Platform to develop targeted therapies for aggressive less common gynecological cancers

项目总结 妇科恶性肿瘤，如子宫癌[如癌肉瘤、乳头状浆液性癌和 平滑肌肉瘤和卵巢癌[例如低级别浆液性和透明细胞卵巢癌]是一种 女性癌症死亡的重要原因。这些子宫癌亚型具有高侵袭性。 复发率影响更多的黑人女性，她们死于疾病的可能性是白人女性的两倍。 这些卵巢癌亚型对化疗耐药，10%-20%的患者对标准治疗有反应 (SoC)以铂为基础的化疗。 这些妇科癌症缺乏有效的治疗方法，很可能是因为缺乏强有力的临床前模型。 用于这些疾病亚型的研究。我的实验室已经开发了一个临床前药物开发平台 寻找利用高级别浆液性卵巢癌遗传易感性的新治疗方案 (最常见的亚型)，最终目标是让它们进入患者的临床试验。我们已经开发出 ~140个PDX模型，采集率为90%，以前优先考虑高级别浆液性卵巢癌。我们有 证明PDX模型和原代肿瘤培养保持了患者原始肿瘤培养的特征 肿瘤，包括突变状态、基因表达和临床行为。此外，患者的移植 小鼠卵巢/海马伞或子宫角原位肿瘤模拟HGSOC的自然进展 和EMCA。 此外，我们还利用这个PDX平台来寻找新的药物组合来克服耐药性 在PDX模型中，然后根据我们的结果将疗法转移到临床试验中。在演示组合之后 在BRCA突变型PDX模型中，PARP和ATR抑制逆转PARPI耐药性，我们验证了这些发现 BRCA突变的HGSOC患者对PARPI(奥拉帕利)伴ATRI的有效率为50% (Ceralasertib)在PARPI耐药疾病(NCT03462342)中。我们的最终目标是开发新的有效 针对这些不太常见的妇科癌症亚型的治疗，满足了临床上未得到满足的需求。我们 提出以下项目目标：具体目标1：开发和分子表征原位PDX和 缺乏治疗的妇科癌症的器官模型。具体目标2：评估一种新的组合 TP53野生型妇科肿瘤有机化合物和PDX模型的治疗。 这些研究最终将为卵巢和子宫提供分子特征的临床前模型。 癌症亚型，目前缺乏体外和PDX模型。这些模型将与科学工作者共享 社区加快对这些罕见但致命的妇科癌症的药物开发。此外，我们还将 验证了初步的体外研究表明，一种新的联合疗法的协同活性，已经在 已建立的PDX模型。研究可能支持通过CTEP将新药组合转移到临床试验 和NRG肿瘤学。

PROJECT SUMMARY Gynecological malignancies such as uterine cancers [e.g carcinosarcomas, papillary serous carcinoma, and leiomyosarcomas (LMS)] and ovarian cancers [e.g low-grade serous and clear cell ovarian cancer] are a significant cause of cancer mortality for women. These uterine cancer subtypes are aggressive with high recurrence rates affecting more black women who are 2 times more likely to die from disease than white women. These ovarian cancer subtypes are chemo-resistant with <10-20% of patients responding to standard of care (SOC) platinum-based chemotherapy. Lack of effective therapies for these gynecologic cancers, is likely due to the lack of robust preclinical models for research for these disease subtypes. My laboratory has developed a preclinical drug development platform to identify new treatment options that exploiting genetic vulnerabilities in high grade serous ovarian cancers (most common subtype) with the ultimate goal to move them into clinical trials for patients. We have developed ~140 PDX models with a >90% take rate, previously prioritizing high grade serous ovarian cancer. We have demonstrated that PDX models and primary tumor cultures maintain characteristics of the patient’s original tumor, including mutation status, gene expression, and clinical behavior. Furthermore, transplantation of patient tumors orthotopically to the mouse ovary/fimbria or uterine horn emulates the natural progression of HGSOC and EMCA, respectively. In addition, we have used this PDX platform to identify new drug combinations to overcome drug resistance in PDX models and then move therapies into clinical trials based on our results. After demonstrating combination PARP and ATR inhibition reverses PARPi resistance in BRCA mutant PDX models, we validated these findings in the clinic in BRCA mutant HGSOC patients showing a 50% response rate for PARPi (olaparib) with ATRi (ceralasertib) in PARPi resistant disease (NCT03462342). Our ultimate goal is to develop new effective treatments for these less common subtypes of gynecological cancers addressing a clinically unmet need. We propose the following project Aims: Specific Aim 1: Develop and molecularly characterize orthotopic PDX and organoid models from gynecological cancers lacking therapies. Specific Aim 2: Evaluate a novel combination therapy in TP53 wild type gynecological cancer organoids and PDX models. These studies will ultimately provide molecularly characterized preclinical models, for ovarian and uterine cancer subtypes, currently lacking in vitro and PDX models. These models will be shared with the scientific community to expedite drug development in these rarer but deadly gynecological cancers. In addition, we will validate preliminary in vitro studies showing synergistic activity of a new combination therapy, in already established PDX models. Studies may support moving a new drug combination into clinical trials through CTEP and NRG Oncology.