Combination therapies throw up roadblocks to oncogenic 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."

Simultaneous blocking

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."

HDAC and mTOR

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."

In other noteworthy research:

• Oncogene-induced senescence represents a barrier to tumorigenesis that must be overcome for tumor development. UK-based researchers examined the effects of the expression of lymphoma-associated Nucleophosmin-Anaplastic Lymphoma Kinase (NPM-ALK) protein on cellular growth and proliferation in early-passage, primary murine embryonic fibroblasts (MEFs). Based on their findings, NPM-ALK induced a cell cycle arrest with features of senescence. NPM-ALK induced a senescent phenotype when expressed in primary cells. In turn, this implied a barrier to lymphomagenesis that must be overcome to enable transformation, they stated (abstract LB-27).
  
   
• Spanish researchers investigated the mechanism by which inhibition of the PI3K pathway led to activation of MAPK kinase signaling in breast cancer cell lines and its relevance in tumor treatment. They noted that the activation of parallel pathways, under the condition of PI3K inhibition, may reduce potential benefits of anti-cancer treatments. They proposed the combination of an anti-HER2 therapy together with PI3K inhibitors for the treatment of HER2 positive tumors (LB-52).
  
   
• A group in Japan has developed a novel PI3K inhibitor (ZSTK474) and demonstrated its efficacy in tumor models in vivo (J Natl Cancer Inst 2006;98:545-556). Pharmacological studies revealed that ZSTK474 could efficiently distribute to the brain, so the researchers examined the therapeutic efficacy of ZSTK474 against an orthotopic brain tumor model. They determined that orally administered ZSTK474 significantly inhibited the tumor growth in the brain and prolonged the survival of the brain tumor-bearing mice. The immediate decrease of p-AKT-positive tumor cells after ZSTK474 administration suggested that the antitumor efficacy resulted from PI3K inhibition (LB-213).
  
   
• Researchers from Portland's Oregon Health & Science University and the University of Colorado Denver, investigated the in vivo roles of PIK3CA, PTEN, and AKT alterations in head and neck tumorigenesis and demonstrated an oncogenic role of PIK3CA and AKT, and a tumor-suppressive role of PTEN in head and neck tumorigenesis in vivo (LB-59).