Study Finds Way to
ID Aggressive Prostate Cancers; Save Men from Aggressive Therapy
Many prostate cancer
patients treated unnecessarily; vast majority would not become
life-threatening, even if left untreated
Feb. 3, 2011 – A
new discovery lays the ground work for the first gene-based test for
determining whether a man's prostate cancer is likely to remain dormant
within the prostate gland, or spread lethally to other parts of the
body. Today, many men, mostly senior citizens, endure drastic procedures
that are used unnecessarily on unaggressive cancers.
Dana Farber
Cancer Institute researchers have found that prostate tumors that carry
a "signature" of four molecular markers have the potential to become
dangerously metastatic if not treated aggressively.
Their study is
reported online today by the journal Nature.
Editorial writers ask if limited benefits are worth
the patient and clinician time and effort;
researchers say 'yes' do to significant, durable improvement in
incontinence and quality of life, - Jan. 12, 2011
By analyzing
prostate cancer tissue from hundreds of men participating in a national
health study, dozens of whom died of the disease, investigators led by
Ronald DePinho, MD,
Lynda Chin, MD, and Zhihu Ding, PhD, of Dana-Farber, found that the
four-gene/protein signature more accurately predicted which patients
would die from metastatic spread than did the conventional method.
The standard
measure of prostate cancer's aggressiveness, known as the Gleason score
(which is based on cancer cells' appearance under a microscope), is
accurate about 60 to 70 percent of the time depending on the skill of
the pathologist. The four-gene signature method alone was accurate 83
percent of the time. Combining the markers and Gleason methods produced
an accuracy of approximately 90 percent.
"It's widely
recognized that many prostate cancer patients are treated
unnecessarily," says DePinho, who is the director of Dana-Farber's
Belfer Institute for Applied Cancer Science.
"The vast
majority of prostate cancers would not become life-threatening, even if
left untreated. But because we can't accurately forecast which are
likely to spread and which aren't, there is a tendency to unnecessarily
subject many men to draconian interventions."
The result,
DePinho says, is that approximately 48 men are treated for prostate
cancer for every life saved. The cost of such overtreatment is estimated
at more than $600 million a year in the United States alone. There is a
physical price as well. The main forms of prostate cancer treatment —
surgery and radiation therapy — can produce a range of lasting
complications, such as impotence and urinary problems, including
incontinence.
The main
obstacle to developing better prognostic tests for prostate cancer has
been the lack of uniformity of cells in different tumors, and even
within a single tumor. In 85 percent of prostate cancer cases, the
prostate gland holds more than one tumor focus, each of which may
contain a different assortment of cancer cells with a distinct set of
gene abnormalities. Such diversity makes it difficult to identify genes
or other features that reliably indicate a tumor's potential to spread.
In the current
study, researchers began with the well-established fact that prostate
cancers without a working copy of the Pten gene tend to remain fairly
idle and don't trespass beyond the prostate gland itself. Researchers
theorized that the loss of Pten in turn activates a collection of genes
— a pathway — functioning to constrain the tumor's growth and invasion.
If that pathway was shut down, they reasoned, the tumor would begin to
break loose from the prostate and spread insidiously through the body.
Using
computational biology techniques to analyze gene activity in mouse
prostate cancer cells with inactive Pten, the investigators found a few
pathways that seemed to play a constraining role. One, known as
TGFβ-SMAD4 (for some of the genes that comprise it), was particularly
intriguing as this pathway had been implicated in the metastasis of
other tumor types in the past.
When researchers
conducted confirmatory molecular signaling studies to see what happens
when Pten is knocked out of commission, signaling in the TGFβ-SMAD4
pathway "shot through the roof," DePinho says, suggesting that the
pathway had sprung into action.
When researchers
generated mice whose prostate cells lacked both Pten and the Smad4 gene,
the animals developed large, fast-growing tumors that spread to their
lymph nodes and beyond. Guided by these insights, they then examined
whether something similar was happening in human prostate cancers.
Comparing the
gene expression profiles of indolent versus aggressive mouse prostate
cancers, they found about 300 genes that distinguished the two groups.
"We then
categorized them for known functions," DePinho says. "We were encouraged
to see that the top functional category were genes playing that have
roles in cell division and movement" — actions that are needed for
cancer cells to grow and spread with lethal consequences.
The researchers
conducted an elaborate series of experiments to identify the genes most
closely linked to the aggressive biology of prostate cancer. Among the
hundreds of genes analyzed, two such genes stood out: SPP1 and CyclinD1,
both of which, intriguingly, are close working partners of Smad4.
The four-gene
signature — Pten, Smad4, SPP1, and CyclinD1 — showed its effectiveness
as a predictive tool for survival when researchers drew on data from the
Physicians' Health Study, which has been tracking the health of
thousands of U.S. physicians for nearly 30 years. When the investigators
screened prostate cancer samples from study participants for the
four-gene/protein signature, it was more accurate in predicting the
ultimate course of the illness than conventional methods were.
Study Leaders are
Co-Founders of Metamark Genetics
“The study
published in Nature represents a landmark breakthrough in our
understanding of proteins that are critical for aggressive forms of
human prostate cancer. We believe that the findings will have important
implications for our ability to improve the prognosis and treatment of
prostate cancer patients," said Peter Blume-Jensen, M.D., Ph.D., Chief
Scientific Officer for Metamark Genetics, Inc., a privately-held
oncology molecular diagnostics company.
Metamark has
exclusively licensed a portfolio of technologies, including those
described in this study, from The Dana Farber Cancer Institute. The
study was led by Metamark scientific co-founders, Lynda Chin, M.D. and
Ronald DePinho, M.D.
Based on the
results of the Nature study, Metamark is developing a novel test for
prostate cancer prognosis. Metamark scientists are also developing
precise, molecularly-based prognostic tests for additional cancer types
that will help guide physicians in determining the most appropriate
treatment for each patient, potentially including the identification of
those that can be spared from unnecessary aggressive treatment and
procedures.
"By integrating
a variety of techniques — computational biology, genetically engineered
model systems, molecular and cellular biology, and human tissue
microarrays — we've identified a signature that has proven effective in
distinguishing which men with prostate cancer are likely to progress and
die from their disease and those who are not," DePinho remarks.
"Efforts are
already underway to use this knowledge to develop a clinical test —
which we hope will occur within a year or so — that will enable doctors
and patients to make more accurate treatment decisions and avoid
unnecessary aggressive interventions which adversely impact on quality
of life and deplete over-extended healthcare resources. This science
holds potential to illuminate a long-sought answer for optimal
management of this complex disease."
Collaborating on
the study were
Massimo Loda, MD, of Dana-Farber and Brigham and Women's Hospital,
and Lorelei Mucci, PhD, of Brigham and Women's and Harvard School of
Public Health,
The paper's
other co-authors are Chang-Jiun Wu, MD, PhD, Gerald C. Chu, MD, Yonghong
Xiao, PhD, Dennis Ho, Samuel R. Perry, Emma S. Labrot, Xiaoqiu Wu,
Rosina Lis, MD, Y. Alan Wang, David E. Hill, PhD Baoli Hu, PhD, Shan
Jiang, PhD, Hongwu Zheng, PhD, Alexander H. Stegh, PhD, Kenneth L.
Scott, PhD, Dana-Farber; Jingfang Zhang, University of Wisconsin,
Madison; Yujin Hoshida, MD, PhD, and Todd R. Golub, MD, Dana-Farber and
the Broad Institute of Harvard and MIT; David Hiller, PhD, and Wing H.
Wong, PhD, Stanford University; Sabina Signoretti, MD,
Dana-Farber/Harvard Cancer Center; Nabeel Bardeesy, PhD, Massachusetts
General Hospital Cancer Center; and Meir J. Stampfer, MD, DrPH, Brigham
and Women's Hospital and Harvard School of Public Health.
The research was
funded in part by the Belfer Institute for Applied Cancer Science and
the National Cancer Institute.
The Belfer
Institute for Applied Cancer Science at Dana-Farber Cancer Institute
says it consists of leading academic and industry seasoned scientists
working as multidisciplinary teams supported by powerful platforms in
computational science, oncogenomics, engineered model systems,
clinicopathological analyses, and drug discovery.
The Belfer
Institute's mission is to convert insights gleaned from cancer genomics
and deep biology research into the next generation of highly effective
drugs and drug combinations, as well as breakthrough diagnostics for
improved patient management. The Belfer Institute technology has
launched a new biotechnology company, Metamark Genetics, and has enabled
cancer drug discovery through highly productive strategic alliances
within the pharmaceutical sector, including Merck and Sanofi-Aventis.
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Feb. 3, 2011 – A
new discovery lays the ground work for the first gene-based test for
determining whether a man's prostate cancer is likely to remain dormant
within the prostate gland, or spread lethally to other parts of the
body. Today, many men, mostly senior citizens, endure drastic procedures
that are used unnecessarily on unaggressive cancers.
