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Dissecting the Therapeutic Role of Pt3K aod AR Pathway Inhibition In Prostate Cancer

剖析 Pt3K aod AR 通路抑制在前列腺癌中的治疗作用

基本信息

批准号：
8730086
负责人：
PIER PAOLO PANDOLFI
金额：
$ 29.32万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8730086
关键词：
Androgens Apoptosis Bicalutamide Biochemical Biological Models Biology Cancer Biology Cell Survival Cessation of life Chemotherapy-Oncologic Procedure Clinical Clinical Trials Combined Modality Therapy Data Development Disease Disease Progression Drug usage ERBB2 gene ERBB3 gene Feedback Future Goals Growth Human IGF1R gene Inhibition of Apoptosis Instruction Malignant Neoplasms Malignant neoplasm of prostate Metastatic Prostate Cancer Molecular Output PTEN gene Paclitaxel Pathway interactions Patients Phase Pre-Clinical Model Primary Neoplasm Prostatic Neoplasms Proto-Oncogene Proteins c-akt Radical Prostatectomy Receptor Protein-Tyrosine Kinases Resistance Role Signal Transduction Testing Therapeutic Therapeutic Agents Time Translations Treatment Efficacy Work advanced disease base castration resistant prostate cancer combinatorial compare effectiveness deprivation high risk in vivo Model inhibitor/antagonist interest novel novel therapeutics pre-clinical prostate cancer cell prostate cancer model response therapeutic target tumor tumor growth

项目摘要

Activation of the PI3K pathway (loss of PTEN) has garnered great interest in prostate cancer as 42% of primary tumors and nearly 100% of metastatic castration-resistant prostate cancers have molecular alterations in this pathway. Thus therapeutic targeting of the PI3K pathway in prostate cancer appears very attractive. Recently, a number of novel inhibitors targeting various components of the PI3K pathway (P13K, AKT, mTORCI, and mTORCI/2) have emerged in early, but promising, clinical development Using preclinical models, we have found that inhibition of the PI3K pathway alone is insufficient to promote tumor regression or apoptosis in PTEN loss prostate cancer. We have generated preliminary data showing that inhibition of the PI3K pathway results in feedback activation of a number of receptor tyrosine kinases (RTK), such as IGF1R and HER2/HER3, that promote prostate cancer cell survival. Furthermore, we find that inhibition of the PI3K pathway induces AR activity in a RTK-dependent manner and concomitant inhibition of AR results in a synergistic profound tumor response in preclinical models. We hypothesize that both AR and PI3K activation suppress prostate cancer cell apoptosis and that inhibition of either pathway alone results in compensatory activation of the other pathway. In this project, we will test this hypothesis and undertake the aggressive preclinical development of combinatorial AR and PI3K pathway inhibition. Specific Aims: 1. To determine the effects of PI3K pathway inhibition in prostate cancer 2. To determine the effects of AR Inhibition on signaling and prostate cancer biology 3. To determine the biologic consequences and antitumor activity of combined PI3K and AR pathway inhibition in prostate cancer

PI3K通路的激活(PTEN的缺失)在前列腺癌中引起了极大的兴趣，因为42%的人原发肿瘤和几乎100%的转移性去势抵抗前列腺癌都有分子这条途径的改变。因此，前列腺癌中PI3K通路的靶向治疗显得非常重要。很有吸引力。最近，一些针对PI3K途径的各种成分的新型抑制剂(P13K， AKT、mTORCI和mTORCI/2)已经出现在早期但有希望的临床开发中，使用临床前模型中，我们发现仅抑制PI3K通路不足以促进肿瘤的发生 PTEN缺失型前列腺癌的消退或细胞凋亡我们已经生成了初步数据，表明抑制PI3K通路导致一些受体酪氨酸激酶(RTK)的反馈激活，如IGF1R和HER2/HER3，可促进前列腺癌细胞存活。此外，我们发现，抑制PI3K通路以RTK依赖的方式诱导AR活性，并伴随着抑制在临床前模型中，AR导致了协同的深刻的肿瘤反应。我们假设AR和 PI3K激活抑制前列腺癌细胞凋亡，且单独抑制任何一条途径都会导致另一条通路的代偿性激活。在这个项目中，我们将检验这一假设，并承担组合AR和PI3K通路抑制的侵袭性临床前发展。具体目标： 1.检测PI3K通路抑制在前列腺癌中的作用 2.明确AR抑制对信号转导和前列腺癌生物学的影响 3.确定PI3K和AR联合途径的生物学效应和抗肿瘤活性前列腺癌的抑制作用