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

(PQC2) .PI3K 网络在休眠早期的可塑性

• 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
• 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

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）：尽管承诺和希望，分子疗法可以为癌症患者带来持久的缓解，但大多数“靶向”药物并没有达到这一期望，由于转移性疾病的出现，仅提供有限的，并且在大多数情况下，短暂的益处。尽管许多努力都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尚未得到广泛考虑。我们通过检查肿瘤对磷脂酰肌醇-3激酶（PI 3 K）网络的靶向抑制的反应来测试这一概念，PI 3 K网络是几乎所有肿瘤中的疾病驱动因素。 人类癌症和重要治疗靶点。我们的初步数据表明，PI 3 K的小分子抑制剂诱导肿瘤中的全局转录和代谢重编程。这种适应性反应赋予了一种新的癌症表型，其结合了延长的增殖和生物能量学静止、衰老的外观、提高的细胞存活和增加的肿瘤细胞侵袭的矛盾特征。这些是休眠的关键标志，休眠是一个难以捉摸的过程，其中肿瘤细胞从原发性病变早期扩散，抵抗凋亡，播种转移部位，并长时间保持静止，只是作为复发性（和不可治愈的）疾病重新唤醒。在机制上，由PI 3 K抑制诱导的肿瘤可塑性涉及胞质溶胶和线粒体中Akt的再活化，以及亲环蛋白D（CypD）（线粒体生物能量学和细胞凋亡的多功能调节剂）的Akt依赖性磷酸化。相反，当与线粒体完整性的小分子拮抗剂加米替尼联合使用时，PI 3 K抑制剂不再触发适应性肿瘤重编程、抑制侵袭并发挥显着增强的抗癌活性。因此，肿瘤休眠可以作为对分子治疗的适应性反应被诱导并且通过线粒体重编程协调的假设可以被制定，并且将构成本申请的焦点。第一个具体目标的实验将概括已建立的休眠模型中PI 3 K抑制素的表型，并剖析该途径关于细胞周期静止、衰老和细胞侵袭的激酶级联的机制要求。在第二个具体目标中，我们将定义休眠中Akt再激活的机制，表征线粒体中CypD-Akt复合物，并剖析CypD的Akt磷酸化在细胞凋亡、生物能量学和自噬中线粒体功能再利用中的作用。第三个具体目标将检查PI 3 K抑制剂加线粒体质量控制拮抗剂Gamitrinib在体内肿瘤细胞杀伤、适应性表型逆转和血管生成、转移和肿瘤休眠模型中的临床前活性的合理组合。总的来说，实验计划将描述肿瘤休眠的新机制，作为对分子治疗的适应性反应。这些结果将证实新的治疗策略，以消除休眠和根除肿瘤的转移能力。