Development of selective HDAC6 inhibitors to improve cancer immunotherapy

开发选择性 HDAC6 抑制剂以改善癌症免疫治疗

基本信息

批准号：
10706017
负责人：
Cyril Barinka
金额：
$ 51.43万
依托单位：
GEORGETOWN 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：
2021-02-01 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10706017
关键词：
Address Adjuvant Advanced Malignant Neoplasm Anti-Inflammatory Agents Antineoplastic Agents Attention Autoimmunity Biological Assay Blocking Antibodies CD8B1 gene CTLA4 gene Cardiac Cell Therapy Cells Characteristics Chronic Clinical Combination immunotherapy Combined Modality Therapy Cytotoxic agent Deacetylase Development Distant Down-Regulation Effectiveness Epigenetic Process Event Generations Genetic Goals Graft Rejection Grant HDAC6 gene Histone Deacetylase Histone Deacetylase Inhibitor Immune Immune system Immunity Immunologic Surveillance Immunologics Immunotherapeutic agent In Vitro In complete remission Infiltration Inflammation Mediators Inflammatory Interleukin-10 Isoenzymes Knowledge Lead Life Expectancy Lung Malignant Neoplasms Measures Mediating Mediator of activation protein Metabolic Metastatic Melanoma Methods Modality Modeling Molecular Target Mus Neoplasm Metastasis Neurodegenerative Disorders Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Phenotype Population Positioning Attribute Process Property Proteins Radiation therapy Rattus Regulation Reporting Research Resistance Role Surface Testing Toxic effect Translating Treatment Efficacy Tubulin Tumor Antigens Tumor Immunity Tumor-associated macrophages Validation Vorinostat Work anti-PD-1 anti-tumor immune response base cancer cell cancer immunotherapy cancer therapy cytokine cytotoxic cytotoxicity design genotoxicity immune checkpoint immune checkpoint blockade immune-related adverse events immunoregulation improved in vivo inhibitor innovation interest macrophage melanoma model design molecular modeling neoplastic cell novel offspring patient derived xenograft model pre-clinical programmed cell death ligand 1 programmed cell death protein 1 rational design receptor restoration scale up side effect targeted agent translational study tumor tumor growth

项目摘要

Project Summary The median survival for metastatic melanoma is approximately 8–16 months, and few therapies offer a significant improvement in overall survival. However, immunotherapeutic strategies that abrogate immunologic checkpoints or improve immunosurveillance have shown promise, especially in melanoma. We have found that both genetic abrogation and pharmacologic inhibition of HDAC6 leads to a decreased infiltration of pro-tumoral tumor-associated macrophages and downregulation of immunosuppressive mediators. These effects translated into a pronounced delay of in vivo melanoma tumor growth, which is, at least in part, dependent on intact immunity, as evidenced by the restoration of tumor growth after CD4+ and CD8+ depletion. Our findings demonstrate a significant immunoregulatory role of HDAC6 in melanoma, providing a rationale for the use of selective HDAC6is to improve antitumor immunity. We are most interested in identifying HDAC6is that are best able to reduce the pro-tumoral phenotype of tumor-associated macrophages and decrease the expression of immunosuppressive surface molecules such as PD-L1 and PD-L2 while showing little cytotoxicity on their own. Our goal is thus to design, synthesize, and test new HDAC6i both in vitro and in vivo for use in the treatment of melanoma and other malignancies. The aims to be accomplished under this grant are as follows: 1. Using molecular modeling, design, and synthesize ~50 new HDAC6is per year, for the first three years and test these for HDAC isozyme selectivity; the last two years of the grant will focus on compound scale-up, preclinical translational studies, and advanced ADMET testing. 2. Evaluate compounds that have IC50 values of <50nM and at least 400-fold HDAC6 selectivity using in vitro melanoma models to measure acetylated tubulin, pSTAT3, PD-L1 levels, and cytotoxicity. For compounds found to decrease levels of pSTAT3 and PD-L1, while increasing acetylated tubulin, conduct early-stage ADMET studies (2 – 3/year) using a CRO, and if needed, modify the compounds using principles of medicinal chemistry and molecular modeling based methods to increase the compound’s drug-like character. 3. Lastly, test the best compounds for their ability to delay tumor growth in syngeneic murine melanoma models, both as stand-alone and in combination with PD-1 blocking antibodies. Additionally, we will evaluate our best candidates using humanized PDX models and as a cell therapy pre-treating macrophages to avoid their switch to M2-like protumoral phenotype. Those candidates showing the best in vivo efficacy will be sent for advanced ADMET, including chronic toxicity studies, cardiac activity, and pulmonary activity in rats. Our proposed work is significant as it helps to fill this critical knowledge gap and thus moves epigenetic- based combination immunotherapies to a new level. The concept to be validated is novel as it significantly deviates from the classical cytotoxic role of HDAC inhibitors as anti-cancer agents.

项目摘要转移性黑色素瘤的中位生存期约为8-16个月，很少有疗法提供总体生存的显着改善。但是，废除免疫学的免疫治疗策略检查点或改善免疫监视已显示出希望，尤其是在黑色素瘤中。我们发现，HDAC6的遗传废除和药物抑制都导致促肿瘤肿瘤相关的巨噬细胞的浸润减少和下调免疫抑制介体。这些作用转化为体内黑色素瘤肿瘤的明显延迟生长至少部分取决于完整的免疫力，如肿瘤的恢复所证明 CD4+和CD8+消耗后的生长。我们的发现表明 HDAC6在黑色素瘤中，为使用选择性HDAC6I的基本原理来改善抗肿瘤免疫力。我们最有兴趣识别最能减少肿瘤表型的HDAC6I 与肿瘤相关的巨噬细胞并降低免疫抑制表面分子的表达作为PD-L1和PD-L2，同时显示出很少的细胞毒性。因此，我们的目标是在体外和体内设计，合成和测试新的HDAC6I 黑色素瘤和其他恶性肿瘤的治疗。根据这笔赠款实现的目的如下： 1。使用分子建模，设计和合成约50个新的HDAC6IS，在头三年，测试这些HDAC同工酶选择性；赠款的最后两年将集中于复合规模，临床前翻译研究和高级ADMET测试。 2。使用体外评估IC50值<50nm和至少400倍的HDAC6选择性的化合物。黑色素瘤模型测量乙酰化的小管蛋白，PSTAT3，PD-L1水平和细胞毒性。对于化合物发现降低PSTAT3和PD-L1的水平，同时增加乙酰化的微管蛋白使用CRO的ADMET研究（2 - 3/年），如果需要，请使用医学原理修改化合物基于化学和分子建模的方法，以增加化合物的类似药物样特征。 3。最后，测试最佳化合物，以延迟合成鼠黑色素瘤中肿瘤生长的能力模型，无论是独立的，都与PD-1阻断抗体结合使用。此外，我们将评估我们使用人源化PDX模型和作为细胞疗法预处理巨噬细胞的最佳候选人，以避免他们切换到类似M2的原始表型。这些表现出最好的体内效率的候选人将被发送对于晚期ADMET，包括大鼠的慢性毒性研究，心脏活性和肺活量。我们提出的工作非常重要，因为它有助于填补这一关键的知识差距，从而使表观遗传学移动基于新水平的基于联合的免疫疗法。要验证的概念是新颖的偏离HDAC抑制剂作为抗癌剂的经典细胞毒性作用。