Platform to develop targeted therapies for aggressive less common gynecological cancers

开发针对侵袭性不太常见妇科癌症的靶向疗法的平台

• 批准号: 10733237
• 负责人: FIONA SIMPKINS
• 金额: $ 25.67万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-05 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10733237
• 关键词: Address; Affect; American Society of Clinical Oncology; Apoptosis; Apoptotic; Behavior; Black Populations; Cancer Etiology; Cancer Model; Cancer Patient; Cancer Therapy Evaluation Program; Carcinoma; Carcinosarcoma; Cell Cycle Arrest; Cell Nucleus; Characteristics; Chemoresistance; Clinic; Clinical; Clinical Trials; Combined Modality Therapy; Communities; DNA Repair; Data; Development; Disease; Disease Resistance; Dose; Drug Combinations; Drug Synergism; Drug resistance; Evaluation; Future; Gene Expression; Genetic Predisposition to Disease; Genomics; Goals; Gynecologic; Histologic; Horns; In Vitro; Laboratories; Lead; Libraries; MDM2 gene; Malignant Epithelial Cell; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Modeling; Molecular; Molecular Profiling; Mus; Mutation; Oncology; Organoids; Ovarian Clear Cell Tumor; Ovarian Serous Adenocarcinoma; Ovary; Papillary; Parents; Patients; Pennsylvania; Phase; Platinum; Poly(ADP-ribose) Polymerase Inhibitor; Pre-Clinical Model; Preclinical Drug Development; Primary Neoplasm; Process; Proteomics; Recurrence; Research; Resistance; Serous; TP53 gene; Techniques; Therapeutic; Transplant Recipients; Transplantation; Tumor Suppressor Proteins; Universities; Uterine Cancer; Uterine Leiomyosarcoma; Uterus; Woman; black women; cancer subtypes; chemotherapy; disorder subtype; drug development; effective therapy; fimbria; in vivo; in vivo Model; ineffective therapies; leiomyosarcoma; mortality; mutant; mutational status; new combination therapies; novel; novel drug combination; novel therapeutics; patient derived xenograft model; potential biomarker; pre-clinical; prevent; response; response biomarker; standard of care; synergism; targeted treatment; tumor

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.

项目摘要 妇科恶性肿瘤，如子宫癌[如癌性肉瘤、乳头状浆液性癌和 平滑肌瘤（LMS）]和卵巢癌[例如低级别浆液性和透明细胞卵巢癌]是一种 女性癌症死亡率的重要原因。这些子宫癌亚型具有高侵袭性， 复发率影响更多的黑人妇女，她们死于疾病的可能性是白色妇女的2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)含铂化疗 这些妇科癌症缺乏有效的治疗方法，可能是由于缺乏强大的临床前模型 用于这些疾病亚型的研究。我的实验室开发了一个临床前药物开发平台 确定新的治疗方案，利用高级别浆液性卵巢癌的遗传脆弱性， (most常见亚型），最终目标是将其用于患者的临床试验。我们已经开发 ~140个PDX模型，采集率>90%，之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物保持了患者原始肿瘤细胞的特征， 肿瘤，包括突变状态，基因表达和临床行为。此外，患者的移植 与小鼠卵巢/伞或子宫角原位的肿瘤模拟HGSOC的自然进展 和EMCA，分别。 此外，我们还利用这个PDX平台来确定新的药物组合，以克服耐药性 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。在演示组合后 在BRCA突变PDX模型中，PARP和ATR抑制可逆转PARPi耐药性，我们验证了这些发现 在BRCA突变型HGSOC患者的临床中，PARPi（奥拉帕尼）与ATRi的缓解率> 50% （ceralasertib）治疗PARPi耐药疾病（NCT 03462342）。我们的最终目标是开发新的有效的 针对这些不太常见的妇科癌症亚型的治疗解决了临床上未满足的需求。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， 缺乏治疗的妇科癌症的类器官模型。具体目标2：评价新组合 在TP 53野生型妇科癌症类器官和PDX模型中的治疗。 这些研究将最终提供分子表征的临床前模型，用于卵巢和子宫 癌症亚型，目前缺乏体外和PDX模型。这些模型将与科学界分享， 社区加快药物开发，在这些罕见的，但致命的妇科癌症。此外，我们将 验证初步的体外研究，显示新的联合治疗的协同活性， 建立PDX模型。研究可能支持通过CTEP将新药组合转移到临床试验中 和NRG肿瘤学。