When we are still embryos, proteins of the so-called “hedgehog” signaling pathway stimulate our cells to develop into different organs.
When we are adults, this pathway falls largely silent, except in certain tissues that constantly regenerate themselves, for example our skin, and the linings of our blood vessels and digestive tract.
Unfortunately, several types of cancer cells are able to reawaken this dormant pathway, causing surrounding healthy cells to produce growth factors (proteins or hormones that stimulate cell growth) that help the cancer cells proliferate and metastasize.
A potent remedy to the problem may be on its way. In a paper published in the Journal of the American Chemical Society, researchers in the laboratory of Rudi Fasan, an associate professor of chemistry at the University of Rochester, describe the development of a cyclic peptide that is able to block the activation of the pathway in live cells.
The next step will be to further optimize the peptide for increased potency, then proceed to animal trials.
The pathway is activated when a ligand (binding molecule) produced by cancer cells interacts with a receptor on the surface of healthy cells, triggering the production of growth factors. The first drug directed against this pathway was approved by the FDA in 2012, but according to Fasan, recent studies have shown that cancer cells become quickly resistant to it.
The cyclic peptide developed in Fasan’s lab blocks the ligand farther “upstream” in the pathway, utilizing a different mode of inhibition compared to the FDA-approved drug. “It is important to have different weapons against this pathway,” Fasan says, “and we have targeted a key component of it.” He adds that the compound is unlikely to develop resistance since it does not target a protein located on cancer cells.
The researchers initially designed a cyclic peptide that mimics a native protein inhibitor of the hedgehog ligand. The researchers then used bacteria to quickly produce and screen large “libraries” of variations of this peptide, from which compounds with improved activity against the cancer ligand could be isolated.
The risk, as in any chemotherapy, is that the drug candidate Fasan’s lab is developing will also inhibit the pathway in healthy skin, blood vessel, and digestive tract tissues that rely on the pathway for normal regeneration. However, the fact that a hedgehog pathway inhibitor was recently approved for use in cancer therapy holds promise that these risks are outweighed by the benefits of inhibiting cancer growth, Fasan says.
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