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. Funded research can 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. Using multiregion sampling from primary and metastatic sites over multiple time points, Dr. Ziv’s team is set to reconstruct tumor phylogeny to determine the timing of the emergence of high grade subclones and to identify subclones selected for after therapy.
Dr. Ziv 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. He is currently 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.
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.
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, Dr. Azhdarinia and his research group will use the clinical positron emission tomography agent 68Ga-DOTA-TOC as the foundation for developing a peptide-drug conjugate with the DNA alkylating agent temozolomide (TMZ). He anticipates that 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.
Dr. Azhdarinia received his 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. He is currently an associate professor of molecular medicine at the Brown Foundation Institute of Molecular Medicine at the University of Texas Health Science Center at Houston. His 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.
Dr. Mazur and his research group previously identified histone lysine N-methyltransferase NSD3 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. They hypothesize that NSD3 enzymatic activity cooperates with oncogenic signaling to promote the unlimited expansion of neuroendocrine cells. They are using 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, they have generated a pre-clinical mouse model of pancreatic neuroendocrine tumors faithfully recapitulating human disease.
Dr. Mazur earned his PhD degree at the Max Planck Institute of Biochemistry and University of Munich, Germany. He completed his postdoctoral fellowship at Stanford University. He is currently an assistant professor at MD Anderson Cancer Center, where he is uncovering the function of several orphan enzymes that provide new links between protein modification and cancer biology. His lab aims to harness protein post translation modification signaling to cancer therapy.
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.