In this application entitled "Evaluating a parthenolide analogue as a new bladder and kidney cancer therapy" a plan to credential dimethylaminoparthenolide (DMAPT) as a new therapy for these cancer types is detailed. DMAPT is an amino analogue of the sesquiterpene lactone parthenolide. The latter is extracted from the plant Tenacetum Parthenium and is listed in the WHO pharmacopeia of Traditional Medical Systems. However, its poor pharmaceutical properties have limited its clinical applicability. DMAPT has mitigated the bioavailability concerns of parthenolide while maintaining the same mechanism of action. In essence, both parthenolide and DMAPT generate brief oxidative stress while concurrently blocking the protective pathway, nuclear factor kappa B (NF?B). This agent therefore has a novel mechanism of action and has the potential to improve the care of patients with kidney or bladder cancer. However, prior to conducting clinical trials there is a need to define the in vivo activity of DMAPT both as a single agent as well as in combination to assess whether it can enhance standard anti-cancer therapies in these cancer types. Successful completion of the work proposed in this R03 application will also fulfill two purposes of Program Announcement - PA-09-168 as it will (i) provide essential data for an R01 grant application to fund the conduct of a clinical trial and (ii) advance the science of Complementary and Alternative Medicine. The latter will be achieved by showing that simple modifications of a botanical product can overcome inherent poor pharmaceutical properties and facilitate the clinical development of an agent that would have otherwise failed. It is also of note that active systemic therapies have been developed for metastatic bladder and kidney cancer. However, only a few patients have long term remissions with these standard therapies and nearly all patients will have died of their cancer by two years. Therefore, there is an urgent need for improved therapy. The potential for DMAPT to be a new agent for bladder and/or kidney cancer in the near future is bolstered by the fact it is currently being evaluated in an ongoing phase 1 clinical trial in hematological malignancies in the United Kingdom and has already demonstrated good pharmaceutical properties, a favorable toxicity profile and evidence of pharmacodynamic (PD) activity. Therefore, the knowledge accumulated from the work proposed in this grant will guide the clinical development of DMAPT in bladder and kidney cancer in the near future.
Dimethylaminoparthenolide is an amino analogue of the natural product, parthenolide and has enhanced bioavailability. This application details the plans to assess DMAPT in bladder and kidney cancer in in vivo models as a single agent and in combination with standard therapies with the goal to guide clinical trial design. If successful, this work has the potential to improve the care of patient with bladder and/or kidney cancer.