Utility and Mechanism of SHetA2 and Paclitaxel for Treatment of Endometrial Cancer

Simple Summary Incidence and death rates for endometrial cancer are steadily rising world-wide. Endometrial cancer patients at high risk for recurrence are treated with chemotherapy, which causes significant toxicity. Molecularly targeted drugs have been found to cause less toxicity than chemotherapy. We studied a low-toxicity drug, called SHetA2, which targets three heat shock A proteins that are highly mutated in endometrial cancers. Our results demonstrated that SHetA2 inhibits endometrial cancer cells and tumors, and enhances therapeutic effects of paclitaxel without increasing toxicity. This information supports development of clinical trials to test if combining SHetA2 with paclitaxel can increase the paclitaxel therapeutic effect without increasing toxicity, or allows a lowered paclitaxel dose to achieve the same level of therapeutic effect, but with reduced toxicity. Our new knowledge about how SHetA2 works can be translated into development of biomarkers to predict with patients would most likely benefit from SHetA2-based therapy. Endometrial cancer patients with advanced disease or high recurrence risk are treated with chemotherapy. Our objective was to evaluate the utility and mechanism of a novel drug, SHetA2, alone and in combination with paclitaxel, in endometrial cancer. SHetA2 targets the HSPA chaperone proteins, Grp78, hsc70, and mortalin, which have high mutation rates in endometrial cancer. SHetA2 effects on cancerous phenotypes, mitochondria, metabolism, protein expression, mortalin/client protein complexes, and cell death were evaluated in AN3CA, Hec13b, and Ishikawa endometrial cancer cell lines, and on growth of Ishikawa xenografts. In all three cell lines, SHetA2 inhibited anchorage-independent growth, migration, invasion, and ATP production, and induced G1 cell cycle arrest, mitochondrial damage, and caspase- and apoptosis inducing factor (AIF)-mediated apoptosis. These effects were associated with altered levels of proteins involved in cell cycle regulation, mitochondrial function, protein synthesis, endoplasmic reticulum stress, and metabolism; disruption of mortalin complexes with mitochondrial and metabolism proteins; and inhibition of oxidative phosphorylation and glycolysis. SHetA2 and paclitaxel exhibited synergistic combination indices in all cell lines and exerted greater xenograft tumor growth inhibition than either drug alone. SHetA2 is active against endometrial cancer cell lines in culture and in vivo and acts synergistically with paclitaxel.