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：
10320460
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/10320460
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 Cross Presentation Cyclic Peptides Data Docking Drug Kinetics ERBB2 gene Event Exhibits Generations Goals HSP 90 inhibition Head Cancer Heat-Shock Proteins 90 Heat-Shock Response Immune Immune Tolerance Immune response Immune system Immunosuppression Immunotherapeutic agent Immunotherapy Infiltration Ligands Light Malignant Neoplasms Malignant neoplasm of urinary bladder Mediating Mediator of activation protein Metastatic Melanoma Minority Modeling Molecular Molecular Chaperones Mus Mutate Mutation Natural Products Neck Cancer 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 Activation T-Lymphocyte Testing Therapeutic Therapeutic Effect Toxic effect Translating Transplantation Treatment Efficacy Tumor-Infiltrating Lymphocytes Tumor-infiltrating immune cells anti-CTLA4 antitumor agent antitumor effect cancer cell cancer therapy cancer type cell mediated immune response chemotherapy clinical efficacy combinatorial cytotoxic design dimer dosage experience 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，许多反应迅速的患者经历了耐用甚至治愈的结果。然而，由于尚不清楚的原因，只有少数癌症患者受益于免疫检查点阻滞（ICB）疗法。扩大这一非凡的大多数癌症患者的成就是通过多种途径积极寻求的联合免疫疗法，例如阻断PD-1和CTLA-4。另外，有希望的结果有当将ICB治疗与可用的化学疗法结合使用时，我们观察到了我们免疫介导的抗肿瘤反应。这打开了使用小分子的可能性恢复免疫系统对癌细胞作为外国实体的认可，从而潜在免疫治疗进展。在这种情况下，我们已经将环状肽ENNA确定为一种新型抑制剂热休克蛋白90（HSP90），具有针对肿瘤细胞的免疫系统的潜在能力。这一发现源于我们努力找到新的HSP90抑制剂，以绕过已知副作用阻碍了第一代抑制剂的临床进展。特别是，该化合物确实不引起热激反应，这通过激活降低了早期抑制剂的效率亲生机制。 ENNA诱导免疫原性癌细胞死亡，促进肿瘤免疫细胞浸润，并释放出强大的T细胞介导的免疫反应，从而高效肿瘤在合成小鼠模型中杀死。分子，ENNA干扰了几种致癌途径并降低了程序性细胞死亡配体1（PD-L1）的蛋白质水平，这是肿瘤的关键介体诱导的免疫耐受性。因此，我们建议ENNA是一种承诺的抗肿瘤剂的靶向 HSP90通过涉及癌细胞毒性的新型作用机理，从而增加了其免疫原性并调节肿瘤微环境以减少免疫耐受性。在AIM 1中，我们将表演 ENNA作为药物的临床前发展，以确定其毒性和ENNA对小鼠免疫系统。我们还将通过突变和生化分析。在AIM 2中，我们将确定ENNA干扰PD-L1对HSP90的抑制伴侣和功能。在AIM 3中，我们将定义ENNA抗肿瘤基础的免疫细胞机制影响。将测试ENNA与抗CTLA-4的结合，并将免疫细胞的全面分析将实施参与抗肿瘤活动的。在AIM 4中，我们将测试ENNA的重要性在免疫依赖性肿瘤放射分析中诱导癌细胞自噬和HSP90细胞表面暴露。如果成功，这些研究将阐明HSP90在促进免疫耐受性中的作用，并将使用新型的HSP90抑制剂提供一种创新的潜在免疫疗法方法。