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Establishing the Repertoire of Actionable Alterations in Appendiceal Adenocarcinoma

Award Number: R01CA258692
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Establishing the Repertoire of Actionable Alterations in Appendiceal Adenocarcinoma - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $477,793 )
2025	2025	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cancer Detection and Diagnosis Research	001	4	6/13/2025	NON-COMPETING CONTINUATION	$47,779
2025	2025	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cancer Detection and Diagnosis Research	000	4	12/4/2024	NON-COMPETING CONTINUATION	$430,014
														Subtotal = $477,793

Issue Date FY: 2024 ( Subtotal = $473,282 )
2024	2024	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cancer Detection and Diagnosis Research	001	3	4/16/2024	NON-COMPETING CONTINUATION	$24,909
2024	2024	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cancer Detection and Diagnosis Research	000	3	12/20/2023	NON-COMPETING CONTINUATION	$448,373
														Subtotal = $473,282

Issue Date FY: 2023 ( Subtotal = $505,425 )
2023	2023	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cancer Detection and Diagnosis Research	001	2	3/21/2023	NON-COMPETING CONTINUATION	$41,260
2023	2023	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cancer Detection and Diagnosis Research	000	2	11/28/2022	NON-COMPETING CONTINUATION	$464,165
														Subtotal = $505,425

Issue Date FY: 2022 ( Subtotal = $513,418 )
2022	2022	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cancer Detection and Diagnosis Research	000	1	12/20/2021	NEW	$513,418
														Subtotal = $513,418

Grand Total All Awards = $1,969,918

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Establishing the Repertoire of Actionable Alterations in Appendiceal Adenocarcinoma

Award Number: R01CA258692

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 01/01/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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