CCE Prostate Cancer: Sloan-Kettering

Memorial Sloan-Kettering Cancer Center
New York, New York

 “Today we cannot cure a man with metastatic prostate cancer,” says Peter T. Scardino, FACS chairman of the Department of Surgery at Memorial Sloan-Kettering Cancer Center (MSKCC).

That will change in the next 10 years for most men, Scardino believes. The MSKCC Sidney Kimmel Center for Prostate and Urologic Cancers is striving to make that happen through aggressive efforts in prevention, detection, diagnosis, research and treatment.

Strong effort in prevention

There are limited options for the prevention of prostate cancer. Lack of genetic testing to indicate a patient’s risk of developing the disease makes it even more difficult to determine.

“We just don’t know enough about the genetic risk factors for prostate cancer to be really able to give people credible information, other than from their family history,” Scardino says. “In the prostate cancer world the most profound thing that has happened in prevention is a study done by the National Cancer Institute (NCI) that looked at Finasteride for the chemotherapy prevention of prostate cancer and that study was a huge success.”

MSKCC is doing studies to identify men at increased risk of developing prostate cancer who might benefit from chemoprevention. Recent trial results indicate that prophylactic use of these agents is not linked to the development of more aggressive tumors, as was shown in a previous study.

“That is the most important thing that is going on in the prevention of prostate cancer today,” Scardino says.

Early diagnosis efforts

Hans Lilja, MD, PhD, a clinical laboratory physician at MSKCC, holds patents for his development of free prostate-specific antigen assays. “Free PSA is now a standard test worldwide in determining who should have a biopsy if they have prostate cancer,” Scardino points out.

In addition, MSKCC researchers are studying how a single PSA test can predict younger men’s risk for prostate cancer. A study published by researchers at MSKCC and Lund University in Sweden found a PSA test taken before the age of 50 can be used to predict who will get advanced prostate cancer in men up to 25 years later. As a result, for men in their 30s and 40s, it might be possible to use the PSA test as a predictive tool to determine their lifetime risk of developing prostate cancer, Scardino explains.

“We have been extremely interested in understanding the powerful predictive nature of PSA levels, and I think this will lead to eventually profound changes in the way we recommend men use PSA testing,” he says.

MSKCC employs a “watchful waiting” approach for those diagnosed with prostate cancers that are not life threatening and do not need immediate treatment. For these patients, MRI and repeat biopsy are regularly used to monitor disease progression and confirm that treatment is not needed. “MRI and repeat biopsy should be more widely used,” Scardino says.

Specialized treatment protocols

The biggest strength of the prostate cancer program is its depth, which allows patients to find comprehensive treatment regardless of the stage of their disease, Scardino says.

“When a patient comes to us, what we can do is offer them one-stop shopping to be able to look at all of the different choices in prostate cancer treatment,” he says.

MSKCC pioneered the use of high-dose intensity-modulated 3-dimensional conformal radiation therapy (IMRT) and helped develop brachytherapy. MSKCC also played an integral role in the development of a prostate cancer nomogram to predict how serious a prostate cancer is and the chances that it might recur after treatment.

Each of the urologic surgeons at MSKCC specializes in only one type of surgical technique for the treatment of prostate cancer and performs that technique exclusively-open, robotic or laparoscopic. “That is a big strength and unique feature of the program,” Scardino stresses.

Based on findings published in the Journal of the National Cancer Institute by Andrew Vickers, PhD, associate attending research methodologist at MSKCC, prostate cancer patients treated by highly experienced surgeons are much more likely to be cancer-free five years after surgery than patients treated by surgeons with less experience.

Patients with advanced prostate cancer will be treated by medical oncologists who are among the world’s leaders in developing new treatments. The world’s largest prostate cancer clinical trial consortium is centered at MSKCC. Led by Howard Scher, MD, chief of Genitourinary Medical Oncology, the consortium of 11 cancer centers is investigating new treatments for advanced prostate cancer.

World-class research

Patient care is backed by groundbreaking research.

The NIH in 2001 awarded MSKCC a grant to establish an ongoing Specialized Program of Research Excellence. The program’s primary goal is to translate population-based clinical investigations and basic research findings into clinical trials of both early and late prostate cancer and eventually reduce the incidence, morbidity from and mortality of prostate cancer.

Another major effort is to further characterize the pathways involved in prostate cancer initiation, progression, and metastasis through molecular analyses of transgenic murine models and well-characterized cohorts of prostate cancer patients at all clinical stages of the disease.

MSKCC also is working on a comprehensive genomic analysis of a series of 200 tumors to characterize all the genetic alterations using a variety of high-throughput technologies. About 80 percent of the research is complete and the data are expected to be published this year. Scardino explains that the research will, “at a deeper level than ever, determine what are the genetic changes that are really driving prostate cancer.”

Currently, phase 1 and 2 trials are being conducted on an androgen-receptor antagonist in patients with hormone-refractory prostate cancer. In preclinical models, the research demonstrated that this agent significantly inhibited the growth of otherwise refractory human prostate tumors.

MSKCC is studying immunotherapy and its potential clinical applications as well. The effort is headed by James Allison, PhD, chairman of the Immunology Program at the Sloan-Kettering Institute.

He is investigating the use of a monoclonal antibody to stimulate the immune system in men with prostate cancer, says Scardino. Allison discovered several key molecules in T cell activation, including cytotoxic T lymphocyte-associated antigen-4 (CTLA-4). The function of CTLA-4 was discovered in Allison’s laboratory and he and his colleagues identified a monoclonal antibody to block it.

He hypothesized that by blocking CTLA-4, it might greatly enhance antitumor T cell responses. He made antibodies to block CTLA-4’s signal so that the T cells could do their work unrestrained.

His hypothesis was demonstrated to be correct and anti-CTLA-4 proved to boost the immune system’s ability to fight cancer. The first in a new class of biologic agents, anti-CTLA-4, is being tested in several clinical trials as a stand-alone treatment and also in combination with vaccines and more traditional chemotherapy drugs.

Based on this research, an antibody that binds to CTLA-4 is in phase 1 and 2 trials for patients with metastatic hormone-refractory prostate cancer.

MSKCC also developed the first knockout mouse model for prostate cancer. The mouse model has varying amounts of the phosphatase and tensin homolog PTEN gene, which is a critical gene in many cases of advanced cancer, Scardino says.

Researchers discovered that the loss of one or more PTEN tumor suppressor genes is found in 70 percent of prostate cancer patients at the time of diagnosis. Studies suggest that the less PTEN function that a cancer retains, the more aggressive it is.

“Animal models for prostate cancer-using them to both understand how cancers develop and metastasize, and how various targeted therapies might stop the development of prostate cancer-has been a major area of interest,” Scardino says.