Read About the Research You Have Helped Make Possible.

How important is seed money? Priceless! Many of the scientists featured in this issue of Discovery jump-started their research careers with awards from the Patrick C. Walsh Prostate Cancer Research Fund. In fact, some of the major advancements in prostate cancer research were made possible by these gifts. One huge example is the worldwide adaptation of PSMA-PET imaging. More than 20 years ago, these funds supported physician-scientist Martin Pomper, M.D., Ph.D., who wanted to develop a molecular bloodhound – a small molecule that could track and find PSMA, made by prostate cancer cells, anywhere in the body – and then attach it to a radioactive tracer, so these hidden cells would light up on a PET scan. He did it! Now known as the imaging agent Pylarify, his molecule was developed and is helping patients worldwide. This Fund owes its existence entirely to patients: patients, who have become partners, make progress happen! Since its inception in 2005, this remarkable Fund has awarded millions of dollars to Johns Hopkins scientists in every discipline with good ideas worth pursuing. Their research has produced better ways to detect, treat, and prevent prostate cancer. This year’s awards are hot off the press! We look forward to reporting on these exciting research projects as they unfold. Remember: without you, their work wouldn’t be possible! 

2023 Awardees

Sarah R. Amend, Ph.D.
The R. Christian B. Evensen Scholar
Department of Urology

Ahmed Ghazi, M.B.B.Ch., M.D.
The Heather and Patrick C. Henry Scholar
Department of Urology

Amin Herati, M.D.
The Keith L. Bremer Scholar
Department of Urology

Laura Sena, M.D., Ph.D.
The Virginia and Warren Schwerin Scholar
Department of Oncology

Karen Sfanos, Ph.D.
The Beth W. and A. Ross Myers Scholar
Departments of Urology, Oncology, and Pathology

Swaroop Vedula, Ph.D.
The William and Carolyn Stutt Scholar
Whiting School of Engineering, Johns Hopkins University

Srinivasan Yegnasubramanian, M.D., Ph.D.
The Mr. and Mrs. Robert Baker Family Foundation Scholar
Department of Oncology

New Insights into Mechanisms that Drive Chemotherapy Resistance 

Scientist Sarah Amend, Ph.D., and colleagues have discovered that certain cells evolve during cancer treatment and enter an alternative pattern of growth that persists despite chemotherapy: the endocycle. “With this grant, we will define the molecular signature of endocycling cancer cells,” she says, “and determine the steps that enable this unconventional way for cancer to grow.”

Designing a Better 3D-Printer for Patient-Specific Surgical Models

“Imagine the day when urologists can rehearse on an accurate replica of a patient’s prostate to optimize the operative approach,” says urologist Ahmed Ghazi, M.B.B.Ch., M.D., “maximizing the benefits, reducing the risks, and foreseeing the outcomes of prostatectomy before even making their first incision!” 

Ghazi and his team have developed a technique for creating hydrogel organ models from a patient’s own scans. These models are made at the Brady’s Surgical Learning and Innovation Center of Excellence (SLICE), and are already being used for training.

But as good as they are, the model-making process has room for improvement. “Manufacturing is laborious, expensive, and time-consuming,” says Ghazi, “taking up to two weeks.” The main reason is that current 3-D printers are a lot better at printing hard things – plastics, for instance – than squishy materials such as Ghazi’s hydrogels. Fortunately, the Brady has a secret weapon: our own in-house genius and builder of technology, engineer Dan Stoianovici, Ph.D., and his Urology Robotics Lab. “Dan has designed and built numerous robots and medical devices since 1996, and has the infrastructure and expertise we need.” With this grant, the two labs will collaborate to build the world’s first 3D printer prototype capable of directly printing a hydrogel surgical model. The implications of this work are exciting, says Ghazi, “extending beyond urology to other medical fields, and potentially to live cell bioprinting and tissue engineering.”

Working on a New Test for Aggressive Prostate Cancer

Hopkins scientists’ studies of molecular biomarkers for aggressive prostate cancer have led to the development of major tests that use blood and urine. But what about semen? The prostate contributes some of the fluid that is in semen, and it makes sense that molecular and genetic changes that are present early on in prostate cancer – maybe before the disease is otherwise detectable – might first be seen in this fluid.

A team of Brady investigators – Amin Herati, M.D., Christian Pavlovich, M.D., and Jun Luo, Ph.D. – is testing a new idea to detect inherited mutations and genomic alterations linked to aggressive and potentially lethal prostate cancer early in the course of the disease, using semen specimens. “If it works,” says Pavlovich, “the test will spare many patients the invasive procedures in the traditional biopsy pathway toward prostate cancer diagnosis.” The team will enroll 25 patients in this preliminary study.

Practice Operating Like an Expert with “Surgical Karaoke”

How do you get to Carnegie Hall? Practice, practice, practice. “The key to achieving true expertise in any skill is simply a matter of practicing, albeit in the correct way, for thousands of hours,” says urologist Ahmed Ghazi, M.B.B.Ch., M.D., “Mastery of a surgical technique is far more complex, involving a combination of technical skill, surgical intuition, and long hours of performing procedures. But in the current era of surgery, it has become almost impossible for trainees to accumulate this mastery.”

“Any surgical procedure of any expert can be converted using our novel invention.” With co-investigators Swaroop Vedula, Ph.D., from the Whiting School of Engineering, and Ryan P. McMahan, Ph.D., from the Department of Computer Science at the University of Central Florida, Ghazi hopes to give surgical trainees new ways to learn from master surgeons. Their proposal: “a ‘Surgical Karaoke’ – coined after the musical karaoke system, but where we track the exact movements from an expert’s surgical procedure” and then replay them to trainees using immersive virtual reality technology, for a surgical trainee to replicate the expert’s exact movements using hand-controllers. “Any expert surgeon's procedure can be converted using our novel invention.”

Navigating the Uncharted DNA of Lethal Prostate Cancer

“Imagine having to navigate through a hostile landscape with inadequate intel and using a map that is half empty or missing,” says Srinivasan Yegnasubramanian, M.D., Ph.D. “This has been our challenge in understanding lethal prostate cancer: half of its DNA map remains in the dark, hiding potential clues to cure it. But we’re about to turn the lights on!”

With co-Principal Investigator Winston Timp, Ph.D., from the Department of Biomedical Engineering, and co-investigators Michael Schatz, Ph.D., from the Departments of Computer Science and Biology, and pathologist Angelo De Marzo, M.D., Ph.D., “We’re setting out to fully map the DNA of the deadliest prostate cancers.”

Using innovative new technology and computer methods, the team will explore “uncharted genetic and epigenetic territories in lethal prostate cancer, the mysterious expanses of the DNA that have been the most challenging to decipher with previous technologies,” Yegnasubramanian says. “We hope to shine a light on 

DNA’s dark corners – to discover the missing links to understanding why these cancers are so lethal.”

They will also be studying the DNA of lethal cancers at the end of life, with deep gratitude for “the courageous spirit of brave men who sadly succumbed to this disease and volunteered to donate their bodies to the fight against prostate cancer. We will study the DNA from the lethal tumors that spread all over their body, and we will stitch together a complete genetic portrait of lethal prostate cancer like never before.”

“This isn’t just science. It can become our blueprint to conquer prostate cancer.” One more thing the team wants you to know: “This isn’t just science. It can become our blueprint to conquer prostate cancer. We aim to better detect, manage, and ultimately defeat this formidable adversary by uncovering its hidden vulnerabilities.”

BAT: Could Gut Bacteria Make a Difference?

“Bipolar” androgen therapy (BAT) is hormonal therapy of highs and lows for men with castrate-resistant, metastatic prostate cancer (mCRPC): high-dose testosterone, followed by very low levels of male hormones. BAT is promising – but could it be even better? A team of investigators – Laura Sena, M.D., Ph.D., Karen Sfanos, Ph.D., and Tracy Murray Stewart, Ph.D. – hopes to find out.

Their focus is on growth-promoting compounds called polyamines, which may limit the effectiveness of BAT. The agent difluoromethylornithine (DFMO) blocks these polyamines and is being tested in the APEX trial at Hopkins. With this grant, the team will look at the gut microbiome (the population of bacteria in the intestine) in participants of the APEX trial.

The team will study whether “polyamines derived from bacteria living in the gut microbiome can promote therapy resistance to both BAT and DFMO,” explains Sfanos. They will characterize the gut bacteria and metabolites (small molecules involved in metabolism), “looking to identify microbiome biomarkers of therapy response and potential strategies to improve this therapy and prolong the lives of patients.”

Gut Bacteria, Soy, and Fighting Prostate Cancer

For years, scientists have known that prostate cancer doesn’t like soy very much. Soy contains isoflavones, which are phytoestrogens, estrogens made by plants. Countries with the highest consumption of soy, as in Asia, have the lowest incidence of prostate cancer. But maybe it’s not the soy itself: maybe it’s what happens in the guts of people who eat it.

Maybe it’s not the soy itself. Maybe it’s what happens in the guts of people who eat it.

Scientist Karen Sfanos, Ph.D., is a renowned expert on the microbiome, the population of bacteria, in various parts of the body – such as the intestine. “The microorganisms that reside in the human gut are responsible for converting dietary substances into active compounds that greatly influence human health and disease,” she says. In exciting research, “we have discovered that a dietary compound called equol – which can only be made by gut bacteria in some people after they eat soy, can inhibit the growth of prostate cancer cells.”

In the Asian countries with the highest consumption of soy and lowest risk of prostate cancer, there are many people who carry the gut bacteria that produce equol. But wait – there’s more! Equol gets even better: “We also found that equol may be a radiosensitizer,” Sfanos says. “It may act in combination with radiation therapy to make it more effective in treating advanced prostate cancer.” And, because equol is a natural molecule, “it may produce fewer treatment side effects than the traditional androgen deprivation therapy (ADT) that is commonly given with radiation therapy.”

Indeed, she continues, equol supplementation in people has been shown to be safe and is already used to improve bone and cardiovascular health, cognitive impairment, dementia, and prostate health. With this grant, Sfanos and colleagues will perform pre-clinical studies in mice using a model of radiation therapy with or without the addition of equol.

“We will study whether equol given in combination with radiotherapy can enhance tumor regression, and we will determine if the immune system plays an important role in the observed response.” If the study goes as well as Sfanos hopes, “we hope to obtain the necessary rationale and preliminary data to pursue clinical studies on the use of equol as a radiosensitizer in the treatment of prostate cancer.”