SDHB Pheo Para Coalition Research Project update: To establish a cell-based model for the discovery of new molecules that inhibit the degradation of altered SDHB and rescue its tumor suppressor function in PPGL
Summary:
In our SDHB PheoPara Coalition funded work, we aim to examine whether we can chemically stabilize pathogenic Succinate Dehydrogenase subunit B (SDHB), a tumor suppressor gene. Pheochromocytomas and Paragangliomas (PPGL) patients harboring a pathogenic mutation in the SDHB experience increased cancer metastasis and limited treatment options. This is because SDHB pathogenic variants are rapidly degraded in PPGL, which inhibits its ability to carry out is usual tumor suppressor function.
With the generous support from the SDHB Pheo Para Coalition in 2024, we established two human succinate dehydrogenase (SDHB) deficient cell models in our lab. With additional support from the US Department of Defense, we are now using genetic engineering approaches, such as inducible expression models, to examine what functional effects of artificially stabilizing SDHB in our models. Our preliminary data suggests that while wildtype SDHB activity can be rescued by protein stabilization, the effectiveness of this approach on altered forms of SDHB found in patients will be dependent on the type of alteration. This is an ongoing area of research, and we are actively exploring different SDHB deficient models and different clinically relevant SDHB mutants.
In a separate but related project, funded by New Zealand’s Maruice Wilkins Centre for Molecular Biodiscovery, we are now using these SDHB inducible expression models and functional genomics (e.g. pooled CRISPR screening) to discover what proteins within the cell are responsible for either enhancing or degrading altered SDHB. Identification of proteins these will direct our drug discovery efforts.
With continued support from the SDHB coalition in 2025, we are exploring new bifunctional therapies for the treatment of SDHB-deficient cancers. Lutetium-177-Dotatate peptide receptor radionuclide therapy (LuTATE PRRT) is a clinically approved and selective bifunctional treatment for PPGL patients (including those that are SDHB-deficient), however there are limitations with its use. Using publicly available proteomics and in-house transcriptomics data, we are designing, synthesizing, and evaluating the selective cancer cell killing potential of new bifunctional compounds called Regulated Induced Proximity targeting chimeras (RIPTACs). RIPTACs are heterobifunctional small molecules that elicit a stable ternary complex between a protein over-expressed in tumor cells and a protein essential for cell survival. This leads to “hold-and-kill” effect, causing selective accumulation of the RIPTAC in cancer cells and selective cell killing versus healthy cells.
We thank the SDHB coalition and their generous donors for their support thus far and look forward to continuing our work together.