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

• 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
• 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

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 这种耐药性发展到一个阶段，称为去势抵抗前列腺癌(CRPC)。前列腺 癌症是一种非炎症性或“免疫沙漠”肿瘤，没有观察到免疫浸润物，这表明 在T细胞启动或T细胞转运回肿瘤的过程中，某个地方发生了失败。不 令人惊讶的是，前列腺癌对免疫检查点阻断(ICB)疗法具有高度的耐受性 临床试验中的边际疗效，无论是作为单一药物还是与其他药物联合使用。确切地说是如何 前列腺癌强制逃避抗肿瘤免疫反应的机制尚不完全清楚。 此前，我们发现了一种非受体酪氨酸激酶，AcK1沉积了新的pY88-H4表观遗传标记 在AR基因增强子中，调节AR/AR-V7的表达。在这一发现的基础上，我们开发了一种新的AcK1 小分子抑制剂(R)-9b，可抑制对苯扎鲁胺耐药的肿瘤生长。检查AcK1的步骤 进一步的信号，我们产生了一个可存活的条件性AcK1基因敲除(KO)小鼠，并注意到显著增加 KO小鼠体内活化的CD4+和CD8+T细胞，导致同基因前列腺癌生长丧失。 随后的研究揭示了AcK1激酶在启动T细胞抗原中的关键作用 受体(TCR)通过磷酸化CSK在以前未知的位置，Tyr18。CSK磷酸化 位于Tyr505的LCK促进自身抑制，抑制适应性免疫反应。因此，AcK1 KO小鼠，或 注射(R)-9b的小鼠表现出CD4+和CD8+T细胞的激活和肿瘤生长的抑制。在……里面 此外，(R)-9b功能恢复CRPC患者的外周血单个核细胞(PBMC)以 针对CRPC类有机物建立强大的免疫反应。总之，这些数据表明(R)-9b满足a 独特的利基，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 系统，以建立强大的‘双重’抗肿瘤反应。该项目的具体目标是： 目的1：研究AcK1介导的CSK Tyr18磷酸化在T细胞静止中的作用 目的2：研究更新的Pack1/pY18-CSK/pY505-LCK信号在抗肿瘤免疫沉默中的作用 响应 目的3：评价(R)-9b对前列腺癌模型的治疗效果