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
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.