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Development of a non-toxic cancer drug that disrupts oncogenic heat shock protein A/client protein interactions

Speaker: Prof. Doris Benbrook
Presbyterian Health Foundation Presidential Professor
Co-Leader, Gynecologic Cancers Program
Co-Principal Investigator, Center for Cancer Prevention and Drug Development, Stephenson Cancer Center
Affiliation: University of Oklahoma Health Sciences Center, Department of Obstetrics and Gynecology, Oklahoma, USA

Sulfur heteroarotinoid A2 (SHetA2) is a small molecule drug that was identified in a screen for compounds that kill cancer cells without harming healthy cells. Drug conjugated magnetic microparticles were used to identify three homologous heat shock protein As (HSPA9/mortalin, HSPA8/hsc70 and HSPA5/Grp78) as SHetA2 binding proteins. These proteins function as molecular chaperones that assure proper folding and cellular localization of client proteins and protein complexes. NMR and SPR analysis demonstrated that SHetA2 binds to the peptide binding domain of mortalin with a 10 µM binding constant. Co-immunoprecipitation assays of treated and control cancer cells demonstrated that SHetA2 causes release of client proteins from mortalin. Western blot and cell imaging studies documented that SHetA2 disruptions of HSPA complexes result in the client proteins being degraded, as is the case for cyclin D1, or relocated within the cell, as in the situation for p53. Comparison of healthy and cancer cells revealed that HSPAs are elevated in cancer cells to protect the cells from deleterious effects of over-expressed oncogenic client proteins, such as apoptosis induced by elevated p53, and also to provide stability to overexpressed complexes that drive cell proliferation, such as the cyclin D1/cyclin dependent kinase 4/6 (CDK4/6) complexes. Combination of SHetA2 with drugs targeted at p53 or CDK4/6 demonstrated synergistic interaction in cell culture and at least additive interaction in animal models with anti-angiogenic activity and no toxicities detected. US National Cancer Institute (NCI) RAID, RAPID and PREVENT programs provided the preclinical testing and drug capsule production needed to submit an Investigational New Drug (IND) application to initiate first-in-human SHetA2 clinical trials. This testing found that SHetA2 was not toxic, mutagenic, carcinogenic, teratogenic or irritating to skin at doses 50 fold above the doses that prevented and reduced tumor burden in animal models. NCI R01 grants are funding a Phase 1 clinical trial of SHetA2 in advanced or recurrent gynecologic cancers at the Stephenson Cancer Center, which will provide a recommended phase 2 dose (RPh2D) by the summer of 2021. Plans are in development to use the RPh2D of SHetA2 in combination with paclitaxel chemotherapy, a p53 inhibitor or CDK4/6 inhibitor in future Phase 1b/2 clinical trials. Suppository, intrauterine delivery and inhaled formulations are in development for application of SHetA2 as a chemoprevention agent.

Seminar language: English

Chairman: Michał Banaszak