(PQC2) Plasticity Of The.PI3K Network In Early Dormancy

(PQC2) .PI3K 网络在休眠早期的可塑性

基本信息

批准号：
8791730
负责人：
Dario C Altieri
金额：
$ 38.39万
依托单位：
WISTAR INSTITUTE
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 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8791730
关键词：
1-Phosphatidylinositol 3-Kinase Aftercare Angiogenic Switch Apoptosis Appearance Autophagocytosis Bioenergetics Cancer Patient Cell Cycle Cell Cycle Checkpoint Cell Survival Cells Combined Modality Therapy Complex Cytosol DNA Damage Data Disease Disease Progression Disease remission Distant Drug Targeting Drug resistance Epithelial Growth Human Induction of Apoptosis Kinetics Laboratories Life Liver neoplasms Malignant Neoplasms Mesenchymal Metabolic Mitochondria Modeling Molecular Morbidity - disease rate Neoplasm Metastasis Organ Organelles Pathway interactions Phenotype Phosphorylation Phosphotransferases Primary Lesion Process Quality Control Recurrence Regimen Regulation Relapse Role Safety Seeds Signal Transduction Site Stress Structure-Activity Relationship Testing Therapeutic Time Tumor Cell Invasion Work Xenograft Model angiogenesis anticancer activity bone cell killing cell motility cyclophilin D expectation fitness improved in vivo inhibitor/antagonist kinase inhibitor mortality neoplastic cell novel novel therapeutics pre-clinical prevent public health relevance research study response senescence serum sodium transport inhibitor small molecule therapeutic target trait tumor

1-Phosphatidylinositol 3-Kinase Aftercare Angiogenic Switch Apoptosis Appearance Autophagocytosis Bioenergetics Cancer Patient Cell Cycle Cell Cycle Checkpoint Cell Survival Cells Combined Modality Therapy Complex Cytosol DNA Damage Data Disease Disease Progression Disease remission Distant Drug Targeting Drug resistance Epithelial Growth Human Induction of Apoptosis Kinetics Laboratories Life Liver neoplasms Malignant Neoplasms Mesenchymal Metabolic Mitochondria Modeling Molecular Morbidity - disease rate Neoplasm Metastasis Organ Organelles Pathway interactions Phenotype Phosphorylation Phosphotransferases Primary Lesion Process Quality Control Recurrence Regimen Regulation Relapse Role Safety Seeds Signal Transduction Site Stress Structure-Activity Relationship Testing Therapeutic Time Tumor Cell Invasion Work Xenograft Model angiogenesis anticancer activity bone cell killing cell motility cyclophilin D expectation fitness improved in vivo inhibitor/antagonist kinase inhibitor mortality neoplastic cell novel novel therapeutics pre-clinical prevent public health relevance research study response senescence serum sodium transport inhibitor small molecule therapeutic target trait tumor

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项目摘要

DESCRIPTION (provided by applicant): Despite the promise, and hope, that molecular therapies could bring durable remissions to cancer patients, most "targeted" drugs did not live up to this expectation, providing only limited, and, in most cases, short-lived benefit due to the emergence of metastatic disease. Although much effort has focused on mechanisms of drug resistance, the possibility that molecular therapies may actually reprogram tumors, and select new cancer phenotypes important for disease progression, or tumor plasticity, has not been widely considered. We tested this concept by examining the response of tumors to targeted inhibition of the phosphatidylinositol-3 kinase (PI3K) network, a disease driver in virtually every human cancer and important therapeutic target. Our preliminary data show that small molecule inhibitors of PI3K induce a global transcriptional and metabolic reprogramming in tumors. This adaptive response imparts a new cancer phenotype that combines paradoxical traits of protracted proliferative and bioenergetics quiescence, appearance of senescence, heightened cell survival and increased tumor cell invasion. These are pivotal hallmarks of dormancy, an elusive process in which tumor cells disseminate early from a primary lesion, resist apoptosis, seed metastatic sites, and remain quiescent for long periods of time only to re-awaken as recurrent (and incurable) disease. Mechanistically, tumor plasticity induced by PI3K inhibition involves reactivation of Akt in cytosol and mitochondria, and Akt- dependent phosphorylation of cyclophilin D (CypD), a multifunctional regulator of mitochondrial bioenergetics and apoptosis. Conversely, when combined with a small molecule antagonist of mitochondrial integrity, Gamitrinib, PI3K inhibitors no longer trigger adaptive tumor reprogramming, suppress invasion and exert considerably enhanced anticancer activity. Therefore, the hypothesis that tumor dormancy can be induced as an adaptive response to molecular therapy and coordinated by mitochondrial reprogramming can be formulated, and will constitute the focus of the present application. Experiments in the first specific aim will recapitulate the phenotype of PI3K inhibitin in established dormancy models, and dissect the mechanistic requirements of this pathway with respect to cell cycle quiescence, senescence, and kinase cascade(s) of cell invasion. In the second specific aim, we will define the mechanism(s) of Akt reactivation in dormancy, characterize a CypD-Akt complex in mitochondria, and dissect the role of Akt phosphorylation of CypD in repurposing of mitochondrial functions in apoptosis, bioenergetics, and autophagy. The third specific aim will examine the rational combination of PI3K inhibitors plus an antagonist of mitochondrial quality control, Gamitrinib, in tumor cell killing, reversal of the adaptive phenotyp, and preclinical activity in models of angiogenesis, metastasis, and tumor dormancy, in vivo. Overall, the experimental plan will characterize a new mechanism of tumor dormancy as an adaptive response to molecular therapy. The results will credential novel therapeutic strategies to obliterate dormancy and eradicate metastatic competency of tumors.

描述（由申请人提供）：尽管有希望和希望，分子疗法可以给癌症患者带来持久的减免，但大多数“有针对性”的药物并没有达到这种预期，只提供有限的，并且在大多数情况下，由于转移性疾病的出现，因此短暂的益处。尽管大量精力集中在耐药性机制上，但分子疗法实际上可能重新编程肿瘤，并且选择对疾病进展或肿瘤可塑性重要的新癌症表型的可能性并未被广泛考虑。我们通过检查肿瘤对靶向抑制磷脂酰肌醇-3激酶（PI3K）网络的反应来测试了这一概念，这几乎是每个疾病的驱动器人类癌症和重要的治疗靶点。我们的初步数据表明，PI3K的小分子抑制剂诱导肿瘤中的全球转录和代谢重编程。这种自适应反应赋予了一种新的癌症表型，该表型结合了旷日持久的增生和生物能静态的矛盾特征，衰老的出现，细胞存活升高和肿瘤细胞侵袭增加。这些是休眠状态的关键标志，这是一个难以捉摸的过程，其中肿瘤细胞早日从原发性病变中传播，抵抗凋亡，种子转移性部位，并长时间保持静止，只能以复发性（和不可治愈的）疾病重新唤醒。从机械上讲，PI3K抑制作用诱导的肿瘤可塑性涉及Akt在细胞质和线粒体中的重新激活，以及依赖于Akt的依赖性磷酸化（CYPD），它是线粒体生物学和凋亡的多功能调节剂。相反，当与线粒体完整性的小分子拮抗剂结合使用时，gamitrinib时，PI3K抑制剂不再触发自适应肿瘤重编程，抑制侵袭并发挥巨大增强的抗癌活性。因此，可以将肿瘤休眠作为对分子治疗的适应性反应并通过线粒体重编程协调的假设，并将构成本应用的重点。第一个特定目标中的实验将在既定的休眠模型中概括PI3K抑制素的表型，并在细胞周期静止，衰老和激酶级联反应（S）中剖析该途径的机械需求。在第二个具体目的中，我们将定义休眠中AKT重新激活的机制，表征线粒体中的CYPD-AKT复合物，并剖析CYPD在重新促进线粒体功能在细胞凋亡，生物生物生物生物学，生物生物和自phapips中的Akt磷酸化中的作用。第三个具体目的将检查PI3K抑制剂的合理组合以及线粒体质量控制的拮抗剂，Gamitrinib，在肿瘤细胞杀伤中，自适应表型的逆转以及在血管生成，转移和肿瘤肿瘤模型中的旋转性逆转和临床前活性。总体而言，实验计划将表征一种新的肿瘤休眠机制，是对分子治疗的适应性反应。结果将证明新颖的治疗策略，以消除休眠状态并消除肿瘤的转移能力。