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. These awards wouldn’t have been possible without the tremendous and amazing generosity of our patients and friends.
For 2019, we asked scientists to submit one of two types of research proposals: for pilot projects, as in previous years, and for team science awards. These team projects are aimed at developing the necessary preliminary data and team structure needed to apply for NIH program project grants (such as P01 or U01), or similar funding from other sponsors. Applications were reviewed by nine separate investigators with appropriate expertise related to each project. Projects were scored on a scale of 1 to 10 (1 being the best possible score) and then ranked, based on their adjusted average (the highest and lowest scores were eliminated before taking the average of the remaining seven scores).
Jun Luo, Ph.D.
The Virginia and Warren Schwerin Scholar, Department of Urology
Precision Medicine in Prostate Cancer: Finding Subsets of Patients
We’ve known for many years that prostate cancer fine-tunes itself from patient to patient. This is why, although two men may appear to have identical prostate cancer, with the same Gleason grade and same stage, one man may respond to a drug, and the other will not. Thanks to advances in prostate cancer genetics – many of them made right here at the Brady – we now know that men with prostate cancer can be divided into subsets. One subset, for example, is men with mutated BRCA1/2 genes, who may do better on PARP inhibitors than other men.
“The treatment landscape for men with advanced prostate cancer is rapidly evolving,” says Brady scientist Jun Luo, Ph.D., who adds that “disruptive changes are being introduced by multiple treatment modalities. Although progress has been made in prostate cancer genetics and genomics, there remains a critical knowledge gap that limits the impact of these advances on the overall goal of prostate cancer control.”
“We will use our team science award to develop genetic marker tests and characterize subsets of patients with distinct treatment responses. Such tests could help choose treatment at critical disease states along the prostate cancer spectrum.”
Luo, with Brady scientists William Isaacs, Ph.D., and Shawn Lupold, M.D., Ph.D., will use a team science award to develop genetic marker tests and characterize subsets of patients with distinct treatment responses. Such tests could help choose treatment “at critical disease states along the prostate cancer spectrum.” These pilot efforts will lead to a NCI PO1 project, “with the overall goal of realizing precision medicine in prostate cancer.”
Bruce J. Trock, M.P.H., Ph.D
The Ambrose Monell Foundation Scholar, Department of Urology
Could Metabolomics Explain Some Racial Differences in Men with Prostate Cancer?
Many metabolic patterns can be modified – by changing diet, exercise, other behaviors, or medications. “Identifying key metabolic differences could provide clues about changes that may help lower the risk in African American men.”
Metabolomics is the study of metabolites: small molecules found inside cells, body fluids, or tissues. Could it help explain racial differences in prostate cancer? Bruce Trock, M.P.H., Ph.D., and co-investigator Angelo De Marzo, M.D., Ph.D., believe it might.
As we discuss elsewhere in Discovery, African American men are more likely to develop prostate cancer, and to die of it, than men of European descent. There’s no simple explanation: in addition to genetic differences, many factors contribute to this discrepancy: certainly, issues such as “differences in income, education, diet, and access to medical care,” are important pieces of this puzzle, Trock notes. “But there also appear to be unexplained differences between African American and white men in the biology of prostate tumors. Although some differences in gene expression or mutations have been identified, they don’t provide a clear indication of how biological functions in the prostate may contribute to the excess risk in African American men.”
Metabolites may provide a new window for discovery. “Unlike genes and proteins, metabolites reflect the actual workings of cells and organs,” says Trock; in other words, what makes the prostate the prostate. Another advantage of studying metabolites is that many metabolic patterns can be modified – by changing diet, exercise, other behaviors, or medications. “Comparing patterns of metabolism between African American and white men with prostate cancer may reveal differences in the underlying biology. Identifying key metabolic differences could, in turn, provide clues about changes that may help to lower the risk in African American men. This type of approach is an example of precision urology.”
With their grant from The Patrick C. Walsh Prostate Cancer Research Fund, Trock and De Marzo will be comparing metabolic patterns in the prostatic fluid taken from men who underwent radical prostatectomy at Johns Hopkins. “This fluid is secreted by glands within the prostate – and these glands are the structures where prostate cancer originates.” The scientists believe these metabolites “should closely reflect the biological activity giving rise to prostate cancer.” They will compare prostatic fluid metabolites between closely matched African American and white prostate cancer patients whose tumors did, or did not, recur after surgery. “This may identify whether the biology leading to aggressive prostate cancer differs between African American and white men,” says Trock, “which will help us form new hypotheses for reducing risk and tailoring treatment to the biological aggressiveness of the tumor.”
Sarah R. Amend, Ph.D.
The Carolyn and Bill Stutt Scholar, Department of Urology
Keystone Cells and Resistance and Lethality of Prostate Cancer
“We will test the ability of α-particle irradiation to eradicate these Keystone cancer cells.”
We talked about “Keystone” cells – so named by scientists Sarah Amend, Ph.D., and Ken Pienta, M.D., because they seem to play a pivotal role in advanced prostate cancer that defies treatment. These Keystone cells – distinctive, large cells that emerge after chemotherapy – “have been recognized for more than 100 years, but are often dismissed as unimportant, thought to be artifacts or dying cells,” says Amend. “However, our preliminary data suggest that, in fact, Keystone cells are the critical mediators of therapy resistance. Therefore, unless they are eradicated, cancer will recur in treated patients.”
In a team project with Brady scientist Angelo De Marzo, M.D., Ph.D., and Stavroula Sofou, Ph.D., a biomolecular engineer at the Johns Hopkins Whiting School of Engineering, Amend will build on this work. “We will determine how and when Keystone cells are formed during prostate cancer progression,” Amend says. “We will also explore how they survive anti-cancer therapy by exiting the cell cycle and how they repopulate a therapy-resistant population. Then we will test the ability of α-particle irradiation to eradicate them.” Amend and colleagues believe the results of this project “will fundamentally change our understanding of how and when therapeutic resistance arises, and will introduce a candidate treatment to eliminate Keystone cells and increase the chances for long-term survival in patients with aggressive disease.”
Hui Zhang, M.S., Ph.D.,
The Beth W. and A. Ross Myers Scholar, Department of Pathology
What Happens at the Beginning of Metastasis?
Many, but not all, men diagnosed with low-risk prostate cancer can be safely monitored without treatment. There’s still some uncertainty, because we don’t have a way to tell who is truly low-risk, and whose risk might go up over time. Much needed, says Hui Zhang, Ph.D., is “a new test that could distinguish patients with truly low-risk disease from patients with high-risk features.” Such a test, she adds, would provide peace of mind to men who choose active surveillance, and allow doctors to recommend this strategy with greater confidence.
“A urine test that could distinguish patients with truly low-risk disease from patients with high-risk features would provide peace of mind to men who choose active surveillance.”
With co-investigator Alan W. Partin, M.D., Ph.D., Director of the Brady Urological Institute, Zhang will work on developing a urinary test to determine cancer risk using urinary glycoproteins, which have proven to be useful biomarkers in detecting prostate cancer from blood. Zhang and Partin have identified four likely candidate glycoprotein biomarkers. Says Zhang: “We will determine the clinical performance of detecting patients with different levels of high-risk tumors, using mass spectrometry as well as immunoassays for these four candidates from urine.”