Elucidation of the impact of commonly co-altered genes on chemosensitivity using a novel model of high-grade serous ovarian cancer

使用高级别浆液性卵巢癌的新型模型阐明常见共同改变基因对化疗敏感性的影响

• 批准号: 9271934
• 负责人: Hsing-Yu Chen
• 金额: $ 1.75万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9271934
• 关键词: Address; Affect; Animal Model; Animals; Ascites; BRCA1 gene; Biological Markers; Biological Models; Cancer Patient; Carboplatin; Cell Culture Techniques; Cells; Chromosomal Instability; Clinic; Clinical; Clinical Oncology; Collaborations; Collection; Copy Number Polymorphism; Development; Diagnosis; Disease; Drug resistance; Engineering; Epithelial; Experimental Models; Female; Foundations; Gene Expression Profile; Genes; Genetic; Genetic Heterogeneity; Genetic Variation; Genomics; Goals; Heterogeneity; Human; In Vitro; Individual; Injectable; Investigation; Laboratories; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Mammalian Oviducts; Mentors; Mission; Modeling; Molecular; Monitor; Mus; Mutation; Neoplasm Metastasis; Outcome; Paclitaxel; Pathologist; Pathway interactions; Patient-Focused Outcomes; Patients; Peritoneal; Peritoneum; Pharmacotherapy; Platinum; Poly(ADP-ribose) Polymerases; Population; Population Analysis; Positioning Attribute; Relapse; Research Personnel; Research Training; Resistance; Resistance development; Scientist; Serous; Solid; Stable Populations; System; Testing; Toxicity due to chemotherapy; Training; Treatment Efficacy; Virus Diseases; Xenograft Model; anticancer research; base; cancer cell; cancer therapy; career; chemotherapy; clinically relevant; combinatorial; design; differential expression; drug standard; effective intervention; experience; improved; in vivo; individualized medicine; inhibitor/antagonist; medical schools; meetings; mortality; mouse model; neoplastic cell; next generation; novel; pressure; programs; public health relevance; response; screening; skills; standard care; taxane; therapy resistant; transcriptome sequencing; translational medicine; tumor; tumor progression; undergraduate student

 DESCRIPTION (provided by applicant): High-grade serous ovarian cancer (HGSC) is the most prevalent gynecological malignancy diagnosed in females and accounts for most ovarian-cancer mortality. Current standard care for these tumors is platinum-based therapies along with taxane agents. While most tumors respond to chemotherapy initially, this is typically followed by relapse and progression to resistance in the clinic. Resistance has been shown to involve many diverse mechanisms. Recent multiplatform genomic analyses have revealed that HGSCs display a high level of chromosomal instability, which leads to extensive copy number variations due to regional amplifications and deletions. The occurrence of different combinations of genetic aberrations among patients as well as genetic diversity within individual tumors provides extraordinary challenges for treatment of this disease. The objective of this project is to investigate molecular mechanisms by which HGSC develops resistance to chemotherapy with a particular focus on analysis of the effects of different combinations of genetic alterations within distinct subpopulations of tumor cells. This investigation will be conducted in cell cultures and i animal models, and we will evaluate the clinical relevance using multiple HGSC patient-derived xenograft models. These approaches provide an integrative framework to discover and evaluate the extent to which the genetic complexity and heterogeneity of HGSC confer differential chemo-sensitivity. The sets of co-altered genes identified in this study could also serve as biomarkers to individualize treatment in ovarian cancer patients. My passion for translational medicine has been leading me into the journey of cancer research with a particular focus on drug resistance since I was an undergraduate student. I recently pursued a postdoctoral position in the laboratory of Dr. Joan Brugge at Harvard Medical School to gain a better understanding of complexity of drug resistance in cancers and to interact with an interdisciplinary group of many intelligent engineers, biologists, and clinician-scientists. My career goal is to become an independent investigator, and my mission will be to make important advances in cancer treatment. These long-term goals will become feasible through the skills that I will develop through pursuit of this project and other aspects of my training, as outlined i my research and training plan. The training will help me enrich my clinical oncology background and deepen my understanding of the mechanisms underlying cancer progression and therapy resistance in the context of clinically important questions. It also gives me the opportunity to be mentored by Dr. Joan Brugge, a renowned basic cancer scientist with an excellent track record in training next generation cancer scientists. The collaborations with gynecological cancer pathologists (Dr. Drapkin) and basic cancer scientists (Dr. Mills) through this project, as well as the courses, seminars and meetings I will attend, will provide me with a strong foundation in basic and clinical ovarian cancer research. This experience will pave my path towards becoming an independent scientist and striving to achieve better outcomes for patients afflicted by ovarian cancer.

 描述（由申请人提供）：高级别浆液性卵巢癌（HGSC）是女性中最常见的妇科恶性肿瘤，导致大多数卵巢癌死亡，目前这些肿瘤的标准治疗是铂类疗法和紫杉烷类药物。虽然大多数肿瘤最初对化疗有反应，但临床上通常会出现复发和耐药性，最近的多平台基因组分析表明，耐药性涉及多种机制。 HGSC表现出高度的染色体不稳定性，由于区域扩增和缺失而导致广泛的拷贝数变异。患者之间不同组合的遗传畸变以及个体遗传肿瘤内的多样性给这种疾病的治疗带来了巨大的挑战。该项目的目的是研究 HGSC 产生化疗耐药性的分子机制，特别关注分析体内不同基因改变组合的影响。 这项研究将在细胞培养物和动物模型中进行，我们将使用多个 HGSC 患者来源的异种移植模型来评估临床相关性。 HGSC 的遗传复杂性和异质性赋予了不同的化疗敏感性，本研究中确定的一组共同改变的基因也可以作为卵巢癌患者个体化治疗的生物标志物。自本科生起，我就一直带领我踏上癌症研究之旅，特别关注耐药性，最近我在哈佛医学院 Joan Brugge 博士的实验室攻读博士后职位，以更好地了解药物的复杂性。我的职业目标是成为一名独立研究者，我的使命是在癌症治疗方面取得重要进展。通过我所掌握的技能将变得可行正如我的研究和培训计划所述，该培训将帮助我丰富我的临床肿瘤学背景，并加深我对临床背景下癌症进展和治疗耐药机制的理解。这也给了我机会去回答重要的问题。 由著名基础癌症科学家 Joan Brugge 博士指导，她在培养下一代癌症科学家方面拥有出色的记录，并通过该项目与妇科癌症病理学家（Drapkin 博士）和基础癌症科学家（Mills 博士）合作。作为 我将参加的课程、研讨会和会议将为我在卵巢癌的基础和临床研究方面打下坚实的基础，这段经历将为我成为一名独立科学家并努力为卵巢癌患者取得更好的结果铺平道路。