Establishing the Repertoire of Actionable Alterations in Appendiceal Adenocarcinoma

建立阑尾腺癌可行的改变方案

• 批准号: 10542791
• 负责人: Lance David Miller
• 金额: $ 50.54万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10542791
• 关键词: Anatomy; Appendix Adenocarcinoma; Behavior; Biological; Biopsy; Cancer Patient; Characteristics; Chemoresistance; Chemotherapy-Oncologic Procedure; Classification; Clinical; Clinical Data; Clinical Management; Clinical Trials; Colon Carcinoma; Custom; DNA Sequence Alteration; Data; Development; Disease; Drug Screening; Drug resistance; Eligibility Determination; Exclusion; Exhibits; Future; Gene Expression; Gene Mutation; Genes; Genetic; Genotype; Goals; Greater sac of peritoneum; Guidelines; Hyperthermia; Institution; Intervention; Knowledge; Left; Literature; Malignant Neoplasms; Malignant neoplasm of appendix; Malignant neoplasm of gastrointestinal tract; Modeling; Molecular; Morbidity - disease rate; Mutation; Nodule; Oncogenic; Operative Surgical Procedures; Organoids; Orphan; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Prognostic Marker; Publishing; Recurrence; Reporting; Research; Resolution; Role; Sampling; Series; Specimen; Survivors; Target Populations; Testing; Therapeutic; Tissues; Training; Transcription Alteration; Translating; Tumor Debulking; Unresectable; Validation; Work; chemotherapy; clinical application; clinical translation; cohort; comparative; design; drug sensitivity; drug testing; drug-sensitive; effective therapy; experience; genetic testing; genomic data; high risk; hospice environment; improved; intraperitoneal therapy; knowledge base; molecular subtypes; mortality; novel; palliative chemotherapy; personalized medicine; personalized strategies; prognostic; prognostic model; prospective; response; survival prediction; targeted exome sequencing; therapy outcome; translational potential; treatment choice; treatment response; tumor

Project Summary The overarching goal of our research is to advance understanding of the clinical utility of genetic alterations underlying appendiceal adenocarcinoma (AA), a rare and often fatal malignancy with limited treatment options. AA is an orphan malignancy for which there is a profound lack of both clinical trials data and molecular understanding to guide treatment. Cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) (CRS/HIPEC, “C/H” for short) is an aggressive but effective treatment for eligible patients. C/H prolongs the lives of eligible patients, while ineligible patients are limited to palliative chemotherapy or hospice and experience dismal outcomes. In Aim 1, we will build on preliminary evidence that a gene-based classifier prognostic of AA patient survival can be translated into an actionable genetic test designed to extend C/H eligibility to a targeted population that may receive benefit, but would otherwise be ruled ineligible. This work will utilize a statistically powered longitudinal patient cohort of AA tissues and patient clinical data and employ unique classification strategies for training and validation. In Aim 2, we will address the considerable knowledge gap in our molecular understanding of AA. We will characterize the prognostic mutational landscape of high-grade AA. Through targeted exome sequencing, we will develop the first working knowledge base of the genetic alterations that underlie appendiceal adenocarcinoma and elucidate gene mutation-survival associations with clinical translation potential. We will also extrapolate our results to other anatomically-related gastrointstinal malignancies to further investigate the clinical and biological implications of our findings. In Aim 3, we will investigate genetic drivers of chemotherapy response using patient-derived tumor organoids. In these studies, we will construct PTOs from a prospective series of AA patients and determine their clonal responses to a panel of relevant drugs. From these data, we will elucidate significant gene-drug response associations and investigate their functional roles in modulating chemoresistant and sensitive phenotypes. These studies will demonstrate a novel use of PTOs for studying gene-drug response associations and identify genes and pathways that impact drug responsiveness in AA. Together, our findings will pave the way for implementation of actionable genetic tests to guide critical AA treatment decisions.

项目摘要 我们研究的首要目标是促进对遗传改变的临床效用的理解 潜在的阑尾腺癌（AA），一种罕见且通常致命的恶性肿瘤，治疗选择有限。 AA是一种罕见的恶性肿瘤，目前严重缺乏临床试验数据和分子生物学证据。 理解，指导治疗。肿瘤细胞减灭术（CRS）联合腹腔热化疗 （HIPEC）（CRS/HIPEC，简称“C/H”）是一种针对符合条件的患者的积极但有效的治疗方法。C/H键 符合条件的患者的生命，而不符合条件的患者仅限于姑息化疗或临终关怀， 经历悲惨的结果。在目标1中，我们将建立在初步证据的基础上，基于基因的分类器 AA患者生存的预后可以转化为可操作的基因检测，旨在延长C/H 有资格的目标人群可能会获得福利，但否则将被裁定为无资格。这项工作将 利用AA组织和患者临床数据的统计功效纵向患者队列，并采用独特的 用于训练和验证的分类策略。在目标2中，我们将解决 我们对AA的分子理解我们将描述高级别AA的预后突变景观。 通过有针对性的外显子组测序，我们将开发第一个遗传改变的工作知识库 其是阑尾腺癌的基础，并阐明了基因突变-生存与临床 翻译潜力。我们还将把我们的结果外推到其他解剖学相关的胃肠 恶性肿瘤，以进一步研究我们的研究结果的临床和生物学意义。在目标3中，我们 使用患者来源的肿瘤类器官研究化疗反应的遗传驱动因素。在这些研究中， 我们将从一系列前瞻性的AA患者中构建PTO，并确定他们对一组 相关药物。从这些数据，我们将阐明显着的基因-药物反应协会，并调查 它们在调节化学抗性和敏感表型中的功能作用。这些研究表明， PTO在研究基因-药物反应关联和鉴定影响基因和途径中的新用途 AA中的药物反应性。总之，我们的研究结果将为实施可操作的遗传学铺平道路。 测试，以指导关键的AA治疗决策。