Physicians have long known that male hormones fuel prostate cancer growth. Thats why therapies that block the production of androgenor testosteroneprovide some of the most effective therapies for advanced prostate cancer. Certain drugs, for example, shrink the tumor and decrease prostate-specific antigen (PSA) levels. 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 light on why existing therapies do not stop the disease from returning. Furthermore, these findings, published in the Journal of the National Cancer Institute (November 3, 1999), challenge current thinking about treatment.
Few Cells Die After Inhibition of Testosterone
Investigators evaluated the effectiveness of hormonal therapy for treating human prostate cancer in mice. They found that withdrawing testosterone caused the majority of tumor cells to go into a dormant or growth-arrested state, but 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 Howard Scher, MD, chief of genitourinary oncology at Memorial Sloan-Kettering Cancer Center and senior author of the study.
To determine why these therapies fail to prevent a recurrence of prostate cancer, researchers injected mice with human prostate cancer cells. Once the disease had developed, they withdrew the testosterone and monitored the cancer cells for changes. This monitoring showed an initial increase in the activity of proteins that control the growth of tumor cells. However, instead of causing all of the tumor cells to die, the proteins only appeared to inactivate the cells or 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 David Agus, MD, an oncologist at Memorial Sloan-Kettering and lead author of the study. The next step is to develop drugs that will target the growth-arrested prostate cancer cells.
Other Research Focuses on New Treatment Approach
These findings dovetail with recent research (also from Memorial Sloan-Kettering) published in Cancer Research (October 1, 1999). 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 trastuzumab(Drug information on trastuzumab) (Herceptin), a monoclonal antibody, and paclitaxel(Drug information on paclitaxel) (Taxol), a chemotherapeutic drug.
These drugs were tested in mice with both androgen-dependent and androgen-independent tumors. Researchers found that trastuzumab combined with paclitaxel caused a marked regression of tumors in both androgen-dependent and androgen-independent disease.
In addition, trastuzumab alone had no effect on tumor growth in any of the androgen-independent or recurrent tumors, but 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.
Clinical Trials of Trastuzumab-Paclitaxel Combination Underway
Research findings conclude that treatment with the combination of both drugs caused the tumors to shrink significantly in mice with recurrent prostate cancer (androgen-independent disease). Clinical trials are currently underway at Memorial Sloan-Kettering to evaluate the effectiveness of both paclitaxel and trastuzumab in treating patients with androgen-dependent and androgen-independent prostate cancer.