University of Massachusetts Medical School Archives - Page 2 of 2

2019

Scholar Grant

Jason Shohet

Worcester, MA

Title: Targeting PRMT5 in high risk neuroblastoma

Executive Summary:
Most deaths from neuroblastoma are due to metastatic disease that has returned after stopping therapy. This is process is likely driven by cancer stem cell subpopulations within the cancer that escape initial treatment. Typically, this recurrent NB is drug resistant and has spread to the liver, bone marrow and other sites. Our laboratory has recently found that blocking the function of a gene called PRMT5 strongly blocks NB metastasis in preclinical tumor models of human NB. We propose that blocking the ability of NB to spread and grow at metastatic sites will reduce disease recurrence and could be incorporated into NB therapy. There are currently two drugs in early phase clinical trials that may be repurposed for use in children (JNJ-64619178 and GSK3326595). We find GSK3326595 kills neuroblastoma cells at very low concentrations in cell culture (below 10 nanomolar) consistent with other drugs that are successful in the clinic. Importantly, this drug almost completely blocks liver metastasis in our established preclinical models of NB. Based on our preliminary data and the literature we propose the following Aims: Aim 1 will identify PRMT5 dependent genes controlling metastasis and Aim 2 with characterize how PRMT5 inhibition alters neuroblastoma cancer stem and their contribution to metastasis in vivo. Both these aims will use in vitro and in vivo tumor models.
Bullet Points:
• PRMT5 is a novel drug target that controls cancer spread in multiple tumor models.
• Small molecule inhibitors against PRMT5 are being tested in phase 1/2 trials for multiple adult cancers.
• New pre-clinical studies in our laboratory suggest that PRMT5 inhibitors are highly effective at blocking neuroblastoma metastasis.
• We will use in vivo pre-clinical models of neuroblastoma to evaluate how these drugs block metastasis.
• Our studies will support the clinical use of PRMT5 inhibitors against neuroblastoma and other aggressive metastatic cancers.

2014

Scholar Grant

Dr. Jack Leonard

Worcester, MA

Pediatric brain tumors like astrocytoma/glioblastoma account for about 8% of childhood cancer but are responsible for up to 25% of pediatric cancer deaths. There is no effective treatment and radiotherapy, a common therapeutic option, appears to do more harm than good. A universal property of cancer and pediatric gliomablastoma is uncontrolled growth, and beta-catenin is the intracellular signaling molecule responsible for cell proliferation. We discovered a new, essential component of the cell machinery that controls beta-catenin stimulated cell proliferation. This tumor suppressor, Inhibitor of Beta-catenin Signaling (IBS) is missing in glioblastoma cells and restoring it to normal stops cell proliferation and initiates tumor cell death; normal cells are unaffected by IBS. In this application, we propose a paradigm shifting approach to the treatment of glioblastoma using an IBS preparation that readily crosses both the cell membrane and the blood-brain barrier, and a novel in vivo xenograph mouse that faithfully mimics the tumor lifecycle of patients. In pilot studies, injection of this IBS into the abdominal cavity of mice with human ovarian cancer quickly silenced tumor growth and led to widespread tumor necrosis. To extend these exciting findings to the treatment of pediatric glioblastoma we need to define the amount of IBS needed to kill tumor cells in vivo, optimize IBS delivery to the brain, and confirm that IBS kills patient-derived primary GBM tumors in vivo. Such studies are impractical in patients so we will use human pediatric astrocytoma cell lines and primary tumors obtained during surgery in our immune incompetent NSG mouse model. As the originators of the NSG mouse, we are poised to exploit the superior human tumor growth in this immune compromised strain to develop a real clinical application of IBS to the treatment of glioblastoma and generate the invaluable preclinical data required for future therapeutic development.