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. 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. CHANGE OF SCOPE There will be no change of scope or in the proposed experiements outlined in the original submission. All supplemental support will go toward the efforts of Dr. McCaw who will assist me over the course of 6 months to return to my original proposed timeline below. Activity Year 1 Year 2 Year 3 Year 4 Year 5 Specific Aim 1: Promotor mapping Specific Aim 2: Nanoparticle description Specific Aim 3: Bioreactor model Manuscript Deadlines X X X X R01 Preparation
Neuroendocrine tumors of the GI tract and pancreas are likely to metastasize, often are incurable, and can have significant symptoms associated with them. We aim to develop targeted treatments to treat these patients with less systemic side effects and to test the efficacy of these treatments in a novel ex vivo model to predict therapeutic response.
