Researchers Identify Genetic Mutation That May Alter Patients' Response to Cancer Therapeutics
July 04 2007 - 1:30PM
PR Newswire (US)
Recurring mutation found in breast, colorectal and ovarian cancers
INDIANAPOLIS, July 4 /PRNewswire-FirstCall/ -- Researchers from Eli
Lilly & Company and the Phoenix-based Translational Genomics
Research Institute (TGen) today announced finding a novel recurring
mutation of the gene AKT1 in breast, colorectal and ovarian
cancers. The altered form of AKT1 appears to cause tumor cell
proliferation and may play a role in making cells resistant to
certain types of therapies. The findings are reported in an advance
online publication (AOP) of the journal Nature. The PI3-Kinase/AKT
pathway is among the most commonly activated cellular pathways in
human cancers and members of this pathway are among the most
frequently targeted for new cancer drug discovery efforts.
Activation of this pathway results in cancer cell growth and cell
survival. Although AKT1 is central to pathway activation, its role
in cancer has been that of an intermediary between mutated upstream
regulatory proteins and downstream survival signaling proteins.
This is the first evidence of direct mutation of AKT1 in human
cancer tumors: it was discovered in clinical samples from cancer
patients, yet has never been detected in cancer cell lines. "This
discovery is a seminal finding in cancer biology that confirms AKT1
as an oncogene in breast, colorectal and ovarian cancer. The
mutation alters the electrostatics of binding pocket in the
pleckstrin homology domain, the portion of the enzyme that docks
with phospholipids on the cell membrane," said Kerry L. Blanchard,
PhD, MD, Executive Director, Discovery Biology Research, Eli Lilly
& Company. To identify the AKT1 mutation, the researchers
analyzed 150 tumor samples from patients with either breast,
colorectal or ovarian cancer (50 samples from each tumor type).
Analysis of the data showed that 8 percent of breast, 6 percent of
colorectal and 2 percent of ovarian tumors had the AKT1 mutation in
the samples that were screened in their study. "Recently, molecular
features such as the AKT1 mutation are beginning to change drug
development efforts. This discovery adds to the short but growing
list of molecular features that may help guide both current and
future cancer drug development," said John Carpten, PhD, Senior
Investigator and Director of TGen's Integrated Cancer Genomics
Division and the study's lead author. "The next step is to
determine the prevalence of the AKT1 mutation in different
populations and, hopefully, use the information gained to stratify
patients going into clinical trials for AKT inhibitors." If
validated by further studies, the identification of this recurring
mutation has the potential to impact cancer treatment and drug
development. "This is a gorgeous study that used a variety of
sophisticated techniques to provide new insights into the
tumorigenic process," said Bert Vogelstein, MD, Director of the
Ludwig Center for Cancer Genetics & Therapeutics at The Johns
Hopkins Kimmel Cancer Center. James E. Thomas, PhD, of Lilly's
Cancer Discovery Research division, ex- plained, "AKT1 is a protein
kinase or enzyme that plays a key role in activating survival,
proliferation and metabolic pathways. Interestingly, other cellular
proteins that regulate this network have also been shown to be
mutated in a variety of cancers including lung, breast ovary,
prostate, colorectal and brain cancers. This mutation in AKT1 is
striking direct evidence for the role of AKT1 in cancer formation."
The identification of the AKT1 mutation was a collaborative effort
between Eli Lilly & Company and TGen. "This discovery
demonstrates the importance of studying the genetic make up of
cancers at the clinical level rather than re- lying on model
systems," adds Jeffrey Trent, PhD, Scientific Director of TGen.
"This is a key study highlighting Lilly's commitment to
translational re- search approaches in cancer drug discovery and
development. Furthermore, this work is a great example of a
successful public-private partnership at a global level that
involves Lilly Research Laboratories in Indianapolis, TGen in
Phoenix, Lilly Singapore Centre for Drug Discovery, and the
Economic Development Board of Singapore," adds Richard Gaynor, MD,
Vice President of Oncology Discovery at Eli Lilly & Company. He
added, "This mutation further validates AKT1 as an attractive drug
target, and it also will be a valuable tool for the stratification
of patients for targeted therapies. This paradigm of identifying
specific defects in cancer cells to successfully develop innovative
therapies has been validated with oncology drugs such as Gleevec in
leukemia and Herceptin in breast cancer." About Lilly Lilly, a
leading innovation-driven corporation, is developing a growing
portfolio of first-in-class and best-in-class pharmaceutical
products by applying the latest research from its own worldwide
laboratories and from collaborations with eminent scientific
organizations. Headquartered in Indianapolis, Ind., Lilly provides
answers -- through medicines and information - for some of the
world's most urgent medical needs. Additional information about
Lilly is available at http://www.lilly.com/. About TGen The
Translational Genomics Research Institute (TGen), a non-profit
501(c)(3) organization, is focused on developing earlier diagnoses
and smarter treatments. Translational genomics research is a
relatively new field employ- ing innovative advances arising from
the Human Genome Project and applying them to the development of
diagnostics, prognostics and therapies for cancer, neurological
disorders, diabetes and other complex diseases. TGen's research is
based on personalized medicine and the institute plans to
accomplish its goals through robust and disease-focused research.
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http://photoarchive.ap.org/ DATASOURCE: Eli Lilly & Company
CONTACT: Asia Martin, Communications Manager, Lilly Research
Laboratories of Eli Lilly and Company, +1-317-276-6987, ; or Amy
Erickson of Translational Genomics Research Institute (TGen)
+1-602-343-8522, Web site: http://www.lilly.com/
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