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开发新的靶向疗法尤其具有挑战性。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、增殖和存活至关重要。尽管在肉瘤中靶向mTOR有令人信服的理由，但临床研究检查雷帕霉素类似物（“雷帕霉素”）疗效的结果令人失望。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激活可能代表了对这类治疗的抗性机制。我们自己的一组肉瘤细胞系数据证实，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的关键机制，未来的治疗策略必须集中在mTOR和Akt的联合抑制上。为此，我们已经确定了两类肉瘤细胞系：1)“依赖IGF-1R”的细胞，IGF-1R和mTOR联合靶向导致p-Akt水平降低，从而增强抗增殖作用；2)“IGF-1R独立”细胞，IGF-1R抑制不能降低p-Akt水平或增强抗肿瘤作用。这些分类不仅将为临床试验中mTOR靶向药物的临床评估提供框架，而且还将突出肉瘤生物学的差异，为克服Akt介导的耐药提供新策略。此外，我们发现黏液状圆细胞脂肪肉瘤中PIK3CA突变的发生率很高，并观察到不同类型的PIK3CA突变对应于患者肿瘤样本中显著不同的Akt激活水平。为了促进我们对如何操纵这些途径进行肉瘤治疗的理解，该项目的具体目标是：1)在肉瘤中进行TORC1和IGF-1R抑制剂以及一流的TORC1/2抑制剂的联合临床试验；2)在IGF-1R依赖性和非依赖性肉瘤细胞中，评估在TORC1抑制的情况下降低活化Akt的策略；3)研究PIK3CA突变对黏液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非常需要新的治疗方法。结合特异性抑制促进肉瘤肿瘤生长通路（mTOR和IGF- 1R/PI3K/Akt）的新一代药物，应该会导致该疾病的治疗和治愈取得重大进展。

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.