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Targeted Treatment of Metastatic Gastroenteropancreatic Neuroendocrine Tumors

Award Number: K08CA234209
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 07/01/2019
PERIOD OF PERFORMANCE END DATE: 12/31/2024

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Targeted Treatment of Metastatic Gastroenteropancreatic Neuroendocrine Tumors - PROJECT SUMMARY Neuroendocrine tumors derived from the tubular GI tract or pancreas (GEP-NETs) represent the second most prevalent GI malignancy. Surgical resection can be curative, but 40% of patients present with metastatic disease limiting resectability. These tumors often secrete bioactive hormones that can cause debilitating symptoms. Debulking operations can provide palliation of symptoms, but are not curative and likely do not confer any survival advantage. Various Notch isoforms have been shown to be tumor suppressive in NETs, as opposed to oncogenic in other solid malignancies. Preliminary studies have suggested the Notch3 isoform acts as a tumor suppressor in GEP-NETs. Histone deacetylase inhibitors (HDACi) have shown potential for upregulating Notch3 expression in NETs and thereby suppresses tumor growth. However, these drugs have had limited clinical applicability in other malignancies; largely in part to their undesirable side effects. Nanoparticle delivery systems have previously been utilized to selectively deliver drugs to NETs by targeting somatostatin receptors (SSTR), which are overexpressed in the vast majority of these tumors. This selected targeting can reduce systemic side effects and improve drug efficacy. Our central hypothesis is that SSTR- targeted HDACi-loaded nanocarriers can induce tumor suppression and decrease bioactive hormone secretion in metastatic GEP-NETs via Notch3 induction. The proposed investigation will evaluate: 1) Mechanisms behind HDACi induction of Notch3, 2) Cytotoxic capabilities of experimental nanoparticles, 3) Ability of targeting system to tumor localize in animal model, and 4) Feasibility of patient-derived bioreactors as a personalized method for drug testing. Specific Aim 1: Identify the regulatory elements responsible for pharmaceutical induction of Notch3. Specific Aim 2: Determine if tumor-targeted drug-loaded nanocarriers are selectively cytotoxic and reduce hormonal secretion in GEP-NETs. Specific Aim 3: Establish if bio-reactors engrafted with patient-derived GEP-NET are a viable model for drug testing. My training will be mentored by Drs. Herbert Chen (Professor of Surgery and Biomedical Engineering), James Bibb (Professor of Surgery and Vice-Chair of Basic Research), and Eugenia Kharlampieva (Associate Professor and Director of the Chemistry Graduate Program); as well as a panel of accomplished scientific advisors within a highly supportive and productive training environment. My background in the pharmaceutical industry and basic laboratory science provide me the resources to explore the mechanisms of Notch3 tumor suppression at a biochemical level; while my position as a surgical oncologist allows for patient centered context and readily accessible tissue. Data and training obtained through this award mechanism will provide the necessary support to translate my preliminary data into preclinical human trials and evaluate new mechanism for restoration of Notch3 by better understanding the epigenetics regulating its expression. This will set the stage for an independent career in mechanistic studies and drug development related to GEP-NETs.


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	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cancer Research Manpower	000	5	4/10/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $158,814 )
2023	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cancer Research Manpower	000	5	6/7/2023	NON-COMPETING CONTINUATION	$158,814
														Subtotal = $158,814

Issue Date FY: 2022 ( Subtotal = $158,814 )
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cancer Research Manpower	000	4	6/20/2022	NON-COMPETING CONTINUATION	$158,814
														Subtotal = $158,814

Issue Date FY: 2021 ( Subtotal = $158,814 )
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cancer Research Manpower	000	3	6/17/2021	NON-COMPETING CONTINUATION	$158,814
														Subtotal = $158,814

Issue Date FY: 2020 ( Subtotal = $212,814 )
2020	2020	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Trans-NIH Research Support	001	2	8/7/2020	SUPPLEMENT FOR EXPANSION	$54,000
2020	2020	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cancer Research Manpower	000	2	6/18/2020	NON-COMPETING CONTINUATION	$158,814
														Subtotal = $212,814

Issue Date FY: 2019 ( Subtotal = $158,814 )
2019	2019	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cancer Research Manpower	000	1	6/13/2019	NEW	$158,814
														Subtotal = $158,814

Grand Total All Awards = $848,070

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Targeted Treatment of Metastatic Gastroenteropancreatic Neuroendocrine Tumors

Award Number: K08CA234209

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 07/01/2019

PERIOD OF PERFORMANCE END DATE: 12/31/2024

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