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

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:
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-07-01 至 2028-06-30

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中文摘要
翻译
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 在KO小鼠中活化的CD4和CD8T细胞,导致同基因前列腺癌的生长丧失。 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CD8T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
英文摘要
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
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Regulation of Mitochondrial Metabolism by Tyr-phosphorylated ATP Synthase Alpha-Subunit and its Therapeutic Implications in Prostate Cancer
  • 批准号:
    10657090
  • 项目类别:
  • 资助金额:
    $47.8万
  • 财政年份:
    2023
  • 负责人:
    Nupam P Mahajan
  • 依托单位:
Targeting a Novel Epigenetic Signaling Nexus ACK1-pY88H4-AR/AR-V7 in Drug Resistant Metastatic Prostate Cancer
  • 批准号:
    9977692
  • 项目类别:
  • 资助金额:
    $33.83万
  • 财政年份:
    2017
  • 负责人:
    Nupam P Mahajan
  • 依托单位:
Targeting a Novel Epigenetic Signaling Nexus ACK1-pY88H4-AR/AR-V7 in Drug Resistant Metastatic Prostate Cancer
Targeting a Novel Epigenetic Signaling Nexus ACK1-pY88H4-AR/AR-V7 in Drug Resistant Metastatic Prostate Cancer
  • 批准号:
    10112834
  • 项目类别:
  • 资助金额:
    $33.87万
  • 财政年份:
    2017
  • 负责人:
    Nupam P Mahajan
  • 依托单位:
海外基金