5 95%CI (1.4–129.7)) and correlated with a limited disease-free survival in PDAC (HR 1.80 95%CI (1.04–3.12)). Conclusion: Survivin is associated with advanced disease stages and poor prognosis. Therefore, survivin will help to identify patients with aggressive tumour phenotypes that could benefit from the inclusion in clinical trials incorporating survivin inhibitors in PDAC.

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Al-Serwi, Rasha H., Mohamed A. Eladl, Mohamed El-Sherbiny, Mohamed A. Saleh, Gamal Othman, Sultan M. Alshahrani, Rasha Alnefaie, et al. "Targeted Drug Administration onto Cancer Cells Using Hyaluronic Acid–Quercetin-Conjugated Silver Nanoparticles." Molecules 28, no. 10 (May 17, 2023): 4146. http://dx.doi.org/10.3390/molecules28104146.

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Quercetin (QtN) displays low systemic bioavailability caused by poor water solubility and instability. Consequently, it exerts limited anticancer action in vivo. One solution to increase the anticancer efficacy of QtN is the use of appropriate functionalized nanocarriers that preferentially target and deliver the drug to the tumor location. Herein, a direct advanced method was designed to develop water-soluble hyaluronic acid (HA)-QtN-conjugated silver nanoparticles (AgNPs). HA-QtN reduced silver nitrate (AgNO3) while acting as a stabilizing agent to produce AgNPs. Further, HA-QtN#AgNPs served as an anchor for folate/folic acid (FA) conjugated with polyethylene glycol (PEG). The resulting PEG-FA-HA-QtN#AgNPs (further abbreviated as PF/HA-QtN#AgNPs) were characterized both in vitro and ex vivo. Physical characterizations included UV-visible (UV-Vis) spectroscopy, Fourier transform infrared (FTIR) spectroscopy, transmission electron microscopy (TEM), particle size (PS) and zeta potential (ZP) measurements, and biopharmaceutical evaluations. The biopharmaceutical evaluations included analyses of the cytotoxic effects on the HeLa and Caco-2 cancer cell lines using the MTT assay; cellular drug intake into cancer cells using flow cytometry and confocal microscopy; and blood compatibility using an automatic hematology analyzer, a diode array spectrophotometer, and an enzyme-linked immunosorbent assay (ELISA). The prepared hybrid delivery nanosystem was hemocompatible and more oncocytotoxic than the free, pure QtN. Therefore, PF/HA-QtN#AgNPs represent a smart nano-based drug delivery system (NDDS) and could be a promising oncotherapeutic option if the data are validated in vivo.

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Bano, Samar, Lubna Rasool, Abdur Rauf, and Shabbir Hussain. "In silico Characterization of Heat Shock Protein HSP27 in Mammals." World Journal of Biology and Biotechnology 8, no. 3 (July 4, 2023): 1. http://dx.doi.org/10.33865/wjb.008.03.0933.

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Dairy animals have a significant role in every country’s agricultural economy. Livestock is the major sub-sector of the agricultural industry and the value of dairy products is increasing globally. Under pathological circumstances heat shock proteins (HSPs) promote protein repair, folding, refolding of misfolded peptides, and possible breakdown of irreparable proteins. Heat shock protein 27 (HSP27) is a member of the small heat shock protein family (sHSPs) also called HSPB1. HSP27 is crucial in the regulation and progression of different types of tumors and also acts as an oncotherapeutic target in humans and other mammals especially sheep. By using computational tools, a detailed in silico investigation of HSP27 sequences from humans and sheep has been examined with respect to their structural, functional, expression and phylogenetic properties. An extensive study has been made to compare the human protein with that of other mammals using computational tools. However, the sequences of HSP27 in humans and sheep are closely linked with each other. Although the sequences of HSP27 vary, their structural characteristics and functional properties remain the same. In this study, hydrophilic proteins with an average molecular weight of 27kDa were discovered both in humans and sheep. This study helps to understand the economic worth of dairy animals worldwide. HSP27 phosphorylation has been predicted as an anticancer agent. Recent research shows that new strategies have been developed for cancer treatment based on therapy of HSP27. This research will highlight the characterization and significant role of HSP27 in sheep.

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Cai, Ruimin, Guangyuan Meng, Yi Li, Wenyang Wang, Youxiang Diao, Shuping Zhao, Qiang Feng, and Yi Tang. "The oncolytic efficacy and safety of avian reovirus and its dynamic distribution in infected mice." Experimental Biology and Medicine 244, no. 12 (July 12, 2019): 983–91. http://dx.doi.org/10.1177/1535370219861928.

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Primary liver cancer is a major public health challenge that ranks as the third most common cause of cancer worldwide despite therapeutic improvement. Reovirus has been emerging as a potential anti-cancer agent and is undergoing multiple clinical trials, and it is reported that reovirus can preferentially cause the cell death of a variety of cancers in a manner of apoptosis. As few studies have reported the efficacy of oncolytic activity and safety profile of avian reovirus, in our study, LDH assay, MTT assay, DAPI staining, and flow cytometry assay were performed to demonstrate the oncolytic effects of avian reovirus against the HepG2 cells, and quantitative real-time PCR (qRT-PCR) and animal experiments were conducted to investigate the dynamic distribution of avian reovirus in infected mice and then illustrate the safety and tissue tropism of avian reovirus. LDH assay, DAPI staining, and flow cytometry assay confirmed the efficacy of the oncotherapeutic effects of avian reovirus, and MTT assay has indicated that avian reovirus suppressed the proliferation of HepG2 cells and decreased their viability significantly. qRT-PCR revealed the dynamic distribution of avian reovirus in infected mice that avian reovirus might replicate better and have more powerful oncolytic activity in liver, kidney, and spleen tissues. Furthermore, histopathological examination clearly supported that avian reovirus appeared non-pathogenic to the normal host, so our study may provide the new insights and rationale for the new strategy of removing liver cancer. Impact statement We demonstrated the efficacy of oncolytic activity of avian reovirus (ARV) by LDH assay, MTT assay, DAPI staining, and flow cytometry assay, and also investigated the dynamic distribution of ARV in infected mice and then illustrated the safety and tissue tropism of ARV by quantitative real-time PCR (qRT-PCR) and animal experiments. Collectively, our study may provide the new insights and rationale for the new strategy of removing liver cancer.

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Rostovsky, Irina, and Claytus Davis. "Induction of an Embryonic Mouse Innate Immune Response following Inoculation In Utero with Minute Virus of Mice." Journal of Virology 89, no. 4 (December 3, 2014): 2182–91. http://dx.doi.org/10.1128/jvi.02908-14.

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ABSTRACTWe used an embryonic-infection model system to show that MVMp, the prototypic minute virus of mice (MVM) serotype and a member of the genusProtoparvovirus, triggers a comprehensive innate immune response in the developing mouse embryo. Direct inoculation of the midtrimester embryoin uterowith MVMp results in a widespread, productive infection. During a 96-h infection course, embryonic beta interferon (IFN-β) and IFN-γ transcription were induced 90- and 60-fold, respectively. IFN-β levels correlated with the embryo viral burden, while IFN-γ levels first increased and then decreased. Production of proinflammatory cytokines, interleukin 1β (IL-1β) and tumor necrosis factor alpha (TNF-α), also increased, but by smaller amounts, approximately 7-fold each. We observed increased levels of downstream antiviral effector molecules, PKR and phosphorylated STAT2. Finally, we showed that there is an immune cell response to the virus infection. Infected tissues in the embryo exhibited an increased density of mature leukocytes compared to the same tissues in uninfected embryos. The responses we observed were almost completely restricted to the infected embryos. Uninfected littermates routinely exhibited small increases in innate immune components that rarely reached statistical significance compared to negative controls. Similarly, the placentae of infected embryos did not show any significant increase in transcription of innate immune cytokines. Since the placenta has both embryonic and maternal components, we suggest there is minimal involvement of the dam in the response to infection.IMPORTANCEInteraction between the small single-stranded vertebrate DNA viruses, the protoparvoviruses, and the host innate immune system has been unclear. The issue is important practically given the potential use of these viruses as oncotherapeutic agents. The data reported here stand in contrast to studies of innate immune response during protoparvovirus infection of adult hosts, which invariably reported no or minimal and sporadic induction of an interferon response during infection. We conclude that under conditions of robust and productive MVM infection, a normal murine host is able to mount a significant and broad innate immune response.

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Krishnamurthyreddy, B., M. S. Vidyasagar, R. Koteshwar, A. Shenoy, L. Viswanath, N. Thimmaiah, G. Babu, B. Joseph, R. Bonnathiya, and P. P. Bapsy. "A phase IIb 4-arm open-label randomized study to assess the safety and efficacy of h-R3 monoclonal antibody against EGFR in combination with chemoradiation therapy or radiation therapy in patients with advanced (stage III or IVA) inoperable head and neck cancer." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 6041. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.6041.

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6041 Background: Patients (pt) with advanced inoperable squamous cell carcinoma of the head and neck (SCCHN) have poor radiotherapy alone (RT) outcome. EGFR is over-expressed in >90% SCCHN. h-R3mAb (BIOMAb/nimotuzumab/TheraCIM) is a humanized monoclonal antibody, a validated oncotherapeutic-targeting EGFR. Objective: To investigate the safety and efficacy of concurrent h-R3mAb in combination with chemoradiotherapy of SCCHN. Methods: September 2004–2005, pt 18–70 yrs, SCCHN stageIII-IVA, 113 screened, 92 enrolled and randomly asssigned to, Group A: radical radiotherapy (pt) and Group B: chemoradiotherapy (pt). Randomization within Group A: [RT]v/s[RT+h-R3mAb] and within Group B: [RT+CT]v/s[RT+CT+ h-R3mAb] (n = 23 in each arm). Protocol: Radiotherapy: TD: 66 Gy,2Gy/Fr,5Fr/w,6.5wks. Radiation sensitizer (chemotherapy): CDDP-50mg/wk x 6wks. Study Drug (h-R3mAb): 200 mg/wk I.V.60min x 6weeks. Results: Evaluable (n = 76) in Group A-36 and Group B-40. F/u Analysis at 30 months after end of RT. Survival rate ITT: Group B: CT+RT+hR3- 69.5% v/s CT+RT-21.7% (p - 0.0011), Group A: RT alone - 21.7% v/s RT+ hR3–39.1% (ns). Progression-free survival: RT alone - 3(13.04 %) v/s RT+hR3mAb-8 (34.78 %), RT+CT-5 (21.74 %) v/s RT+CT+hR3mAb-13 (56.52%). Median overall survival (OS): CT+RT+hR3 - NR* v/s CT+RT- 21.96 months (hazard ratio [HR]-0.337, p - 0.0018) and RT alone - 25.02 v/s RT+hR3 - NR*(HR-0.678, p - 0.39). Disease-free survival: CT+RT+hR3- NR*v/sCT+RT-21.30 mths (HR-0.344, p - 0.0052) and RT alone-25.02 v/s RT+hR3- NA* (HR-0.599, p - 0.32). (NR*- median OS is yet to be reached). Safety: few grade - 1/2AE, no HAMA observed. OS per protocol - adding h-R3mAb to chemoradiation resulted in a reduction in risk of death (rrd) by 85% (HR 0.15, p - 0.0006) and to RT a 36 % rrd (HR0.64, p - 0.33). Conclusions: Concurrent use of h-R3mAb with RT or RT+CT is safe and efficacious. It enhances radiation and chemotherapy responses. Concurrent use of h-R3mAb with chemoradiotherapy enhances long-term loco-regional control and survival. Adding biological agents to physically targeted modality improves long-term therapeutic outcome of SCCHN. No significant financial relationships to disclose.

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Wrangle, John M., Mark P. Rubinstein, Caroline Mart, Joseph H. Azar, Cameron Williams, Marzena Swiderska-Syn, Linda Macpherson, et al. "Phase I trial characterizing the pharmacokinetic profile and NK and CD8+ t cell expansion with n-803, a chimeric IL-15 superagonist, in healthy volunteers." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e15008-e15008. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e15008.

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e15008 Background: The oncotherapeutic promise of IL-15, a potent immune stimulant, is limited by short serum half-life. The fusion protein N-803 is an IL-15 superagonist complex that has > 20-fold longer half-life in vivo vs IL-15. This study characterized the pharmacokinetic (PK) profile, biological activity, and safety of N-803 after subcutaneous administration to healthy human volunteers. Methods: Volunteers were randomized 1:1 to receive 1 mg/mL or 2 mg/mL N-803. Each subject received 2 doses of N-803: 10 µg/kg followed 24 days later by 20 µg/kg. After each dose, PK and safety measures were assayed for 9 successive days. Primary endpoint was the PK profile of N-803; secondary was safety; and exploratory endpoints were cytokine levels, immune cell characterization, and immunogenicity. Results: N-803 resulted in no grade ≥3 or serious adverse events (AEs). Mild injection site reactions, chills, and pyrexia were the most common AEs. Serum N-803 concentrations peaked 10.3-15.4 hours after administration and declined with a half-life of 20.0-20.7 hours. Peak N-803 serum concentrations were dose-dependent, with a 1.5-fold increase in Cmax after administration of 20 µg/kg vs 10 µg/kg. In the peripheral blood, N-803 induced a transient decline, followed by a significant increase (3-fold) in NK cell number that persisted for ≥24 days. N-803 also caused a significant proliferation of NK (22-fold increase in Ki-67+ cells), CD8+ (27-fold) and CD4+ T (11-fold) cells; however, increased cell number occurred only in NK cells. N-803 administration also increased serum levels of interferon gamma, IL-10, and IL-6. One of 14 evaluable subjects had measureable anti-N-803 antibodies at the end-of-study visit. Conclusions: N-803 results in prolonged elevation of drug serum concentrations, contrasting with rapid clearance of recombinant human IL-15 (ie, half-life of ~20 vs < 1 hour). N-803 administration was well-tolerated in healthy volunteers, without evidence of adverse systemic inflammatory responses, and resulted in proliferation of NK cells and CD8+ T cells, as well as sustained increases in NK cell number. Findings in this study are consistent with published results from N-803 administration in treating liquid tumors and lung cancer. Our results demonstrate N-803 administration potentiates the proliferation and activity of lymphocytes with antitumor and antivirus properties, and suggest this investigational product holds promise in treatment of cancer as well as infectious disease such as HIV. Clinical trial information: NCT03381586 .

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Sainathan, Satheesh K., Justin H. Lipner, Jennifer I. Drake, Brogan A. Epkins, Brianna M. Roux, and Alastair J. King. "Abstract 1877: Measurement of cytosolic DNA sensing cGAS-STING pathway functional activity using in vitro phenotypic assay models." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1877. http://dx.doi.org/10.1158/1538-7445.am2022-1877.

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Abstract Innate immunity plays a vital role in detecting cytoplasmic nucleic acids resulting from viral infection or the presence of tumor cells. Cytosolic DNA is sensed by the cyclic-GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, and in the case of tumors, activation of this pathway has potential to both positively and negatively modulate cancer development. Activation of the STING pathway is a key prerequisite for type I IFN production that is needed for either endogenous or treatment-induced cancer immune responses, and reduced cGAS-STING expression is associated with poorer survival of patients with lung adenocarcinoma, invasive breast ductal carcinoma, and gastric cancer. Intrinsic activation of the cGAS-STING pathway in the tumor microenvironment (TME) promotes cancer cell-intrinsic senescence and recruitment of immune cells, resulting in antitumor effects. For cancers that are difficult to treat and characterized by immune tolerance, combination therapies of STING agonists with immune checkpoint inhibitors represents a new paradigm in disease management. To date, only two early clinical trials of the STING agonist ADU-S100 in combination with checkpoint inhibitors are underway (NCT02675439 and NCT03172936). To progress clinical trials more rapidly and with better safety outcomes for patients with advanced treatment-refractory metastatic solid tumors or lymphomas, being able to reliably screen a variety of STING agonists in different types of in vitro cancer models is of paramount importance. We have previously reported a novel functional assay that is capable of demonstrating the potency level of different STING agonists, based on the IFNβ response in THP-1 monocytic leukemia cells. We further investigated the role of newly developed STING agonists and clinical compounds in phenotypic in vitro cancer cell and TME models to inform on oncotherapeutic development. STING-expressing cancer cell lines, chosen based on microarray mRNA expression, were treated with agonists and assayed for cGAS-STING activation status using a fully automated platform for high-content imaging. In vitro analysis demonstrated high phospho-STING activation at 4 hours. In the BioMAP® Oncology Colorectal TME model, STING activation increased IL-6 release and the effect on other primary immune and tissue remodeling biomarkers will be discussed. Preclinical studies indicate that STING agonists, used as adjuvants in combination with other agents or radiation therapy, suppress tumor progression, reduce cellular toxicity, and eliminate metastases in breast and pancreatic cancer models. Phenotypic assays that provide human, translational data early in discovery are a valuable tool to accelerate progress in this area. Citation Format: Satheesh K. Sainathan, Justin H. Lipner, Jennifer I. Drake, Brogan A. Epkins, Brianna M. Roux, Alastair J. King. Measurement of cytosolic DNA sensing cGAS-STING pathway functional activity using in vitro phenotypic assay models [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 1877.

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Kívés, Zsuzsanna, Dóra Endrei, Diána Elmer, Tímea Csákvári, Luca Fanni Kajos, Imre Boncz, László Mangel, and Réka Mihály-Vajda. "A vastag- és végbéldaganat okozta országos epidemiológiai és egészségbiztosítási betegségteher Magyarországon." Orvosi Hetilap 162, Supplement-1 (March 28, 2021): 14–21. http://dx.doi.org/10.1556/650.2021.32152.

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Összefoglaló. Bevezetés: Magyarországon a vastag- és a végbéldaganat mindkét nem esetében a harmadik leggyakoribb daganatos megbetegedés és a második leggyakoribb halálok. Célkitűzés: Elemzésünk célja volt a vastag- és végbéldaganat okozta éves epidemiológiai és egészségbiztosítási betegségteher meghatározása Magyarországon. Adatok és módszerek: Az adatok a Nemzeti Egészségbiztosítási Alapkezelő (NEAK) finanszírozási adatbázisából származnak, és a 2018. évet fedik le. A daganat típusait a Betegségek Nemzetközi Osztályozása (BNO, 10. revízió) szerinti C18-as, C19-es, C20-as, C21-es, D010–D014-es és D12-es kóddal azonosítottuk. Meghatároztuk az éves betegszámokat korcsoportos és nemek szerinti bontásban, a prevalenciát 100 000 lakosra, az éves egészségbiztosítási kiadásokat valamennyi ellátási formára és daganattípusra vonatkozóan. Eredmények: A vastag- és végbéldaganatok kezelésére a NEAK 21,7 milliárd Ft-ot (80,2 millió USD; 68,0 millió EUR) költött 2018-ban. A költségek 58,0%-át az aktívfekvőbeteg-szakellátás költségei teszik ki. Az összköltségek megoszlása szerint a legmagasabb költségek a férfiaknál (4,98 milliárd Ft) és a nőknél (3,25 milliárd Ft) is a 65–74 éves korcsoportban figyelhetők meg. A legnagyobb betegszámot a járóbeteg-szakellátás esetében találtuk: 88 134 fő, ezt a háziorvosi ellátás (55 324 fő) és a CT, MRI (28 426 fő) követte. A vastagbél rosszindulatú daganata esetében az egy betegre jutó aktívfekvőbeteg-kassza alapján az éves egészségbiztosítási kiadás 1,206 millió Ft (4463 USD/3782 EUR) volt a férfiak és 1,260 millió Ft (4661 USD/3950 EUR) a nők esetében. Következtetés: Hazánkban az aktívfekvőbeteg-szakellátás bizonyult a fő költségtényezőnek, mely magában foglalja az onkoterápiás gyógyszeres költségeket is. Orv Hetil. 2021; 162(Suppl 1): 14–21. Summary. Introduction: Colorectal cancer is the third most common type of cancer and the second most common cause of mortality in Hungary in both sexes. Objective: The aim of our study was to determine the annual epidemiological disease burden and health insurance cost of colorectal cancer in Hungary. Data and methods: Data were derived from the financial database of the National Health Insurance Fund Administration (NHIFA) of Hungary for the year 2018. Types of cancer were identified with the following codes of the International Classification of Diseases, 10th revision: C18, C19, C20, C21, D010–D014, D12. The data analysed included annual patient numbers according to age groups and sex, prevalence of care utilisation per 100 000 population, and annual health insurance costs for all types of care and all cancer types. Results: In 2018, NHIFA spent 21.7 billion HUF (80.2 million USD, 68.0 million EUR) on the treatment of colorectal cancer. 58.0% of the costs was spent on acute inpatient care. Regarding total costs, the highest costs were found in the 65–74 age group in both men (4.98 billion HUF) and women (3.25 billion HUF). The highest patient numbers were in outpatient care: 88 134 patients, general practice care (55 324 patients) and CT, MRI (28 426 patients). The annual health care treatment cost per patient was 1.206 million HUF (4463 USD/3782 EUR) in men and 1.260 million HUF (4661 USD/3950 EUR) in women. Conclusion: Acute inpatient care, including the costs of oncotherapeutic pharmaceuticals, was found to be the major cost driver in Hungary. Orv Hetil. 2021; 162(Suppl 1): 14–21.

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Ghosh, Dr Sayantan, and Ms Manaswi N. "Oncotherapeutics: A General Overview." Journal of Current Medical Research and Opinion 4, no. 04 (April 30, 2021). http://dx.doi.org/10.15520/jcmro.v4i04.418.

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Experimental oncotherapeutics programs have been in place at major academic centres for over four decades. The emergence of molecular targeting agents and the recent introduction of immuno-oncology drugs have expanded the scope and eligibility for first-in-human trials. Improved understanding of tumor biology coupled with the ability to screen for tumor associated targets, as well as, genetic alterations have heralded the era of personalized (personalized or precision) cancer treatment. Molecular targeting agents with their improved tolerability and sustained responses compared to conventional cytotoxic chemotherapy have contributed to remarkable improvements in clinical outcomes Dramatic phase 1 observations of anti-tumor activity of novel molecules in the relapsed or refractory setting have ofen led to their investigation as monotherapy or in combinatorial strategies early in the course of cancer treatment. Studies have thus evolved from the traditional role of dose and toxicity-fnding studies to innovative enrichment study designs which match patients with study agents, thus increasing the potential of clinical efcacy, even in the early dose escalation setting.

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Mandal, Saurabh, Naisarg Gamit, Subhankar Biswas, C. Mallikarjun Rao, Gautam Sethi, and Sudha Warrier. "An efficient human stem cells derived cardiotoxicity testing platform for testing oncotherapeutic analogues of quercetin and cinnamic acid." Scientific Reports 12, no. 1 (December 9, 2022). http://dx.doi.org/10.1038/s41598-022-21721-3.

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AbstractOncotherapeutics research is progressing at a rapid pace, however, not many drugs complete the successful clinical trial because of severe off-target toxicity to cardiomyocytes which ultimately leads to cardiac dysfunction. It is thus important to emphasize the need for early testing for possible cardiotoxicity of emerging oncotherapeutics. In this study, we assessed a novel stem cell-derived cardiac model for testing for cardiotoxicity of novel oncotherapeutics. We evaluated the cardiotoxic effect of synthesized derivatives of oncotherapeutics, quercetin (QMJ-2, -5, and -6) and cinnamic acid (NMJ-1, -2, and -3) using human Wharton's jelly mesenchymal stem cells-derived cardiomyocytes (WJCM) against known cardiotoxic oncologic drugs, doxorubicin, 5-fluorouracil, cisplatin. QMJ-6, NMJ-2, and NMJ-3 were not cardiotoxic and had minimum cardiac side effects. They did not show any effect on cardiomyocyte viability, caused low LDH release, and intracellular ROS production kept the calcium flux minimal and protected the active mitochondrial status in cardiomyocytes. They persevered cardiac-specific gene expression as well. However, compounds QMJ-2, QMJ-5, and NMJ-1 were cardiotoxic and the concentration needs to be reduced to prevent toxic effects on cardiomyocytes. Significantly, we were able to demonstrate that WJCM is an efficient cardiac testing model to analyze the cardiotoxicity of drugs in a human context.

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Kumar, Lalit. "Exploring therapeutic potential of plga nanoparticles in oncotherapeutics." Micro and Nanosystems 14 (May 4, 2022). http://dx.doi.org/10.2174/1876402914666220504143153.

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Dailey, Kaitlin M., Reed I. Jacobson, Paige R. Johnson, Taylor J. Woolery, Jiha Kim, Rick J. Jansen, Sanku Mallik, and Amanda E. Brooks. "Methods and Techniques to Facilitate the Development of Clostridium novyi NT as an Effective, Therapeutic Oncolytic Bacteria." Frontiers in Microbiology 12 (March 29, 2021). http://dx.doi.org/10.3389/fmicb.2021.624618.

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The tumor microenvironment is characterized by anomalous vascularization, hypoxia, and acidity at the core of solid tumors that culminates in concentrated necrosis and immune system dysregulation among other effects. While this environment presents several challenges for the development of oncotherapeutics that deliver their activity via the enhanced permeability and retention (EPR) effect of the leaky blood vessels around a tumor, oncolytic bacteria, or a class of bacteria with a noted capacity to lyse solid tumors, are attracted to the very environment found at the center of solid tumors that confounds other therapeutics. It is this capacity that allows for a potent, active penetration from the tumor margins into the core, and subsequent colonization to facilitate lysis and immune reactivation. Clostridium novyi in particular has recently shown great promise in preclinical and clinical trials when administered directly to the tumor. These studies indicate that C. novyi is uniquely poised to effectively accomplish the long sought after “holy grail” of oncotherapeutics: selective tumor localization via intravenous delivery. This study reports the development of efficient methods that facilitate experimental work and therapeutic translation of C. novyi including the ability to work with this obligate micro-anaerobe on the benchtop. Additionally, this study seeks to utilize this newfound experimental flexibility to address several gaps in the current knowledge regarding the efficacy of CRIPSR/Cas9-mediated gene insertion in this species to further develop this oncolytic bacteria and the genetic customization of bacteria in general.

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Traba, Javier, Michael N. Sack, Thomas A. Waldmann, and Olga M. Anton. "Immunometabolism at the Nexus of Cancer Therapeutic Efficacy and Resistance." Frontiers in Immunology 12 (May 17, 2021). http://dx.doi.org/10.3389/fimmu.2021.657293.

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Constitutive activity of the immune surveillance system detects and kills cancerous cells, although many cancers have developed strategies to avoid detection and to resist their destruction. Cancer immunotherapy entails the manipulation of components of the endogenous immune system as targeted approaches to control and destroy cancer cells. Since one of the major limitations for the antitumor activity of immune cells is the immunosuppressive tumor microenvironment (TME), boosting the immune system to overcome the inhibition provided by the TME is a critical component of oncotherapeutics. In this article, we discuss the main effects of the TME on the metabolism and function of immune cells, and review emerging strategies to potentiate immune cell metabolism to promote antitumor effects either as monotherapeutics or in combination with conventional chemotherapy to optimize cancer management.

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Zaborowski, Alexandra M., Des C. Winter, and Lydia Lynch. "The therapeutic and prognostic implications of immunobiology in colorectal cancer: a review." British Journal of Cancer, July 23, 2021. http://dx.doi.org/10.1038/s41416-021-01475-x.

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AbstractColorectal cancer represents the second leading cause of cancer-related death worldwide. The therapeutic field of immuno-oncology has rapidly gained momentum, with strikingly promising results observed in clinical practice. Increasing emphasis has been placed on the role of the immune response in tumorigenesis, therapy and predicting prognosis. Enhanced understanding of the dynamic and complex tumour-immune microenvironment has enabled the development of molecularly directed, individualised treatment. Analysis of intra-tumoural lymphocyte infiltration and the dichotomisation of colorectal cancer into microsatellite stable and unstable disease has important therapeutic and prognostic implications, with potential to capitalise further on this data. This review discusses the latest evidence surrounding the tumour biology and immune landscape of colorectal cancer, novel immunotherapies and the interaction of the immune system with each apex of the tripartite of cancer management (oncotherapeutics, radiotherapy and surgery). By utilising the synergy of chemotherapeutic agents and immunotherapies, and identifying prognostic and predictive immunological biomarkers, we may enter an era of unprecedented disease control, survivorship and cure rates.

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Paluri, Ravi K., Peng Li, Ashley Anderson, Lakshminarayana Nandagopal, Traci McArdle, Matthew Young, Franscisco Robert, Gurudatta Naik, and Mansoor Saleh. "First-In-Human Phase 1 Clinical Trials – A Single-Center Experience In The Era Of Modern Oncotherapeutics." Scientific Reports 10, no. 1 (May 13, 2020). http://dx.doi.org/10.1038/s41598-020-64906-4.

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Lewis, Lionel D. "Medicamenta ad sentinam, et defectum vitae: Drugs and failure of the pump of life‐cardiotoxicity of oncotherapeutics." British Journal of Clinical Pharmacology, October 18, 2020. http://dx.doi.org/10.1111/bcp.14558.

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Ghazy, Esraa, Arun Kumar, Mahmood Barani, Ishnoor Kaur, Abbas Rahdar, and Tapan Behl. "Scrutinizing the therapeutic and diagnostic potential of nanotechnology in thyroid cancer: Edifying drug targeting by nano-oncotherapeutics." Journal of Drug Delivery Science and Technology, November 2020, 102221. http://dx.doi.org/10.1016/j.jddst.2020.102221.

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Oleas, Diana, and Ana Saurina. "Case report: Anti-PLA2R positive membranous nephropathy associated with atezolizumab." Journal of Onco-Nephrology, September 28, 2022, 239936932211254. http://dx.doi.org/10.1177/23993693221125487.

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Background: Immunotherapy has transformed cancer treatment in advanced malignancies. Increased survival compared with the standard of care has made immunotherapy a fundamental component of oncotherapeutics. Immune checkpoint inhibitors (ICI) trigger a stimulus to kill cancer cells. Immune-related adverse events (irAEs), derived from its potent stimulus, affect diverse organs. Acute interstitial nephritis (AIN) is the most frequent kidney irAE. Glomerulopathies, although rare, constitute a more challenging diagnosis and treatment. Case presentation: A 72-year-old man with lung adenocarcinoma treated with Bevacizumab and Atezolizumab. During treatment, he developed nephrotic syndrome. A diagnosis of a phospholipase A2 receptor positive primary membranous nephropathy associated with atezolizumab was made. After failing to respond to steroid therapy, treatment with rituximab was the preferred option. Eight months after being treated with rituximab and 10 months after atezolizumab was stopped, the patient maintained preserved renal function and negativization of anti-PLA2R was achieved. Proteinuria declined to half of its initial value 5 months following anti-PLA2R negativization. Conclusion: Monitoring proteinuria as well as declining kidney function in patients being treated with ICI is a valuable measure to determine an indication for a timely kidney biopsy and treatment.

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Yu, Yunhe, and Lin Fang. "CircRPAP2 regulates the alternative splicing of PTK2 by binding to SRSF1 in breast cancer." Cell Death Discovery 8, no. 1 (April 2, 2022). http://dx.doi.org/10.1038/s41420-022-00965-y.

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AbstractBreast cancer is the most commonly diagnosed malignant tumor and the second-highest cause of cancer-related deaths in women worldwide. Circular RNAs (circRNAs) are associated with the development of numerous cancers, including breast cancer. Here, we present the first report that circRPAP2 (hsa_circ_0000091) is downregulated in breast cancer tissue samples and cell lines. Furthermore, the expression level of circRPAP2 in breast cancer tissues was correlated with axillary lymph node metastasis and TNM stage. Biological function studies demonstrated that circRPAP2 inhibited the proliferation and migration of breast cancer in vivo and in vitro. The mechanistic evaluation indicated that circRPAP2 can bind to the oncoprotein SRSF1, likely competing with the binding between SRSF1 and PTK2 pre-mRNA, thereby attenuating SRSF1-mediated alternate splicing of PTK2, an effector of SRSF1 oncogenic activity, resulting in the reduction of PTK2 mRNA and protein expression. Overall, our findings suggest that circRPAP2 plays a tumor suppressor role and may serve as a biomarker in breast cancer. In addition, the identification of the circRPAP2/SRSF1/PTK2 axis provides new insights into the pathogenesis of breast cancer and highlights a novel target for the development of oncotherapeutics.

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Thomas, Dilip, Sushma Shenoy, and Nazish Sayed. "Building Multi-Dimensional Induced Pluripotent Stem Cells-Based Model Platforms to Assess Cardiotoxicity in Cancer Therapies." Frontiers in Pharmacology 12 (February 18, 2021). http://dx.doi.org/10.3389/fphar.2021.607364.

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Cardiovascular disease (CVD) complications have contributed significantly toward poor survival of cancer patients worldwide. These complications that result in myocardial and vascular damage lead to long-term multisystemic disorders. In some patient cohorts, the progression from acute to symptomatic CVD state may be accelerated due to exacerbation of underlying comorbidities such as obesity, diabetes and hypertension. In such situations, cardio-oncologists are often left with a clinical predicament in finding the optimal therapeutic balance to minimize cardiovascular risks and maximize the benefits in treating cancer. Hence, prognostically there is an urgent need for cost-effective, rapid, sensitive and patient-specific screening platform to allow risk-adapted decision making to prevent cancer therapy related cardiotoxicity. In recent years, momentous progress has been made toward the successful derivation of human cardiovascular cells from induced pluripotent stem cells (iPSCs). This technology has not only provided deeper mechanistic insights into basic cardiovascular biology but has also seamlessly integrated within the drug screening and discovery programs for early efficacy and safety evaluation. In this review, we discuss how iPSC-derived cardiovascular cells have been utilized for testing oncotherapeutics to pre-determine patient predisposition to cardiovascular toxicity. Lastly, we highlight the convergence of tissue engineering technologies and precision medicine that can enable patient-specific cardiotoxicity prognosis and treatment on a multi-organ level.

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Gall, Louis, Ferran Jardi, Lieve Lammens, Janet Piñero, Terezinha M. Souza, Daniela Rodrigues, Danyel G. J. Jennen, et al. "A dynamic model of the intestinal epithelium integrates multiple sources of preclinical data and enables clinical translation of drug‐induced toxicity." CPT: Pharmacometrics & Systems Pharmacology, August 24, 2023. http://dx.doi.org/10.1002/psp4.13029.

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AbstractWe have built a QST modelling framework focussed on the early prediction of oncotherapeutics‐induced clinical intestinal adverse effects. The model describes stem and progenitor cell dynamics in the small intestinal epithelium and integrates heterogeneous epithelial‐related processes, such as transcriptional profiles, citrulline kinetics and probability of diarrhea.We fitted a mouse‐specific version of the model to quantify doxorubicin and 5‐fluorouracil (5‐FU) induced toxicity, which included pharmacokinetics and 5‐FU metabolism and assumed that both drugs led to cell cycle arrest and apoptosis in stem cells and proliferative progenitors. The model successfully recapitulated observations in mice regarding dose‐dependent disruption of proliferation which could lead to villus shortening, decrease of circulating citrulline, increased diarrhea risk and transcriptional induction of the p53 pathway.Using a human‐specific epithelial model, we translated the cytotoxic activity of doxorubicin and 5‐FU quantified in mouse into human intestinal injury and predicted with accuracy clinical diarrhea incidence. However, for gefitinib, a specific‐molecularly targeted therapy, the mouse failed to reproduce epithelial toxicity at exposures much higher than those associated with clinical diarrhea. This indicates that, regardless of the translational modelling approach, preclinical experimental settings have to be suitable to quantify drug‐induced clinical toxicity with precision at the structural scale of the model.Our work demonstrates the usefulness of translational models at early stages of the drug development pipeline to predict clinical toxicity and highlights the importance of understanding cross‐settings differences in toxicity when building these approaches.

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Kan, Peter, Visish M. Srinivasan, Joy Gumin, Roberto Garcia, Stephen R. Chen, Jeremiah N. Johnson, Dalis E. Collins, et al. "Development of a Rabbit Human Glioblastoma Model for Testing of Endovascular Selective Intra-Arterial Infusion (ESIA) of Novel Stem Cell-Based Therapeutics." Neuro-Oncology, August 21, 2023. http://dx.doi.org/10.1093/neuonc/noad152.

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Abstract Background Endovascular selective intra-arterial (ESIA) infusion of cellular oncotherapeutics is a rapidly evolving strategy for treating glioblastoma. Evaluation of ESIA infusion requires a unique animal model. Our goal was to create a rabbit human GBM model in order to test IA infusions of cellular therapies and to test its usefulness by employing clinical-grade microcatheters and infusion methods to deliver mesenchymal stem cells loaded with an oncolytic adenovirus, Delta-24-RGD (MSC-D24). Methods Rabbits were immunosuppressed with mycophenolate mofetil, dexamethasone, and tacrolimus. They underwent stereotactic xenoimplantation of human GBM cell lines (U87, MDA-GSC-17, and MDA-GSC-8-11) into the right frontal lobe. Tumor formation was confirmed on magnetic resonance imaging, histologic, and immunohistochemistry analysis. Selective microcatheter infusion of MSC-D24 was performed via the ipsilateral internal carotid artery to assess model utility and the efficacy and safety of this approach. Results Twenty-five rabbits were implanted (18 with U87, 2 MDA-GSC-17, and 5 MDA-GSC-8-11). Tumors formed in 68% of rabbits (77.8% for U87, 50.0% for MDA-GSC-17, and 40.0% for MDA-GSC-8-11). On MRI, the tumors were hyperintense on T2-weighted image with variable enhancement (evidence of blood brain barrier breakdown). Histologically, tumors showed phenotypic traits of human GBM including varying levels of vascularity. ESIA infusion into the distal internal carotid artery of 2 ml of MSCs-D24 (10 7 cells) was safe in the model. Examination of post infusion specimens documented that MSCs-D24 homed to the implanted tumor at 24 hours. Conclusions The intracranial immunosuppressed rabbit human GBM model allows testing of ESIA infusion of novel therapeutics (e.g., MSC-D24) in a clinically relevant fashion.

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Anand, Apoorva, Jacob Bigio, Emily MacLean, Talya Underwood, Nitika Pant Pai, Sergio Carmona, Samuel G. Schumacher, and Amy Toporowski. "317. Use cases for rapid antigen-detecting tests for COVID-19 screening and surveillance: a systematic review." Open Forum Infectious Diseases 9, Supplement_2 (December 1, 2022). http://dx.doi.org/10.1093/ofid/ofac492.395.

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Abstract Background Testing remains critical to controlling the COVID-19 pandemic. Antigen-detecting rapid diagnostic tests (Ag-RDTs), which can be used at the point of care, have the potential to increase access to COVID-19 testing, particularly in settings with limited laboratory capacity. This systematic review synthesized literature on specific use cases and performance of Ag-RDTs for detecting SARS-CoV-2, for the first comprehensive assessment of Ag-RDT use in real-world settings. Methods We searched three databases (PubMed, EMBASE and medRxiv) up to 12 April 2021 for publications on Ag-RDT use for large-scale screening and surveillance of COVID-19, excluding studies of only presumptive COVID-19 patients. We tabulated data on the study setting, populations, type of test, diagnostic performance, and operational findings. We assessed risk of bias using QUADAS-2 and an adapted tool for prevalence studies. Results From 4313 citations, 39 studies conducted in asymptomatic and symptomatic individuals were included. Of 39 studies, 37 (94.9%) investigated lateral flow Ag-RDTs and 2 (5.1%) investigated multiplex sandwich chemiluminescent enzyme immunoassay Ag-RDTs. Six categories of testing initiatives were identified: mass screening (n=13), targeted screening (n=11), healthcare entry testing (n=6), at-home testing (n=4), surveillance (n=4) and prevalence survey (n=1). Sensitivity and specificity values by testing category are shown in the table. Ag-RDTs were noted as convenient, easy-to-use, and low cost, with a rapid turnaround time and high user acceptability. Risk of bias was generally low or unclear across studies. Conclusion During the first year of the COVID-19 pandemic, Ag-RDTs were used across a wide range of real-world settings for screening and surveillance of COVID-19 in both symptomatic and asymptomatic individuals. Ag-RDTs were fast and simple to run, but due to their often low sensitivity, careful consideration must be given to their implementation and interpretation. Ag-RDTs have subsequently been rolled out more broadly and recommended for COVID-19 self-testing. Disclosures Talya Underwood, MPhil, Oncotherapeutics: Medical writing.

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