Discovery provides new hope to cancer patients with few
treatment options
PHOENIX, Ariz. - July 8, 2010 - Investigators at the Translational
Genomics Research Institute (TGen) have discovered a way that may
help ovarian cancer patients who no longer respond to conventional
chemotherapy.
A scientific paper that will be published in the September issue of
the journal Gynecologic Oncology describes how the inhibition of a
protein, CHEK1, may be an effective element to incorporate into
therapies for women with ovarian cancer.
The research led by TGen's Dr. David Azorsa, a Senior Investigator,
and Dr. Shilpi Arora, a Staff Scientist, found that inhibiting
CHEK1 by a small molecule known as PD 407824, enabled ovarian
cancer cells to be attacked again by cisplatin, a widely used
platinum-based chemotherapy drug for women with ovarian
cancer.
"PD 407824 is only available for laboratory research, but other
drugs inhibiting CHEK1 are already used to treat patients in the
clinic," said Dr. Raoul Tibes, one of the paper's senior a
co-authors and an Associate Investigator in TGen's Clinical
Translational Research Division.
The prognosis remains poor for patients with ovarian cancer, which
kills nearly 14,600 women in the U.S. annually. The standard
treatment for cancer of the ovaries, which produce human egg cells,
is surgical removal of the cancer, followed by chemotherapy.
The TGen team proved their method in the research laboratory, which
is very encouraging, considering that the use of protein inhibitors
in combination with cisplatin, is also proving to be effective in
clinical trials with cancer patients.
"The clinical relevance is high, as such novel molecular concepts -
inhibiting the repair of cancer cells after treatment with
chemotherapies - are in development for many different cancers,"
said Dr. Tibes, a medical oncologist who treats patients with
advanced cancers at TGen Clinical Research Services (TCRS) at
Scottsdale Healthcare.
"We actually have similar drug combinations that go after
preventing cancer cells to repair themselves, in the clinic
already, and we have seen early exciting results. Patients whose
tumors had stopped responding to conventional chemotherapy have
been made sensitive again, meaning some of these patients responded
again to the chemotherapy. The importance of the paper is that it
provides evidence that combinations of cisplatin and CHEK1
inhibitors may be worthwhile pursuing in patients with ovarian
cancer," said Dr. Tibes.
TCRS is a partnership between TGen and Scottsdale Healthcare that
enables laboratory discoveries to be quickly translated into
effective therapies for patients at the Virginia G. Piper Cancer
Center at Scottsdale Healthcare.
For this research, TGen investigators used cutting-edge technology
to screen 572 kinases, the body's protein enzymes that affect how
cells function. They discovered 55 siRNAs - strands of RNA
molecules that affect the expression of genes - that to some degree
enabled cisplatin to slow the growth of cancer cells.
According to the paper, one of those small molecule inhibitors, PD
407824, was especially effective in sensitizing ovarian cancer
cells, SKOV3 and OVCAR3, to the growth inhibiting effects of
cisplatin. PD 407824 and SB 218078 were the two small molecule
inhibitors to CHEK1, that were found to sensitize pancreatic cancer
cells to the chemotherapy drug gemcitabine, according to a paper
published by the same group last year in the Journal of
Translational Medicine. "Our new data provide kinase targets that
could be exploited to design better therapeutics for ovarian cancer
patients," said Dr. David Azorsa, Head of TGen's Biological
Therapeutics Lab and the senior author of the paper published in
Gynecologic Oncology.
In addition, Dr. Shilpi Arora, a TGen Staff Scientist and the
paper's lead author, said this data, "also demonstrate the
effectiveness of high-throughput RNAi screening as a tool for
identifying sensitizing targets to known and established
chemotherapeutic agents."