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Scientists Strive to Develop Precision Medicine and Combat Treatment Resistance in Prostate Cancer

Philip Kantoff, MD (DFCI/BWH), leader of the DF/HCC Prostate Cancer Program.

January 2014 | eNews

Nearly all men with early stage prostate cancer are alive five years after diagnosis, but for patients with metastatic prostate cancer, only one third to one half of men are alive at that time. However, promising new treatments are now available and others are emerging. Ten years ago, only one drug, docetaxel, showed an ability to prolong survival in men with metastatic prostate cancer, but in the last four years, several additional agents have shown a survival benefit. These new agents include Provenge (the first cell-based immunotherapy for cancer), cabazitaxel, radium-223, abiraterone, and enzalutamide. Denosumab has also shown a bone protective effect in metastatic prostate cancer. “Our Cancer Center has played a leadership role in developing these drugs,” says Philip Kantoff, MD (DFCI/BWH), leader of the DF/HCC Prostate Cancer Program, which is co-led by Steven Balk, MD, PhD (BIDMC); Adam Kibel, MD (BWH); and Matthew Smith, MD, PhD (MGH). “These advances will definitely translate into an improved prognosis for men with this disease,” Kantoff adds.  

Major research goals being tackled by the DF/HCC Prostate Cancer Program include developing more personalized treatment for patients through genome sequencing, a term called “precision medicine.” A better understanding of each patient’s genomics will help establish which of the newer treatments to give to which patients. Another goal is to learn more about why patients develop resistance to treatment, and potential ways to combat this resistance. In addition, Omid Farokhzad, MD, is conducting important new research on nanoparticle therapies designed to deliver drugs directly to cancer cells in a controlled manner (see accompanying story).

Precision Medicine in Prostate Cancer

With respect to precision medicine, Eliezer M. Van Allen, MD (DFCI/Broad), a computational biologist and clinical oncologist, is using genome sequencing of prostate cancers to establish which treatments might benefit which patients. Van Allen's research involves prospectively taking prostate cancer biopsies from patients, both prior to treatment and then again after treatment, evaluating the patient's outcome, and comparing the before and after genomics between the two biopsies. In this way, he may be able to uncover clues to which treatment might produce the best outcomes for patients.  

“Although we've pushed the envelope with these new drugs, some patients still fail to respond or develop resistance to them,” Van Allen says. “If we can figure out the genomic changes correlating to each patient’s outcome, we could conceivably use treatments that would produce the best outcomes.”

Van Allen's research builds on previous studies led by Levi Garraway MD, PhD (DFCI/Broad), and other researchers at the Broad Institute, which involved an intensive exome sequencing of prostate tumors and normal tissue pairs. Garraway and colleagues found that mutations in the speckle-type POZ protein (SPOP) constitute one major pathway in prostate cancer, present in up to 15% of cases; the so-called “ETS” fusion genes, such as TMPRSS2-ERG, are present in 50%; and mutations in FOXA1 and MED12 genes occur in about 4% of prostate cancers.

According to Van Allen, selecting the most appropriate treatment in prostate cancer has been especially challenging compared with other tumor types due to the fact that specific alterations in prostate cancer cells have remained elusive. “For some tumor types, researchers have identified many clinically actionable alterations—for example, erlotinib can be used to target epidermal growth factor receptor mutations in lung cancer. By contrast, in prostate cancer we are really just starting to appreciate where those opportunities in treating genomic alterations may lie.”

Teasing Out the Mechanisms of Resistance to New Prostate Cancer Treatments

Steven Balk, MD, PhD (BIDMC) is investigating the mechanisms that promote tumor growth in the castration-resistant state in more advanced prostate cancers and trying to identify what causes relapse after standard androgen deprivation therapy, as well as after newer agents, such as abiraterone and enzalutamide.

According to Balk, abiraterone can further block the synthesis of androgens and is effective in a substantial fraction of patients who have castration-resistant prostate cancer. In addition, enzalutamide directly blocks the androgen receptor. However, patients' responses to both of these drugs are relatively short lived. “Researchers in the field are now asking how the androgen receptor becomes activated again after these drugs have been used,” Balk explains. “We are trying to find out the basis for resistance to these new agents targeting the androgen receptor.”

Immunohistochemistry indicated decreased PSA protein and decreased nuclear ERG and AR after abiraterone treatment, suggesting that AR activity in the tumor cells is driven by CYP17A1 dependent intratumoral androgen synthesis.

According to Balk, it's likely that all of the mechanisms that contribute to the initial androgen receptor activation after standard androgen deprivation therapy also participate in the abiraterone- or enzalutamide-resistant phase. ”We believe that residual androgen is still being produced by the tumor cells, so if we could eliminate this residual androgen production, the response rate to these drugs may be even better, although additional mechanisms may be involved.”

Identifying the Best Therapies for a Long, Healthy Life

Paul Nguyen, MD, (BWH), works on issues related to survivorship in prostate cancer. “Quality of life is something that is very important for patients with prostate cancer, many of whom survive with the disease for years,” he says. Nguyen says they are using genetic predictors to determine which therapies might produce the best quality of life in patients. “For example, if you could predict who is going to have a better quality of life after radiation versus after surgery, then that might point you in one direction or another in terms of treatment,” he says.

Another aspect that Nguyen is evaluating is the link between anti-androgen therapy and cardiovascular disease. “Anti-androgen therapy seems to induce insulin resistance, diabetes, and associated cardiovascular effects, so it is important to be able to identify which patients might experience the worst cardiovascular effects from hormone therapy and why.”

“It is unclear exactly what the mechanism for cardiovascular changes is,” Nguyen says. He is currently working with colleagues in cardiology to understand the differences in vasculature before and after the administration of anti-androgen therapy to determine whether endovascular dysfunction might be one of the important mechanisms. In an ongoing study, Nguyen and colleagues are prospectively measuring the endovascular function of patients before hormone therapy and then 3 months and 12 months after hormone therapy. “The hope is that if you can understand the mechanism for cardiovascular changes, then maybe you can do something to prevent them.”

The Road Ahead: Selecting Patients for Treatment and Selecting Treatments for Patients

Kantoff notes that two big research questions going forward will be to differentiate those people with early prostate cancer who need to be treated from those who do not need to be treated, for example, those who would benefit from a watchful waiting approach. “We also need to figure out how to select the best available treatments and develop new therapeutics for these patients,” says Kantoff.  

In a disease that affects 1 in 6 men, many research questions remain, but Kantoff points out that the prostate cancer program at DF/HCC is well recognized as a leading prostate cancer program in the country. Future research in prostate cancer is likely to build on these and many other recent accomplishments, and given the extensive burden of this disease, these advances will hopefully translate to an improved life for millions of men.     

Research detailed in the article was funded in part by NIH grants P50CA090381 and P01CA163227, and a Stand Up to Cancer grant.

— Emma Nichols