Defining Response and Resistance to PI3K and AR inhibition in Prostate Cancer
定义前列腺癌对 PI3K 和 AR 抑制的反应和抵抗
基本信息
- 批准号:8926908
- 负责人:
- 金额:$ 43.94万
- 依托单位:
- 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:2014-09-12 至 2019-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAnabolismAndrogen ReceptorAndrogensBackBiopsyBiopsy SpecimenCell LineCell SurvivalClinicClinicalClinical TrialsCombined Modality TherapyCritical PathwaysDNA Sequence RearrangementDataDatabasesDevelopmentDisease ProgressionEnrollmentEventFutureGenerationsGenomic approachGoalsHealthIndividualMalignant NeoplasmsMalignant neoplasm of prostateMemorial Sloan-Kettering Cancer CenterMetastatic LesionMetastatic Prostate CancerMethodologyMethodsModelingMolecularMolecular BiologyOrganoidsPTEN genePathway interactionsPatientsPhasePhase III Clinical TrialsPlayPositioning AttributePre-Clinical ModelPublishingResistanceRoleSDZ RADSafetySignal TransductionSpecimenTP53 geneTherapeuticTranslatingTreatment EfficacyTumor Suppressor ProteinsWorkbasecancer regressioncombinatorialfeedingimprovedinhibitor/antagonistmalignant breast neoplasmneoplastic cellnovelpersonalized medicinepre-clinicalpreclinical studyprostate cancer cellprostate cancer modelresistance mechanismresponsesuccesstargeted treatmenttumor
项目摘要
DESCRIPTION (provided by applicant): The discovery that persistent androgen signaling is present in castrate resistant prostate cancer has led to the development of second generation AR inhibitors that have demonstrated modest improvements in survival. In addition to alterations leading to aberrant AR signaling, a number of other molecular alterations are frequently observed in metastatic prostate cancer specimens, including loss of the tumor suppressors PTEN and TP53, and genomic rearrangements involving ERG. Several novel therapies targeting the PI3K pathway have been developed, with the goal of improving survival in patients with advanced malignancies. We have recently demonstrated that the PI3K and AR pathways cross- regulate each other by reciprocal feed-back whereby, inhibition of one activates the other, maintaining tumor cell survival. Importantly, we have shown that combined pharmacologic inhibition of PI3K and AR signaling caused near complete prostate cancer regressions in pre-clinical models. Based this data, and the success of the recently completed BOLERO2 trial demonstrating therapeutic efficacy of targeting the PI3K and ER pathways in breast cancer, we have initiated a phase Ib clinical trial evaluating PI3K and AR inhibition in patients with castrat resistant prostate cancer. The long-term objective of the current proposal is to define the molecular biology of response and resistance to PI3K/AR inhibition that will be informative for individual patients and the development of clinical trials. To accomplish these aims we will employ the use of GEM models and a novel methodology for the study of individual patient derived prostate cancer organoids (cell lines) derived from biopsy specimens of patients on clinical trials of PI3K/AR inhibitors. Aim 1 will focus on evaluating pre-clinical response to PI3K
and AR inhibitors in individual prostate cancer organoids and correlate these findings with the patient response observed in the clinic. Aim 2 will address the role ERG plays in promoting resistance to combined PI3K and AR pathway inhibition using GEM models of prostate cancer and novel cell lines that have been derived. The focus of Aim 3 will be to identify mechanisms of acquired resistance to combination therapy. We will utilize the Pten p53 conditional null model of prostate cancer that displays an initial dramatic response to PI3K and AR inhibition followed by disease progression, as well as our newly derived prostate cancer organoids. Focused and broad genomic approaches will be used to identify alterations associated with resistance which will be validated. Collectively, this work will improve our molecular understanding of castrate resistant prostate cancer where alterations in AR and PI3K signaling coordinately regulate cell survival, guide the development of future clinical trials, and transform our approach to personalized medicine.
描述(由申请人提供):去势抵抗性前列腺癌中存在持续雄激素信号传导的发现导致了第二代 AR 抑制剂的开发,该抑制剂已证明可以适度改善生存。除了导致异常 AR 信号传导的改变之外,在转移性前列腺癌样本中还经常观察到许多其他分子改变,包括肿瘤抑制因子 PTEN 和 TP53 的丢失,以及涉及 ERG 的基因组重排。几种针对 PI3K 通路的新疗法已经开发出来,目的是提高晚期恶性肿瘤患者的生存率。我们最近证明,PI3K 和 AR 通路通过相互反馈相互交叉调节,其中一种途径的抑制会激活另一种途径,从而维持肿瘤细胞的存活。重要的是,我们已经证明,在临床前模型中,PI3K 和 AR 信号传导的联合药物抑制导致前列腺癌几乎完全消退。基于这些数据,以及最近完成的 BOLERO2 试验的成功证明了针对乳腺癌的 PI3K 和 ER 通路的治疗效果,我们启动了一项 Ib 期临床试验,评估 PI3K 和 AR 抑制对去势抵抗性前列腺癌患者的影响。当前提案的长期目标是定义对 PI3K/AR 抑制的反应和耐药的分子生物学,这将为个体患者和临床试验的发展提供信息。 为了实现这些目标,我们将采用 GEM 模型和一种新的方法来研究来自 PI3K/AR 抑制剂临床试验患者活检标本的个体患者前列腺癌类器官(细胞系)。目标 1 将重点评估对 PI3K 的临床前反应
和 AR 抑制剂在个体前列腺癌类器官中的作用,并将这些发现与临床观察到的患者反应相关联。目标 2 将利用前列腺癌的 GEM 模型和衍生的新型细胞系来探讨 ERG 在促进对 PI3K 和 AR 通路联合抑制的抵抗中所发挥的作用。目标 3 的重点是确定联合治疗获得性耐药的机制。我们将利用前列腺癌的 Pten p53 条件无效模型,以及我们新衍生的前列腺癌类器官,该模型对 PI3K 和 AR 抑制表现出最初的显着反应,随后出现疾病进展。将使用集中和广泛的基因组方法来识别与耐药性相关的改变,并对其进行验证。总的来说,这项工作将提高我们对去势抵抗性前列腺癌的分子理解,其中 AR 和 PI3K 信号传导的改变协调调节细胞存活,指导未来临床试验的发展,并改变我们的个性化医疗方法。
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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Brett Stewart Carver其他文献
Brett Stewart Carver的其他文献
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{{ truncateString('Brett Stewart Carver', 18)}}的其他基金
PSMA’s enzymatic activity as new target for Prostate Cancer diagnosis and therapy
PSMA 酶活性成为前列腺癌诊断和治疗的新靶点
- 批准号:
10436370 - 财政年份:2021
- 资助金额:
$ 43.94万 - 项目类别:
PSMA’s enzymatic activity as new target for Prostate Cancer diagnosis and therapy
PSMA 酶活性成为前列腺癌诊断和治疗的新靶点
- 批准号:
10311708 - 财政年份:2021
- 资助金额:
$ 43.94万 - 项目类别:
PSMA’s enzymatic activity as new target for Prostate Cancer diagnosis and therapy
PSMA 酶活性成为前列腺癌诊断和治疗的新靶点
- 批准号:
10656491 - 财政年份:2021
- 资助金额:
$ 43.94万 - 项目类别:
Project 3: Defining the appropriate context for targeting kinase signaling in combination with androgen receptor blockade to enhance therapeutic response in metastatic prostate cancer
项目 3:确定靶向激酶信号传导与雄激素受体阻断相结合的适当背景,以增强转移性前列腺癌的治疗反应
- 批准号:
10250363 - 财政年份:2017
- 资助金额:
$ 43.94万 - 项目类别:
Project 3: Defining the appropriate context for targeting kinase signaling in combination with androgen receptor blockade to enhance therapeutic response in metastatic prostate cancer
项目 3:确定靶向激酶信号传导与雄激素受体阻断相结合的适当背景,以增强转移性前列腺癌的治疗反应
- 批准号:
10005212 - 财政年份:2017
- 资助金额:
$ 43.94万 - 项目类别:
Defining Response and Resistance to PI3K and AR inhibition in Prostate Cancer
定义前列腺癌对 PI3K 和 AR 抑制的反应和抵抗
- 批准号:
8760826 - 财政年份:2014
- 资助金额:
$ 43.94万 - 项目类别:
Defining Response and Resistance to PI3K and AR inhibition in Prostate Cancer
定义前列腺癌对 PI3K 和 AR 抑制的反应和抵抗
- 批准号:
9331474 - 财政年份:2014
- 资助金额:
$ 43.94万 - 项目类别:
Defining Response and Resistance to PI3K and AR inhibition in Prostate Cancer
定义前列腺癌对 PI3K 和 AR 抑制的反应和抵抗
- 批准号:
9118938 - 财政年份:2014
- 资助金额:
$ 43.94万 - 项目类别:
Project 2: Overcoming Microenvironment-Mediated Resistance to AR Pathway Inhibition in High-Risk Prostate Cancer
项目 2:克服微环境介导的高危前列腺癌 AR 通路抑制耐药性
- 批准号:
10707969 - 财政年份:2001
- 资助金额:
$ 43.94万 - 项目类别:
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