A novel therapeutic strategy to eradicate breast cancer through Hsp90 inhibition and reduced immune tolerance

通过抑制 Hsp90 和降低免疫耐受来根除乳腺癌的新治疗策略

基本信息

批准号：
10591405
负责人：
Ahmed Chadli
金额：
$ 34.52万
依托单位：
AUGUSTA UNIVERSITY
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：
2021-03-01 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10591405
关键词：
4T1 Achievement Affect Amino Acids Antigen-Presenting Cells Antigens Antitumor Response Apoptotic Autophagocytosis Binding Binding Sites Biochemical Breast Cancer Model Breast Cancer Patient Breast Cancer therapy CD28 gene CD8-Positive T-Lymphocytes CTLA4 blockade CTLA4 gene Cancer Patient Cell Death Cell membrane Cell surface Cells Client Clinical Combination immunotherapy Cross Presentation Cyclic Peptides Data Docking Drug Kinetics ERBB2 gene Event Exhibits Generations Goals HSP 90 inhibition Head and Neck Cancer Heat-Shock Proteins 90 Heat-Shock Response Immune Immune Tolerance Immune response Immune system Immuno-Chemotherapy Immunosuppression Immunotherapeutic agent Immunotherapy Infiltration Ligands Malignant Neoplasms Malignant neoplasm of urinary bladder Mediating Mediator Membrane Metastatic Melanoma Minority Modeling Molecular Molecular Chaperones Mus Mutate Mutation Natural Products Neoplasm Transplantation Non-Small-Cell Lung Carcinoma Oncogenic Outcome Pathway interactions Pharmaceutical Preparations Play Population Prognosis Proteins Regimen Renal carcinoma Role Site Solid Neoplasm Surface Surface Plasmon Resonance System T cell infiltration T-Cell Activation T-Lymphocyte Testing Therapeutic Therapeutic Effect Toxic effect Translating Transplantation Treatment Efficacy Tumor Promotion Tumor-Infiltrating Lymphocytes anti-CTLA4 antitumor agent antitumor effect cancer cell cancer therapy cancer type carcinogenesis cell mediated immune response chemotherapy clinical efficacy combinatorial cytotoxic design dimer dosage experience immune cell infiltrate immune checkpoint blockade immunogenic immunogenic cell death immunogenicity improved inhibitor innovation insight interest malignant breast neoplasm melanoma mouse model neoplastic cell novel novel therapeutic intervention overexpression patient response preclinical development programmed cell death ligand 1 programmed cell death protein 1 protein expression receptor recruit side effect small molecule stem success targeted agent therapeutic effectiveness treatment response triple-negative invasive breast carcinoma tumor tumor eradication tumor growth tumor microenvironment

项目摘要

Abstract: Immunotherapy is becoming a pillar of cancer treatment, and many responsive patients have experienced durable, or even curative, outcomes. For reasons that remain unclear, however, only a minority of cancer patients benefit from immune checkpoint blockade (ICB) therapies. Expanding this remarkable achievement to most cancer patients is being actively sought through multiple avenues, including combined immunotherapy, such as blocking both PD-1 and CTLA-4. In addition, promising results have been observed when ICB therapies were combined with available chemotherapies that potentiate the immune-mediated anti-tumor response. This opens the possibility that the use of small molecules could restore the immune system’s recognition of cancer cells as a foreign entity and thus would potentiate immunotherapeutic progress. In this context, we have identified a cyclic peptide, EnnA, as a novel inhibitor of heat shock protein 90 (Hsp90), with a potent ability to unleash the immune system against tumor cells. This discovery stemmed from our effort to find new Hsp90 inhibitors that circumvent known side effects that have hampered the clinical progress of first-generation inhibitors. In particular, this compound does not induce a heat shock response, which had reduced the efficacy of early inhibitors through activation of pro-survival mechanisms. EnnA induces immunogenic cancer cell death, promotes tumor immune cell infiltration, and unleashes a powerful T cell-mediated immune response, resulting in highly efficacious tumor killing in a syngeneic mouse model. Molecularly, EnnA interferes with several oncogenic pathways and reduces the protein level of the programmed cell death ligand-1 (PD-L1), a key mediator of tumor- induced immune tolerance. We therefore propose that EnnA is a promising anti-tumor agent targeting Hsp90 through a novel mechanism of action involving cancer cell toxicity that increases its immunogenicity and modulation of the tumor microenvironment to reduce immunotolerance. In Aim 1, we will perform preclinical development of EnnA as a drug to determine its toxicity and the potential impact of EnnA on the immune system of mice. We will also characterize the EnnA-Hsp90 interaction through mutational and biochemical analyses. In Aim 2, we will determine how inhibition of Hsp90 by EnnA interferes with PD-L1 chaperoning and function. In Aim 3, we will define immune cell mechanisms underlying EnnA’s anti-tumor effect. Combining EnnA with anti-CTLA-4 will be tested, and comprehensive profiling of immune cells involved in the anti-tumor activity will be implemented. In Aim 4, we will test the importance of EnnA- induced cancer cell autophagy and Hsp90 cell surface exposure in immune-dependent tumor eradication. If successful, these studies will shed light on the role of the Hsp90 in promoting immune tolerance and will provide an innovative approach to potentiate immunotherapy using a novel Hsp90 inhibitor.

抽象的：免疫疗法正在成为癌症治疗的支柱，许多有反应的患者都经历过然而，由于尚不清楚的原因，只有少数癌症具有持久的甚至治愈性的结果。患者受益于免疫检查点阻断（ICB）疗法。大多数癌症患者正在通过多种途径积极寻求成就，包括联合免疫疗法，例如同时阻断 PD-1 和 CTLA-4，也取得了有希望的结果。当 ICB 疗法与可增强疗效的现有化疗相结合时，观察到免疫介导的抗肿瘤反应开启了使用小分子的可能性。恢复免疫系统对癌细胞作为外来实体的识别，从而增强在这种背景下，我们发现了一种环肽EnnA作为一种新型抑制剂。热休克蛋白 90 (Hsp90)，具有释放免疫系统对抗肿瘤细胞的强大能力。这一发现源于我们努力寻找新的 Hsp90 抑制剂来规避已知的副作用阻碍了第一代抑制剂的临床进展，特别是该化合物。不诱导热休克反应，热休克反应通过激活降低了早期抑制剂的功效 EnnA 诱导免疫原性癌细胞死亡，促进肿瘤免疫细胞。渗透，并释放强大的 T 细胞介导的免疫反应，从而产生高效的同基因小鼠模型中的肿瘤杀伤作用从分子角度来说，EnnA 干扰多种致癌途径。并降低程序性细胞死亡配体 1 (PD-L1) 的蛋白质水平，PD-L1 是肿瘤的关键介质因此，我们认为 EnnA 是一种有前景的抗肿瘤靶向药物。 Hsp90 通过涉及癌细胞毒性的新型作用机制增加其免疫原性在目标 1 中，我们将进行肿瘤微环境的调节以降低免疫耐受性。 EnnA 作为药物的临床前开发，以确定其毒性以及 EnnA 对药物的潜在影响我们还将通过突变和突变来表征 EnnA-Hsp90 相互作用。在目标 2 中，我们将确定 EnnA 对 Hsp90 的抑制如何干扰 PD-L1。在目标 3 中，我们将定义 EnnA 抗肿瘤的免疫细胞机制。将测试 EnnA 与抗 CTLA-4 组合的效果，并对免疫细胞进行全面分析。在目标4中，我们将测试EnnA-的重要性。诱导癌细胞自噬和 Hsp90 细胞表面暴露在免疫依赖性肿瘤根除中的作用。如果成功，这些研究将揭示 Hsp90 在促进免疫耐受中的作用，并将提供了一种使用新型 Hsp90 抑制剂增强免疫治疗的创新方法。