Scientists have found a new way to control an overactive Hedgehog. But we’re not talking about slipping small prickly mammals a chill pill. Hedgehog, in this instance, refers to a cellular signaling pathway (yes, part of it is even called Sonic hedgehog, whatever keeps scientists amused) that can cause cancer when it goes awry, including the most common type of pediatric brain tumor.
Unfortunately for many patients with such cancers, drug resistance can develop and render the current treatment ineffective. But hope may not be lost for these individuals, as Stanford scientists think they have found a new way to target this hyperactive system in tumor cells. And it has been under scientists’ noses the whole time, in the form of an FDA-approved drug used to treat certain lung diseases.
Impressively, the drug, called Roflumilast, exerted powerful effects on drug-resistant brain tumors in mice, stalling growth from as early as day one. But there is a catch: it causes serious side effects in humans. So although the treatment is already available, scientists will likely have to find ways to reduce these adverse effects before it can be used in cancer patients, or alternatively use this research as a foundation to find another way to target the same system and achieve a similar outcome.
But first things first, let’s get back to Hedgehog. During animal development, the Hedgehog signaling pathway plays a crucial role in helping cells to come together in the right patterns to form tissues and organs. It’s a tightly regulated pathway, but if it gets disrupted, certain tumors can ensue. For example, mutations in the gene that produces the system’s negative regulator can cause it to go into overdrive, excessively stimulating cell growth. Ultimately, this can lead to a range of different cancers, including medulloblastoma, the most common brain tumor in children, and basal cell carcinoma, the most common type of cancer.
Although both of these cancers are treatable by a drug called Vismodegib, the tumor cells have a tendency to mutate further and develop resistance, leading to efficacy rates that are much lower than desirable. Since Vismodegib works by targeting a particular component of the Hedgehog signaling pathway, the researchers wondered whether it might be possible to attack it from a different angle and thus reduce the problem of resistance, so they began a detailed interrogation of the system.
As described in the journal eLife, the researchers discovered that a protein called Semaphorin 3 encourages the accumulation of an enzyme called PDE4D which ultimately blocks an inhibitor of Hedgehog signaling. Without this “stop” signal, cell division can go on unregulated. Interestingly, Semaphorin 3 has been found in unusually high levels in medulloblastoma, so the team wondered whether it might be possible to block its effects.
This led them to Roflumilast, a PDE4D inhibitor. In mice with medulloblastomas that were Vismodegib-resistant, the researchers were able to demonstrate not only that Roflumilast was capable of suppressing Hedgehog signaling, but that it could inhibit tumor growth too. And as overactivation of this pathway is responsible for basal cell carcinoma, the team is hopeful it could also prove to be an effective treatment for this cancer.
While the process of getting this treatment to patients should be streamlined as it is already FDA-approved, the researchers face problems with its side effects.
“PDE4 is implicated in many biological events,” lead author Xuecai Ge told IFLScience. “The side effects include mental health problems, such as depression,” alongside weight loss, nausea and headache. However, Ge said that these arise when the drug is used long-term, which shouldn’t be necessary in cancer patients, so hopefully they could be tolerable.
2