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.