Precision Targeting of Castration-Resistant Prostate Cancer with a Novel Ferrous Iron-Dependent Therapeutic Delivery and Tumor Imaging Strategy
Abstract
Although the recent approval of Enzalutamide and Abiraterone was a milestone for the treatment of castration-resistant prostate cancer, patient responses are variable and short-lived. There is an urgent need to develop new strategies to treat tumors refractory to standard-of-care therapy. The proteins, MYC and mTOR, are well-validated drivers of castration-resistant prostate cancer and have been implicated in resistance to androgen receptor inhibitors. In this project, we will employ a new therapeutic strategy to specifically target cancer cells with hyperactive MYC/mTOR by targeting a key pathological event induced by these oncogenes. Our approach involves a new chemical strategy to “unmask” and localize a potent anticancer therapy exclusively in cancer cells with hyperactive MYC or mTOR. The unmasking chemistry is based on a new class of antimalarials that has proven to be very safe and well tolerated in human clinical trials. We will study the unmasking of three different therapeutic agents in the proposed project—a potent DNA-modifying chemotherapeutic, the drug Enzalutamide, and the therapeutic radionuclide 177Lu. Our approach to “indirect” targeting of MYC/mTOR is entirely new to cancer research and could have dramatic implications for the treatment of other MYC/mTOR driven cancers. Moreover, our new indirect approach to targeting key drivers of cancer could also be cross-applied to other proteins that are key drivers of cancer, but challenging to directly target. In addition to this innovation in cancer therapeutics, we have developed a companion diagnostic for the therapy that can be used to detect tumors most likely to respond to the drug with positron emission tomography. This is also significant, as new imaging probes are significantly quicker and less expensive to gain Food and Drug Administration approval for first-in-human studies. Consequently, we can reasonably project that a first-in-man imaging study could take place within 2 years after the completion of the grant. We expect that promising imaging data will, in turn, stimulate great enthusiasm for the translation of the tumor-targeted therapies. Lastly, there is a well-recognized need for better prostate cancer imaging tools to improve the detection of micrometastases and monitoring tumor burden post-therapy. Based on our remarkable preliminary data showing unprecedented uptake of the imaging probe in a prostate cancer model, we anticipate our new imaging tool could have important applications beyond patient selection for therapy. In summary, this project outlines an unprecedented chemical approach to specifically target and eliminate castration-resistant prostate cancer cells harboring one of most important and therapeutically intractable drivers of cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810757
Entities
People
- Davide Ruggero
Organizations
- United States Army
- University of California, San Francisco