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Targeting a Novel Signaling Nexus pACK/pCSK/pLCK in Immune Checkpoint Blockade (ICB)-Resistant Prostate Cancer

靶向新型信号转导 Nexus pACK/pCSK/pLCK 治疗免疫检查点阻断 (ICB) 耐药性前列腺癌

基本信息

批准号：
10734202
负责人：
Nupam P Mahajan
金额：
$ 48.44万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10734202
关键词：
ACK1 Gene AR gene Ablation Antitumor Response Back CD8-Positive T-Lymphocytes Cancer Etiology Cancer Patient Cell Separation Cessation of life Chemotactic Factors Clinical Trials Data Deposition Enhancers Epigenetic Process Exhibits Failure Genetic Growth Immune Immune response Immune system Immunologic Surveillance Interleukin-2 Knock-in Knockout Mice Ligand Binding Lymphocyte Activation Lymphocyte-Specific p56LCK Tyrosine Protein Kinase Malignant neoplasm of prostate Mediating Modality Mus Oral Organoids PTEN gene PTPN11 gene Patients Peripheral Blood Mononuclear Cell Phosphorylation Phosphotransferases Process Production Property Prostate Prostatic Neoplasms Protein Tyrosine Kinase Protein Tyrosine Phosphatase Receptor Activation Receptor Signaling Recurrent disease Refractory Resistance Resistance development Role Series Signal Transduction Site T-Cell Activation T-Cell Receptor T-Lymphocyte TP53 gene Therapeutic Treatment Efficacy Ubiquitination abiraterone adaptive immune response androgen deprivation therapy antagonist anti-tumor immune response cancer immunotherapy castration resistant prostate cancer chemokine enzalutamide immune cell infiltrate immune checkpoint blockade inhibitor insight men mouse model neoplastic cell novel paracrine pharmacologic prostate cancer model protein-tyrosine kinase c-src restraint small molecule inhibitor src-Family Kinases suicidal trafficking transcriptome sequencing tumor tumor growth tumor-immune system interactions ubiquitin-protein ligase virtual

项目摘要

Project Abstract Prostate cancer (PC) patient although initially respond to androgen deprivation therapy, most patients develop the resistance developing a stage referred to as the Castration Resistant Prostate Cancer (CRPC). Prostate cancer is a non-inflamed or “Immune desert” tumor where no immune infiltrate is observed, suggesting that failure has occurred somewhere in the process of T-cell priming, or T-cell trafficking back to the tumor. Not surprisingly, prostate cancer is highly refractory to immune checkpoint blockade (ICB) therapies exhibiting marginal efficacy in clinical trials, both as a single agent or in combination with other agents. Precisely how prostate cancer enforce evasion of anti-tumor immune response is not fully understood. Previously, we uncovered that a non-receptor tyrosine kinase, ACK1 deposited novel pY88-H4 epigenetic marks in AR gene enhancer, regulating AR/AR-V7 expression. Building on this discovery, we developed a new ACK1 small molecule inhibitor, (R)-9b, which suppressed enzalutamide-resistant tumor growth. To examine ACk1 signaling further, we generated a viable conditional ACK1 knockout (KO) mice, and noticed a significant increase in activated CD4+ and CD8+ T cells in KO mice, causing loss of syngeneic prostate tumor growth. The subsequent studies have revealed a crucial role for ACK1 kinase in the initiation of T cell antigen receptor (TCR) signaling by phosphorylation of CSK at a previously unknown site, Tyr18. CSK phosphorylated LCK at Tyr505 promoting auto-inhibition, inhibiting an adaptive immune response. Thus, ACK1 KO mice, or the (R)-9b injected mice exhibited increased CD4+ and CD8+ T cells activation and inhibition of tumor growth. In addition, (R)-9b functionally reinvigorated peripheral blood mononuclear cells (PBMCs) of the CRPC patients to mount robust immune response against CRPC organoids. Together, these data indicate that (R)-9b fulfills a unique niche, wherein it not only suppresses AR/AR-V7 within the tumor cells, but also activates host immune system to mount a robust `dual’ anti-tumor response. The specific aims of this project are: Aim 1: Examine roles of ACK1-mediated CSK Tyr18-phosphorylation in T cell quiescence Aim 2: Interrogate role of renewed pACK1/pY18-CSK/pY505-LCK signaling in silencing of anti-tumor immune response Aim 3: Evaluate therapeutic efficacy of (R)-9b in models of prostate cancer

项目摘要前列腺癌（PC）患者虽然最初对雄激素剥夺治疗有反应，但大多数患者发展为该抗性发展到称为去势抵抗性前列腺癌（CRPC）的阶段。前列癌症是未观察到免疫浸润的非炎症或“免疫沙漠”肿瘤，这表明失败发生在T细胞启动过程中的某个地方，或T细胞运输回肿瘤。不令人惊讶的是，前列腺癌对免疫检查点阻断（ICB）疗法是高度难治的，在临床试验中，作为单一药物或与其他药物组合的边际疗效。是如何前列腺癌强制逃避抗肿瘤免疫应答的机制还不完全清楚。以前，我们发现一种非受体酪氨酸激酶，ACK 1沉积了新的pY 88-H4表观遗传标记，在AR基因增强子中，调节AR/AR-V7的表达。基于这一发现，我们开发了一种新的ACK 1 小分子抑制剂（R）-9b，其抑制恩杂鲁胺抗性肿瘤生长。检查ACk 1 进一步地，我们产生了一个可行的条件性ACK 1敲除（KO）小鼠，并注意到显着增加，在KO小鼠中活化的CD 4+和CD 8 + T细胞中，导致同基因前列腺肿瘤生长丧失。随后的研究揭示了ACK 1激酶在T细胞抗原启动中的关键作用受体（TCR）信号传导通过CSK在以前未知的位点Tyr 18磷酸化。磷酸化CSK Tyr 505处的LCK促进自身抑制，抑制适应性免疫应答。因此，ACK 1 KO小鼠或注射（R）-9b的小鼠表现出增加的CD 4+和CD 8 + T细胞活化和肿瘤生长抑制。在此外，CRPC患者的（R）-9b功能性复苏的外周血单核细胞（PBMC），对CRPC类器官产生强大的免疫应答。总之，这些数据表明（R）-9b满足了预期目标。独特的生态位，其中它不仅抑制肿瘤细胞内的AR/AR-V7，而且还激活宿主免疫建立一个强有力的“双重”抗肿瘤反应的系统。该项目的具体目标是：目的1：检测ACK 1介导的CSK Tyr 18磷酸化在T细胞静止中的作用目的2：探讨pACK 1/pY 18-CSK/pY 505-LCK信号通路在抗肿瘤免疫沉默中的作用响应目的3：评估（R）-9b在前列腺癌模型中的治疗功效