Establishing the Repertoire of Actionable Alterations in Appendiceal Adenocarcinoma

项目摘要 我们研究的首要目标是增进对基因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。 再生障碍性贫血是一种罕见的恶性肿瘤，其临床试验数据和分子水平都非常缺乏。 了解以指导治疗。细胞减灭术(CRS)加腹腔温热化疗 (HIPEC)(CRS/HIPEC，简称“C/H”)对符合条件的患者是一种积极但有效的治疗方法。C/H延长 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和 体验令人沮丧的结果。在目标1中，我们将基于基于基因的分类器的初步证据 再生障碍性贫血患者存活的预后可以转化为可操作的基因测试，旨在延长C/H 有资格获得可能获得福利，但否则将被裁定为不符合资格的目标人群。这项工作将 利用统计支持的AA组织和患者临床数据的纵向患者队列，并采用独特的 用于培训和验证的分类策略。在目标2中，我们将解决以下方面的巨大知识差距 我们对再生障碍性贫血的分子理解。我们将描述高级别再生障碍性贫血的预后突变情况。 通过有针对性的外显子组测序，我们将建立第一个关于基因改变的工作知识库 这是阑尾腺癌的基础，并阐明了基因突变-生存与临床的关系 翻译潜力。我们还将把我们的结果外推到其他与解剖学相关的胃肠道 以进一步调查我们发现的临床和生物学意义。在《目标3》中，我们将 使用患者来源的肿瘤有机化合物研究化疗反应的遗传驱动因素。在这些研究中， 我们将构建一系列预期的再生障碍性贫血患者的PTO，并确定它们对小组的克隆性反应 相关药物。从这些数据中，我们将阐明显著的基因-药物反应关联，并调查 它们在调节化疗耐药和敏感表型中的功能作用。这些研究将证明 PTOS在研究基因-药物反应关联和识别影响基因和途径的新用途 再生障碍性贫血的药物反应性。总而言之，我们的发现将为实施可操作的遗传 指导关键的AA治疗决定的测试。

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.