For decades, physicians have known that male hormones fuel prostate cancer growth. That's why therapies that block the production of androgen - or testosterone - provide some of the most effective treatments for men with advanced prostate cancer. Certain drugs, for example, cause the tumor to shrink and PSA levels to decline. But despite initial success with therapies that block testosterone production, prostate tumors inevitably return and are resistant to further treatment.
Now, research conducted by Memorial Sloan-Kettering Cancer Center investigators sheds new light on why existing therapies don't stop the disease from returning. The findings, published in the November 3rd issue of the Journal of the National Cancer Institute, challenge current thinking about how to treat prostate cancer. The study dovetails with recent research also published by Memorial Sloan-Kettering investigators that offers new strategies to treat this lethal form of the disease.
In the current study, investigators at Memorial Sloan-Kettering evaluated the effectiveness of hormonal therapy to treat human prostate cancer in mice. They found that withdrawing testosterone caused the majority of the tumor cells to go into a dormant, or growth arrested state, but that very few cells died.
"Until now we thought that blocking the production of testosterone killed most of the prostate cancer cells and that the few remaining "resistant" cells were what caused the disease to recur. But this study suggests that few cells die after testosterone is blocked," said Dr. Howard Scher, Chief of Genitourinary Oncology at Memorial Sloan-Kettering Cancer Center and senior author of the study in the Journal of the National Cancer Institute.
To determine why therapies that block the production of testosterone ultimately fail to prevent a recurrence of prostate cancer, the researchers injected mice with human prostate cancer cells and once the disease had developed, withdrew testosterone. The investigators then monitored changes in the cancer to determine the effects of testosterone withdrawal. They found that there was an initial increase in the activity of proteins that control the growth of tumor cells. But instead of causing all the tumor cells to die, the proteins only appeared to inactivate the cells, or to stop them from growing.
"We found that the increase in these proteins reflected an initial cell stress response that stopped the majority of the cells from growing. But ultimately the prostate cancers came back because cell death did not occur," said Dr. David Agus, an oncologist at Memorial Sloan-Kettering Cancer Center and lead author of the study. "The next step is to develop drugs that will target the growth arrested prostate cancer cells."
Recent research conducted by Memorial Sloan-Kettering investigators may offer one such approach. In a separate laboratory study aimed at developing therapies to treat prostate cancer, human prostate tumors were grown in mice to determine the effectiveness of a monoclonal antibody called Herceptin® (trastuzumab) and a chemotherapy drug called Taxol® (paclitaxel). These drugs were tested in mice with both androgen-dependent tumors - tumors that need testosterone to grow - and androgen-independent tumors - recurrent tumors that grow independent of hormone stimulation. They found that Herceptin® combined with Taxol® caused a marked regression of tumors in both androgen-dependent and independent disease. This work, conducted by Memorial Sloan-Kettering researchers, was published in the October 1 issue of Cancer Research.
In addition, the investigators found that Herceptin® alone had no effect on tumor growth in any of the androgen-independent or recurrent tumors, but that the drug caused significant tumor regression in androgen-dependent or initial prostate cancer tumors.
"It appears that Herceptin® has different effects depending on whether or not testosterone is present, which means that treatment with the combination of both drugs may lead to a new way to treat the recurrence of this disease," said Dr. Agus.
In mice with recurrent prostate cancer - or androgen independent disease, the investigators found that treatment with the combination of both drugs caused the tumors to shrink significantly.
Clinical trials are currently underway at Memorial Sloan-Kettering to evaluate the effectiveness of both Taxol® and Herceptin® to treat patients with androgen-dependent and independent prostate cancer.
This research was supported in part by the National Cancer Institute, the Eleanor and Paul Stephens Foundation and CaP CURE.
Memorial Sloan-Kettering Cancer Center is the world's oldest and largest private institution devoted to prevention, patient care, research, and education in cancer. Throughout its long distinguished history, the Center has played a leadership role in defining the standard of care for patients with cancer. In 1999, Memorial Sloan-Kettering was named the nation's best cancer care center for the seventh consecutive year by U.S. News and World Report.
Journal
JNCI Journal of the National Cancer Institute