New Molecular Targets in Colorectal Cancer

Advances in metastatic colorectal cancer will require identification of other targets and pathways that contribute to colorectal cancer progression and metastasis. Inhibitors of several key molecules and pathways are currently being studied. Three candidate proteins and pathways are active areas of research in colorectal cancer: insulin-like growth factor-I receptor (IGF-IR), Src, and toll-like receptor 9 (TLR9).

IGF-IR is a cellular protein, and activation of the IGF-IR pathway results in increased cellular proliferation, malignant transformation, resistance to apoptosis (programmed cell death), tissue invasion and metastasis, and angiogenesis.16 IGF-IR is overexpressed in colon cancer, but activation rather than overexpression may play a more important role. There is substantial overlap in signaling between the IGF-IR and EGFR pathways, raising the possibility that activation of the IGF-IR pathway may be one way in which cells can escape EGFR inhibition. The first IGF-IR inhibitors to enter Phase I clinical testing have been monoclonal antibodies:

Src is a nonreceptor protein that is found on the intracellular portion of the cell membrane and was the first oncogene (a potentially cancer-inducing gene) discovered.17 Src promotes angiogenesis, the formation of new blood vessels to tumors, and is overexpressed in more than 80 percent of human colorectal cancers. Its activity increases with cancer progression, with higher levels found in metastases than in primary tumors. Src inhibitors are currently in clinical development; they are unlikely to cause shrinkage of solid tumors and are more likely to influence tumor progression, invasion, and metastasis.

TLR9 has a role in immune regulation in the gastrointestinal tract. It may also have a role in modulating cell signaling, including signaling through the EGFR pathway. Clinical evaluation of TLR9 agonists in cancer patients is under way.

Clinical TrialsPeople with colorectal cancer should always ask their physician if there is a clinical trial indicated for their type and stage of cancer. The recent advancements in the treatment of colorectal cancer emanate from results of large clinical trials investigating whether new drugs in combination with chemotherapy and radiation therapy improve survival. Members of the cancer healthcare team can help people with a colorectal cancer diagnosis decide whether to enroll in a clinical trial and to choose a trial that is right for them.