Tufts Medical Center – Lead Investigator Dr. Arthur Tischler

Paragangliomas are rare neuroendocrine tumors that typically arise along the distribution of sympathetic nerves in the abdomen and chest and branches of cranial nerves in the head and neck. A paraganglioma that develops in the adrenal gland is called a pheochromocytoma. Paragangliomas can be caused by hereditary mutations of at least 19 different genes.  Those caused by SDHB mutations are particularly aggressive and prone to metastasize. The development of effective treatments has been hampered by lack of valid models for pre-clinical testing and basic research.

The molecular and metabolic characteristics of SDHB-associated PCPG are fundamentally different from those of most other PCPG. Although researchers have attempted for many years to establish cell lines and xenografts from these tumors, until now there has been no model fully representing the distinctive characteristics of the actual tumors that occur in affected patients. Notably, attempts to establish mouse models have been unsuccessful. Using a novel strategy employing rats instead of mice, the Tischler laboratory recently established a cell line and xenograft model called RS0 (for rat Sdhb null), from heterozygous genetically engineered rats with a germline deletion in one Sdhb allele. Extensive, multiinstitutional, collaborative studies published in Endocrine Related Cancer in April 2020 showed that RS0 has lost the normal Sdhb allele, lacks Sdhb protein, and closely resembles SDHB-mutated human paragangliomas genetically and metabolically. It therefore appears to be the first example of a genetically and phenotypically valid model that many researchers in the field have been looking for. Fortuitously, a second model called RS1/2 developed in parallel from the same rat strain has lost the mutated SDHB gene and retains the normal one. RS1/2 may therefore serve as a control for experiments on RS0. Ongoing studies employ the RS0 and RS1/2 models to test prototype drugs using strategies that selectively target the distinctive vulnerabilities of Sdh deficient tumors and to determine the mechanisms of antitumoral effects by querying changes in relevant RNA and protein expression, and metabolic pathways critical to tumor growth. This integrated approach may lead to new strategies for slowing or preventing the growth of PCPG caused by mutations of the SDHB gene and improving the lives of affected patients.

Sdh-deficient paragangliomas are essentially a metabolic disease, characterized by expression of hypoxia-associated genes and altered metabolism that may result in a fragile, energy-compromised state. These characteristics suggest that drugs which compromise energy production or target hypoxic signaling pathways could be effective therapies alone or in combination. studies employing cultured RS0 cells have demonstrated antiproliferative and cytotoxic effects of several candidate drugs. Other laboratories in Australia, Europe and the United States have requested or already received the RS0 model for related studies..

The complete published paper describing the RS0 and RS1/2 models, which includes extensive background information, supplementary data and links to raw data files, can be accessed at https://doi.org/10.1530/ERC-19-0474.