Acid Sphingomyelinase Inhibition to Mitigate the Environmental Exposure Risks of Ultraviolet Light-Induced Actinic Neoplasia and Squamous Cell Carcinoma in US Veterans

Actinic neoplasia (precancerous actinic keratosis [AK] and non-melanoma skin cancer) is the most common type of human neoplasia, and the most common diagnosis in VA dermatology clinics. The high incidence of actinic neoplasia amongst our veterans is not surprising as most served in areas with considerable ultraviolet (UV) light exposure. Indeed, UV light is a ubiquitous environmental exposure for our service members, especially during wartime deployments. Hence, studies to improve the treatment of our veterans with multiple AK will be impactful in our veteran patients. Our research group has a long track record of successful investigations in the mechanisms by which aging and ultraviolet B radiation (UVB) contribute to actinic neoplasia, as well as how stressors such as UVB and the AK treatment photodynamic therapy (PDT) interact with skin. Our group has recently discovered that PDT, like UVB, can generate subcellular microvesicle particles (MVP) in keratinocytes and human/murine skin. Of importance, pharmacologic and genetic approaches neutralizing the key MVP-generating enzyme acid sphingomyelinase (aSMase) has revealed that PDT-induced immunosuppression is dependent upon MVP. Since PDT-induced immunosuppression is an unwanted side effect of PDT that limits its effectiveness in treating precancerous AK, blocking aSMase should significantly improve the effectiveness of PDT. PDT has a number of advantages over the other secondary prevention strategies that we utilize to prevent skin cancers in our veterans. To that end, this new MERP proposal will test the hypothesis that treatment of human subjects undergoing PDT with topical aSMase inhibitor imipramine will increase the effectiveness of this therapy. Moreover, characterization of the contents of PDT-generated MVP will allow an enhanced understanding of their biologic effects. Aim 1 will consist of a double-blinded placebo-controlled clinical trial using split-sides of topical imipramine versus vehicle for patients undergoing PDT for field treatment of multiple AKs to either face/scalp or forearms. The outcomes will consist of testing effectiveness of left/right sided treatments on AK counts at 6 and 12 months (and likely much longer). Moreover, we will employ a novel strategy using mesoscopic imaging that can discern and quantitate subclinical actinic damage based upon light scattering characteristics. We will also test if topical imipramine blocks PDT-induced immunosuppression by skin testing and tissue RNA-seq for subjects undergoing PDT to forearms. As agents that inhibit aSMase such as imipramine also exhibit nociceptive qualities, these studies will also assess if this intervention affects acute inflammation and pain/itch associated with PDT. Aim 2 will consist of mechanistic studies to characterize the bioactive cytokine and lipid mediator contents of PDT- generated MVP from human keratinocytes and human skin explants subjected to experimental PDT. PDT- generated MVP will be compared to UVB- and phorbol ester-generated MVP which have distinct biologic & immunologic effects. Since PDT as currently practiced for treating large areas of skin has limited effectiveness and is associated with considerable pain, the current studies can provide a modification which could be highly effective and increase the use of this potentially life-saving modality. These studies will improve the care of veterans served in our dermatology clinics. Moreover, the successful employment of mesoscopic imaging will further validate a valuable clinical tool that can stratify risk of actinic neoplasia even when skin appears clinically normal. This non-invasive, image-based contrast mapping approach could serve to propel research in field cancerization using skin as a model system, which could be adapted to other epithelial cancers relevant to the veteran population such as colon, esophageal, and lung cancers. Finally, these studies can provide important insights into the biological effects of subce Project Number: 1I01CX002927-01 | Fiscal Year: 2025 | NIH Institute/Center: Veterans Affairs (VA) | Principal Investigator: Jeffrey Travers (+1 co-PI) | Institution: DAYTON VA MEDICAL CENTER, DAYTON, OH | Activity Code: I01 | Study Section: Special Emphasis Panel[ZRD1 ONCE-A (01)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11051941