Neuroendocrine Tumor Research Foundation-AACR Grant
Formerly the Caring for Carcinoid Foundation, the Neuroendocrine Tumor Research Foundation updated its name in 2015 to better reflect the current medical terminology for the disease and to include all those who are affected by neuroendocrine cancer in their community of support. The Neuroendocrine Tumor Research Foundation-AACR Grant represents a joint effort to promote and support innovative cancer research. This grant is available to independent junior and senior investigators to develop and study new ideas and innovative approaches that have direct application and relevance to neuroendocrine tumors. Proposed research may be in any discipline of basic, translational, clinical, or epidemiological cancer research.
Well-differentiated pancreatic neuroendocrine tumors (pNETs) represent a heterogeneous group of tumors with variable degree of aggressiveness. Treatment response and overall prognosis is largely determined by tumor grade. It is unknown when and how high-grade tumors arise in the overall course of the disease and in relation to treatment. This proposal seeks to resolve these issues by exploiting recent advances in tumor evolution biology. Using multiregion sampling from primary and metastatic sites over multiple time points, Dr. Ziv’s team will reconstruct tumor phylogeny to determine the timing of the emergence of high grade subclones and to identify subclones selected for after therapy. By tracing the subclonal origin of high grade and treatment resistant tumors, this proposal will have important consequences regarding the role of tumor debulking, optimal treatment sequencing, and predictive biomarkers. Moreover, the findings will shed light on pNET tumor evolution, a poorly understood but important aspect of pNETs.
Dr. Ziv is an interventional radiologist at Memorial Sloan Kettering Cancer Center and Director of the Laboratory for Interventional Oncology. His research efforts are focused on understanding neuroendocrine tumor evolution and transformation using a combination of computational techniques and cell line models. He is a recipient of the 2019 Gary Becker Young Investigator Award from the Society of Interventional Radiology. He earned a dual MD, PhD degree at Columbia University, where his dissertation focused on developing machine learning tools to understand the structure and function of gene networks. He completed his intern year at Mount Sinai University, and his residency and fellowship at the University of California, San Francisco.
Acknowledgement of Support
We are very grateful for the 2020 Neuroendocrine Tumor Research Foundation-AACR Grant that will enable us to catalog the subclonal evolution of pancreatic neuroendocrine tumors in order to decipher when and how the most aggressive subclones emerge.
Traditional chemotherapeutics induce systemic toxicities that limit treatment protocols to conservative clinical endpoints instead of seeking long-term tumor regression and cure. Given the goal of maximizing therapeutic index, drug delivery systems have been used to actively target cytotoxics and reduce off-target effects. Image-guided drug delivery is uniquely suited to enhance the therapeutic index of chemotherapy agents based on its intrinsic ability to monitor and quantify drug distribution. To demonstrate the translational feasibility of this approach, the clinical positron emission tomography agent 68Ga-DOTA-TOC will be used as the foundation for developing a peptide-drug conjugate with the DNA alkylating agent temozolomide (TMZ). Receptor-mediated TMZ delivery could overcome the effects of neuroendocrine tumor heterogeneity, potentially making it a universal, tumor-specific chemotherapy agent for somatostatin receptor subtype 2-positive tumors. Targeted TMZ delivery may also produce sufficiently high tumor doses capable of overcoming resistance mechanisms in a manner that is not possible with systemic administration.
Dr. Azhdarinia is an associate professor of molecular medicine in the Brown Foundation Institute of Molecular Medicine at the University of Texas Health Science Center at Houston. Dr. Azhdarinia received his bachelor’s degree in biology from the University of Houston, followed by completion of his master’s degree and PhD in pharmacology from the University of Texas Graduate School of Biomedical Sciences in Houston. His research training was in the area of contrast agent development with a focus on radiopharmaceutical development. Dr. Azhdarinia’s research interests are in utilizing molecular targeting strategies for the detection and treatment of cancer.
Acknowledgement of Support
The 2019 Neuroendocrine Tumor Research Foundation-AACR Grant will allow my laboratory to develop a drug delivery approach that uniquely combines clinically proven imaging and therapy moieties into a single agent. The funding critically supports my long-term goal of introducing new precision therapies for patients with neuroendocrine tumors.
Our overarching goal is to better understand the role of lysine methylation of cellular proteins in neuroendocrine tumor development. To explore possible connections between over 100 methyltransferases and tumorigenesis we performed a high-content genetic screen. We identified NSD3 enzyme as a key driver of neuroendocrine tumor progression and drug resistance. However, the catalytic activity and substrate specificity of NSD3 in neuroendocrine tumors remains unknown. We hypothesize that NSD3 enzymatic activity cooperates with oncogenic signaling to promote the unlimited expansion of neuroendocrine cells. We will use a multi-disciplinary strategy to characterize NSD3 methylation activity and elucidate the molecular mechanisms and pathways by which NSD3 promotes tumorigenesis. To validate the function and therapeutic potential of NSD3 we have generated a pre-clinical mouse model of pancreatic neuroendocrine tumors faithfully recapitulating human disease. The major, long-term impact of our studies will be the development of novel therapeutic strategies to treat several types of devastating neuroendocrine cancers.
Dr. Mazur earned his PhD degree in 2011 in the Max Planck Institute of Biochemistry and University of Munich, Germany. From 2011 to 2016 Dr. Mazur completed his postdoctoral fellowship at Stanford University, in the laboratory of Dr. Julien Sage. Since 2017, Dr. Mazur is an assistant professor at MD Anderson Cancer Center. Dr. Mazur’s research uncovered the function of several orphan enzymes that provided new links between protein modification and cancer biology. His lab aims to harness protein post translation modification signaling to cancer therapy. Dr. Mazur’s work is supported by the NIH Pathway to Independence, CPRIT Rising Star Award and Sanofi Innovation Award.
Acknowledgement of Support
Unique mechanisms that drive neuroendocrine tumors development are not fully recognized. Our progress is hindered by the lack of proper pre-clinical models of the disease. The award provides critically needed resources to build a comprehensive cancer modeling platform to identify and validate novel therapeutics using accurate animal models that faithfully recapitulate human disease.