Targeting tumor repopulation and the immune microenvironment to overcome chemoresistance

项目摘要 此应用程序是在响应PAR-19-183：膀胱癌的生物学。肌肉浸润性膀胱癌 MIBC每年在美国造成约18，000人死亡。资金和研究专门用于 这种类型的癌症比例明显不足。MIBC治疗的未满足的临床需求在于 患者对化疗的反应较差，治疗仅提供了令人沮丧的5%的改善， 总体生存率。这项申请的长期目标是解决这种对辅助治疗的迫切需求 以改善化疗反应。化疗的成功历来被认为仅仅取决于 对肿瘤细胞的直接细胞毒作用。然而，越来越多的证据表明，我们自己的 研究和其他研究表明，化疗的疗效也取决于1）成功预防癌症 干细胞在重建残余肿瘤中的作用和2）有效的抗肿瘤免疫应答。这两 对各种现象的调查往往是分开进行的，但却忽视了它们之间可能的协同作用。我们的研究 该项目在概念上是创新的，旨在研究一种共同的上游途径， 繁殖和免疫反应。我们假设，抑制这一共同途径将提供 临床转化的有效治疗靶点。我们的具体目标包括：目标1）破译这条通路 通过研究导致多效性细胞外释放的非经典下游机制， 因素这是有意义的，因为这些细胞外因子可以调节肿瘤再增殖和肿瘤生长。 免疫反应目的2）评估这些细胞外因子及其同源受体如何驱动细胞外基质， 静止期癌症干细胞的再增殖。目的3）研究如何抑制这一上游途径， 共同消除肿瘤再增殖和免疫抑制，从而增强化疗效果， 反应这项提议的成功将提出能够增强患者对以下疾病反应的药物靶点： 化疗此外，这些发现将为这些药物如何重建免疫系统提供见解。 MIBC中的免疫刺激肿瘤微环境。总之，本提案中概述的研究包括： 重要的是解决未满足的需求，即，改善MIBC患者对标准 化疗这项研究的概念性进展可能会超越MIBC，使患者受益 与其他上皮恶性肿瘤无关

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.