University of Arizona – Lead Investigator Dr. James Bibb

The University of Arizona’s current research supported by the SDHB PheoPara Coalition is to “Develop Diagnostic Biomarkers and Therapeutic Drug Screening for SDHB Mutation Driven Pheochromocytoma”. This research extends previously supported work in which we developed novel animal models of pheochromocytoma (PC) and characterize mechanisms by which SDHB mutations drive tumorigenesis. The rationale for this research is that over just the past few years, we have made major advances in understanding the mechanisms driving PC/PG, generating novel models of the disease, and introducing novel treatment strategies. While we very much wish to continue and expand our mechanistic studies, our overarching ambition is to leverage our discoveries to bring a cure to this disease in the fastest and most direct route possible. This update, hopefully, demonstrates the seriousness of our effort toward this obligation as our highest priority that we share with your organization.

One goal is focused on advancing a biomarker detection system based on the generation of recombinant monospecific antibodies to detect protein phosphorylation sites we showed drive PC cell neoplasia. We showed these biomarkers predicted patient derived xenograft responsiveness to experimental anti-Cdk5. We have completed preclinical studies showing the biomarker detection reagents at the immunohistological level. What will now expand this proof of utility to patient derived pheochromocytoma and paraganglioma tissue and adapt the antibodies to a clinical assay such as ELISA. The goal of this work is to develop a clinical assay to direct anti-Cdk5 therapy as novel precision medicine approach.

We also wish to develop a drug screen to identify novel compounds that target Cdk5/p25 as inhibitors, disrupters of Cdk5/p25 protein-protein interactions, or binding compounds to be developed into targeted protein degradation (PROTAC) reagents. The rational for this is to pursue new classes of compounds that do not have the specificity and toxicity limitations of purine analogs which target the catalytic ATP binding site of the kinase.. Additional components of this research include development of a Cdk5 bioreporter for high throughput screening in SDHB knockout hPheo1 cells. For PROTAC discovery, Cdk5, p35 and p25 degradation reporter systems will be developed in SDHB KO hPheo1 cells. I.e., we will derive stable transfected lines of SDHB KO hPheo1 cells with reporter systems for Cdk5 activity and PROTAC efficacy.  Novel compounds that arresting PC cell proliferation will undergo toxicity and pharmacokinetic analysis as early as possible in the process.

We want to bring compounds that show efficacy and safety across the preclinical testing process so that they will receive FDA approval for Phase 0/1 clinical testing as quickly as possible.

 These advances and this ongoing work would not be possible without the support of the SDHB PheoPara Coalition, and we are grateful to this foundation for their support in funding our research.