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

基本信息

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
项目类别：
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

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

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项目摘要

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，例如子宫癌[例如癌肉瘤，乳头状浆膜癌和平滑肌肉瘤（LMS）]和卵巢癌[例如低度浆液和清晰的细胞卵巢癌] 女性癌症死亡率的重要原因。这些子宫癌亚型具有侵略性，高复发率影响更多的黑人妇女，他们死于疾病的可能性是白人妇女的2倍。这些卵巢癌亚型具有化学耐药性，<10-20％的患者应对护理标准（SOC）基于铂的化学疗法。这些妇科癌症缺乏有效的疗法，可能是由于缺乏强大的临床前模型所致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确定在高级浆液卵巢癌中利用遗传脆弱性的新治疗选择（最常见的亚型）最终目标是将其带入患者的临床试验。我们已经发展了〜140个PDX模型> 90％的率，以前优先考虑高级浆液卵巢癌。我们有证明PDX模型和原发性肿瘤培养物保持患者原始的特征肿瘤，包括突变状态，基因表达和临床行为。此外，患者的移植肿瘤与小鼠卵巢/纤维膜或子宫角截止性和EMCA。此外，我们使用此PDX平台来识别新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。演示组合后 PARP和ATR抑制逆转BRCA突变体PDX模型中的PARPI抗性，我们验证了这些发现在BRCA突变体HGSOC患者的诊所中，PARPI（Olaparib）的反应率为50％（Ceralasertib）抗parpi疾病（NCT03462342）。我们的最终目标是发展新的有效这些不常见的妇科癌的亚型的治疗方法，这些癌症解决了临床上未满足的需求。我们提案以下项目目的：特定目标1：开发和分子表征原位PDX和来自缺乏疗法的妇科癌的类器官模型。特定目标2：评估新型组合 TP53野生型妇科癌癌和PDX模型中的治疗。这些研究最终将为卵巢和子宫提供分子表征的临床前模型目前缺乏体外和PDX模型的癌症亚型。这些模型将与科学共享在这些稀有但致命的妇科癌症中加快药物开发的社区。此外，我们将验证初步的体外研究，显示了一种新组合疗法的协同活性，已建立的PDX模型。研究可能支持通过CTEP将新药物组合转移到临床试验中和NRG肿瘤学。