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

描述（由申请人提供）：肉瘤是一种异质性疾病，至少有50种不同的亚型。这种遗传多样性使得新靶向疗法的开发特别具有挑战性。然而，现在出现的一个一致的主题是IGF-1 R/PI 3 K/Akt和mTOR通路的激活对于肉瘤肿瘤的发生、增殖和组织学亚型的存活至关重要。尽管在肉瘤中靶向mTOR的理由令人信服，但来自检查雷帕霉素类似物（“雷帕霉素类似物”）的功效的临床研究的结果令人失望。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活化可能代表对这类疗法的抗性机制。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激活是临床肉瘤对雷帕霉素类似物抑制mTOR耐药的关键机制，未来的治疗策略必须集中在联合mTOR和Akt抑制上。为此，我们已经鉴定了两类肉瘤细胞系：1）“IGF-1 R依赖性”细胞，其中组合的IGF-1 R和mTOR靶向导致p-Akt水平降低并因此增强抗增殖作用;和2）“IGF-1 R非依赖性”细胞，其中IGF-1 R抑制未能降低p-Akt水平或增强抗肿瘤作用。这些分类不仅将提供在临床试验中临床评估mTOR靶向药物的框架，而且还突出了肉瘤生物学的差异，这些差异提示了克服Akt介导的耐药性的新策略。此外，我们已经鉴定了粘液样圆细胞脂肪肉瘤中高比率的PIK 3CA突变，并观察到不同类别的PIK 3CA突变对应于患者肿瘤样品中显著不同的Akt活化水平。为了促进我们对如何操纵这些途径用于肉瘤治疗的理解，本项目的具体目标是：1）用TORC 1和IGF-1 R抑制剂的组合以及一流的TORC 1/2抑制剂在肉瘤中进行临床试验; 2）评估在IGF-1 R依赖性和非依赖性肉瘤细胞中在TORC 1抑制的背景下减少活化Akt的策略;和3）研究PIK 3CA突变对粘液样圆细胞脂肪肉瘤生物学的影响以及这些肿瘤对mTOR靶向的易感性。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迫切需要新的治疗方法。结合新一代药物，特异性抑制促进肉瘤肿瘤生长的途径（mTOR和IGF-1 R/PI 3 K/Akt），应该会在治疗和治愈这种疾病方面取得重大进展。

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.