Dermatologic Disease-Directed Targeted Therapy (D ³T ²): The Application of Biomarker-Based Precision Medicine for the Personalized Treatment of Skin Conditions—Precision Dermatology

Abstract

Precision dermatology uses individualized dermatologic disease-directed targeted therapy (D ³T ²) for the management of dermatoses and for the evaluation and therapy of cutaneous malignancies. Personalized/precision strategies are based on biomarkers that are most frequently derived from tissue transcriptomic expression or genomic sequencing or from circulating cytokines. For instance, the pathologic diagnosis of a pigmented lesion and determining the prognosis of a malignant melanocytic neoplasm can be enhanced by genomic/transcriptomic analysis. In addition to biopsy, innovative techniques have been developed for obtaining transcriptomes in skin conditions; as an example, patches can be applied to a psoriasis plaque for a few minutes to capture the epidermis/upper dermis transcriptome. Atopic dermatitis and prurigo nodularis may also be candidate conditions for precision dermatology. Precision dermatology has a role in managing melanoma and nonmelanoma skin cancers and rare cutaneous tumors—such as perivascular epithelioid cell tumor (PEComa)—that can originate in or metastasize to the skin. For instance, advanced/metastatic basal cell carcinomas can be treated with Hedgehog inhibitors (vismodegib and sonidegib) targeting the smoothened ( SMO) or patched 1 ( PTCH1) gene alterations that are a hallmark of these cancers and activate the Hedgehog pathway. Advanced/metastatic basal and cutaneous squamous cell cancers often have a high tumor mutational burden (which predicts immunotherapy response); immune checkpoint blockade with cemiplimab, a programmed cell death protein 1 (PD1) inhibitor, is now approved for these malignancies. Gene expression profiling of primary cutaneous squamous cell carcinoma can identify those individuals at high risk for subsequent metastases. In the realm of rare neoplasms, PEComas—which can originate in the skin, albeit uncommonly—have tuberous sclerosis complex 1 ( TSC1)/tuberous sclerosis complex 2 ( TSC2) gene alterations, which activate mammalian target of rapamycin (mTOR) signaling, and can be suppressed by nab-sirolimus, now approved for this condition. In summary, precision dermatologic techniques/strategies are an important emerging approach for evaluation and management of skin disorders and cutaneous neoplasms, and may serve as a paradigm for the application of precision medicine beyond dermatology.