Targeting Ovarian Cancer via Cooperative Oncogene Interactions

项目摘要 卵巢癌是妇科恶性肿瘤中死亡率最高的一种。某些卵巢肿瘤可能特别 难以治疗，因为它们通常对化疗药物无反应或产生耐药性， 目前用于治疗卵巢癌。最近发现，透明细胞和类胶质细胞 卵巢癌具有ARID 1A基因突变并且缺乏ARID 1A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，这表明肿瘤细胞的丢失与肿瘤细胞的丢失之间存在因果关系。 ARID 1A蛋白与肿瘤发生或生长这一突破，沿着其他测序工作， 根据基因型对卵巢癌进行分类，可以为定制治疗提供第一步， 生存结果。奇怪的是，ARID 1A的缺失导致生长停滞和细胞死亡，而不是不受控制的细胞 在癌症中发生的分裂。因此，在其他蛋白质中一定有突变与突变协同作用， ARID 1A驱动肿瘤形成。最近的数据表明，ARID 1A的突变最常与 PIK 3CA中的激活突变，PIK 3CA是磷脂酰肌醇3-激酶（PI 3 K）的催化亚基，其使用ATP 将磷脂酰肌醇4，5-二磷酸（PIP 2）转化为磷脂酰肌醇3，4，5-三磷酸（PIP 3）。 已经开发了PI 3 K和PI 3 K途径的下游组分的小分子抑制剂， 目前用作化疗药物。我的目标是了解这两种蛋白质的突变如何导致细胞 ARID 1A突变体细胞是否来自人卵巢透明细胞和类卵巢上皮细胞 由于这种配对，癌症对PI 3 K抑制剂更敏感。由于PIK 3CA突变可能只是 细胞克服ARID 1A突变转化的机制，我计划进行高- 对人ARID 1A突变卵巢癌特异性细胞毒性的小分子的通量筛选 细胞系然后，我希望确定这种抑制剂如何使ARID 1A突变细胞衰弱，目的是提供 更好更个性化的化疗总之，这些研究将验证 ARID 1A缺失作为卵巢癌诊断中的生物标志物，并提供机制见解和潜在的 用于治疗透明细胞和类卵巢癌的新疗法。

Project Summary 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.