Ben Ho Park, MD, PhD

2012-2013 BCRF Project:
The overarching goal of Dr. Park's research program is to identify and validate genetic targets in the PI3Kinase pathway for breast cancer therapy and translate these findings for clinical benefit. His team continues to make significant progress with their research. During the past six months, they have uncovered that mutations in the cancer-causing gene PIK3CA impart some of their cancerous effects through their interactions with Ras proteins, which does not occur with normal PIK3CA. This finding opens the possibility of targeting a protein-protein interaction with drugs that would have specificity for breast cancers harboring PIK3CA mutations.

In addition, Dr. Park's team is finalizing their experiments examining key downstream genes that mediate the cancer phenotype and drug resistance seen with PIK3CA mutations in breast cancer. In addition, using genetically modified cell lines they developed, Dr. Park's team has identified additional compounds that could be potential drugs useful for targeting specific mutations in the PIK3CA gene. They are now poised to perform laboratory model studies, which if successful would allow them to move these compounds forward into early phase clinical trials for breast cancer patients with these mutations. Excitingly, these future trials, as well as current trials of PI3Kinase inhibitors, rely upon the ability to accurately detect PIK3CA mutations in patients with breast cancer. Dr. Park's team recently published a study demonstrating that PIK3CA mutations can be accurately detected using peripheral blood and has thus established the feasibility of a "liquid biopsy" for determining mutation status of breast cancers and eligibility for targeted therapies. Dr. Park's ongoing studies will push this concept further so that his team will be able to correctly identify the mutations found in a woman's breast cancer using only peripheral blood, and thus use this knowledge for making informed decisions regarding systemic therapies.

During the upcoming year, Dr. Park's team will continue with this overall objective using their prior work as a foundation. This includes developing new drugs against mutant genes (mutant PIK3CA) within the PI3Kinase pathway as well as the development of new technologies and clinical protocols to quantitatively identify these mutations in blood for measuring disease burden and response to therapies.

Mid-year Progress: Dr. Park's laboratory continues to make significant progress on their project. Their first objective was to determine whether the gene GSK3β truly mediates the effects of PIK3CA mutations in terms of cellular growth and targeted therapy with drugs such as lithium. Their results demonstrate that GSK3β is not mediating the growth inhibitory effects of lithium, however, GSK3β does indeed regulate some of the growth promoting effects of PIK3CA mutations. Dr. Park's team is finalizing these experiments with the goal of submitting the results for publication within the next six months. Their second objective was to further develop mutation specific inhibitors by using their genetically engineered cell lines to screen for drugs that specifically inhibit cancer cells harboring one type of mutation in PIK3CA versus another.

During the past six months, they have confirmed that these compounds do indeed retain PIK3CA mutation specificity using additional cancer cell lines, and they have recently had more of these compounds synthesized to begin in vivo studies. Ultimately if successful this would lead to early phase clinical trials. Dr. Park's third and last objective was to continue with tissue and blood collection to further develop data and assays for qualitatively and quantitatively measuring PIK3CA mutations using blood as a "liquid biopsy." The investigators have additional data demonstrating that a new platform called droplet digital PCR can in fact detect mutations with superior sensitivity than current standard sequencing. They are in the process of applying this technology to the blood samples from matched patient tumor specimens with known PIK3CA mutations to further push the sensitivity of this assay. Thus the past six months have demonstrated significant progress in developing mutant specific PIK3CA inhibitors and blood tests that will easily allow investigators to identify tumors with PIK3CA mutations and, importantly, use this knowledge for making informed decisions regarding targeted systemic therapies.

Bio:
Dr. Park is an Associate Professor of Oncology with a Joint Appointment in the Whiting School of Engineering. He grew up in Saginaw, Michigan and attended The University of Chicago receiving his A.B. degree in Biology in 1989. He then pursued dual degree training at The University of Pennsylvania School of Medicine where he received both his MD and PhD degrees in 1995. Dr. Park then trained in Internal Medicine and Hematology/Oncology at The Hospital of The University of Pennsylvania prior to coming to Johns Hopkins where he completed a post-doctoral fellowship in cancer genetics in the laboratory of Drs. Ken Kinzler and Bert Vogelstein.

In 2002, Dr. Park joined the faculty at The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in the Breast Cancer Research Program. His lab utilizes sophisticated genetic models to identify, validate and develop targeted therapies for breast cancer. Currently the lab is focused on the PI3 Kinase/AKT signaling pathway, based on the lab's initial finding that the PIK3CA gene is mutated at high frequency in human breast cancers

Dr. Park remains actively involved with all aspects of biomedical research training including teaching of graduate and medical students, post-doctoral fellows, interns, residents and clinical fellows. In addition, Dr. Park continues clinical duties including attending on the inpatient oncology service and seeing breast cancer patients in the outpatient setting.