PHILADELPHIA – A groundbreaking topical cream has shown the potential to activate the skin’s immune defenses and suppress tumor growth in preclinical models of cutaneous squamous cell carcinoma (cSCC), one of the most prevalent cancers globally. This promising development was detailed in a study published today in the Journal of Clinical Investigation. Developed by researchers at the Perelman School of Medicine at the University of Pennsylvania, the cream functions by inhibiting LSD1, an enzyme that typically suppresses immune-activating pathways in the skin.
“What’s striking is that a simple topical cream can use the skin’s own machinery to recruit and activate immune cells that attack tumors,” stated senior author Dr. Brian C. Capell, an assistant professor of Dermatology at Penn. “We are carrying out more studies to refine the formulation this coming year, and we hope to begin a phase 1 clinical trial in the next 1-2 years. Ideally, this cream could be used directly on cancerous and precancerous spots.”
A Common Cancer with Limited Treatment Options
cSCC is one of the most frequently diagnosed cancers, with approximately one million Americans affected annually. The incidence continues to rise due to an aging population and increased sun exposure. Although most cases are treatable with surgery, up to five percent of tumors metastasize, resulting in thousands of deaths each year in the United States. For many older or immunocompromised patients, the development of numerous precancerous lesions across large skin areas makes repeated surgical procedures burdensome and sometimes unfeasible.
Current treatments for widespread lesions, such as chemotherapy, are not cancer-specific, and other targeted treatments can be painful. While surgery remains effective, it is invasive and carries risks like infection and scarring. A topical treatment that locally activates anti-tumor immune responses could significantly reduce the need for repeated procedures and help prevent the progression to invasive cancer.
Innovative Approach to Stimulating the Skin’s Immune Response
In their study, Penn researchers developed a low-dose topical inhibitor of LSD1, an enzyme that usually acts as a “brake” on certain immune-activating pathways in epidermal cells. By “lifting the brake,” the cream encouraged skin cells to signal for immune assistance, playing a crucial role in slowing tumor growth.
The study also revealed that blocking retinoic acid signaling, a naturally occurring and essential type of cellular signaling that guides cell growth and development, reversed many of the skin-level changes induced by the cream. Furthermore, the destruction of CD4⁺ T cells, a type of immune cell, nullified its tumor-suppressing effects. These findings suggest that the therapy works by priming communication between skin cells and the immune system to enable targeted anti-tumor responses.
Implications for Skin Cancer Prevention and Treatment
While treating existing skin cancer is a significant benefit, preventing cancer from forming could have an even greater impact. An estimated 58 million Americans live with skin precancers or early squamous cell carcinomas each year. A topical treatment could reduce the need for repeated surgeries and decrease the number of lesions that progress to invasive cancer. Researchers are also investigating whether LSD1 inhibitors taken orally or via injection could enhance the efficacy of immune checkpoint cancer therapies, which are currently effective in only a subset of patients with advanced cSCC.
Other contributors to this study from Penn include first author Nina Kuprasertkul, along with Alyssa F. Moore, Carina A. D’souza, Julia Chini, Eun-Kyung Ko, Sijia Huang, Shuo Zhang, Ashley S. Anderson, Shaun Egolf, Laura V. Pinheiro, Alison Jaccard, Claudia T. Magahis, Lydia Bao, Yann Aubert, Cyria Olingou, Stephen M. Prouty, Donna Brennan-Crispi, David A. Hill, John T. Seykora, and Kathryn E. Wellen.
This research received support from the National Institutes of Health (K08AR070289, P30-AR069589, R01AR077615, R01CA262055, R01HL162715, T32GM007170, T32AR007465), the Damon Runyon Cancer Research Foundation, the Dermatology Foundation, and the Skin Cancer Foundation.
