Abstract In this application, I propose a novel precision medicine approach aimed at enhancing the therapeutic effect of peptide receptor radionuclide therapy (PRRT) in gastroenteropancreatic neuroendocrine carcinomas (GEP- NET)s. This award will provide protected research time and training in preparation for independent R01 funding. Over the past decade, there has been a fundamental paradigm shift in the management of GEP-NETs through use of somatostatin receptor type 2 (SSTR2) targeted PRRT. The FDA has recently approved clinical use of 177Lu-DOTATATE (Lutathera), a somatostatin analog loaded with the therapeutic radionuclide 177Lutetium, for PRRT of SSTR2-expressing GEP-NETs. Patients with low SSTR2 expressing tumors are often unresponsive to PRRT, leaving them with limited treatment options. Low SSTR2 expression is mainly mediated through epigenetic gene silencing. Here we propose to upregulate SSTR2 expression by using short-term pulsed epigenome-modulating chemotherapy to re-sensitize NETs to PRRT and improve its therapeutic index while reducing the non-target side effects of PRRT. In preliminary experiments we have shown dose-dependent robust upregulation of SSTR2 both in vitro and in vivo by targeting a series of ploycomb group proteins (PcG) involved in gene silencing. We propose to assess this approach in a range of models with the goal of optimizing the dosing and timing of the de-repression chemotherapy. If successful, this study will pave the way for clinical trials and near-term translation using clinically approved imaging and PRRT agents to markedly improve the effectiveness of therapy by increasing the radiation dose delivered to tumors relative to non-target organs. This proposal will enable me to become an independent investigator in translational precision imaging. My ultimate goal is to lead an independently-funded research program in the translation of novel theranostics for improving cancer care. To facilitate my progression to independence, I have designed with my mentors a career development plan involving tailored didactic coursework, workshops, seminars, and hands-on training that will provide me with formal education in epigenetics, computational biology, radiochemistry and radiotherapy dosimetry. The primary mentor for this project is Dr. Umar Mahmood, a renowned expert in translational precision imaging. Drs. Adam Bass and Ciprian Catana will serve as secondary mentors, lending their expertise in cancer genetics and epigenetics, and radiation dosimetry modeling, respectively. In addition, I will work with a team of advisors/consultants from MGH, including Drs. David Ryan, Daniel Chung, Ryan Corcoran, and Peter Caravan who will provide additional expertise and guidance as part of my scientific advisory committee. This research will be performed at the Martinos Center, a world-leading institution for translational imaging research. The project will greatly benefit from the unique resources of the Martinos Center, MGH C...