Identification of new drugs for the treatment of malignant pheochromocytomas and paragangliomas (PPGLs)
The project aims to identify new treatment opportunities for malignant pheochromocytomas and paragangliomas (PPGLs), particularly tumors associated with loss of function of the SDHB gene. Building on the previously reported development and characterization of an SDHB-deficient human pheochromocytoma cell model, we have completed a large drug-repurposing screen and advanced the most promising findings through several stages of validation.
Nearly 8,000 clinically relevant compounds were screened for their ability to reduce the survival of SDHB-deficient tumor cells while having less effect on the corresponding non-deficient cells. Successive confirmation and concentration-response experiments narrowed the initial candidates to a small group with reproducible and selective activity. The strongest candidates act by blocking cellular survival proteins that normally protect tumor cells from programmed cell death. Two lead compounds showed particularly marked activity at low concentrations, with substantially greater effects in SDHB-deficient cells than in control cells.
The selective effect was confirmed in both standard two-dimensional cultures and three-dimensional tumor-like cell models, increasing confidence that the finding is robust. The lead compounds were also evaluated in a living zebrafish tumor model, where they significantly reduced tumor growth. Importantly, the effect was greater in tumors with reduced SDHB activity, supporting the possibility of a targeted treatment strategy for the patient group with the greatest unmet clinical need.
These preliminary results represent a major step forward from broad drug screening to the identification of a focused therapeutic avenue. The next phase will determine whether the lead compounds can safely and effectively suppress tumor growth in a mammalian preclinical model, both alone and in combination with an established anticancer treatment. The study will also examine biological markers of treatment response. If successful, this work will provide essential evidence for future clinical development and for a more personalized treatment approach guided by the molecular characteristics of each patient’s tumor.
The support provided by the SDHB Coalition has been important in enabling this progression from model development and large-scale screening to the validation of promising treatment candidates. The project team is grateful for this contribution and looks forward to reporting further progress as the next preclinical phase is completed.