1. Neff Newitt, Valerie

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"Prostate cancer is heavily entrenched in therapies that target androgen receptor signaling, creating great leaps in the field for most prostate cancers," said Paul Viscuse, MD. Prostate cancer is most common in older men, and because of a long duration of response to treatment, many patients often die of something else before their cancer becomes lethal.

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"But there is an unmet need for a subset of patients of all ages we see in the clinic. We term them as having 'aggressive variant prostate cancer.' These tumors are aggressive, do not respond to therapy targeting androgen receptor signaling, and the men do poorly. We don't have a lot of options for them," he noted.


Small cell prostate cancer traditionally has been known to be the difficult-to-treat variety. "This is a rare subset which doesn't look like normal prostate cancer under the microscope. The small cell variety is classically known to be indifferent to hormones [and] behave very badly," explained Viscuse. "But we have been finding more and more prostate cancer that looks like normal prostate adenocarcinoma under the microscope, yet behaves like small cell prostate cancer. So we know there is more to it than just the histology, but what? That's what we're trying to define."

Paul Viscuse, MD. Pa... - Click to enlarge in new windowPaul Viscuse, MD. Paul Viscuse, MD

Of approximately 174,000 men diagnosed with prostate cancer in 2019, "only about 1 percent presented with small cell prostate cancer, while 20-30 percent developed aggressive variant prostate cancer, treatment-related or otherwise. We see patients in clinic with that unfortunate biology," said Viscuse, adding that in 2019 there were about 31,000 prostate cancer-related deaths in the U.S.


Work at a New Location

In the final months of a 3-year hematology/oncology fellowship at University of Texas MD Anderson Cancer Center in Houston (which followed medical school training at Marshall University and an internal medicine residency at Mayo Clinic), Viscuse will begin a new position as Assistant Professor in Genitourinary Malignancies at the University of Virginia in August.


He'll be settling into an entirely new personal lifestyle, because he'll also be reuniting with his wife of 3 years, Brittany Wall, MD, from whom he's necessarily been estranged for 6 years for training. Specializing in lung diseases, she also is finishing a fellowship in Indiana and has accepted a position at the University of Virginia in pediatric pulmonology.


Though his geographic location will change, Viscuse is determined to continue his work from afar with his mentor, Ana Aparicio, MD, at MD Anderson, on the development of a framework to identify men whose disease is indifferent to the usual therapies targeting androgen receptor signaling.


"Dr. Aparicio has developed clinical and molecular criteria for this population," he explained. "She's honed in on combined defects in two out of three tumor suppressor genes. If we see those when we sequence a tumor, it would suggest the cancer is going to behave in a more virulent manner. So, if patients meet some of these clinical or molecular criteria, we would define them as having aggressive variant prostate cancer, which will likely behave in an androgen-indifferent manner.


"It's not perfect; there's a lot of heterogeneity even when we examine for these criteria. The aggressive variant can occur in different ways. Some patients have it up front, right away. Other patients appear to have normal prostate cancer at first; but after a prolonged period of time on androgen deprivation therapy, the cancer becomes aggressive. We're trying to better identify these patients and understand their disease."


Aparicio has published two papers on this work, both in Clinical Cancer Research (2013; doi: 10.1158/1078-0432.CCR-12-3791 and 2016; doi: 10.1158/1078-0432.CCR-15-1259).


As a greater understanding of aggressive variant prostate cancer is gained, researchers hope to be able to explore and exploit new avenues for novel therapies.


"We're hoping to develop therapies outside of targeting the androgen receptor and its signaling. Right now, when patients' prostate cancers are indifferent to hormone therapy, they are stuck with chemotherapy," said Viscuse. "It works for a bit and then it stops working. A trial showed patients with this molecular signature may benefit from the addition of carboplatin to cabazitaxel (Lancet Oncol 2019: doi: 10.1016/S1470-2045(19)30408-5). They have a very robust response to the chemo; but, unfortunately, it too is short lived-usually a matter of months. The cancer ultimately recurs and we run low on options."


Though novel therapies are sorely needed, "we're just not at that point yet," lamented Viscuse. "Dr. Aparicio is running some trials looking at immunotherapy, looking at PARP inhibitors. And I'm exploring metabolic defects, such as arginine metabolism, to see if there are any areas that we can exploit therapeutically."


In further explanation, Viscuse noted, "There are different ways to address cancer, such as genomic defects, epigenetic defects, immune targets. What I'm looking at specifically are areas of metabolism that the tumor has altered when compared to normal cells.


"There are some examples of tumors that change how they metabolize arginine, which in turn may make them vulnerable to certain treatments, including platinum chemotherapy and the novel investigational agent ADI-PEG 20. I'm trying to discover if there is a similar avenue to explore in these androgen-indifferent prostate cancers because, as mentioned earlier, they're sensitive to platinum-based chemotherapy. If there is a way to improve on outcomes with chemotherapy by targeting arginine metabolism and/or other metabolic vulnerabilities, it could greatly benefit patients."


The Road Ahead

At an academic center like University of Virginia, Viscuse hopes to do additional clinical work in various genitourinary malignancies, while expanding the clinical investigation platform through the clinical trials and translational studies in collaboration with basic scientists. He anticipates splitting his time between the clinic caring for patients with genitourinary cancers, and devoting time for clinical research.


"You have to know the clinical side to be a good investigator," said Viscuse. "One of the strengths clinicians bring to medical research is the clinical acumen of understanding what might be important to the patient, which complements the impressive work carried out by scientists in the lab. Important questions come up in the clinic, sparking research interests. That clinical component is essential to medical research."


Specifically, Viscuse wants to continue to work on prostate cancer with his mentors (who, in addition to Aparicio, include Daniel Frigo, PhD, at MD Anderson) and explore other grant options. "As we start to find answers to certain questions, new questions arise. There's always additional work to be done," he said.


Extremely hopeful his work in metabolism will yield a more successful ability to treat patients with aggressive variant prostate cancer, Viscuse believes cancer metabolism has the potential to be a new pillar of cancer treatment, in the same way immunology and immunotherapy came onto the scene and was a real game-changer.


"The more we learn about metabolism and the better we get at assessing and targeting it, the greater chance we have at seeing metabolism as another pillar of therapy that we can exploit in some of these tumors," Viscuse stressed. "After all, if you were listening to scientists years ago, many weren't talking about the immune system. It was kind of a niche arena, until it led to significant therapeutic advances in oncology. Metabolism may do the same by offering similarly important avenues of therapeutic opportunities. We just need to keep working on it."


Valerie Neff Newitt is a contributing writer.