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：
10298977
负责人：
Keith Syson Chan
金额：
$ 47.27万
依托单位：
CEDARS-SINAI MEDICAL CENTER
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/10298977
关键词：
Address Adjuvant Therapy Attenuated Automobile Driving Biology Bladder Neoplasm CASP1 gene Cancer Model Cancer Patient Cancer Survivor Cells Cessation of life Chemoresistance Clinical DNA Dinoprostone Drug Targeting Epithelial Extravasation FDA approved Fibrinogen 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 Periodicity Pharmaceutical Preparations Pharmacology Process Publishing Regulation Reporting Research Research Project Grants Residual Tumors Rest Signal Pathway Signal Transduction T-Lymphocyte TLR4 gene Testing Transcription Repressor United States Up-Regulation WFDC2 gene anti-tumor immune response base cancer cell cancer prevention cancer stem cell cancer therapy cancer type cell injury chemotherapy clinical translation cytotoxic druggable target ds-DNA extracellular improved in vivo inhibitor/antagonist innovation insight muscle invasive bladder cancer neoplastic cell novel strategies patient response prevent 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.

项目概要此应用程序是对 PAR-19-183：膀胱癌生物学的回应。肌层浸润性膀胱癌 (MIBC) 声称美国每年约有 18,000 人死亡。资金和研究致力于这种癌症类型的比例明显不足。 MIBC 治疗尚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 5% 的改善总体生存率。该应用的长期目标是解决辅助治疗的迫切需求以改善化疗反应。历史上认为化疗的成功完全取决于其对肿瘤细胞的直接细胞毒作用。然而，正如我们自己的研究所表明的，越来越多的证据表明研究和其他研究表明，化疗效果还取决于 1) 成功预防癌症干细胞重建残留肿瘤；2) 有效的抗肿瘤免疫反应。这两个现象常常被单独研究，但它们可能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，旨在检查调节肿瘤的共同上游途径人口再生和免疫反应。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) 破译这条途径通过研究导致多效性细胞外释放的非典型下游机制因素。这很重要，因为这些细胞外因子可以调节肿瘤的再增殖和免疫反应。目标 2) 评估这些细胞外因子及其同源受体如何驱动静止的癌症干细胞的重新增殖。目标 3) 研究抑制该上游途径如何影响共同消除肿瘤再增殖和免疫抑制，从而增强化疗效果回复。该提案的成功将提出能够增强患者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 MIBC 中的免疫刺激肿瘤微环境。总之，本提案中概述的研究是对于解决未满足的需求具有重要意义，即改善 MIBC 患者对标准的不良反应化疗。这项研究的概念进展可能会超越 MIBC 范围，使患者受益来自其他上皮恶性肿瘤。