The ability of stem cells to develop in a variety of ways has led researchers to use them to inhibit cancers, but those same qualities can cause stem cells to mutate and lead to the development of cancers. Researchers, though, are overcoming that obstacle by learning more about the factors that influence stem cells so skin cancer therapies can be more effective.
“There are different kinds of hair around the body and different pigments, and the question is, ‘What determines that precise patterning?’ Cancers arise from inappropriate signaling from these key stem cell factors that pattern the body. We want to understand more about how these stem cell factors operate both normally and in cancer and use that understanding to develop novel therapies — both cell-based and small-molecule therapies,” said Anthony Eugene Oro, MD, PhD.
Dr. Oro, a professor of medicine at Stanford University Medical School, discussed these factors when he presented the Marion B. Sulzberger Memorial Award and Lectureship, “Heal Thyself: Using Stem Cell Biology for Skin Diseases,” on Sunday.
Two areas of focus for Dr. Oro and other researchers in the drive to develop cancer therapies have been the much-studied Hedgehog pathway and lesser known Polarity pathway, sometimes called an “escape pathway.”
“The mutations in the Hedgehog pathway are incredibly important for hair follicle formation in the skin — where hair follicles are and the number of hair follicles,” he said. “We spent a lot of time understanding how the body uses Hedgehog to stimulate hair follicle stem cells to grow. We also found that when you have too much of it, you get basal cell carcinoma.
“Over the past few years, we have done clinical trials with a number of companies to help put in place the first Hedgehog pathway inhibitor for advanced metastatic basal cell carcinomas as well as unfortunate patients with Gorlin’s syndrome.”
However, the molecule developed to inhibit basal cell carcinomas (BCCs) sometimes did not work because the stem cells changed.
“The cells evolve and generate resistance to the pathway. We are studying the resistance, how the tumors evolve over time, and how to develop new therapies as the cancer stem cells change,” Dr. Oro said.
A key finding in this quest was the discovery of the Polarity pathway, which helps BCCs escape the treatment.
“It is a great example of how the body uses different types of molecules on a stem cell to cause it to grow, but then in cases where it gets stressed, the body can change the stem cell and evade inhibition of a cancer. The Polarity pathway, and in particular protein kinase C (PKC) lambda, is the target for additional products we are developing to treat resistant BCCs,” Dr. Oro said, adding that his team is working to develop small peptides to block the pathway.
Another solution being studied is to remove the stem cells, purify them, and grow them for tissue regeneration. A promising complement to this research is a recent discovery that has been in the news in which mature tissue was changed to a stem cell-like state for possible tissue regeneration.
“If you don’t have the stem cells you need, you can use these stem cell pathways to make them, or if you can purify the cells you need, you can use those to return to tissue as well,” Dr. Oro said. “That is all in this concept of stem cell biology.”
For now, the focus of much cancer research is on the roles of the Hedgehog and Polarity pathways, he said. In particular, Hedgehog is linked to BCCs, medulloblastoma brain cancer, pancreatic cancer, and lung cancer.
“In the phase II clinical trials we showed that pathway inhibitors will work well in locally invasive and metastatic basal cell carcinomas,” he said. “More recently, other investigators at Stanford have used this as a surgical adjuvant for bigger, surgically difficult BCCs. The Hedgehog inhibitors may be most useful in normal practice as a surgical adjuvant for Mohs. If you have a big tumor on the face and you don’t want to have a major surgery, you can shrink the tumor quite effectively, and then have a smaller Mohs procedure. We are trying to find other drugs that can be equally or more effective for our patients.”