We are looking for innovative ways to stop lethal prostate cancer and to make life better for men with localized prostate cancer: these are the exciting research projects you helped us fund this year. 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.
A New Target to Keep Lethal Cancer Cells from Leaving Home
Men who have higher levels of this gene tend to do better.
Before it can leave the prostate and invade other sites, aggressive cancer needs to be able to take that first step: it needs the ability to move. “Cancers derive from epithelial cells,” says Sarah R. Amend, Ph.D., The Donald E. Graham Scholar. “These are highly proliferative cells,” but normally they don’t move around very much. In metastatic cells, however, a critical event occurs: “a population of cells gains movement ability,” a feature of a different type of cell called mesenchymal cells. “This little bit of cancer evolution is called the epithelial-to-mesenchymal transition (EMT).”
What drives EMT? In looking for specific culprits, Amend and colleagues found an unnamed gene, called C1orf116. Much about this gene is a mystery: “It remains largely uncharacterized, and its biological and molecular functions remain unknown,” says Amend. But her preliminary data suggests that C1orf116 keeps prostate cancer from spreading. Men who have higher levels of C1orf116 tend to do better; in lab studies, this gene seems to restrict movement of prostate cancer cells.
In research funded by The Patrick C. Walsh Prostate Cancer Research Fund, Amend and colleagues will work to clarify the function of this mystery gene in restricting metastasis.
Chemoreceptors and Prostate Cancer
Understanding how this “sensory” class of cell surface receptors works might lead to new markers to identify men at risk of developing lethal prostate cancer.
What if lethal prostate cancer has a lot more going on than we ever knew? What if it has, in its own tiny, molecular way, senses like we all have – sight, smell, taste, sound, and touch? In new research funded by The Patrick C. Walsh Prostate Cancer Research Fund, Steven An, Ph.D., The Frank E. Rath Spang & Company Charitable Trust Scholar, is envisioning “an entirely new mechanistic framework for lethal prostate cancer.”
An and colleagues are exploring the idea that metastatic prostate cancer “is disseminated in time and space through a discriminatory repertoire of chemoreceptors” linked to a particular protein, called specialized G protein-coupled receptors (GPCRs). This new repertoire involves visual, taste, and smell perceptions
Just imagine,” he continues, “that there are ‘eyes’, ‘nose’, and ‘taste buds’ on individual prostate cancer cells. What would they ‘see’, ‘smell’, and ‘taste’? “Understanding how this “sensory” class of cell surface receptors works might lead to new markers to identify men at risk of developing lethal prostate cancer, An continues. Furthermore, “what if We are looking for innovative ways to stop lethal prostate cancer and to make life better for men with localized prostate cancer: these are the exciting research projects you helped us fund this year. 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. 16 17 THE PATRICK C. WALSH PROSTATE CANCER RESEARCH FUND ‘sensory’ perceptions or photo/chemosensory transductions are hard-wired to cellular motions? Are there pathways by which the forces of light might interfere with cellular motions?” Could something that smells bad or tastes bitter to these chemoreceptors be used to stop cancer from spreading?
An plans to find out. He hopes to create a functional map of the “sensory” GPCR landscape in prostate cancer and then to correlate the “photo/chemo-mechanical gene signature” he finds to the progression of metastatic disease.
DNA Repair Mutations and PARP Inhibitors
“PARP inhibitors may be able to replace or postpone the need for androgen deprivation therapy.”
Emmanuel S. Antonarakis, M.D., The George and Mary Nell Berry Scholar, sees great promise in PARP inhibitors. This new class of oral drugs has helped some men with advanced prostate cancer – particularly those who have mutations in certain “DNA repair” genes, such as BRCA1, BRCA2 and ATM.
In some men, he believes, “PARP inhibitors may be able to replace or postpone the need for androgen deprivation therapy (ADT).” These drugs seem to work best in patients who either were born with an inherited inability to fix DNA damage, or those who acquired a mutation in a DNA-repairing gene over time, as prostate cancer grew and advanced.
However, it’s not always clear who will benefit, and who will not. “While many patients with inherited or acquired mutations in these genes show a favorable response to treatment with a PARP inhibitor, some do not benefit at all,” he explains, “while others may benefit even without having one of these mutations.
With funding from The Patrick C. Walsh Prostate Cancer Research Fund, Antonarakis is working to find a new test to detect DNA damage in the cancer cells themselves – using tumor biopsies from patients with localized or metastatic prostate cancer. He hopes this test, which uses standard biopsy materials called formalin-fixed paraffin-embedded specimens, will be “a better predictor of sensitivity or resistance to PARP inhibitor therapy compared to DNA testing.”
The first step is to validate the new test, called the In situ DNA Damage Response Assay, in the laboratory. Next, “we will use this method to test biopsies from patients undergoing therapy with PARP inhibitors, either olaparib (Lynparza) or rucaparib (Rubraca) on one of two clinical trials,” to determine if the assay is accurate in predicting the success of these drugs in prostate cancer.
What Happens at the Beginning of Metastasis?
We know a lot about what happens next, after cancer escapes from the prostate. But what happens at the very beginning?
Robert H. Austin, Ph.D., The Luciana and Joe Vittoria Scholar, is a professor of Biophysics at Princeton and a Visiting Scientist at The Brady. In a joint project between The Brady and Princeton, Austin and a team of investigators have developed a way to study metastatic prostate cancer on a very small scale, at the level of microfluids.
“Lethal metastases are the end-result of a cancer cell that escapes the primary tumor, travels through the vasculature, and eventually invades a secondary site,” Austin says. We know a lot about what happens next, after cancer escapes from the prostate. But what happens at the very beginning?
“The critical early events in the metastatic process remain largely unknown,” Austin says. This prison break, scientists suspect, is launched by just a few particularly bad cells. “We hypothesize that the harsh, low- oxygen, acidic, and low-nutrient conditions generated by the rapidly growing, organ-confined tumor exert the necessary pressure that causes the lethal disseminating tumor cells to emerge,” and that this is “the critical early step in prostate cancer metastasis.”
The Brady and Princeton team has developed a microfluidic device that can not only mimic these harsh conditions in laboratory studies; it can “simultaneously monitor the complex dynamics in response to this stress” in a heterogeneous cell population, reproducing these early metastatic- causing events.
“The overarching goal of our project is to identify and characterize these lethal disseminating tumor cells,” Austin says. “Understanding the early steps of metastasis will lead to new therapies to disrupt and revert this process.”
Can Droplets of RNA in Blood or Urine Predict Aggressive Cancer?
In this new project, the team will isolate these RNA biomarkers from the blood or urine of radical prostatectomy patients.
Extracellular vesicles (EVs) are little, membrane-wrapped droplets shed by prostate tumors into blood and urine. Small as they are, they’re packed with information – particularly, with molecules of RNA that can say a lot about the tumor they came from.
Shawn Lupold, Ph.D., The Jean and Ian MacKechnie Scholar, and Brady investigator Liang Dong, M.D., hope to use these RNA molecules as windows that will show the nature of localized prostate cancer. “Our goal is to identify RNA biomarkers capable of distinguishing men with more aggressive prostate cancer from men with less aggressive cancer,” says Lupold. “Tumors produce high levels of EVs,” and the membrane serves as a kind of bubble-wrap that “shields the RNA cargo from harsh conditions in the blood and urine.”
With funding from The Patrick C. Walsh Prostate Cancer Research Fund, Lupold and Dong will focus on two types of RNA molecule: microRNAs and alternatively polyadenylated (APA’d) mRNAs. Both are familiar to these investigators: “Our laboratory has previously identified specific microRNAs and APA’d mRNAs that are associated with high Gleason Grade prostate cancer,” says Lupold. In this new project, the team will isolate these RNA biomarkers from the blood or urine of radical prostatectomy patients, and then will compare them with the pathological results after surgery to see which men turn out to have higher Gleason Grade or more extensive disease.
Can PSMA-PET Predict the Risk of Metastasis?
“Certain men are at high risk of developing metastatic disease and may benefit from early treatment.”
After radical prostatectomy, the PSA level should be undetectable. If PSA comes back, this does not always require immediate treatment, or treatment at all – but sometimes, it does. “Certain men are at high risk of developing metastatic disease,” cancer that can be detected on a CT or bone scans, “and may benefit from early treatment,” says Mark C. Markowski, M.D., Ph.D., The Virginia and Warren Schwerin Scholar.
With support from The Patrick C. Walsh Prostate Cancer Research Fund, he hopes to clarify which men need extra help by using PSMA-targeted PET scans, “which can detect prostate cancer at low levels before it can be seen on conventional imaging. We will obtain PSMA- targeted PET scans in patients with biochemically recurrent prostate cancer,” and then follow them to see if they develop metastatic cancer as detected on CT or bone scans.
“Our goal is to use the findings on the PSMA-PET scan to predict the imminent development of metastatic disease,” with the hope of identifying which men will benefit from starting further treatment sooner.
A Molecular Urine Test for Aggressive Prostate Cancer
Wouldn’t it be nice if a simple urine test could tell whether localized prostate cancer has aggressive potential?
Wouldn’t it be nice if a simple urine test could tell whether localized prostate cancer has aggressive potential? This goal may be achieved soon, with a molecular urine test developed by three Brady scientists, says Christian Pavlovich, M.D., The Irene and Bernard L. Schwartz Scholar. With co-investigators Jun Luo, Ph.D., and William Isaacs, Ph.D., and support from The Patrick C. Walsh Prostate Cancer Research Fund, “we will validate and refine this test in 300 men with cancers of varying aggressiveness, who will be undergoing radical prostatectomy.”
In this study, the investigators will compare results of the urinary test, taken before surgery, with pathologic findings after surgery. “We hope to determine how accurate the test is in finding aggressive prostate cancer,” and will seek to optimize it for greater accuracy.
This test uses specific RNA probes to identify prostate cancer cells in urine samples collected after digital rectal examination. “It is more often positive in men who have aggressive forms of prostate cancer,” says Pavlovich. The investigators hope the test will prove particularly helpful in men who are considering Active Surveillance, “to tease out which of these men actually harbor more aggressive cancers that were missed on prostate biopsy.”
Alpha-Particle Radiotherapy: Targeting Every Cancer Cell
If we can see it, how can we kill it?
With PSMA-targeting molecules, scientists can find metastatic sites of prostate cancer that may be too resistant to kill. If we can see it, how can we kill it? Stavroula Sofou, Ph.D., The R. Christian B. Evensen Scholar, believes the answer is synergy. “Alpha-particle radiopharmaceutical therapy has been shown to be impervious THE PATRICK C. WALSH PROSTATE CANCER RESEARCH FUND 19 to most of cancer’s resistance mechanisms, if it’s optimally delivered,” she says. A mixed approach seems to be even more effective: “We recently observed that combining two types of carriers (a radiolabeled nanoparticle and radiolabeled-antibody) of the same alpha-particle emitter results in a greater delay of tumor growth compared to that of the same dose when delivered by each of the carriers alone.”
Sofou suspects that this approach exposes a greater population of cancer cells to more drug, and for longer periods of time, as two forms of the same drug attack the cancer. In work supported by The Patrick C. Walsh Prostate Cancer Research Fund, she and colleagues will extend their initial observations to animal models.
Immune Profiling of High-Risk Prostate Cancer
Why doesn’t immunotherapy work as well in prostate cancer as it does in other forms of cancer?
It may have something to do with what’s happening with immune cells – which, if they were doing their job, would be attacking the enemy – in and near the cancer, in the cancer’s microenvironment. For example, one kind of immune cell, called CD8+ T cell, is a mighty warrior in other settings.
But in prostate cancer, it is only present in low numbers, says Jelani Zarif, Ph.D., The Keith L. Bremer Scholar. “At the same time, prostate cancer tumors are infiltrated with immunosuppressive cells,” called M2-macrophages, which can reduce T cell function and prevent them from getting to prostate tumors and attacking them. But that’s not the only problem: When compared to other cancers, prostate cancers have far fewer genetic mutations. Each mutation makes the cancer cell look slightly different. To the immune system, a cancer cell with many mutations sticks out like the proverbial sore thumb; it’s much more likely to recognize such a cell as something that doesn’t belong, and to attack it. But prostate cancer cells, with fewer mutations, don’t stand out so clearly.
These are two good reasons why “we hypothesize that anti-tumor T cell responses are not generated in advanced prostate cancer,” says Zarif, “and why checkpoint- inhibiting drugs aren’t as effective for many patients.” In work funded by The Patrick C. Walsh Prostate Cancer Research Fund, Zarif is conducting a comprehensive analysis of the anti-tumor T cell response in prostate cancer tissue samples.
Better Treatment for Urethral Structures After Prostate Cancer Treatment
Urethral stricture – the formation of scar tissue, with narrowing at the bladder neck and urethra – “can be a devastating side effect of prostate cancer therapy, leading to infection, bladder dysfunction and urinary retention,” says E. James Wright, M.D., The Carolyn and Bill Stutt Scholar. There are two basic ways to treat such a stricture and expand the narrowed area: a minimally invasive approach, with an incision into the scar to break its hold on the urethra, or a more complex procedure, open surgical graft repair.
Neither procedure is perfect, says Wright: “The minimally invasive approach is simpler to perform, but it has a high failure rate; meanwhile, the complex repair procedure is technically challenging.” A third procedure, combining both internal incision and grafting, “is a viable option with development of a suitable temporary implant to expand the urethra and hold a graft in place.”
Graft healing requires two things, says Wright: “adequate blood flow to the urethra and accurate assessment after expansion, to ensure successful grafting without urethral injury.” In work funded by The Patrick C. Walsh Prostate Cancer Research Fund, Wright will use laser Doppler flowmetry to measure blood flow changes in the expanded urethra in men undergoing radical cystoprostatectomy (surgery to remove the bladder, prostate, and seminal vesicles). He hopes the study’s results will help guide development of a novel device and more effective treatment for these strictures.
Making PARP Inhibitors Safer for Normal Tissue
Can we make PARP inhibitors more cancer-specific, and more likely to leave normal cells alone?
PARP inhibitors are new drugs that have great promise in treating several forms of cancer. They block poly(ADP-ribose) polymerase (PARP) proteins, and seem to work best in patients with certain genetic mutations. But they can have “off-target” effects, says Fengyi Wan, Ph.D., The Charlton C. and F. Patrick Hughes Scholar.
The current PARP inhibitors, including Olaparib, all work in such a way that “therapeutic targeting of PARP1 using these inhibitors could negatively impact numerous key procedures in normal cells,” Wan explains. “There is an urgent clinical need for improving the specificity and lowering the off-target effects of PARP1 inhibitors.”
Wan’s laboratory recently discovered a crucial protein that also stimulates DNA damage-induced PARP1 activation. In work supported by The Patrick C. Walsh Prostate Cancer Research Fund, he plans to target this protein’s effect as a novel strategy to develop a new category of PARP1 inhibitors – agents that might be kinder to normal cells and processes. “Our specific aims during this project are to screen and validate potent drugs” that specifically inhibit this protein’s activation of PARP1, “and to assess their effect on the survival of advanced prostate cancer cells.”