A genotype-phenotype study of tumors from patients with inherited mutations in DNA repair genes

DNA修复基因遗传性突变患者肿瘤的基因型-表型研究

• 批准号: 10092970
• 负责人: KARA N MAXWELL
• 金额: $ 17.4万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10092970
• 关键词: ATM gene; Advisory Committees; Alleles; BRCA mutations; BRCA1 gene; BRCA2 Mutation; BRCA2 gene; Basic Science; Biological; Biology; Breast; Breast Cancer Patient; Breast Cancer cell line; CHEK2 gene; CRISPR/Cas technology; Cancer Patient; Cancer cell line; Categories; Cells; Clinical; Clinical Sciences; Clinical Trials; Coupled; DNA Damage; DNA Repair; DNA Repair Gene; DNA replication fork; Data; Development Plans; Doctor of Philosophy; Double Strand Break Repair; Evaluation; Five-Year Plans; Funding; Genes; Genetic Predisposition to Disease; Genomics; Genotype; Germ-Line Mutation; Goals; Grant; Human Genetics; Inherited; Laboratory Study; Lead; Loss of Heterozygosity; Malignant Neoplasms; Malignant neoplasm of ovary; Mammary Neoplasms; Medical Oncology; Medicine; Mentored Clinical Scientist Development Award (K08); Mentors; Modeling; Molecular; Mutate; Mutation; Neoplasm Metastasis; Pancreas; Patient Selection; Patients; Pennsylvania; Phenotype; Physicians; Platinum; Platinum Compounds; Poly(ADP-ribose) Polymerases; Positioning Attribute; Production; Program Development; Prostate; Proteins; Research; Resistance; Resources; Role; Running; Sampling; Scientist; Selection for Treatments; Somatic Mutation; Testing; Tissues; Training; Translational Research; Universities; Update; base; brca gene; cancer genetics; cancer risk; cancer therapy; cancer type; career; career development; chemotherapy; crosslink; exome sequencing; experimental study; genomic signature; homologous recombination; human genomics; improved; in vitro Model; inhibitor/antagonist; instructor; interest; malignant breast neoplasm; mutant; ovarian neoplasm; patient registry; precision medicine; preclinical study; repaired; resistance mechanism; response; skills; targeted treatment; tool; transcriptomics; translational study; treatment response; tumor

PROJECT SUMMARY This Mentored Clinical Scientist Development Award (K08) details a five year plan to promote the independent career of Dr. Kara Maxwell as a physician scientist in translational cancer genetics. Dr. Maxwell is a PhD trained molecular and cellular biologist who is board certified in Medical Oncology. Her clinical focus is in cancer risk evaluation. Dr. Maxwell is currently an Instructor of Medicine at the University of Pennsylvania and is performing her postdoctoral research in human genetics and genomics with Dr. Katherine Nathanson. Dr. Maxwell is interested in inherited susceptibility to cancer and, specifically, how inherited mutations in DNA repair genes can direct targeted treatment of cancer. Most tumors in patients with germline mutations in the homologous recombination DNA repair genes BRCA1/2, respond to platinum agents and PARP inhibitors due to synthetic lethality. However, tumors with primary and acquired resistance to these agents exist. Dr. Maxwell's preliminary studies have shown that absence of BRCA locus-specific loss of heterozygosity (LOH) is observed in approximately 25% of primary BRCA1/2 germline mutation-associated breast and ovarian tumors. Absence of locus-specific LOH was associated with significantly lower genomic signatures of deficiency in homologous recombination DNA repair. Absence of locus-specific LOH was associated with decreased overall survival in ovarian cancer patients treated with platinum-based chemotherapy. These data suggest that BRCA1/2 locus-specific LOH could be a mechanism of primary platinum and PARP inhibitor resistance. This grant proposes to expand these preliminary studies into two clinically important categories of patients: 1) patients with inherited BRCA1/2 mutations with non-breast/ovarian tumors (Aim 1) and 2) breast cancer patients with inherited mutations in the DNA repair genes ATM and CHEK2, the two most commonly identified genes in BRCA1/2 negative breast cancer patients (Aim 2). Some tumors with primary resistance to platinum and PARP inhibitors demonstrate locus-specific LOH; therefore, other mechanisms exist. Hypomorphic, or partially functional, mutations may retain sufficient DNA repair activity to lead to primary resistance. Dr. Maxwell will test the hypothesis that hypomorphic BRCA2 mutations may demonstrate primary PARP inhibitor resistance using CRISPR-Cas9 modelling of mutations in breast cancer cell lines (Aim 3). She will supplement these studies with a career development program that takes advantage of the resources of the Basser Center for BRCA Research and broadly at UPenn. Dr. Maxwell has assembled a mentoring and advisory team of successful physician scientists and basic scientists in the biology of DNA repair to guide her career development. She will engage in didactic and hands-on training to update her molecular and cellular biological skills necessary for research in DNA repair. This career development plan and the experiments detailed in the Research Strategy will provide Dr. Maxwell the tools necessary to achieve her long-term goal of a career as a physician scientist running an independently funded laboratory studying inherited susceptibility to cancer.

项目摘要 这个指导临床科学家发展奖（K 08）详细介绍了一个五年计划，以促进独立的 卡拉麦克斯韦博士的职业生涯作为一个医生科学家在转化癌症遗传学。麦克斯韦博士是 训练有素的分子和细胞生物学家，获得医学肿瘤学委员会认证。她的临床重点是 癌症风险评估麦克斯韦博士目前是宾夕法尼亚大学的医学讲师， 正在与凯瑟琳内桑森博士一起进行人类遗传学和基因组学的博士后研究。博士 麦克斯韦感兴趣的是遗传性的癌症易感性，特别是遗传性的DNA突变 修复基因可以指导癌症的靶向治疗。大多数肿瘤患者的生殖系突变发生在 同源重组DNA修复基因BRCA 1/2，对铂类药物和PARP抑制剂有反应， 合成致命性。然而，存在对这些药剂具有原发性和获得性抗性的肿瘤。博士 麦克斯韦的初步研究表明，BRCA基因座特异性杂合性缺失（洛）的缺失， 在约25%的原发性BRCA 1/2生殖系突变相关乳腺和卵巢肿瘤中观察到。 基因座特异性洛缺失与显著较低的基因组标记缺陷相关， 同源重组DNA修复。基因座特异性洛缺失与总体降低相关。 以铂类为基础的化疗治疗卵巢癌患者的生存率。这些数据表明 BRCA 1/2位点特异性洛可能是原发性铂类和PARP抑制剂耐药的机制。这 格兰特建议将这些初步研究扩展到两类临床重要的患者：1） 患有遗传性BRCA 1/2突变的非乳腺/卵巢肿瘤患者（Aim 1）和2）乳腺癌 在DNA修复基因ATM和CHEK 2中存在遗传突变的患者，这两种基因是最常见的 BRCA 1/2阴性乳腺癌患者中的基因（Aim 2）。一些原发性铂类耐药的肿瘤 和PARP抑制剂显示基因座特异性洛缺失;因此，存在其他机制。亚形态，或 部分功能性的突变可以保留足够的DNA修复活性以导致原发性抗性。博士 麦克斯韦将检验假设，即亚型BRCA 2突变可能表明原发性PARP抑制剂 使用CRISPR-Cas9建模乳腺癌细胞系中的突变的耐药性（Aim 3）。她将补充 这些研究与职业发展计划，利用巴瑟中心的资源优势 为BRCA研究所和宾夕法尼亚大学提供服务。麦克斯韦博士组建了一个指导和咨询团队， 成功的医生科学家和DNA修复生物学的基础科学家来指导她的职业生涯 发展她将参与教学和实践培训，以更新她的分子和细胞生物学， 研究DNA修复所需的技能。这一职业发展计划和实验中详细介绍了 研究战略将为麦克斯韦博士提供必要的工具，以实现她作为一个职业生涯的长期目标。 医生科学家运行一个独立资助的实验室研究遗传易感性癌症。