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
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 (Herceptin), a monoclonal
antibody, and 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.