Activation of the hedgehog pathway has been implicated in the development of cancers in various organs, including brain, lung, mammary gland, prostate and skin. Basal cell carcinoma, the most common form of cancerous malignancy, has the closest association with hedgehog signaling. Loss-of-function mutations in Patched and activating mutations in Smoothened have been identified in patients with this disease. Abnormal activation of the pathway probably leads to development of disease through transformation of adult stem cells into cancer stem cells that give rise to the tumor. Cancer researchers hope that specific inhibitors of hedgehog signaling will provide an efficient therapy for a wide range of malignancies.
Biotech companies are also attempting to turn this pathway on after a patient has a stroke or heart attack. Since the pathway has been implicated in a number of lethal cancers Curis and Wyeth have devised a stable hedgehog protein that can cross the blood brain barrier. In pre-clinical animal models it has shown that the pathway is up regulated upon a stroke or heart attack event. The pathway provides a protective barrier against cell death and ischemia. Agonizing the pathway this way allows the PTCH to be up regulated providing a negative feedback system. This might help minimize the side effects.
Activation of the Hedgehog pathway leads to an increase in angiogenic factors (angiopoietin-1 and angiopoietin-2), Cyclins (cyclin D1 and B1), anti-apoptotic genes and a decrease in apoptotic genes (Fas).
Earlier this year, we took a look at how robotnikinin blocks hedgehog signaling in cancer development. We discovered that researchers had achieved a feat drug developers had thought difficult, if not impossible discovering a compound that blocks the functioning of a key developmental protein by binding to an undruggable target an advance that may provide a new avenue to fight skin, pancreatic, prostate, and other cancers.