As a VA Research Career Scientist, Dr. Timothy J. Hoffman’s research activities span 5 distinct but interrelated areas involving translational drug development in oncology-predominantly related to molecular imaging and targeted radiotherapy. The primary research activity is currently focused on developing radiolabeled receptor targeted theranostic (diagnostic and therapeutic) drugs for use in diagnosing, staging, and treating advanced prostate cancer (PC). To achieve this programmatic goal, we are evaluating a combination of Ga-68 diagnostic positron emitting agents for use in clinical nuclear medicine PET imaging and Pb-212 alpha particle therapeutic agents for the systemic delivery of targeted radiotherapy to Bombesin (BB2) receptor positive prostate cancers. This bench to bedside program involves 1) basic radiochemical synthesis of novel radiopharmaceuticals, 2) In vitro evaluation of cytotoxicity using a panel of human prostate cancer cell lines representative of the spectrum of prostate cancer from androgen dependent to androgen independent as well as incorporating chemotherapy naïve and resistant cell lines, 3) In vivo investigation into the utility of these systemically administered theranostic agents to accurately target receptor positive cells permitting quantitative PET imaging for diagnosis and staging of the Ga-68 labeled agent, 4) Assessing the therapeutic efficacy of the Pb-212 labeled agent for treating human PC xenografts, and 5) Performing the necessary tissue dosimetry and toxicity studies to enable the filing of a Physician sponsored IND application to the FDA as one of the final steps toward translating these agents into clinical trials. The second focus of program activity involves establishing the Truman VA Clinical Research Radiopharmacy (CRR) through VA ShEEP-IC funding for the production of novel short lived PET radiopharmaceuticals to be utilized in clinical oncology and nuclear medicine research. The lack of research radiopharmacy infrastructure as a major roadblock preventing the translation of drug discoveries from the bench to the clinic. The CRR infrastructure and necessary hot cell shielding technology is currently being procured with a goal of having a fully operational CRR that is compliant with FDA, NRC, NHPP regulations and USP guidelines by the Fall of 2019. The third focus of program activity involves directing the operation of the VA Biomolecular Imaging Center which is operated as a shared core research service to provide preclinical molecular imaging services utilizing PET, SPECT, CT, 7T MRI, Optical, and Bioluminescent technologies to VA research investigators primarily in the areas of oncology, cardiology, and neuroscience. The fourth and fifth foci of program activity involves formal scientific collaboration and scientific mentorship of clinicians and basic scientists in the areas of oncology and molecular imaging on 4 active VA Merit awards, the new VA Open Field Blast Core, 1 VA CDA2 award, 1 NIH RO1 award, and 1 NCRR T32 award.

Prostate cancer remains the second leading cause of male death and the most commonly diagnosed cancer in male veterans in the United States. The research program currently being performed by VA Research Career Scientist Dr. Timothy Hoffman is focused on developing a novel cancer cell targeted radioactive drug therapy called targeted alpha therapy (TAT) to deliver effective prostate tumor targeted radiation therapy. TAT has the potential to be used in patients at all stages of disease, independent of androgen status or chemotherapy resistance status; thereby, offering a new paradigm in treatment for those patients who have progressive disease that is not controlled by currently available treatment options. The types of drugs under development in the Hoffman laboratory belong to a class of drugs called theranostics because the same drug can be used for both therapeutic applications to treat disease and also used for diagnostic applications to identify the presence and extent of disease when the appropriate radioisotope (diagnostic or therapeutic) is employed.