Stanford University – Lead Investigator Dr. Justin Annes

Pheochromocytomas and Paragangliomas (PPGLs) are genetically heterogenous neuroendocrine tumors that frequently occur in the context of an inherited predisposition. Over the past few decades, germline mutations in more than 12 genes have been causally associated with PPGL risk. While PPGLs are often considered to have low malignant potential, metastatic risk is in fact highly variable and strongly influenced by the specific genetic driver. Most notably, PPGLs that result from an inherited pathogenic SDHB gene mutation have substantial metastatic risk, estimated to be ~40-50%. Unfortunately, no effective treatment for metastatic SDHB-related PPGLs exists. Hence, developing a deep molecular understanding of SDHB-related tumorigenesis to enable discovery of effective treatments is an urgent priority. Indeed, a critical step along the therapeutic development pathway is establishment of an animal model that faithfully recapitulates human disease and allows therapeutic discovery. Regrettably, numerous efforts over the past 20 years failed to generate an SDHB-related PPGL mouse model, leading to concerns about feasibility. Despite this sentiment, my laboratory successfully undertook the challenge of generating an SDHB PPGL mouse model. These mice provided several key insights. First, SDHB deficiency is compatible with mouse chromaffin cell viability. Second, although SDHB is a tumor suppressor gene (loss of both copies is required for tumorigenesis), loss of SDHB expression and succinate accumulation are not sufficient for tumorigenesis. Third, SDHB deficiency recapitulates several cardinal features of human SDHB-deficient tumors, including succinate accumulation, mitochondrial swelling/expansion and histone hypermethylation; however, the absence of tumor formation demonstrates the insufficiency of the prevailing “oncometabolite hypothesis.” Fourth, SDHB-deficient tumorigenesis requires disruption of additional, unidentified, tumor suppressor gene(s) that promote cellular replication and enable succinate-dependent cellular reprograming (hypermethylation). Herein, we propose to generate an improved SDHB-deficient PPGL mouse model by identifying missing/unknown genetic driver(s) of tumorigenesis. Additionally, we will leverage our SDHB-deficient PPGL model to explore the therapeutic value of dietary modification (alone and in combination with well-tolerated medications). These experiments have the potential to fill an important gap in our mechanistic understanding of SDHB-dependent tumorigenesis and, possibly, uncover an actionable/testable dietary intervention that slows progression of SDHB-deficient PPGLs.