Forget the theory of diminishing returns: If one is good, then two must be better. As a result, cancer researchers are turning their attention to combination therapies, particularly for blocking tumor signaling pathways.
DENVER-Forget the theory of diminishing returns: If one is good, then two must be better. As a result, cancer researchers are turning their attention to combination therapies, particularly for blocking tumor signaling pathways.
"Most people believe that in many forms of human cancer, this pathway is incredibly complicated," said Owen O'Connor, MD. "There are all sorts of new therapeutics, which target biology, that we didn't have before. We can now rationally combine them in a strategic way to block the ability of the cell to become resistant to these therapies."
The RAS/MAPK and PI3K pathways are necessary for malignant cell growth and survival and these pathways are frequently mutated in cancer. But targeting RAS directly poses a challenge. Two small molecules, a PI3K inhibitor (GDC-0941) and an MEK inhibitor (GDC-0973), are currently undergoing phase I studies.
"We're getting to the stage of trying to define and understand...how we can best combine these inhibitors to get the best efficacy and maintain the best safety profile," said Lori S. Friedman, PhD, director of cancer signaling and translational oncology at Genentech.
Dr. Friedman's group carried out in vitro and in vivo combination studies and found that concurrent daily dosing of MEK and PI3K inhibitors in vivo resulted in sustained efficacy in several xenograft tumor models. Intermittent dosing of both compounds also resulted in efficacy (abstract 1890).
"There's a lot of flexibility," she explained. "We can give them both as daily oral doses or as intermittent doses; either method will produce efficacy. We think this is because of the co-blocking of these two downstream pathways that support apoptosis."
Pancreatic cancers are resistant to almost all chemotherapy and radiation regimens, and even response to gemcitabine has been modest. Use of mTOR inhibitors as a single agent has demonstrated some clinical activity, but investigators at the Mayo Clinic in Rochester, Minn, report that cells from pancreatic cancer lines (MIAPaCa-2, Pnac-1 and BxPc-3) display persistent activation of the mTOR pathway.
"How can we overcome mTOR inhibitor-induced resistance?" asked Mamta Gupta, PhD.
They found success by combining rapamycin, an mTOR inhibitor, with LBH589, a histone deacetylase (HDAC) inhibitor to enhance mTOR-targeted therapy.
"The combined treatment with LBH and rapamycin synergistically inhibited growth of pancreatic cell lines and induced apoptosis," the investigators reported.
Specifically, the pharmacological inhibition of the mTOR pathway by rapamycin and LBH interfered with essential survival and proliferating pathways in pancreatic cancer cells (LB-261).
"We have the potential to use this new therapeutic intervention against this deadly disease," Dr. Gupta said. "The only thing we don't know is: What is the molecular mechanism behind this combination? We are working on that."
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