Spreading a topical cream on the face might seem like it only goes skin deep, but the medication in the cream often seeps through all three layers of the skin into muscle. If the drug reaches the bloodstream, molecules meant for the skin soon reach every organ in the body. 

To treat dermatological disorders, developing topical gels or creams that stop at the skin is a crucial but difficult endeavor, as dermatologist and researcher Kenneth Tsai recently learned. In 2016, Tsai’s group at the Moffitt Cancer Center was one of the first to identify the genomic signatures that drive the progression of actinic keratosis, a precancerous skin condition, into a specific type of skin cancer called cutaneous squamous cell carcinoma (cSCC) (1). Based on their work, Tsai’s team realized that they could use a mitogen-activated protein kinase (MEK) inhibitor to target a key pathway and stop the cancer-inducing process from starting. Tsai’s team set out to prevent systemic side effects by developing a topical MEK inhibitor that only acts on the skin.

Tsai quickly realized he had underestimated how challenging this would be, though. “I had naively thought, well, why don't we just grind up the existing MEK inhibitor, literally make them into a powder, stick them in some Vaseline, and you just spread it around on your skin,” he said. “But really, there’s so much more than that.”

To make a safe topical version of the drug, Tsai joined forces with dermatology researcher Kavita Sarin at Stanford University and NFlection Therapeutics. After several years, the team developed NFX-179, which liver cells metabolized so rapidly that it successfully prevented the progression of cSCC without systemic side effects in mice (2). Now, Tsai is excited about this approach and hopes it will inspire others to consider the importance of developing topical drugs that don’t reach other organs.

Why did you and your collaborators decide to develop a topical gel version of a MEK inhibitor to prevent skin cancer?

As a dermatologist, I see a lot of patients that get actinic keratosis, and to treat that we typically destroy it by spraying the skin patch with liquid nitrogen. But it's very painful, and nobody likes it. We also have some topical agents that work very well, but the challenge there is that they're very difficult to tolerate. They're very inflammatory and can cause huge reactions. With drugs for prevention, there's a much higher safety bar than for treatments because we're preventing disease in someone who doesn't have the disease. If someone has metastatic cancer, they’re more willing to tolerate a drug that has a high risk of bad side effects because metastatic cancer can be fatal. In that scenario, the risk-benefit ratio is different.

We felt like this was a nice preclinical demonstration that this kind of topical approach is feasible and effective.
– Kenneth Tsai, Moffit Cancer Center

Back in 2016, after our first paper identified the MEK signaling pathway as a potentially big driver of both the development of actinic keratosis and the subsequent progression to carcinoma, we published a short follow up paper where we treated our mouse model with an oral MEK inhibitor, and it worked brilliantly (2,3). That validated that the target is reasonable, but because oral MEK inhibitors also have serious side effects, it didn't solve our problem of safe delivery. 

Throughout this whole process, I learned that making an existing drug into a powder and just putting it into a topical drug is a very inefficient way of reaching the epidermis and parts of the dermis of the skin. Actinic keratosis and even superficial squamous cell carcinomas of the skin have a little bit of depth to them, so we needed the new topical drug to get past the upper layers of the skin, the epidermis, and even a little bit deeper. 

How did you make the safe topical MEK inhibitor, NFX-179?

To create a new topical gel without systemic effects, NFlection Therapeutics' team brought two levels of novelty. The first was the idea that we could make a small molecule that's purposely selected to be metabolically labile, meaning that it is quickly metabolized before it can reach other organs. With most drugs, you want maximum bioavailability. You want it to be oral, and you want it to hang out in the body for as long as possible because you want it to get to all the tissues. Here, with a metabolically labile drug, we wanted the exact opposite: We wanted it to hit the target with a very high potency, but then we wanted it to be destroyed quickly if it got into the circulation. That's novel because NFlection Therapeutics' goal was specifically to identify drugs that would be destroyed extremely quickly, in this case, by the liver. As soon as it hit the liver, the drug would get wiped out and become totally inactive in humans, probably something on the order of within half an hour. Secondly, NFlection Therapeutics was able to make clever vehicles to put this small molecule in and get it not only past the epidermis, but also into the dermis to treat actinic keratosis and prevent the progression to skin cancer. 

How successful was NFX-179 at preventing skin cancer in mice without systemic effects?

To test for a chemoprevention effect, first we irradiated mice, and normally we would expect an average of 10 tumors to grow. We found that at a dose of 0.1 percent and up, we were able to suppress around 92 percent of all new tumors compared to the control. We felt like this was a nice preclinical demonstration that this kind of topical approach is feasible and effective. 

It was important to us to also demonstrate that the effects were local. If I slathered it on the skin, it should only work on that area of the skin. So, we did the split-mouse experiment where we basically drew a line down the middle of the mice bodies and then treated one half of the mouse with the active drug and treated the other half of the mouse with the control. The idea was to prove that the squamous cell carcinomas only regressed on the side that actually got the active drug, which is what we found. That experiment helped us gain confidence that the effect was truly localized.

Mice aren't a great predictor of toxicity in humans, but nevertheless, we also tried to look for evidence of toxicity in the mouse model. We looked at some internal organs like the gastrointestinal tract and liver and didn't detect any toxicity in those organs.

What’s next for NFX-179?

The next step is probably trying to get this into patients. That's a very important part of showing that this principle of inhibiting MEK for the purpose of chemoprevention is a viable approach. It’s nice that we didn’t observe systemic toxicities in mice, but ultimately, we’ve got to show it works in people. 

What was the most exciting part of this work?

The most exciting part was to really be able to show that we can go after a target and inhibit it in a way that's clever and also has an additional safety factor built in. It's designed to be a thoughtful deployment to get a drug to affect only the areas that you're interested in — in this case, the skin. 

There's so much opportunity in this space to think about how we can treat things locally in a way that is much safer and more effective in the end. Most of our topicals are not developed with this kind of thinking in mind. That's why I'm excited about this approach because we really think that there's opportunity in expanding that part of therapy design so that we’re being thoughtful about delivery — not just targets. That's a space where I would love to do more personally.

This interview has been condensed and edited for clarity.

References

1. Chitsazzadeh, V. et al. Cross-species identification of genomic drivers of squamous cell carcinoma development across preneoplastic intermediates. Nat Commun  7, 12601 (2016).
2. Sarin, K.Y. et al. Development of a MEK inhibitor, NFX-179, as a chemoprevention agent for squamous cell carcinoma. Sci Transl Med  15, eade1844 (2023).
3. Adelmann, C.H. et al. MEK is a therapeutic and chemopreventative target in squamous cell carcinoma. J Invest Dermatol  136, 1920–1924 (2016).