Discovery 
November 30, 2017

The Patrick C. Walsh Prostate Cancer Research Fund

We are funding the cure. Since its inception in 2005, the Patrick C. Walsh Prostate Cancer Research Fund has awarded
millions of dollars to Johns Hopkins scientists in every discipline with good ideas worth pursuing that can help us
understand more about prostate cancer - to help us save lives, to find better ways to treat it at every stage, and even to help prevent it. Applications are reviewed by a Scientific Advisory Board composed of noted Hopkins scientists and lay members. These awards wouldn’t have been possible without the tremendous and amazing generosity of our patients and friends. On these pages you’ll find some of the exciting work this year’s award winners are doing to make life better for men with prostate cancer and their families.

Using Robotics to Improve Prostate Biopsy

In the U.S. alone, about one million prostate biopsies are performed every year. If each biopsy takes at least a dozen cores of tissue, that’s an awful lot of needle sticks – especially for men who are getting a repeat biopsy.

Most of those biopsies are done freehand with transrectal ultrasound (TRUS) guidance – and there is room for improvement.Previously, in an effort to make prostate biopsy more accurate, the Brady’s own master mechanical engineer, Dan Stoianovici, Ph.D., director of the Urology Robotics Program, designed and developed a novel robot to hold and move the ultrasound probe accurately and to track the exact location of the ultrasound target. Misop Han, M.D., the David Hall McConnell Professor in Urology, collaborated with Stoianovici to test the device during prostate biopsy in five men.“We found that the TRUS Robot could handle the ultrasound probe well, with no complications,” says Han. With newly developed software, they were able to reconstruct the 3-D image of the prostate and the biopsy cores within it.“We proved that 3-D, image-guided robotic biopsy is both feasible and safe,” Han adds. “We believe that the use of the TRUS Robot can potentially improve the accuracy of prostate biopsies and detect prostate cancer better than a freehand biopsy.”

Now, with funding from the Patrick C. Walsh Prostate Cancer Research Fund, Stoianovici is building on this success. He has developed a novel ultrasound probe for imaging the prostate and guiding needle biopsies. “The probe combines imaging and robotic components,” says Stoianovici. “It is an entirely novel concept that offers fundamentally accurate ultrasound-guided needle targeting independent of the physician’s skill.”The versatile device’s potential applications include “transrectal or transperineal access, systematic or fusion biopsy, and needle-based focal ablations.”The pair will be bringing the probe to its first clinical trial for safety and feasibility.

Precision Treatment in Men with CRPC

Previously in Discovery, we reported an important breakthrough in understanding why two second-line hormonal therapy drugs for metastatic castration-resistant prostate cancer (CRPC) don’t help some men. The drugs, enzalutamide (Xtandi) and abiraterone (Zytiga) are very expensive, and if they are not going to work, men can save thousands of dollars a month – and better yet, try something different that may prove more successful. Both drugs target the androgen receptor, but like a key trying to fit the wrong lock, the drugs fail to work in men who develop a mutated androgen receptor. Brady scientists Jun Luo, Ph.D., and Emmanuel Antonarakis, M.D., not only discovered this variant receptor, called AR-V7; they developed a blood test for it.

Now, they would like to refine their test even further to offer “precision detection,” says Luo, “to focus on a patient’s individual variant androgen receptor burden.” To do this, in tissue studies conducted by Brady pathologist Angelo De Marzo, M.D., Ph.D., they are using a novel RNA in situ hybridization (RISH) method they developed “to visualize AR-V7, achieving a resolution of a single splice junction.” Basically, this means that they can look for variant receptors on the molecular level – one molecule at a time – “to determine a patient’s overall variant androgen receptor burden beyond AR-V7.” A study using their new technology was recently published in European Urology. Postdoctoral fellow Yezi Zhu, Ph.D., is a co-investigator on this project.”

Long-Distance Cancer Care

All men with prostate cancer don’t have access to good medical care. In fact, men in rural areas and in remote parts of the world don’t have ready access to medical care at all. But just about everybody has a cell phone, and most of us have access to a computer and the internet. Is there a way to tap into the technology we have to provide the care some of us don’t have?

Urologist Michael Johnson, M.D., believes the answer is yes – and that remote clinical care can provide Hopkins medicine to men who aren’t able to come to Baltimore. “For many men with prostate cancer, where you live determines your cancer care. My goal is to find a way for digital and internet- based technologies to overcome this barrier and allow men worldwide to have access to the expertise at Hopkins.”

To do this, Johnson is using telemedicine to provide “remote clinical visits.” He is also designing an app for smart phones that will allow men to track their progress after radical prostatectomy “and make sure they are recovering as expected.”

Why Do Some Men Do Better With Immunotherapy?

Some men with widely metastatic prostate cancer have had spectacular results on immunotherapy drugs like pembrolizumab. Other men – whose scans show very similar metastases, whose Gleason and PSA numbers are the same – aren’t helped much at all.

Why is it that some men’s immune systems can be whipped up into a frenzy and can attack metastatic cancer, causing it to melt away? The secret doesn’t lie in what pathologists can see in prostate tissue or a lab test. It’s much smaller than that: it’s in the genes. Specifically, it’s on the number of mutations a cancer has, or its “mutational burden.”

This means, basically, that the cancer has so much baggage – think of a whale , with barnacles all over it – that it looks different enough to cause the immune system to take notice. All the immune system needs, in this case, is a little kickstart – the immunotherapy drug – and it’s ready for battle. “Hypermutation is thought to be caused by inactivation of DNA mismatch repair genes – genes like MSH2,” explains Brady scientist Paula Hurley, Ph.D., “It’s the normal job of these genes to fix damaged DNA.”

“We hypothesize that some men with metastatic castration resistant prostate cancer (CRPC) have resistance to antiandrogen drugs – enzaludamide and abiraterone – because they have many mutations,” says Hurley. Now she wants to prove it. With co-investigator Brian Simons, D.V.M., Ph.D., she will be looking at the genes of men with metas tatic CRPC before they start on androgen receptor drugs and later, if their cancer stops responding to these drugs.

“These studies will provide critical information on how mutational burden leads to resistance to androgen receptor drugs, and will help determine who might respond well to immunotherapy.

Can PSMA PET Help Determine Which Men Have Significant Prostate Cancer that Needs to be Treated?

Earlier in this issue we’ve talked about Martin Pomper’s PSMA-targeting small molecule, and how well it can show otherwise hidden metastatic cancer on a PET scan. Can it be used even earlier – at the time of diagnosis – to help determine which men have clinically significant, high-grade tumors?

There is a critical need for such discernment, says urologist Michael Gorin, M.D., because PSA is often not that helpful. “A major shortcoming of the PSA test is that it is not specific for detecting clinically significant, highgrade tumors, leading to overdiagnosis of low-grade or indolent prostate cancer that probably doesn’t even need to be treated.”

It would be nice to have more insight before prostate biopsy – so men who probably have indolent cancer wouldn’t have to have needles stuck in their prostate. “PSMA is expressed by prostate cancer cells, and the degree of expression directly correlates with prostate cancer grade and stage.” To this end, Gorin is testing how well PSMA-targeted PET/CT scanning works before biopsy in men who are being screened for prostate cancer.

A Better Model for Aggressive Prostate Cancer

This project is dedicated to the nearly 30,000 American men who die each year of prostate cancer. “While great progress has been made, there is a pressing need to develop better treatment,” explains pathologist Angelo De Marzo, M.D., Ph.D. “Sadly, about 95 percent of new cancer drugs fail in clinical trials – sometimes after investments of more than a billion dollars.” A major contributing factor to this high failure rate is “a lack of animal models in which new drugs and drug combinations can be tested.”

About 95 percent of new cancer drugs fail in clinical trials – sometimes after investments of more than a billion dollars. A major reason why is a lack of good animal models.

With Charles Bieberich, Ph.D., of the University of Maryland-Baltimore County, whose lab has expertise in genetic engineering of mice, De Marzo is developing a better animal model. “Human cancers arise due to the accumulation of mutations in DNA, and we can now easily make the same mutations happen in the DNA of mice,” says De Marzo. “This has allowed Dr. Bieberich’s laboratory to engineer a state-of-the-art mouse model of human prostate cancer – giving us, for the first time, a powerful platform to test new drugs.” However, there’s more to do: “We are learning that mice often don’t metabolize drugs the same way that humans do.” Another drawback to mice is that they are really small, which “makes it difficult to test new ways of imaging growing prostate cancers.”

With this Patrick C. Walsh award, De Marzo and Bieberich will “leverage our experience with mice to develop a state-of-the-art rat model of human prostate cancer.” Rats tend to metabolize drugs in much the same way that humans do, and their prostates are nearly ten times bigger than those of mice. “When this work is completed, we will have developed a powerful new tool in the fight against prostate cancer: a next-generation animal model in which the safety and effectiveness of new drugs and imaging methods can be carefully tested.”

Helping Men Recover After Radical Prostatectomy

Brady surgeons know that for many of their radical prostatectomy patients, recovery can take weeks to months. They also know that some things, such as exercising and maintaining a healthy lifestyle, can help men recover faster and do better. But after the men leave the hospital, they don’t always report back in a regular or detailed way. Here’s where Peter Searson, Ph.D., an engineer with the Johns Hopkins Whiting School of Engineering, may be able to use technology to help make life better for these men and their partners.

“Exercise is known to improve the health and well-being of prostate cancer patients,” Searson explains. With funding from the Patrick C. Walsh Prostate Cancer Research Fund, he aims to use remote monitoring technologies to track the physical activity and weight of men after radical prostatectomy. He also wants to find out “whether men who receive personalized feedback of their physical activity levels and weight are more likely to stick to exercise and dietary programs, and whether they have improved quality of life.”

Making Radiation More Effective: Breaking Cancer’s DNA

For men with localized but aggressive prostate cancer, combining radiation and androgen deprivation therapy (ADT) has been shown to make a big improvement in survival. This treatment is effective,” explains radiation oncologist Daniel Song, M.D., because of a double- whammy effect: “radiation breaks the cancer cell’s DNA, which can kill it, while hormones starve the cancer of its need for testosterone.”

Breaking the DNA strand makes the whole tumor more sensitive to radiation.

Another benefit of breaking the DNA strand: it makes the whole tumor more sensitive to radiation. “We have found that flutamide, a well-established drug that treats prostate cancer, can also produce DNA strand breaks,” Song continues. With co-principal investigators Srinivasan Yegnasubramanian, M.D., Ph.D., and Theodore DeWeese, M.D., Ph.D., “our strategy is to confirm these findings in men who have chosen to receive testosterone suppression and prostate brachytherapy,” or seed implant. In this project, men will be given a dose of flutamide before the procedure, and while they are already anesthetized for brachytherapy, they will undergo a prostate biopsy. “We will examine the biopsies to check for DNA strand breaks induced by flutamide, and if they are positive, we will move this work into a clinical trial for men with localized, aggressive prostate cancer.” Co-investigators are pathologists Angelo De Marzo, M.D., Ph.D., and Michael Haffner, M.D., and Jonathan Coulter, Ph.D., from the Department of Radiation Oncology.

A New Way to Study Prostate Cancer Cells in Real Time

It turns out that prostate cancer cells don’t need much oxygen; in fact, they thrive in a low-oxygen environment. Scientists have much to learn about what goes on in this weird environment of hypoxia, because it’s hard to study. Now, thanks to Sharon Gerecht, Ph.D., from the Johns Hopkins Department of Chemical and Biomolecular Engineering, scientists can study oxygen-starved tumor cells in real time.

“Rapid growth and proliferation of tumor cells depletes nearby oxygen concentrations,” Gerecht explains. “This hypoxia, in turn, alters cancer cells’ behavior,” making them move faster, more likely to invade other tissue – and also less sensitive to drugs. “In fact, many studies indicate that hypoxia is a major driver of metastasis – which suggests that drugs to target metastasis must be developed in the context of hypoxia.”

Gerecht developed “novel, hypoxiainducible hydrogels,” which allow scientists to watch how prostate cancer cells respond in an oxygen-starved environment. Using these hydrogels, “we will measure characteristics of prostate cancer motility and invasion and response to therapeutics.” They will watch how these cancer cells interact with immune cells – which may lead to better ways to make immunotherapy more effective. “We will also use an inhibitor of metastasis, identified by our group in sarcoma, in combination with current prostate cancer therapies to block metastasis in hypoxia. We hope our work will contribute to the understanding of prostate cancer biology and potentially identify new strategies for treatment.”