Developing New Strategies for Targeting mTOR and IGF-1R/PI3K/Akt Pathways in Sarc

开发针对 Sarc 中 mTOR 和 IGF-1R/PI3K/Akt 通路的新策略

• 批准号: 7698068
• 负责人: GARY K SCHWARTZ
• 金额: $ 73.63万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-16 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7698068
• 关键词: Biology; CCI-779; Cell Line; Cells; Classification; Clinical; Clinical Research; Clinical Trials; Complex; Conduct Clinical Trials; Critical Pathways; Data; Development; Disease; Future; Gene Mutation; Generations; Genetic Variation; Growth; Histologic; In Vitro; Malignant Neoplasms; Mediating; Multiprotein Complexes; Mutation; Myxoid/Round Cell Liposarcoma; Nutrient; PIK3CA gene; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphorylation; Predisposition; Publishing; Reporting; Resistance; Sampling; Signaling Molecule; Sirolimus; Therapeutic; chemotherapy; clinical efficacy; effective therapy; in vivo; inhibitor/antagonist; mTOR protein; novel strategies; public health relevance; resistance mechanism; response; sarcoma; success; tumor; tumor growth; tumorigenesis

DESCRIPTION (provided by applicant): Sarcoma is a heterogeneous disease with at least 50 different subtypes. This genetic diversity makes the development of new targeted therapies particularly challenging. However, one consistent theme now emerging is that activation of the IGF-1R/PI3K/Akt and mTOR pathways are critical for sarcoma tumor oncogenesis, proliferation, and survival across histologic subtypes. Despite the compelling rationale to target mTOR in sarcomas, results from clinical studies examining the efficacy of rapamycin analogues ("rapalogues") have been disappointing. Several studies to date have suggested that persistent or increased Akt activation in the context of mTOR inhibitors may represent a mechanism of resistance to this class of therapies. Our own data in a panel of sarcoma cell lines confirms that rapamycin induces increased Akt phosphorylation. We hypothesize that persistent or increased Akt activation is a critical mechanism of clinical sarcoma resistance to mTOR inhibition with rapamycin analogues and that future therapeutic strategies must be focused upon combined mTOR and Akt inhibition. Towards this end, we have identified two classes of sarcoma cell lines: 1) "IGF-1R dependent" cells for which combined IGF-1R and mTOR targeting results in decreased p-Akt levels and hence enhanced anti-proliferative effects; and 2) "IGF-1R independent" cells for which IGF-1R inhibition fails to decrease p-Akt levels or enhance anti-tumor effects. These classifications not only will provide the framework by which to clinically evaluate mTOR targeting agents in clinical trials, but also highlight differences in sarcoma biology that suggest novel strategies for overcoming Akt mediated resistance. Additionally, we have identified a high rate of PIK3CA mutations in myxoid-round cell liposarcomas and observed that different classes of PIK3CA mutations correspond to dramatically different levels of Akt activation in patient tumor samples. In order to advance our understanding of how to manipulate these pathways for sarcoma therapy, the specific aims of this project are to 1) conduct clinical trials in sarcoma with combinations of TORC1 and IGF-1R inhibitors, as well as a first-in-class TORC1/2 inhibitor; 2) evaluate strategies for reducing activated Akt in the context of TORC1 inhibition in IGF-1R -dependent and -independent sarcoma cells; and 3) study the impact of PIK3CA mutations upon myxoid-round cell liposarcoma biology and the susceptibility of these tumors to mTOR targeting. PUBLIC HEALTH RELEVANCE: Given the lack of effective chemotherapy, patients with advanced and metastatic sarcoma are in great need of new therapies. Combining new generation drugs that specifically inhibit pathways that promote sarcoma tumor growth (mTOR and IGF- 1R/PI3K/Akt) should result in major advances in the treatment and cure of this disease.

描述（由申请人提供）：肉瘤是一种至少50种不同亚型的异质疾病。这种遗传多样性使得开发新的目标疗法特别具有挑战性。但是，现在出现的一个一致的主题是，IGF-1R/PI3K/AKT和MTOR途径的激活对于跨组织学亚型的肉瘤肿瘤肿瘤发生，增殖和存活至关重要。尽管在肉瘤中靶向MTOR的基本原理令人信服，但临床研究的结果研究了雷帕霉素类似物的功效（“ apapalogues”）令人失望。迄今为止的几项研究表明，在MTOR抑制剂的背景下，持续或增加的AKT激活可能代表对这类疗法的抵抗机制。我们在肉瘤细胞系小组中自己的数据证实，雷帕霉素会诱导Akt磷酸化增加。我们假设持续或增加的AKT激活是抗雷帕霉素类似物对MTOR抑制的临床肉瘤耐药性的关键机制，并且必须将未来的治疗策略集中在MTOR和AKT抑制上。为此，我们已经确定了两类的肉瘤细胞系：1）“ IGF-1R依赖性”细胞，其中IGF-1R和MTOR靶向的组合导致P-AKT水平降低，从而增强了抗增殖作用； 2）“ IGF-1R独立”细胞，IGF-1R抑制作用无法降低P-AKT水平或增强抗肿瘤效应。这些分类不仅将提供临床评估MTOR靶向药物的框架，而且还强调了肉瘤生物学的差异，这些差异提出了克服AKT介导的耐药性的新型策略。此外，我们已经确定了粘液样细胞脂肪肉瘤中PIK3CA突变的高率，并观察到不同类别的PIK3CA突变对应于患者肿瘤样品中AKT激活的水平急剧不同。为了促进我们对如何操纵这些肉瘤治疗的途径的理解，该项目的具体目的是1）在肉瘤中进行临床试验，其中具有TORC1和IGF-1R抑制剂的组合，以及第一类TORC1/2抑制剂； 2）评估在IGF -1R依赖性和非依赖性肉瘤细胞中TORC1抑制作用中减少激活AKT的策略； 3）研究PIK3CA突变对粘液样细胞脂肪肉瘤生物学的影响以及这些肿瘤对MTOR靶向的敏感性。公共卫生相关性：鉴于缺乏有效的化学疗法，患有晚期和转移性肉瘤的患者非常需要新疗法。结合新一代药物，这些药物专门抑制促进肉瘤肿瘤生长的途径（MTOR和IGF-1R/PI3K/AKT），这将导致这种疾病的治疗和治疗方面的重大进展。