State-of-the-Art of Monoclonal Antibodies for the Treatment of Gastric Cancer
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ABSTRACT:
SUBMITTER: Basile D
PROVIDER: S-EPMC8572727 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Many phase III trials failed to demonstrate a survival benefit from the addition of molecular therapy to conventional chemotherapy for advanced and metastatic gastric cancer, and only three agents were approved by the FDA. We examined the efficacy and safety of novel drugs recently investigated. PubMed, Embase and Cochrane Library were searched for phase III randomized controlled trials published from January 2016 to December 2020. Patients in the experimental arm received molecular therapy with or without conventional chemotherapy, while those in the control arm had conventional chemotherapy alone. The primary outcomes were overall and progression-free survival. The secondary outcomes were the rate of tumor response, severe adverse effects, and quality of life. Eight studies with a total of 4223 enrolled patients were included. The overall and progression-free survival of molecular and conventional therapy were comparable. Most of these trials did not find a significant difference in tumor response rate and in the number of severe adverse effects and related deaths between the experimental and control arms. The survival benefits of molecular therapies available to date for advanced and metastatic gastric cancer are rather unclear, mostly due to inaccurate patient selection, particularly concerning oncogene amplification and copy number.
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Project description:Over the past decade, the clinical utility of monoclonal antibodies has been realized and antibodies are now a mainstay for the treatment of cancer. Antibodies have the unique capacity to target and kill tumor cells while simultaneously activating immune effectors to kill tumor cells through the complement cascade or antibody-dependent cellular cytotoxicity (ADCC). This multifaceted mechanism of action combined with target specificity underlies the capacity of antibodies to elicit anti-tumor responses while minimizing the frequency and magnitude of adverse events. This review will focus on mechanisms of action, clinical applications and putative mechanisms of resistance to monoclonal antibody therapy in the context of cancer.
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Project description:PurposeRecent studies have suggested that molecular targets for the anti-angiogenic therapy might constitute a basis for additional therapy in gastric cancer treatment. A vast number of molecules, receptors, pathways, specific interactions, and thus strategies that target gastric cancer angiogenesis specifically have been reported in numerous research articles and clinical trials.MethodsWe conducted a systematic literature review of molecularly targeted treatment strategies in gastric cancer on the following databases-PubMed, Google Scholar, and Scopus-on September 20, 2020. Multiple articles and evaluations were searched for studies reporting newly found and promising molecular anti-angiogenic therapy pathways. Eventually, 39 articles regarding the anti-angiogenic therapy in gastric cancer were included in the final analysis.ResultsAs a consequence of the release of the pro-angiogenic molecules from the tumour cells, gastric cancer presents high angiogenic capability. Therefore, potential schemes for future treatment strategies include the decrease of the process ligands as well as the expression of their receptors. Moreover, the increase in the angiogenic inhibitor levels and direct aim for the inner walls of the endothelial cells appear as a promising therapeutic strategy. Beyond that, angiogenesis process inhibition seems to indirectly exaggerate the effects of chemotherapy in the considered patients.ConclusionsThe anti-angiogenic treatment in gastric cancer patients evaluates its significance especially in the early stages of the malignancy. The studies conducted so far show that most of the meaningful angiogenic factors and receptors with the potential molecular pathways should be further evaluated since they could potentially play a substantial role in future therapies.
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Project description:CD24 is a potential oncogene reported to be overexpressed in a large variety of human malignancies. We have shown that CD24 is overexpressed in 90% of colorectal tumors at a fairly early stage in the multistep process of carcinogenesis. Anti-CD24 monoclonal antibodies (mAb) induce a significant growth inhibition in colorectal and pancreatic cancer cell lines that express the protein. This study is designed to investigate further the effects of CD24 down-regulation using mAb or small interfering RNA in vitro and in vivo. Western blot analysis showed that anti-CD24 mAb induced CD24 protein down-regulation through lysosomal degradation. mAb augmented growth inhibition in combination with five classic chemotherapies. Xenograft models in vivo showed that tumor growth was significantly reduced in mAb-treated mice. Similarly, stable growth inhibition of cancer cell lines was achieved by down-regulation of CD24 expression using short hairpin RNA (shRNA). The produced clones proliferated more slowly, reached lower saturation densities, and showed impaired motility. Most importantly, down-regulation of CD24 retarded tumorigenicity of human cancer cell lines in nude mice. Microarray analysis revealed a similar pattern of gene expression alterations when cells were subjected to anti-CD24 mAb or shRNA. Genes in the Ras pathway, mitogenactivated protein kinase, or BCL-2 family and others of oncogenic association were frequently down-regulated. As a putative new oncogene that is overexpressed in gastrointestinal malignancies early in the carcinogenesis process, CD24 is a potential target for early intervention in the prevention and treatment of cancer.
2009-03-07 | GSE15102 | GEO
Project description:Monoclonal antibody-based immunotherapy is now considered to be a main component of cancer therapy, alongside surgery, radiation, and chemotherapy. Monoclonal antibodies possess a diverse set of clinically relevant mechanisms of action. In addition, antibodies can directly target tumor cells while simultaneously promoting the induction of long-lasting anti-tumor immune responses. The multifaceted properties of antibodies as a therapeutic platform have led to the development of new cancer treatment strategies that will have major impacts on cancer care. This review focuses on the known mechanisms of action, current clinical applications for the treatment of cancer, and mechanisms of resistance of monoclonal antibody therapy. We further discuss how monoclonal antibody-based strategies have moved towards enhancing anti-tumor immune responses by targeting immune cells instead of tumor antigens as well as some of the current combination therapies.
| S-EPMC7551545 | biostudies-literature
Project description:CD24 is a potential oncogene reported to be overexpressed in a large variety of human malignancies. We have shown that CD24 is overexpressed in 90% of colorectal tumors at a fairly early stage in the multistep process of carcinogenesis. Anti-CD24 monoclonal antibodies (mAb) induce a significant growth inhibition in colorectal and pancreatic cancer cell lines that express the protein. This study is designed to investigate further the effects of CD24 down-regulation using mAb or small interfering RNA in vitro and in vivo. Western blot analysis showed that anti-CD24 mAb induced CD24 protein down-regulation through lysosomal degradation. mAb augmented growth inhibition in combination with five classic chemotherapies. Xenograft models in vivo showed that tumor growth was significantly reduced in mAb-treated mice. Similarly, stable growth inhibition of cancer cell lines was achieved by down-regulation of CD24 expression using short hairpin RNA (shRNA). The produced clones proliferated more slowly, reached lower saturation densities, and showed impaired motility. Most importantly, down-regulation of CD24 retarded tumorigenicity of human cancer cell lines in nude mice. Microarray analysis revealed a similar pattern of gene expression alterations when cells were subjected to anti-CD24 mAb or shRNA. Genes in the Ras pathway, mitogenactivated protein kinase, or BCL-2 family and others of oncogenic association were frequently down-regulated. As a putative new oncogene that is overexpressed in gastrointestinal malignancies early in the carcinogenesis process, CD24 is a potential target for early intervention in the prevention and treatment of cancer. The study compared gene expression profiles between human CRC cells HT29 before and after expression of 1 and 2 shRNA vectors directed at the human CD24 gene, GFP control gene, HT29 cells and Colo357, human pancreatic cancer cells, before and after the inhibition of the CD24 molecule using 72h treatment with anti-CD24 monoclonal antibodies.
2009-03-07 | E-GEOD-15102 | biostudies-arrayexpress
Project description:BackgroundFor the past two decades, there has been a huge expansion in the development of therapeutic antibodies, with 6 to 10 novel entities approved each year. Around 70% of these Abs are delivered through IV injection, a mode of administration allowing rapid and systemic delivery of the drug. However, according to the evidence presented in the literature, beyond the reduction of invasiveness, a better efficacy can be achieved with local delivery. Consequently, efforts have been made toward the development of innovative methods of administration, and in the formulation and engineering of novel Abs to improve their therapeutic index.ObjectiveThis review presents an overview of the routes of administration used to deliver Abs, different from the IV route, whether approved or in the clinical evaluation stage. We provide a description of the physical and biological fundamentals for each route of administration, highlighting their relevance with examples of clinically-relevant Abs, and discussing their strengths and limitations.MethodsWe reviewed and analyzed the current literature, published as of the 1 April 2022 using MEDLINE and EMBASE databases, as well as the FDA and EMA websites. Ongoing trials were identified using clinicaltrials.gov. Publications and data were identified using a list of general keywords.ConclusionsApart from the most commonly used IV route, topical delivery of Abs has shown clinical successes, improving drug bioavailability and efficacy while reducing side-effects. However, additional research is necessary to understand the consequences of biological barriers associated with local delivery for Ab partitioning, in order to optimize delivery methods and devices, and to adapt Ab formulation to local delivery. Novel modes of administration for Abs might in fine allow a better support to patients, especially in the context of chronic diseases, as well as a reduction of the treatment cost.
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