Establishing the Repertoire of Actionable Alterations in Appendiceal Adenocarcinoma

建立阑尾腺癌可行的改变方案

基本信息

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
项目类别：
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

项目摘要

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总体目标是提高对遗传改变的临床了解潜在的阑尾腺癌（AA）是一种罕见且通常是致命的恶性肿瘤，治疗方案有限。 AA是一种孤儿恶性肿瘤，严重缺乏临床数据和分子理解用于指导治疗。（HIPEC）（简称CRS/HIPEC，“ C/H”）是一种侵略性但符合条件的患者。符合条件的患者的生活，而不合格的患者仅限于姑息化疗或临终关怀，在AIM 1中经历令人沮丧的结果，我们将基于基于基因的分类器 AA患者存活的预后可以转化为可起作用的基因检测，旨在延长C/H 可能获得受益的目标人群的资格利用AA组织和患者临床数据的统计动力纵向患者，并采用独特 AIM 2中的培训和验证策略。 OUL分子对AA的了解。通过靶向的外显子组测序，我们将建立遗传改变的第一个工作知识基础阑尾腺癌和阐明基因突变 - 阴性关联与临床的基础翻译潜力。我们还将推断出我们的结果在AIM 3中，我们将进一步研究我们发现的临床和生物学意义。在这些研究中使用患者衍生的肿瘤器官研究化学疗法反应的遗传驱动因素。我们将从AA患者的前瞻性AA患者中构建PTO，并确定其对面板的克隆反应在这些数据中，我们将阐明重要的基因抗反应协会它们在调节化学抗性和敏感表型中的功能。 PTO的新型使用用于研究基因 - 药物反应关联并确定影响的基因和途径 AA的药物反应性。指导关键AA治疗决策的测试。