December 22, 1998. New treatments for men with metastatic
prostate cancer could develop from recent discoveries about a pathway
that can flood prostate cells with growth signals, causing prostate
cancer. The hope is to find a way to shut down that pathway.
A team led by Dr. Charles Sawyers made
its discovery almost simultaneously with related findings by several
other scientists worldwide. In the past year or two, a lot of work
has looked at damage to a specific gene called PTEN in prostate cancer
as well as other cancers. The UCLA team, focusing on prostate cancer,
has discovered that PTEN acts like a gate, opening and shutting access
to the Akt pathway, which carries the growth-regulating signals.
Under normal conditions, PTEN keeps growth
of cells in check so they won't divide inappropriately. One of its
jobs is performed very early in life  it makes sure the embryo develops
properly.
PTEN is a tumor suppressor gene on chromosome
10q23 (other suppressor genes you may know of are BRCA1 and p53).
If the PTEN gene mutates and stops working properly, the gate won't
close, causing too many growth signals to drive prostate cells to
divide out of control, which can lead to cancer.
"When PTEN is operating normally,
it serves as a brake regulating cell growth," said Sawyers, who
is director of the Prostate Cancer Program at UCLA's Jonsson Cancer
Center. "When the gene is mutated, the brake fails and the Akt
pathway operates at runaway levels, promoting rapid cell growth always
found in cancer."
Sawyers said the next step is for pharmaceutical
companies to develop a new drug that can block the Akt pathway, thereby
inhibiting prostate cancer growth in men with damaged PTEN genes.
This finding will be especially relevant
to metastatic prostate cancer if indeed the PTEN gene alters as the
cancer progresses. Research at Columbia University in New York has
found that the PTEN gene stops working in roughly 10-15% of primary
stage B prostate cancers. But Johns Hopkins reported last January
that PTEN alterations "occur frequently in lethal prostate cancer."
In previous experiments, Dr. Sawyers found that about half of men
with metastatic prostate cancer have a mutated form of the PTEN gene.
Sawyers' work on the PTEN gene mutation
and its relationship to the protein pathway sheds new light on prostate
cancer, a disease that for years has frustrated scientists trying
to target the killer of nearly 40,000 men every year. "Prostate
cancer has been a black box for years," Sawyers said. "Now
we know there's a common genetic alteration in prostate cancer and
we have proof of a pathway that regulates cell growth and is very
amenable to drug development. This could be very good news for prostate
cancer patients."
Also good news is the fact that scientists
already know a lot about the Akt pathway, Sawyers said. This should
allow development of a new drug to occur more quickly than usual.
"There already may be a drug in development that attacks this
pathway," Sawyers said.
A new treatment for prostate cancer that
attacks the Akt pathway would be the latest in targeted therapies,
which determine what is broken in a cancer cell and attempt to fix
it. Herceptin, a breast cancer drug, works in the same way  targeting
a genetic mutation linked to cancer. Developing a new drug that acts
as a gate is a "very rationally designed therapy," Sawyers
said.
Sawyers said exciting work is being done
in prostate cancer, particularly in the last two or three years. "There
is tremendous interest now in finding a way to fight this disease,"
he said. M.D. Anderson Cancer Center at the University of Texas, UC
San Francisco, and the University of Toronto are among other centers
working on PTEN.
Dr. Charles Sawyers recently received a Competitive Research Award
from the Association for the Cure of Cancer of the Prostate (CaP CURE)
to investigate new prostate cancer treatments that attack the Akt
pathway.
These links will take you to abstracts.
Dr. Charles Sawyers and his colleagues outline their research in:
Proc Natl Acad Sci 1998 Dec 22;95(26):15587-15591:
The PTEN/MMAC1 tumor suppressor phosphatase functions as a
negative regulator of the phosphoinositide 3-kinase/Akt pathway.
Whang YE, Sawyers CL, et al. Department of Medicine, University of
California School of Medicine, Los Angeles, CA. [click on title to
read the abstract]
An earlier paper by Dr. Sawyers appeared last spring: Proc Natl
Acad Sci U S A 1998 Apr 28;95(9):5246-50 Inactivation
of the tumor suppressor PTEN/MMAC1 in advanced human prostate cancer
through loss of expression.
Whang YE, Sawyers CL et al.
Other recent work on the PTEN tumor suppressor
gene and prostate cancer includes:
Br J Cancer 1998 Nov;78(10):1296-300 Mutation
and expression analysis of the putative prostate tumour-suppressor
gene PTEN. Snary D. et al.
Imperial Cancer Research Technology, Applied Development Laboratory,
St Bartholomew's Hospital, London, UK.
Oncogene 1998 Oct 15;17(15):1979-82 PTEN/MMAC1
is infrequently mutated in pT2 and pT3 carcinomas of the prostate.
Dong JT, et al. Department of Pathology, University of Virginia Health
Sciences Center, Charlottesville
Oncogene 1998 Jun 4;16(22):2879-83 PTEN/MMAC1/TEP1
involvement in primary prostate cancers. Pesche S, et
al. Lidereau R Laboratoire d'Oncogenetique, Centre Rene Huguenin,
St-Cloud, France.
Cancer Res 1998 Jul 1;58(13):2720-3 Frequent
inactivation of PTEN in prostate cancer cell lines and xenografts.
Vlietstra RJ, van Alewijk DC, Hermans KG, van Steenbrugge GJ, Trapman
J Department of Pathology, Erasmus University, Rotterdam, The Netherlands.
Oncogene 1998 Apr 2;16(13):1743-8 Analysis
of PTEN and the 10q23 region in primary prostate carcinomas.
Feilotter HE, Mulligan LM et al. Department of Pathology, Queen's
University, Kingston, Ontario, Canada.
Clin Cancer Res 1998 Mar;4(3):811-5 Homozygous
deletion of the PTEN tumor suppressor gene in a subset of prostate
adenocarcinomas. Wang SI, Parsons R, Ittmann M Department
of Pathology, College of Physicians and Surgeons, Columbia University,
New York, NY.
Cancer Res 1998 Jan 15;58(2):204-9 Interfocal
heterogeneity of PTEN/MMAC1 gene alterations in multiple metastatic
prostate cancer tissues. Suzuki H, Isaacs WB, Bova GS
et al.Department of Urology, Johns Hopkins University School of Medicine,
Baltimore, Maryland.
Science 1997 Mar 28;275(5308):1943-7 PTEN,
a putative protein tyrosine phosphatase gene mutated in human brain,
breast, and prostate cancer. Li J, et al. Parsons R Department
of Pathology, College of Physicians & Surgeons, Columbia University,
630 West 168 Street, New York, NY
December 28, 1998
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