Targeting tumor repopulation and the immune microenvironment to overcome chemoresistance

靶向肿瘤增殖和免疫微环境以克服化疗耐药性

• 批准号: 10781577
• 负责人: Keith Syson Chan
• 金额: $ 22.64万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10781577
• 关键词: Targeting; tumor; repopulation; immune; microenvironment

PROJECT SUMMARY This application is in response to PAR-19-183: Biology of Bladder Cancer. Muscle invasive bladder cancer (MIBC) claims approximately 18,000 deaths annually in the United States. Funding and research devoted to this cancer-type are significantly under-proportioned. An unmet clinical need for MIBC treatment lies in the poor patient response towards chemotherapy, with treatments providing only a dismal 5% improvement in overall survival. The long-term goal of this application is to address this urgent need for adjuvant therapies to improve chemotherapeutic response. The success of chemotherapy is historically thought to solely depend on its direct cytotoxic effects on tumor cells. However, there is growing evidence, as shown by our own research and others, that chemotherapeutic efficacy is also dependent on 1) successful prevention of cancer stem cells in repopulating residual tumors and 2) an effective anti-tumoral immune response. These two phenomena are often investigated separately but their possible synergy has been overlooked. Our research project is conceptually innovative to examine a common upstream pathway that regulates both tumor repopulation and immune response. We hypothesize that the inhibition of this common pathway will provide an effective therapeutic target for clinical translation. Our specific aims include: Aim 1) Decipher this pathway by investigating the non-canonical downstream mechanism leading to the extracellular release of pleiotropic factors. This is significant, since these extracellular factors can modulate both tumor repopulation and immune response. Aim 2) Evaluate how these extracellular factors and their cognate receptors drive the repopulation of quiescent cancer stem cells. Aim 3) Investigate how inhibition of this upstream pathway can collectively abrogate tumor repopulation and immunosuppression, and thus, enhance chemotherapeutic response. Success of this proposal will pose drug targets capable of augmenting patient response to chemotherapy. Moreover, these findings will provide insights to how these drugs can reestablish an immunostimulatory tumor microenvironment in MIBCs. In summary, the studies outlined in this proposal are significant to address an unmet need, i.e., to improve a dismal response of MIBC patients to standard chemotherapy. The conceptual advance from this study will likely extend beyond MIBC to benefit patients from other epithelial malignancies.

项目总结