Developing a New Precision Treatment Strategy for SDHB-Deficient Cancers
At the University of Auckland, we (Drs Daniel Conole and Dr Susan Richter) are working to develop a new generation of targeted therapies for SDHB-deficient pheochromocytoma and paraganglioma (PPGL). Our goal is to create treatments that can selectively kill cancer cells while reducing effects on healthy tissues.
Current targeted therapies can provide clinical benefit for patients with SDHB-deficient tumours, but disease progression and treatment resistance can still occur over time. To address this challenge, we are investigating an emerging drug technology known as Regulated Induced Proximity Targeting Chimeras (RIPTACs). These innovative molecules are designed to recognize proteins that are highly abundant in cancer cells and use them to trigger selective cancer cell death.
Over the past year, we have made excellent progress toward this goal. We completed large-scale protein analysis studies in laboratory models of SDHB-deficient cancer, identifying more than 6,500 proteins and pinpointing a number of promising targets that may be exploited by future therapies. By comparing our findings with data from patient tumours, we identified key proteins that appear consistently associated with SDHB-deficient cancers and could form the basis of a highly selective treatment strategy.
Using these results, we designed a novel RIPTAC approach that brings together two carefully selected protein targets. This strategy is intended to create a “hold-and-kill” effect, where the therapeutic molecule preferentially accumulates in cancer cells and disrupts vital cellular processes, leading to selective tumour cell death.
A major focus of the project has been the complex chemistry required to build these new drug candidates. We successfully synthesized several critical chemical building blocks and developed new synthetic routes to overcome technical challenges encountered during the project. We have now completed most of the chemical steps needed to produce our lead RIPTAC candidate and are progressing toward its final assembly.
The next phase of our work will focus on completing synthesis of the lead compound and testing its activity in laboratory models of SDHB-deficient cancer. We will also compare its performance with a range of control compounds to confirm that any cancer-killing effects are driven by the RIPTAC mechanism itself.
This project represents one of the first attempts to apply RIPTAC technology to SDHB-deficient cancers. If successful, it could establish a completely new therapeutic approach for people living with these rare tumours and help pave the way for future precision medicines targeting the unique vulnerabilities of SDHB-deficient cancer cells.
We are grateful to the SDHB Pheo Para Coalition for their support, which has enabled us to advance this promising research program.