Combining c-Myc inhibitor and SHetA2 for cervical cancer: A promising low-to-no toxicity therapeutic strategy - Cervical cancer is the deadliest female cancer worldwide due to inadequate screening programs and disparities based on the healthcare system, income, race, and ethnicity. Patients with advanced and recurrent cervical cancer have complicated clinical management and are often incurable, which worsens their quality of life. Therefore, alternative treatment strategies focusing on new investigational agents and drug combinations are needed to improve cervical cancer patients’ outcomes. Metabolic reprogramming, a key hallmark of cancer that defines malignant behavior and chemoresistance, is a rational target for these strategies. Cervical cancer metabolism is targeted by our novel investigational agent, SHetA2, which inhibited cervical cancer xenograft growth without toxicity in preclinical studies. SHetA2 is currently in a Phase-1 gynecologic cancer clinical trial that kills cancer cells by binding to three heat shock proteins A (Grp78, hsc70, and mortalin) and releasing their client proteins. SHetA2 disrupts mitochondrial dynamics and functions in cervical cancer cells, thereby inhibiting oxidative phosphorylation and metabolic viability. However, these cells responded by upregulating glycolysis as a resistance mechanism. Inhibition of glycolysis increased SHetA2 sensitivity in cervical cancer cells both in vitro and in vivo, suggesting significant promise of SHetA2 combination therapy for cervical cancer. Our preliminary study demonstrated SHetA2-mediated c-Myc upregulation and the synergistic anticancer activity of the combination of a c-Myc inhibitor (Myci975) and SHetA2 in cervical cancer cells. Therefore, we hypothesized that Myc inhibitors would enhance the therapeutic efficacy of SHetA2 in cervical cancer without toxicity by counteracting the c-Myc-associated growth and metabolic pathways. Furthermore, our preliminary data suggested an important role for mortalin and calpain in SHetA2-mediated c-Myc upregulation; however, the exact underlying mechanism of c-Myc upregulation by SHetA2 treatment, the relationship between mortalin and c-Myc stability, calpain activity vs. c-Myc expression, and the functional role of c-Myc in glycolysis upregulation upon SHetA2 treatment remain unexplored. This study aims to evaluate the clinical applicability and mechanism of combining SHetA2 with a c-Myc inhibitor for cervical cancer therapy. In Aim 1, we will perform in vitro combination studies of SHetA2 and c-Myc inhibitors to select a specific Myc inhibitor that demonstrates better synergy without toxicity with SHetA2 compared to Myci975, if any. Subsequently, the efficacy of the selected drug combination will be evaluated in cervical cancer PDX animal model. Molecular markers and metabolic regulators of improved therapeutic responses will also be investigated. In Aim 2, we will investigate whether: a) Mortalin stabilizes c- Myc through direct/indirect binding, and SHetA2 interrupts this binding; b) SHetA2 mediated reduction in calpain- 1 expression and activity accounts for c-Myc upregulation; and c) c-Myc upregulation contributes to increased glycolysis upon SHetA2 treatment. Overall, this study is designed to generate preliminary data that could guide a cervical cancer clinical trial evaluating our novel drug combination to improve the quality of life.
