In the United States, about 17 percent of men will develop prostate cancer, and three percent of all men will die from it. To help answer the most pressing questions about a disease that affects so many, Northwestern Medicine scientists have received a five-year, $11 million grant from the National Institutes of Health National Cancer Institute (NCI) to lead a Specialized Program of Research Excellence (SPORE) in prostate cancer.
The SPORE comes with demanding requirements, notably completing four studies that span the full translational research spectrum during the funding period.
“The whole philosophy of a SPORE grant is that you have to take basic science from the research bench and move it to the patient’s bedside in five years,” says William Catalona, MD, principal investigator of the program. “Many projects could never qualify because you won’t see results in such an accelerated timeline. We’re driven to apply this research to help patients as soon as we can.”
The NCI supports SPOREs devoted to 18 different organs and systems across the body, from the brain to the lungs, breast, kidneys, skin and so on. The program is highly competitive: Northwestern has one of only eight prostate SPOREs in the country, and the only SPORE of any kind in Illinois.
Northwestern’s program was first funded in 2001 and renewed in 2009. The brand-new grant represents an updated research agenda, with new collaborative projects that will be carried out by scientists and clinicians at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, the University of Chicago, and NorthShore University HealthSystem.
Identifying High-Risk Disease
The team’s research focuses on two urgent issues in prostate cancer today. The first is differentiating between patients who have aggressive disease that requires immediate treatment and those who have milder disease that can be monitored with active surveillance, an approach involving regular tests to see if the cancer is growing to a point where it should be treated.
“A big controversy in the field is that there might be over-diagnosis and over-treatment of some patients who really don’t need to be treated,” says Dr. Catalona, who is also a professor of Urology at Feinberg. “But the problem with putting patients who appear to have low-risk prostate cancer on active surveillance is that up to 40 percent of them actually have areas of cancer that are much more aggressive than you think.”
Previous studies show that patients whose aggressive prostate cancer is treated too late—usually with surgery or radiation therapy—are cured in just half of all cases, highlighting the need for a better way of identifying them in the first place.
In one of the SPORE projects, Dr. Catalona and collaborators from the University of California, San Francisco and NorthShore will study patients’ germline genetic variants for differences in their inherited DNA. Using patient blood or saliva samples, the scientists hope to determine the genetic factors correlated with failed active surveillance. Ideally, the project will help clinicians decide which patients need therapy right away.
“Knowing which variants can predict who is going to fail and who is going to succeed in active surveillance will also give us clues about the cell signaling pathways that are associated with the aggressive cancer,” he says. “These pathways could be targets for new therapies.”
Developing Better Therapies
The second urgent need is better treatment options for patients whose prostate cancer persists against all available therapies. When active surveillance, surgery and radiation don’t work, clinicians treat advanced-stage prostate cancer with hormonal therapy. This strategy isn’t curative; it just slows the disease for a while. Cancer that has become resistant to hormonal therapy is called castrate-resistant prostate cancer—it’s this disease that kills three percent of U.S. men.
“When hormonal drugs stop working, the only thing we have left is chemotherapy, which can prolong life just three or four months,” explains Dr. Catalona. “Castrate-resistant prostate cancer is the second leading cancer killer after lung cancer. It’s a major health problem. Our SPORE’s other three projects are all focused on developing ways to reverse this using precision medicine approaches.”
One project, led by Jindan Yu, MD, PhD, associate professor of Hematology/Oncology in the Department of Medicine, aims to block prostate cancer progression by restoring the function of a protein called FOXA1, which is decreased in castration-resistant prostate cancer. The gene that encodes this protein is mutated in up to 10 percent of patients with the cancer.
“We pinpointed two essential signaling pathways that are downstream of FOXA1, which may be targeted through a combination of therapeutic approaches,” says Dr. Yu. “Our study will evaluate the efficacy of this drug combination in metastatic prostate cancer, with the ultimate goal to provide targeted therapy to patients with FOXA1 dysfunction.”
Sarki Abdulkadir, MD, PhD, John T. Grayhack, MD, Professor of Urological Research, leads the next project. He previously found that the development of some aggressive prostate cancers involves alterations in specific genes. With investigators at the University of Southern California, he identified that a protein called the EHPB4 receptor is important for this cancer cell growth and survival.
“We are using a novel inhibitor of EHPB4 as a drug to investigate treatment of therapy-resistant prostate cancer in animal models and in an early-stage clinical trial in humans,” says Dr. Abdulkadir.
The final project, led by Suzanne Conzen, MD, and Russell Szmulewitz, MD, both from the University of Chicago’s Comprehensive Cancer Center, will focus on the function of the body’s stress hormone receptor, the glucocorticoid receptor. Past research has shown that prostate cancers express receptors that respond to androgens—male sex hormones such as testosterone—and stress hormones such as cortisol.
“We will examine whether targeting the pro-tumor effects of these two receptors simultaneously can improve tumor shrinkage compared to current treatment that primarily targets the androgen receptor,” explains Dr. Conzen. “Collaboration between the University of Chicago and Northwestern will increase the breadth of expertise at the individual institutions so that we can make meaningful progress in advanced prostate cancer biology and treatment.”
Under previous SPORE grant cycles, Northwestern investigators already took strides to improve the current state of prostate cancer.
“We built a repository of specimens containing thousands of tissue, blood and DNA samples from patients to share with researchers,” says Robin Leikin, ’83 PhD, scientific administrator of the grant. “We also developed a more accurate blood test to identify prostate cancer and educated more than 4,000 men about cancer risk at screening events.”
In the next phase of research—and beyond—the team hopes to accomplish much more. Their model for prostate cancer could even extend to other diseases in the future.
“The prostate SPORE grant is an honor and a reflection of the strength of our programs in the Lurie Cancer Center,” says Leonidas Platanias, MD, PhD, director of the center. “We are now working to develop other SPORE applications in brain tumors, leukemia and breast cancer.”