Targeting tumor repopulation and the immune microenvironment to overcome chemoresistance

项目总结 此应用程序是对PAR-19-183：膀胱癌生物学的响应。肌肉浸润性膀胱癌 (MIBC)在美国每年声称约有18,000人死亡。致力于以下方面的资金和研究 这种癌症类型的比例明显偏低。MIBC治疗的一个未得到满足的临床需求在于 患者对化疗的反应较差，治疗仅有5%的令人沮丧的改善 总体存活率。这一应用的长期目标是解决这种对辅助疗法的迫切需求 以提高化疗疗效。化疗的成功在历史上被认为完全取决于 关于它对肿瘤细胞的直接细胞毒作用。然而，有越来越多的证据表明，我们自己的 研究和其他研究表明，化疗效果还取决于1)癌症的成功预防 干细胞在重建残留肿瘤中的作用和2)有效的抗肿瘤免疫反应。这两个 现象往往被单独研究，但它们可能产生的协同作用却被忽视了。我们的研究 该项目在概念上具有创新性，旨在研究调节两种肿瘤的共同上游途径 再繁殖和免疫反应。我们假设，抑制这一共同途径将提供 临床翻译的有效治疗靶点。我们的具体目标包括：目标1)破译这条路径 通过研究导致多效性药物胞外释放的非正则下游机制 各种因素。这一点意义重大，因为这些细胞外因子既可以调节肿瘤的再繁殖，也可以调节 免疫反应。目的2)评估这些细胞外因子及其同源受体是如何推动 静止的癌症干细胞重新繁殖。目的3)研究抑制这一上游途径如何 集体消除肿瘤再繁殖和免疫抑制，从而加强化疗 回应。这项提议的成功将提供能够增强患者对 化疗。此外，这些发现将为这些药物如何重建 MIBCs的免疫刺激肿瘤微环境。综上所述，这项提案中概述的研究包括 对解决未得到满足的需求具有重要意义，即改善MIBC患者对标准的令人沮丧的反应 化疗。这项研究的概念进步可能会延伸到MIBC之外，使患者受益 来自其他上皮性恶性肿瘤。

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.