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

基本信息

批准号：
10683096
负责人：
Keith Syson Chan
金额：
$ 41.89万
依托单位：
METHODIST HOSPITAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
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/10683096
关键词：
Address Adjuvant Therapy Attenuated Automobile Driving Biology Bladder Neoplasm CASP1 gene Cancer Model Cancer Patient Cells Cessation of life Chemoresistance Clinical DNA Dinoprostone Drug Targeting Epithelium Extravasation FDA approved Funding Genetic Goals HMGB1 gene Immune Immune response Immuno-Chemotherapy Immunosuppression Inflammasome Interleukin-1 beta Intervention Studies Knock-out Malignant Neoplasms Malignant neoplasm of urinary bladder Mediating Molecular Mus Myelogenous Myeloid-derived suppressor cells Nature PTGS2 gene Pathway interactions Patients Peptide Hydrolases Pharmaceutical Preparations Population Process Proliferating Publishing Regulation Reporting Research Research Project Grants Residual Neoplasm Rest Signal Pathway Signal Transduction T-Lymphocyte TLR4 gene Testing Transcription Repressor Treatment Efficacy United States Up-Regulation WFDC2 gene antagonist anti-tumor immune response cancer cell cancer prevention cancer stem cell cancer survival cancer therapy cancer type cell injury chemotherapy clinical translation cytotoxic druggable target ds-DNA extracellular improved in vivo inhibitor innovation insight muscle invasive bladder cancer neoplastic cell novel strategies patient response pharmacologic prevent programs protein complex receptor response sensor stem cells success synergism therapeutic target therapeutically effective treatment response tumor tumor microenvironment tumor xenograft tumor-immune system interactions wound wound response

项目摘要

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.

项目摘要该应用是响应于第19帕尔：膀胱癌的生物学。肌肉侵入性膀胱癌（MIBC）每年约有18,000人死亡。资金和研究专门这种癌症类型的比例不足。对MIBC治疗的未满足的临床需求在于患者对化学疗法的反应不佳，疗法仅提供5％的惨淡改善总体生存。该应用程序的长期目标是解决这种急需辅助疗法的需求改善化学治疗反应。从历史上看，化学疗法的成功仅取决于关于其直接细胞毒性对肿瘤细胞的作用。但是，越来越多的证据，如我们自己的研究和其他研究，化学治疗功效也取决于1）成功预防癌症干细胞可重现残留肿瘤和2）有效的抗肿瘤免疫反应。这两个现象经常被单独研究，但它们可能的协同作用被忽略了。我们的研究项目在概念上是创新的，可以检查一种调节这两种肿瘤的通用上游途径重生和免疫反应。我们假设抑制这种通用途径将提供有效的临床翻译治疗靶标。我们的具体目的包括：目标1）破译这一途径通过研究导致多效性细胞外释放的非规范下游机制因素。这很重要，因为这些细胞外因子可以调节肿瘤再生和免疫反应。目标2）评估这些细胞外因子及其同源受体如何驱动静态癌干细胞的重生。目标3）研究如何抑制这种上游途径共同废除肿瘤再现和免疫抑制，从而增强化学治疗性回复。该建议的成功将构成能够增强患者反应的药物靶标化学疗法。此外，这些发现将提供有关这些药物如何重新建立的见解 MIBC中的免疫刺激性肿瘤微环境。总而言之，该提案中概述的研究是对于满足未满足的需求，即改善MIBC患者对标准的惨淡反应的意义很大化学疗法。这项研究的概念进步可能会超越MIBC，以使患者受益来自其他上皮恶性肿瘤。