Andrzej A. Dlugosz M.D.: ‘It suggests that perhaps that blocking the pathway would be all it takes to reduce growth or perhaps inhibit growth in those tumors.'

During his presentation of the Marion B. Sulzberger, M.D., Memorial Award and Lectureship, Andrzej A. Dlugosz M.D., discussed breakthroughs leading to new experimental treatments for basal cell carcinoma involving signaling pathways named after a cute spiny mammal.

Hedgehog pathways were the topic of the lecture presented during the Sunday Plenary by Dr. Dlugosz, Poth Professor of Cutaneous Oncology and professor in the departments of dermatology and cell and developmental biology at the University of Michigan.

Cancer development is frequently associated with aberrant activation of embryonic signaling pathways. The Hedgehog pathway normally controls hair follicle growth and development, but when deregulated, it leads to the formation of basal cell carcinomas. Dr. Dlugosz presented an overview of Hedgehog pathway signaling in the skin using mouse models, and previewed possible new treatment approaches for patients with basal cell carcinoma and other Hedgehog-activated cancers.

Although the Hedgehog pathway leads to the development of multiple basal cell carcinomas when continuously activated in the skin of a genetically engineered mouse, he said something amazing happens once the pathway is inactivated.

"In our gene switch mouse models, turning off the pathway leads to rapid tumor regression," Dr. Dlugosz said. "The tumors, within a few weeks, return to a small fraction of their original size. This points to the possibility that in human basal cell carcinomas, drugs that block the Hedgehog pathway might lead to tumor regression in patients.

"Most cancers require multiple genetic abnormalities, multiple pathways, to work together to bring about cancer development and progression, but basal cell cancers might be relatively unique. They might require primarily just an abnormality in the Hedgehog pathway. That's exciting because it suggests that perhaps that blocking the pathway would be all it takes to reduce growth or perhaps inhibit growth in those tumors."

Results from clinical trials using a systemic Hedgehog pathway inhibitor for locally advanced or metastatic basal cell carcinomas are encouraging, he said. In at least some cases an inhibitor appears to be very effective in treating some advanced forms of basal cell cancer.

"The beauty of it is if it's really an embryonic pathway where its major function is an embryonic development and after birth it's not that critical in the organism anymore, then if you're treating patients it's probably not going to do much to most of the body," Dr. Dlugosz said. "But if the cancer has the pathway cranked up and it requires a pathway, then it should get rid of the cancer."

However, the clinical studies are still early studies, so there are many unanswered questions that will need to be addressed in future clinical trials.

While the initial link between abnormalities in the Hedgehog pathway and cancer was made in basal cell carcinoma, it's been discovered that the Hedgehog pathway is abnormally activated in a variety of cancers throughout the body, including some cancers that arise in the brain, pancreas, stomach, lungs and muscle, Dr. Dlugosz said.

"If the pathway is as important in those cancers as it is in basal cell cancer and if these inhibitors are now available to block the pathway, there's hope that it could be used for the treatment of some of those cancers as well," he said.