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:
- 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
- 起止时间:2023-07-01 至 2028-06-30
- 项目状态:未结题
- 来源:
- 关键词:ACK1 GeneAR geneAblationAntitumor ResponseBackCD8-Positive T-LymphocytesCancer EtiologyCancer PatientCell SeparationCessation of lifeChemotactic FactorsClinical TrialsDataDepositionEnhancersEpigenetic ProcessExhibitsFailureGeneticGrowthImmuneImmune responseImmune systemImmunologic SurveillanceInterleukin-2Knock-inKnockout MiceLigand BindingLymphocyte ActivationLymphocyte-Specific p56LCK Tyrosine Protein KinaseMalignant neoplasm of prostateMediatingModalityMusOralOrganoidsPTEN genePTPN11 genePatientsPeripheral Blood Mononuclear CellPhosphorylationPhosphotransferasesProcessProductionPropertyProstateProstatic NeoplasmsProtein Tyrosine KinaseProtein Tyrosine PhosphataseReceptor ActivationReceptor SignalingRecurrent diseaseRefractoryResistanceResistance developmentRoleSeriesSignal TransductionSiteT-Cell ActivationT-Cell ReceptorT-LymphocyteTP53 geneTherapeuticTreatment EfficacyUbiquitinationabirateroneadaptive immune responseandrogen deprivation therapyantagonistanti-tumor immune responsecancer immunotherapycastration resistant prostate cancerchemokineenzalutamideimmune cell infiltrateimmune checkpoint blockadeinhibitorinsightmenmouse modelneoplastic cellnovelparacrinepharmacologicprostate cancer modelprotein-tyrosine kinase c-srcrestraintsmall molecule inhibitorsrc-Family Kinasessuicidaltraffickingtranscriptome sequencingtumortumor growthtumor-immune system interactionsubiquitin-protein ligasevirtual
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
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Nupam P Mahajan其他文献
Nupam P Mahajan的其他文献
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{{ truncateString('Nupam P Mahajan', 18)}}的其他基金
Regulation of Mitochondrial Metabolism by Tyr-phosphorylated ATP Synthase Alpha-Subunit and its Therapeutic Implications in Prostate Cancer
酪氨酸磷酸化 ATP 合酶 α 亚基对线粒体代谢的调节及其在前列腺癌中的治疗意义
- 批准号:
10657090 - 财政年份:2023
- 资助金额:
$ 48.44万 - 项目类别:
Targeting a Novel Epigenetic Signaling Nexus ACK1-pY88H4-AR/AR-V7 in Drug Resistant Metastatic Prostate Cancer
靶向治疗耐药转移性前列腺癌的新型表观遗传信号 Nexus ACK1-pY88H4-AR/AR-V7
- 批准号:
9977692 - 财政年份:2017
- 资助金额:
$ 48.44万 - 项目类别:
Targeting a Novel Epigenetic Signaling Nexus ACK1-pY88H4-AR/AR-V7 in Drug Resistant Metastatic Prostate Cancer
靶向治疗耐药转移性前列腺癌的新型表观遗传信号 Nexus ACK1-pY88H4-AR/AR-V7
- 批准号:
9308352 - 财政年份:2017
- 资助金额:
$ 48.44万 - 项目类别:
Targeting a Novel Epigenetic Signaling Nexus ACK1-pY88H4-AR/AR-V7 in Drug Resistant Metastatic Prostate Cancer
靶向治疗耐药转移性前列腺癌的新型表观遗传信号 Nexus ACK1-pY88H4-AR/AR-V7
- 批准号:
10112834 - 财政年份:2017
- 资助金额:
$ 48.44万 - 项目类别:
Ack1: A Critical Regulator of Hormone-Refractory Prostate Cancer
Ack1:激素难治性前列腺癌的关键调节因子
- 批准号:
8082792 - 财政年份:2010
- 资助金额:
$ 48.44万 - 项目类别:
Ack1: A Critical Regulator of Hormone-Refractory Prostate Cancer
Ack1:激素难治性前列腺癌的关键调节因子
- 批准号:
8460126 - 财政年份:2010
- 资助金额:
$ 48.44万 - 项目类别:
Ack1: A Critical Regulator of Hormone-Refractory Prostate Cancer
Ack1:激素难治性前列腺癌的关键调节因子
- 批准号:
8246962 - 财政年份:2010
- 资助金额:
$ 48.44万 - 项目类别:
Ack1: A Critical Regulator of Hormone-Refractory Prostate Cancer
Ack1:激素难治性前列腺癌的关键调节因子
- 批准号:
7985538 - 财政年份:2010
- 资助金额:
$ 48.44万 - 项目类别:
Ack1: A Critical Regulator of Hormone-Refractory Prostate Cancer
Ack1:激素难治性前列腺癌的关键调节因子
- 批准号:
8657844 - 财政年份:2010
- 资助金额:
$ 48.44万 - 项目类别:
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