HSP70 as a therapeutic target of pancreatic cancer

Sandra Helinski

Diagnosis of Pancreatic cancer portends poor prognosis due to its aggressive biology and resistance to conventional chemotherapy. Hence there is an urgent need for novel and effective treatments. We have previously shown that heat shock protein 70 (HSP70), a pro-survival protein, is overexpressed in pancreatic cancer cells and its downregulation leads to apoptotic cell death in pancreatic cancer cells. We have also shown that triptolide, a diterpene triepoxide extracted from a Chinese herb, is an effective inhibitor of heat shock response in pancreatic cancer cells. We have evaluated triptolide as a novel therapy for pancreatic cancer and have demonstrated that at nanomolar doses triptolide inhibits HSP70 and induces cell death in various pancreatic cancer cell lines. To facilitate its use in clinics, we have now developed a water soluble pro-drug of triptolide. Minnelide, the pro-drug of triptolide, demonstrates similar efficacy against pancreatic cancer. In an effort to generate pre-clinical data we have now tested Minnelide against pancreatic cancer in various animal models, simulating multiple clinical scenarios. We have shown the Minnelide prevents growth and metastases of pancreatic cancer and also prevents recurrence, even when the treatment is stopped. Currently, Minnelide is in phase I clinical trial against advanced GI malignancies. We are hopeful that Minnelide will emerge as novel and effective therapy against this dreadful disease.