Converting Cold to Hot Tumor Microenvironment in Prostate Cancer by Targeting Chromatin Effector

通过靶向染色质效应器将前列腺癌中的冷肿瘤微环境转变为热肿瘤微环境

基本信息

批准号：
10395485
负责人：
Xin Lu
金额：
$ 35.4万
依托单位：
UNIVERSITY OF NOTRE DAME
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10395485
关键词：
1q21 Ablation American Antibodies Attenuated Binding CTLA4 gene Cancer Etiology Cancer Patient Cell Proliferation Cells Chromatin Clinical Combination immunotherapy Correlation Studies Cytotoxic T-Lymphocytes Data Development Diagnosis Dioxygenases Enzymes Epigenetic Process Family Fostering Gene Amplification Gene Expression Regulation Genetic Genetic Models Genetic Transcription Goals Histone H3 Immune Immune Evasion Immunologics Immunosuppression Immunotherapy Infiltration Knock-out Lysine Malignant Neoplasms Malignant neoplasm of prostate Mediating Metastatic Prostate Cancer Molecular Mus Mutation Myeloid-derived suppressor cells Neoplasm Metastasis Oncogenic Outcome PHD Finger Pathway interactions Patients Pharmacology Play Population Prostate Cancer therapy Prostatic Neoplasms Public Health Refractory Resistance Role Shapes Signal Transduction Study models Tail Testing Therapeutic Tryptophan 2,3 Dioxygenase Tumor Burden Tumor Escape Up-Regulation advanced prostate cancer anti-CTLA4 anti-PD1 antibodies antitumor effect base bench-to-bedside translation beta catenin cancer cell cancer therapy cancer type curative treatments cytokine cytotoxic CD8 T cells genetic regulatory protein immune checkpoint immune checkpoint blockade improved inhibitor men mortality mouse model new therapeutic target novel pre-clinical programmed cell death protein 1 prostate cancer cell prostate cancer model prostate cancer progression research clinical testing response small molecule inhibitor therapeutically effective tumor tumor microenvironment tumor-immune system interactions

项目摘要

PROJECT SUMMARY/ABSTRACT Metastatic prostate cancer (PCa) remains incurable and lethal. Immunotherapy using immune checkpoint blockade (ICB) antibodies revolutionized cancer treatment, yet advanced PCa is refractory to ICB therapy. PCa has limited infiltration of effector cytotoxic T lymphocytes (CTLs), which may contribute to ICB resistance. However, the mechanism shaping the cold microenvironment of PCa is poorly understood. Recently, we identified chromatin effector PYGO2 in the 1q21.3 amplicon as an oncogenic and metastatic driver for PCa (Lu et al, 2018). PYGO2 binds to histone H3 tail methylated at lysine 4 (H3K4me) and modulates transcription. Our preliminary results suggest that PYGO2 is an emerging signaling hub to control immunosuppression and CTL infiltration in a Wnt/β-catenin-independent manner, yet the precise mechanism for PYGO2 function in PCa immune evasion is unclear. Moreover, the effect of targeting PYGO2 with selective inhibitors on PCa progression and response to immunotherapy is unknown. Therefore, there is a significant need to unravel the function, mechanism and targeting strategy of PYGO2 in order to enhance immunotherapy of PCa. Our central hypothesis is that PYGO2 is a major cancer cell-intrinsic mechanism to shape the immunosuppressive microenvironment in PCa, and ICB therapy can be significantly enhanced by PYGO2 inhibition using novel small molecule inhibitors. We propose to accomplish three Specific Aims: (Aim 1) Elucidate the epigenetic mechanism of PYGO2 function in the immunosuppression of PCa by integrating targeted and unbiased approaches. (Aim 2) Determine the synergistic anti-tumor effect on PCa progression and metastasis by combining PYGO2 ablation and ICB therapy. (Aim 3) Identify small molecule inhibitors of PYGO2 with anti- tumor activity as single agent and in combination with immunotherapy. Upon completion of the project, we expect to illuminate novel molecular and cellular mechanisms underlying the role of PYGO2 in immune evasion of the PCa tumor microenvironment, establish the key preclinical evidence on co-targeting PYGO2 and immune checkpoint pathways as a new strategy of effective combination immunotherapy, and identify selective PYGO2 inhibitors with potent anti-tumor activity when used as single agent or in combination with immunotherapy. Our results will advance understanding of how genetic changes in cancer cells (i.e. PYGO2 amplification) can shape the cold tumor microenvironment. Given the aberrant upregulation of PYGO2 in many cancer types, our studies are relevant to a large population of cancer patients. In the long term, we envision that the bench-to-bedside translation of our findings through development and clinical testing of the PYGO2 inhibitor(s) may accelerate the therapeutic application of the combined epigenetic modulation and immunotherapy to the curative treatment of PCa and other cancers.

项目摘要/摘要转移性前列腺癌（PCA）仍然无法治愈和致命。使用免疫检查点的免疫疗法胃（ICB）抗体彻底改变了癌症治疗，但是晚期PCA对ICB治疗却是难治性的。 PCA 效应子细胞毒性T淋巴细胞（CTL）的浸润有限，这可能有助于ICB耐药性。但是，塑造PCA冷微环境的机制知之甚少。最近，我们在1q21.3 Amplicon中鉴定出染色质效应pygo2是PCA的致癌和转移驱动器（LU）等，2018）。 PYGO2与在赖氨酸4（H3K4ME）处甲基化组蛋白H3尾结合并调节转录。我们的初步结果表明，PYGO2是一个用于控制免疫抑制和CTL的新兴信号枢纽以Wnt/β-catenin独立的方式浸润，但PCA中PYGO2功能的精确机制免疫进化尚不清楚。此外，用选择性抑制剂靶向PYGO2对PCA进展的影响对免疫疗法的反应尚不清楚。因此，很需要揭示功能， PYGO2的机制和靶向策略，以增强PCA的免疫疗法。我们的中心假设是PyGO2是塑造癌细胞内的主要机制 PCA中的免疫抑制微环境和ICB治疗可以通过PYGO显着增强使用新型的小分子抑制剂抑制。我们建议实现三个具体目标：（目标1）阐明 PYGO2的表观遗传机理在PCA的免疫抑制中功能通过整合靶向和公正的方法。（AIM 2）确定对PCA进展和转移的协同抗肿瘤效应通过结合PYGO2消融和ICB治疗。（AIM 3）鉴定PYGO2的小分子抑制剂肿瘤活性作为单一药物，与免疫疗法结合使用。项目完成后，我们期望阐明新颖的分子和细胞机制 PYGO2在PCA肿瘤微环境的免疫远程中的作用的基础，建立关键关于共同靶向pygo2和Immunocheckpoint途径的临床前证据作为有效的新策略合并免疫疗法，并在使用时鉴定具有潜在抗肿瘤活性的选择性PYGO2抑制剂作为单一药物或与免疫疗法结合使用。我们的结果将进一步了解通用癌细胞的变化（即PYGO2扩增）可以塑造冷肿瘤微环境。鉴于在许多癌症类型中，PYGO2的异常上调，我们的研究与大量癌症有关患者。从长远来看，我们设想我们发现的基准对卧式的翻译 PYGO2抑制剂的临床测试可能会加速合并的治疗应用对PCA和其他癌症的治疗治疗的表观遗传调节和免疫疗法。