Topical MEK Inhibitor, NFX-179, Prevents Cutaneous Squamous Cell Carcinoma in Pre-Clinical Model

WAYNE, Pa., May 4, 2021 /PRNewswire/ -- In research to be shared during a plenary talk at the Society for Investigative Dermatology's 2021 Virtual Meeting, data from investigators at the Tsai Lab at Moffitt Cancer Center, Sarin Lab at the Stanford University School of Medicine and NFlection Therapeutics demonstrate positive efficacy in preclinical models for the use of a topical gel — NFX-179 — to prevent cutaneous squamous cell carcinoma (cSCC).

In a UV-induced mouse model of cutaneous squamous cell carcinoma, topical application of NFX-179 gel reduced the formation of new cSCCs by an average of 92% at doses of 0.5% and greater, at 28 days. No systemic or skin toxicities were observed. The researchers also conducted a split-back randomized controlled study in 5 mice per group. NFX-179 0.5% gel was applied to half of the back, and vehicle was applied to the other half of each of the UV-irradiated mice. Near-complete suppression of cutaneous squamous cell carcinoma was observed only in the drug-treated area, demonstrating the targeted and local effect of the drug candidate. Furthermore, the team found that NFX-179 inhibits the growth of human cutaneous squamous cell carcinoma cell lines in a dose-dependent manner and that topical NFX-179 application penetrates human skin and inhibits ERK signaling in human cSCC explants.

"We are thrilled with the compelling evidence these data provide, that topical application of NFX-179 has the potential to be a safe, effective strategy for prevention of cutaneous squamous cell carcinoma in high-risk individuals, and we feel very optimistic about moving into clinical trials," said Dr. Kenneth Tsai, M.D., Ph.D., Senior Member, Anatomic Pathology and Tumor Biology at Moffitt Cancer Center. "These data also validate a rational design approach for the precision targeting of diseases of the skin, particularly for cancer prevention — I hope this is just the beginning of more research that rationally targets disease-driving molecular changes in the skin."

NFX-179 and the Ras/MEK Pathway
Aberrant activation of the Ras/MEK pathway is connected to a collection of rare disorders and the formation of tumors, and prior research from the Tsai Lab and others has concluded that this pathway is integral to developing cutaneous squamous cell carcinoma, predicting that MEK1, 2 could be a target for preventing these carcinomas.^1,2 Re-analysis of this data performed by the  Sarin Lab further predicted that the FDA-approved MEK1, 2 inhibitor, selumetinib, could be used as a therapeutic agent for cutaneous squamous cell carcinoma based on its ability to reverse transcriptional signatures associated with cSCC development. As a regulator of ERK activity, the team reasoned MEK would be a viable chemopreventative target.

Although systemic MEK inhibition suppresses tumor formation, it also causes significant adverse effects. For this reason, the team decided to work with NFX-179, a topical MEK inhibitor developed by NFlection Therapeutics. NFX-179 is a proprietary, metabolically labile, or "soft" compound — designed to concentrate key biological effects at the site of application while considerably reducing systemic exposure and thus side effects.

"We are excited about this result because it demonstrates that we can target a specific pathway directly in the skin, achieving clinical efficacy while minimizing systemic toxicity," said Christopher Powala, president & CEO of NFlection Therapeutics. "This topically targeted approach is of critical importance to the immunosuppressed, who are at high risk for this aggressive cancer and require an effective chemoprevention strategy that also minimizes systemic exposure. We looks forward to taking NFX-179 gel into clinical trials."

Key Application for Solid Organ Transplant Recipients
Cutaneous squamous cell carcinoma is one of the most common cancers, with an estimated 700,000 cases diagnosed in the United States annually. Risk factors for cutaneous squamous cell carcinoma include older age, male sex, fair pigmentation, ultraviolet exposure and immunosuppression. In particular, solid organ transplant recipients (SOTRs) have a 65- to 250-fold increased incidence of immunosuppressant-mediated cSCC compared to the general population, and up to 3.2% of SOTRs die from cutaneous squamous cell carcinoma.

"We believe this research, led by Dr. Tsai's lab, is significant for solid organ transplant recipients, who often face a more aggressive cutaneous squamous cell carcinoma, with up to 25% mortality," said Dr. Guy Webster, Chief Medical Officer of NFlection. "There is currently no preventive treatment for immunosuppressed cSCC individuals, and the surgical options leave scars and commonly lead to recurrence. A topical, precision approach that these patients can tolerate would be an important advance."

Details of Plenary Session
"Topical MEK Inhibition as Precision Targeted Chemoprevention" will be presented during Plenary Session #3, which begins at 10:30 am ET on Thursday, May 6.

About NFX-179
NFX-179 is an investigational mitogen-activated protein kinase kinase inhibitor. NFX-179 is designed as a "soft" (metabolically labile) drug designed to concentrate at the site of action while significantly reducing side effects of systemically available MEK inhibitors.

About NFlection Therapeutics, Inc.
NFlection Therapeutics focuses on the discovery and development of effective, targeted therapies for rare disorders. NFlection is chiefly concerned with rare disorders known as RASopathies that are driven by the aberrant activation of the Ras/Raf/MEK/ERK pathway. NFlection is working to address RASopathies through the development of first-in-class soft MEK (mitogen-activated protein kinase kinase) inhibitors as topical treatments to mitigate or treat cutaneous neurofibromas in neurofibromatosis type 1, congenital birthmarks and immunosuppressant-mediated squamous cell carcinoma. NFlection's topical MEK inhibitors are designed to degrade rapidly in circulation to avoid systemic side effects. To learn more about the company, please visit www.nflectionrx.com.

References

1. Adelmann, C.H., Truong, K.A., Liang, R.J., Bansal, V., Gandee, L., Saporito, R.C., Lee, W., Du, L., Nicholas, C., Napoli, M., Mino, B., South, A.P., Proby, C.M., Leigh, I.M., Coarfa, C., Flores, E.R. & Tsai, K.Y. MEK Is a Therapeutic and Chemopreventative Target in Squamous Cell Carcinoma. J Invest Dermatol 136, 1920-4 (2016)
   
   
2. Chitsazzadeh, V., Coarfa, C., Drummond, J.A., Nguyen, T., Joseph, A., Chilukuri, S., Charpiot, E., Adelmann, C.H., Ching, G., Nguyen, T.N., Nicholas, C., Thomas, V.D., Migden, M., MacFarlane, D., Thompson, E., Shen, J., Takata, Y., McNiece, K., Polansky, M.A., Abbas, H.A., Rajapakshe, K., Gower, A., Spira, A., Covington, K.R., Xiao, W., Gunaratne, P., Pickering, C., Frederick, M., Myers, J.N., Shen, L., Yao, H., Su, X., Rapini, R.P., Wheeler, D.A., Hawk, E.T., Flores, E.R. & Tsai, K.Y. Cross-species identification of genomic drivers of squamous cell carcinoma development across preneoplastic intermediates. Nat Commun 7, 12601 (2016).PMC5013636

SOURCE NFlection Therapeutics

Related Links

http://www.nflectionrx.com