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: 8327269
• 负责人: GARY K SCHWARTZ
• 金额: $ 38.22万
• 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 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8327269
• 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; Health; 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; 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(申请人提供)：肉瘤是一种至少有50种不同亚型的异质性疾病。这种遗传多样性使得开发新的靶向疗法特别具有挑战性。然而，现在出现的一个一致的主题是，IGF-1R/PI3K/Akt和mTOR通路的激活对肉瘤肿瘤的发生、增殖和跨组织亚型的生存至关重要。尽管在肉瘤中靶向mTOR有令人信服的理由，但检测雷帕霉素类似物(“雷帕洛”)疗效的临床研究结果一直令人失望。到目前为止的几项研究表明，在mTOR抑制剂的背景下，持续的或增加的Akt激活可能代表了对这类治疗的抵抗机制。我们自己在一组肉瘤细胞系中的数据证实，雷帕霉素诱导Akt磷酸化增加。我们假设持续或增加的Akt激活是临床肉瘤抵抗雷帕霉素类似物mTOR抑制的关键机制，未来的治疗策略必须集中在联合抑制mTOR和Akt上。为此，我们确定了两类肉瘤细胞系：1)IGF-1R依赖的细胞，IGF-1R和mTOR联合靶向可导致p-Akt水平降低，从而增强抗增殖作用；2)IGF-1R抑制未能降低p-Akt水平或增强抗肿瘤效果的“IGF-1R非依赖”细胞。这些分类不仅将提供在临床试验中评估mTOR靶向药物的框架，而且还将突出肉瘤生物学方面的差异，这些差异为克服Akt介导的耐药性提供了新的策略。此外，我们已经在粘液样圆形脂肪肉瘤中发现了高比例的PIK3CA突变，并观察到不同类别的PIK3CA突变对应于患者肿瘤样本中Akt激活的显著不同水平。为了促进我们对如何操纵这些途径用于肉瘤治疗的了解，本项目的具体目标是：1)联合使用TORC1和IGF-1R抑制剂以及一流的TORC1/2抑制剂进行肉瘤的临床试验；2)在IGF-1R依赖和独立的肉瘤细胞中，评估在TORC1抑制的背景下减少激活的Akt的策略；以及3)研究PIK3CA突变对粘液样圆形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：由于缺乏有效的化疗，晚期和转移性肉瘤患者非常需要新的治疗方法。结合新一代的药物，特别是抑制促进肉瘤肿瘤生长的途径(mTOR和IGF-1R/PI3K/Akt)，应该会在治疗和治愈这种疾病方面取得重大进展。