Targeting Ovarian Cancer via Cooperative Oncogene Interactions

描述（申请人提供）：卵巢癌是妇科恶性肿瘤中最致命的。某些卵巢肿瘤可能特别难以治疗，因为它们通常对目前用于治疗卵巢癌的化疗药物没有反应或产生耐药性。最近发现透明细胞和子宫内膜样卵巢癌存在ARID1A基因突变，缺乏ARID1A蛋白表达。这些突变在肿瘤中发现，但在同一患者的正常组织中没有发现，这表明ARID1A蛋白的缺失与肿瘤的发生或生长之间存在因果关系。这一突破，以及其他通过基因型对卵巢癌进行分析和分类的测序工作，可能为定制治疗提供更有效的生存结果的第一步。矛盾的是，ARID1A的缺失导致生长停滞和细胞死亡，而不是癌症中发生的不受控制的细胞分裂。因此，必须有其他蛋白的突变与ARID1A中的突变合作来驱动肿瘤的形成。最近的数据表明，ARID1A的突变最常与PIK3CA的激活突变配对，PIK3CA是磷脂酰肌醇3-激酶（PI3K）的催化亚基，利用ATP将磷脂酰肌醇4,5-二磷酸（PIP2）转化为磷脂酰肌醇3,4,5-三磷酸（PIP3）。PI3K的小分子抑制剂和PI3K途径的下游组分已经被开发出来，目前被用作化疗药物。我的目的是了解这两种蛋白的突变如何导致细胞转化，以及来自人类透明细胞和子宫内膜样卵巢癌的ARID1A突变细胞是否通过这种配对对PI3K抑制剂更敏感。由于PIK3CA突变可能只是细胞克服ARID1A突变而转化的机制之一，我计划对人类ARID1A突变卵巢癌细胞系具有特异性细胞毒性的小分子进行高通量筛选。然后，我希望确定这些抑制剂如何使ARID1A突变细胞衰弱，以提供更好、更个性化的化疗治疗。总之，这些研究将验证ARID1A缺失作为卵巢癌诊断的生物标志物的使用，并为透明细胞和子宫内膜样卵巢癌的治疗提供机制见解和潜在的新疗法。

DESCRIPTION (provided by applicant): Ovarian cancer is the most lethal of the gynecological malignancies. Certain ovarian tumors can be particularly difficult to treat as they are often not responsive or become resistant to the chemotherapeutics that are currently in use for the treatment of ovarian cancer. Recently, it was found that clear cell and endometrioid ovarian cancer have mutations in the ARID1A gene and lack ARID1A protein expression. These mutations were found in tumors, but not in normal tissue from the same patient, suggesting a causal link between loss of ARID1A protein and tumor initiation or growth. This breakthrough, along with other sequencing efforts to profile and categorize ovarian cancer by genotype, could provide the first step in tailoring treatment for more effective survival outcomes. Paradoxically, loss of ARID1A causes growth arrest and cell death, not the uncontrolled cell division that occurs in cancer. Thus, there must be mutations in other proteins that cooperate with mutations in ARID1A to drive tumor formation. Recent data suggests that mutations in ARID1A are most often paired with activating mutations in PIK3CA, the catalytic subunit of Phosphatidylinositol 3-Kinase (PI3K), which uses ATP to convert phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-trisphosphate (PIP3). Small molecule inhibitors of PI3K and downstream components of the PI3K pathway have been developed and are currently in use as chemotherapeutics. I aim to understand how mutations in these two proteins cause cells to become transformed and whether ARID1A mutant cells from human clear cell and endometrioid ovarian cancers are more sensitive to PI3K inhibitors by virtue of this pairing. As PIK3CA mutation may be only one of the mechanisms by which cells overcome ARID1A mutation to become transformed, I plan to perform high- throughput screens for small molecules that are specifically cytotoxic to human ARID1A mutant ovarian cancer cell lines. I then hope to determine how such inhibitors debilitate ARID1A mutant cells with the aim of providing better, more personalized chemotherapeutic treatment. In summary, such studies will validate the use of ARID1A loss as a biomarker in the diagnosis of ovarian cancer and provide mechanistic insight and potentially new therapeutics for the treatment of clear cell and endometrioid ovarian cancer.