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Engineered Enteric Nervous System-Peri Neural Invasion platform to improve predictive preclinical screens in early-stage colorectal adenocarcinomas

Award Number: R21CA263768
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2021
PERIOD OF PERFORMANCE END DATE: 06/30/2024

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Engineered Enteric Nervous System-Peri Neural Invasion platform to improve predictive preclinical screens in early-stage colorectal adenocarcinomas - PROJECT SUMMARY The objective of this proposal is to engineer and utilize enteric nerve plexi as a tool to improve predictive accuracy of preclinical screens in early stage II-III colorectal cancer (CRC). Peri-neural invasion (PNI) or CRC spread through nerves (especially nerves of the enteric nervous system; ENS) is an independent predictor of poor prognosis. Not only do CRC tumors actively recruit nerves, the ENS-nerves then have the ability to control epithelial cell proliferation and epithelial stem cell differentiation. This is noteworthy because both of these processes can alter CRC dynamics and modulate its response to adjuvant chemotherapy. In current clinical practice, PNI is established by pathological grading, but PNI into the ENS specifically is not considered. We believe that ENS-PNI is an important consideration in clinical decision making, because it could fundamentally alter tumor dynamics and response to adjuvant chemotherapy. Despite clear evidence that PNI is an active contributor to CRC, there are currently no preclinical models of ENS-PNI in CRC which severely limits our ability to investigate and target ENS-PNI. We propose to address this limitation through the development and validation of a novel 3D autologous patient-derived ENS-PNI platform, derived from patient-derived tumor epithelial cells and engineered nerves from adult enteric neural stem cells (ENSCs). We hypothesize that the engineered ENS-PNI platform can predict patient response to adjuvant chemotherapy with high fidelity via ENS regulation of CRC dynamics and cancer stem cell self-renewal. This proposal uniquely leverages the PI’s (Raghavan) published expertise with advanced biomaterial and bioengineered based platforms for engineering the tumor and colon microenvironment, combined with the Co-I’s (Esnaola) clinical expertise and access to patient biospecimen. Through our approach, we will examine the following aims: (1) Develop and validate an in vitro platform of ENS-PNI in CRC; (2) Utilize the engineered ENS-PNI platform to screen patient-derived early stage CRC tumors for adjuvant chemotherapy. We will validate the ENS-PNI platform using histopathology of the patient tumors they are derived from, and compare responses to chemotherapy to clinical responses. This will be the first instance of an in vitro 3D model of ENS-based PNI in CRC. The proposed work fits well into the Exploratory/Developmental Bioengineering Research Grant program, owing to its development of tissue- engineering based technology to improve the capability of preclinical cancer screening. This novel technology will be leveraged to develop a high-throughput amenable screen of stage II/III CRCs with a PNI component, for the purpose of identifying new avenues of targeted adjuvant therapy.


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 = $0 )
2025	2022	TEXAS A&M ENGINEERING EXPERIMENT STATION	3124 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Cancer Treatment Research	000	2	11/6/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $169,272 )
2022	2022	TEXAS A&M ENGINEERING EXPERIMENT STATION	3124 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Cancer Treatment Research	000	2	8/12/2022	NON-COMPETING CONTINUATION	$169,272
														Subtotal = $169,272

Issue Date FY: 2021 ( Subtotal = $219,700 )
2021	2021	TEXAS A&M ENGINEERING EXPERIMENT STATION	7607 EASTMARK DR	COLLEGE STATION	TX	77840	BRAZOS	USA	Cancer Treatment Research	000	1	6/28/2021	NEW	$219,700
														Subtotal = $219,700

Grand Total All Awards = $388,972

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Engineered Enteric Nervous System-Peri Neural Invasion platform to improve predictive preclinical screens in early-stage colorectal adenocarcinomas

Award Number: R21CA263768

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2021

PERIOD OF PERFORMANCE END DATE: 06/30/2024

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