Prostate cancer is the most common cancer in men and, when caught and treated early, is considered curable. But when prostate cancer becomes metastatic, meaning it spreads to distant organs, it is no longer considered curable and novel treatment strategies are needed.
Prostate cancer is the second most common and deadly cancer in the United States. The American Cancer Society estimates that 1 in 8 men will receive a prostate cancer diagnosis in their lifetime. Treatment techniques range from aggressive therapies such as radical prostatectomy or radiation therapy to targeted therapies that treat only the affected cancer cells.
The prostate-specific antigen (PSA) is a protein produced by the prostate gland. The PSA test is a blood test used to measure the amount of this protein found in the blood. Results are reported (ng/mL), which means nanograms of PSA per milliliter of blood. High levels of PSA have been found in men with advanced prostate cancer.
Hormone therapy is often used to treat prostate cancer that has spread to other parts of the body, but many patients develop resistance to hormone therapy, causing their disease to become more aggressive and potentially more deadly.
Ashton Villars has always been a problem solver. As a competitive athlete in basketball, waterskiing, and tennis and an actual rocket scientist, Villars has tackled every challenge in life head on — including his prostate cancer diagnosis. Now, he’s bringing that same problem-solving spirit to supporting cancer research.
When prostate cancer spreads, it most often spreads to bone. And while the 5-year survival rate for prostate cancer that has not spread is nearly 100 percent, once the disease reaches bone, the 5-year survival rate is only 29 percent. Now a University of Colorado Cancer Center study published in the Journal for Immunotherapy of Cancer suggests a new approach, or, possibly two new approaches against these bone metastases: While targeted therapies and anti-cancer immunotherapies have not been especially successful against primary prostate cancers, the study suggests that both these approaches may be effective against the bone metastases that grow from primary prostate cancers, and, in fact, the type of bone metastasis may dictate which targeted therapies and immunotherapies work best.
Since the 1940’s, blocking the body’s production of androgen has been the only systemic therapy against prostate cancer. Today, while we’ve gotten better at targeting androgen signaling, treatments targeting the genetic causes of prostate cancer have lagged behind those for other forms of the disease.
The National Cancer Institute (NCI) is set up to fund individual projects in fields like genomics, computational biology, and pathology. Now researchers at University of Colorado Cancer Center are taking advantage of an innovative new program in cancer systems biology to combine the three research areas, earning a prestigious “U01” grant to study the complex genetic drivers of aggressive prostate cancer. By combining the tools of pathology, computational modeling and genomics, the project hopes to discover and test therapeutic interventions for three molecularly distinct types of prostate cancer.
“Prostate cancer is defined by its pathology – you take a biopsy, give it to a pathologist, and they score it, for example they will characterize it as ‘pathological stage 3 disease.’ What we want to do is to understand how genetics contributes to driving aggressive pathology. By understanding what pathways and processes are dysregulated by distinct genetic alterations, we can start to explore therapeutic options to match the genetic alterations,” says James Costello, PhD, CU Cancer Center investigator and assistant professor in the Department of Pharmacology at the CU School of Medicine.
In cancers like melanoma, there tends to be a single genetic driver.
“You have mutations in oncogenes such as BRAF or RAS that drives disease,” says Scott Cramer, PhD, investigator at the CU Cancer Center and professor in the CU School of Medicine Department of Pharmacology. “But in prostate, it’s tricky. Prostate cancer tends to be driven by the loss of tumor-suppressor genes – for example, you lose TP53 and the tumor can grow. In prostate, we find that aggressive disease is often associated with loss of multiple tumor suppressors.”
The field of cancer research is getting better and better at turningoffoncogenes that cause cancer. However, the field is far less adept at therapeutically targeting cancers where good genes are lost.This means that in prostate cancer and other cancers created bylossof tumor suppressors, treatment isn’t as simple as switching these lost genes back on. Instead, this project hopes to discover what else happens in prostate cancers with loss of these tumor suppressor genes – possibly, in this tangled network of cause-and-effect, turningoffa tumor suppressor like TP53 may turnonanother gene that aids cancer growth. And if that’s the case, Costello, Cramer, and colleagues would have a target they could do something about – a target gene they could turn off.
Likewise, “In prostate, you get big deletions in chromosomes – there are multiple genes in there and we need to know which ones are the causal drivers of aggressive disease,” Cramer says.
In other words, deleted along with these known tumor-suppressor genes like TP53, may be the loss of many other genes. Some of these losses are unimportant – only about 1.2 percent of our genome is actually manufactured into proteins. But some losses may be additional drivers of cancer.
To discover these genetic drivers of prostate cancer, Costello and Cramer will turn off various combinations of genes in mouse models of the disease to see which combinations grow into aggressive cancers. Then the team will look inside these models of aggressive cancer to see which genetic pathways are affected.
“We end up with the genetically altered cells that drive the disease, which allows us to ask what is the most likely therapeutic target? Then we can treat mouse models with drugs and see if it’s successful,” Costello says. If these studies are promising the next step may be clinical trials in men with this aggressive form of prostate cancer.
Until recently, the project would have struggled to find funding.
“When you submit a grant, it gets evaluated by a ‘study section,’” says Cramer. “Most study sections are very focused – you submit this project to a pathology study section and they might not get the computational modeling that is used to help make sense of genome-wide measurements to identify therapeutic targets. But if you submit the grant to a computational modeling study section, they don’t get the pathology side and tend to score it poorly. The balance is tricky.”
With only 8 percent of cancer research project grant applications earning funding, even perceived weakness or misinterpretations by a reviewer in the study section can be fatal.
“The National Institutes of Health recognized there were research areas they wanted to fund that weren’t getting funded in standard study sections, so they developed the Cancer Systems Biology Consortium, for which the U01 is one mechanism to foster collaborations like this,” Costello says.
Despite decades of effort, no one set of tools has been able to point to the genes driving prostate cancer. Now with three sets of tools – genomics, computational modeling, and pathology – Cramer, Costello and CU Cancer Center colleagues hope to finally pinpoint the causes of aggressive prostate cancers. Knowing the cause is an important step toward finding a cure.
For most people finding out that they have prostate cancer multiple times in the span of just a few years seem like a cruel joke. But Jonathan Ormes is not most people. After being told for the third time that he had the disease he decided to take a chance on a University of Colorado Cancer Center study drug that, so far, is controlling his cancer. Ormes is not letting prostate cancer slow him down. In fact, he is using his experience to create poetry.
A University of Colorado Cancer Centerstudypublished ahead of print in the journalBrachytherapyshows that intermediate risk prostate cancer patients experience modest benefit from the addition of external beam radiation therapy (EBRT) to brachytherapy. The study is based on the results of 10,571 patients, of which 3,148 received brachytherapy plus EBRT and 7,423 received brachytherapy alone. Overall survival rates were 91.4 percent versus 90.2 percent at five-year follow up, and 85.7 percent versus 82.9 percent at seven-year follow up.