Discovery Groups: Prostate Cancer
The Prostate Cancer Discovery Group’s goals are to generate trans-disciplinary collaborations that address important problems in prostate cancer biology and to work toward the development of novel early detection, imaging and treatment approaches. The interactions through the Prostate Cancer Discovery Group generated 2 NIH and 2 DOD peer-reviewed grants and 12 publications. The proof-of-principle clinical study with the prostate cancer targeting ligand validated the compound’s specificity, and led to its licensing and placement for a Phase I clinical therapeutic trial by Endocyte, Inc. In addition, PCCR’s coordination of the trial provided the foundation for the development of the 501(c)(3) (Boilermaker Health Innovations) drug development accelerator that now is active at Purdue University.
Discovery Group Leaders
- Timothy L. Ratliff
- Comparative Pathobiology
- Chang-Deng Hu
- Medicinal Chemistry and Molecular Pharmacology
A summary of recent outcomes are listed below
Dr. R. Graham Cooks, an analytical chemist who developed desorption electrospray ionization mass spectrometry (DESI-MS), has had a strong impact on discovery in prostate cancer. He utilized DESI-MS to image prostate cancer based on metabolite profiles and observed that cholesterol sulfate is overexpressed in many prostate cancers (Anal Chem, 82:3430, 2010). This led to studies to determine whether cholesterol sulfate provides an advantage to prostate cancer cells.
- The cholesterol sulfonation enzyme, SULT2B1b, is an important enzyme in prostate cancer metabolism. Genetic knockdown of SULT2B1b results in inhibition of prostate cancer cell growth. Dr. Andrew Mesecar is working to identify inhibitory compounds, which resulted in a collaborative Prostate Cancer DoD grant with Dr. Timothy Ratliff.
- Dr. Ji-Xin Cheng utilizes Stimulated Raman Loss microscopy to visualize and identify lipids in unfixed tissue. Since cholesterol sulfate appeared to be overexpressed in prostate cancer, Dr. Cheng began analyzing tissue with Dr. R. Graham Cooks and discovered that cholesterol esters in lipid droplets within prostate cancer cells is a prominent feature of cancer (Cell Metab. 19(3):393, 2014). Dr. Cheng determined that available inhibitors of ACAT-1 and -2 (Avasimibe) inhibited prostate cancer cell proliferation in cell culture and, through the Biological Evaluation Shared Resource, determined that Avasimibe also inhibited prostate tumor growth in vivo. Plans for clinical evaluation are being developed.
- As a result of interactions in the Prostate Cancer Discovery Group, a study was designed, and a first in man Phase 0 clinical trial was completed that tested the ability of a small molecule developed by Dr. Phillip Low to specifically target prostate cancer. The PCCR held the IND (#108096) and Dr. Thomas Gardner (IU Simon Cancer Center) was the principal investigator on the clinical study. The study was completed in 2013.
- Dr. Mary Wirth developed silicon-based protein separation materials that were adapted for high-throughput isoelectric focusing (100 samples completed in 10 minutes). Dr. Wirth is collaborating with Dr. Donald J. Tindall (Mayo Cancer Center) to determine whether serum PSA glycosylation types can segregate aggressive from non-aggressive cancer (NCI R21 grant awarded).
- Dr. Chang-Deng Hu identified molecular mechanisms linked to radiation-induced neuroendocrine differentiation. The work was a collaborative effort and included Noah Hahn (IU Simon Cancer Center now at John Hopkins) and Dr. Timothy Ratliff. The work resulted in receipt of a DOD Prostate Cancer Program Idea Award and a publication (Am J Cancer Res, 1:834, 2011).
- Dr. James Fleet and Dr. Timothy Ratliff are collaborating to determine the impact of vitamin D on myeloid derived suppressor cells (MDSC). Dr. Ratliff observed that active MDSC expressed high levels of the vitamin D receptor. Dr. Fleet, a vitamin D expert, worked with Dr. Ratliff to define the impact of vitamin D on the activation and regulatory activity of MDSC. An NIH R01 and an NIH R21 have been submitted. The R01’s goal is to define vitamin D functional impact and the R21’s goal is to define the impact of vitamin D receptor-expressing MDSC on vascularization of cancers.