Phuoc T. Tran, MD, PhD: Focus on Translational Medicine

Phuoc T. Tran, MD, PhD— Professor and Vice Chair for Research in the Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore—  speaks about his career path and how his distinguished mentors helped guide him in applying his laboratory research to leading clinical trials in cancer diagnosis and treatment. 

Dr Phuoc Tran recently joined the University of Maryland after spending 12 years at the Johns Hopkins University School of Medicine as Assistant Professor, then Professor of Radiation Oncology, Oncology, and Urology. He remains a member of the Johns Hopkins Bloomberg School of Public Health, Biochemistry & Molecular Biology. Dr. Tran also holds leadership roles as the NRG Oncology GU Translational Science chair, ASTRO Research Funding Development chair and Senior Editor/Editorial Board member for Cancer Research and the Journal of Clinical Oncology.

Although he is committed, through his current work, to addressing clinical problems in cancer in the laboratory and translating the results into strategies for cancer care, in particular prostate cancer, Dr Tran’s early goal was to focus solely on laboratory research. That he is now a leader in translational medicine, he attributes in large part to the encouragement of his mentors, as well as his good fortune in working with so many distinguished researchers in translational medicine during his training.

Dr Tran was born in June 1974 in Saigon (now Ho Chi Minh City) during the war in Vietnam. His family was able to leave Vietnam with the evacuation of US military personnel one year later. “My family and I were very lucky,” he acknowledges. “I don’t recall any of this, but what I owe to my parents’ coming to the United States, literally giving up everything, and working hard, starting from scratch, to build a life for us, is firmly entwined into the DNA of who I am,” he says.

Dr Tran grew up in San Diego, Southern California, and from 1992 to 1996 attended the University of California, San Diego (UCSD), where he was awarded a prestigious Regents Scholarship. During his sophomore year, he took a job working in the laboratory of Dennis Carson, MD, director of the UCSD Stein Institute for Research on Aging (SIRA) and director of the Moores Cancer Center. Dr Carson was already well known for identification and development of cladribine (2-chlorodeoxyadenosine), a highly effective treatment for hairy cell leukemia.

Dr Tran describes his position in Dr Carson’s laboratory as “the lowest possible entry level lab technician, making LB agar plates and autoclaving petri dishes” for his first mentor, Tsutumo Nobori, MD, PhD (later Professor and Dean of the Graduate School of Medicine at Mie University, Japan). “I had never thought about medicine until I met Dr Nobori and saw all the other physician-scientists working in the Carson lab,” he recalls. “Dr Carson was one of the first people I knew who ran a truly multidisciplinary research program, with clinicians, biologists, and organic chemists – a small but very diverse village. I still look back very fondly on that time.”

As a result of this experience, after graduating from UCSD with a BS in molecular biology, Dr Tran went into the MD/PhD program at Oregon Health and Science University (OHSU) in Portland, which offered training in a wide range of scientific disciplines and laboratory science, as well as exposure to clinical and translational research. He trained with R. Michael Liskay, PhD, now professor emeritus of Molecular and Medical Genetics at OHSU, whose research focused on the genetic and molecular mechanisms of DNA mismatch repair, Dr Tran studied yeast genetics and was awarded his PhD in 2001. “I had a terrific time. The training there was incredible,” he recalls.

Another person who greatly influenced Dr Tran was MD/PhD director, Brian J Druker, MD, Director of the Knight Cancer Institute at OHSU. Dr Druker is especially known for his research that led to the development of imatinib, a treatment for chromic myeloid leukemia and the first drug to target the molecular defect of a cancer while leaving healthy cells unharmed. This early discovery in precision medicine spurred the development of similar therapies for other cancers.

Around that time, Dr Tran realized how much he appreciated interactions with patients and the opportunity to help patients facing one of the most difficult times of their lives, cancer diagnosis and treatment. So he decided to go into postgraduate training in radiation oncology, encouraged by Dr Liskay, who had been professor in the Department of Therapeutic Radiology at Yale University School of Medicine. Dr Tran spent 2004-2009 at Stanford University Medical Center in the department of radiation oncology, a leading department in its field known for development of new applications of radiotherapy for prostate cancer, and pioneering therapy with high-energy radiation produced by the first medical linear accelerator in the Western hemisphere.

During his medical residency, Dr Tran worked under Dean W. Felsher, MD, PhD, currently Professor of Medicine (Oncology) and Pathology and Director of Translational Research and Applied Medicine, whose work involved transgenic mouse models of human cancers. Dr Tran recognized how this technology could fit with the concept of personalized medicine. During this time, he worked on creating animal models that could turn on and off the epithelial-mesenchymal transition (EMT), a process in cancer cells that enables them to migrate from the primary tumor to other parts of the body to form metastases.

Dr Tran joined Johns Hopkins in 2009, where he continued to investigate the natural history of metastasis with the goal of creating interventions around molecular targets. “Until recently, the process of metastasis was thought to be a binary state, so either you’re not metastatic and curable or you’re metastatic and you’re not curable,” explains. However, the current view of metastasis is as a spectrum ranging from a few (“oligo”) metastases to widely metastatic disease, each state requiring different therapeutic options.

In 2016 Dr Tran and his colleagues at the Johns Hopkins Sidney Kimmel Cancer Center set up a trial to determine whether stereotactic ablative radiotherapy (SABR) would improve oncologic outcomes in men with recurrent hormone-sensitive prostate cancer and 1 to 3 metastases. The ORIOLE (Observation versus stereotactic ablative RadiatIon for OLigometastatic prostate CancEr) trial (named after the Baltimore baseball team by Dr Tran, a self-confessed sports fanatic) and the STOMP trial, carried out around the same time in Belgium, are the only two randomized trials that have been carried out in this prostate cancer population, Dr Tran notes. Both were positive,^1,2 showing that when potentially curative therapy (SABR) is administered to patients previously thought not curable, we see improved outcomes, Dr Tran stresses, adding that this should be validated in larger trials.

Dr Tran and his team noted that in some ORIOLE patients and others treated outside of the ORIOLE trial who progressed following SABR, those with metastatic lesions in the bone were more likely to have recurrence in a new bone site. “So we are trying to match that pattern of recurrence with a bone-targeting radiopharmaceutical, radium Ra 223 dichloride in the RAVENS (RAdium-223 and SABR Versus SABR for oligomEtastatic prostate caNcerS) trial, to see whether it benefits these patients,” Dr Tran explains.³ (This trial is named after the Baltimore Ravens NFL team.) “The trial is more than half way accrued and my hope is that we will have results by the end of 2022 or early 2023,” he says.

One question still to be answered is whether patients with de novo oligometastatic prostate cancer will benefit from treatment of their metastases as well as their primary tumor. “We will shortly launch a trial to address this, called TERPS (Total Eradication of disease following Radical Prostate-directed radiotherapy in oligometastatic de novo castration-Sensitive prostate cancer), which is named after University of Maryland athletics teams, which are known as the Terrapins, Dr Tran explains. TERPS will be one of the first prospective, randomized attempts to determine whether treating metastases is beneficial in a patient with newly diagnosed oligometastatic disease.

Because metastatic disease is very heterogeneous, another goal is to use genomics and advanced imaging to better define oligometastasis to be able to refine treatment groups. “We know the biology of some oligometastatic patients is much more aggressive, so these patients should probably be treated with aggressive systemic therapies in combination with potential curative metastasis-directed therapies,” Dr Tran  suggests. “This again goes back to my training with Drs Carson, Druker, and Felsher, and thinking about cancer in the context of a precision medicine paradigm; better understanding of the underlying metastatic biology, trying to find agents that can target that underlying biology, to target the metastatic process itself,” he says. “I think this will be  the next big leap, and we hope we will be among the investigators who help pioneer this strategy.”

Studies at Maryland are looking at particular molecular aberrations in oligometastatic prostate cancer patients and new drugs to target them, with initial data expected in 2022. Meantime, Dr Tran expects to begin additional first-in-human trials (with sports-related names) during the following year.

Linda Brookes, MSc is a freelance medical writer/editor based in New York and London.

References

1. Phillips R, Shi WY, Deek M, et al. Outcomes of observation versus stereotactic ablative radiation for oligometastatic prostate cancer – The ORIOLE phase 2 randomized clinical trial. JAMA Oncol. 2020;6(5):650-659. DOI: 1001/jamaoncol.2020.0147
2. Ost P, Reynders D, Decaestecker K, et al. Surveillance or metastasis-directed therapy for oligometastatic prostate cancer recurrence: a prospective, randomized, multicenter phase II trial. J Clin Oncol. 2018;36(5):446-453. DOI: 1200/jco.2017.75.4853
3. Hasan H, Deek MP, Phillips R, et al. A phase II randomized trial of RAdium-223 and SABR Versus SABR for oligomEtastatic prostate caNcerS (RAVENS). BMC Cancer. 2020;20(1):492. DOI: 1186/s12885-020-07000-2