Research Abstract
Dr. Frank serves as Professor of Pediatrics at Harvard Medical School and holds the endowed John T. Herrin Chair in Nephrology at Boston Children’s Hospital. His laboratory research, conducted in the Transplantation Research Program of Boston Children's Hospital and the Department of Dermatology at Brigham and Women's Hospital, focuses on the physiological and pathological roles of the human P-glycoprotein family of ATP-binding cassette (ABC) transporters.
Dr. Frank's laboratory first cloned and characterized the human P-glycoprotein family member, ABCB5, which regulates maintenance and differentiation of normal tissue-specific stem cells (e.g., ABCB5+ limbal stem cells (LSC) and ABCB5+ dermal mesenchymal stem cells (MSC)), and, when overexpressed in tumor cells, serves as a multidrug resistance mediator in cancer stem cells (CSC) in several human malignancies, conferring resistance to chemotherapy. Specifically, his work has shown that 1) ABCB5 marks malignant melanoma subpopulations of cancer stem cell phenotype and function that possess specific roles in the evasion of antitumor immunity and tumor-promoting vasculogenic mimicry; 2) ABCB5 correlates with cancer progression in melanoma patients and serves as a clinical prognostic marker of disease recurrence; and 3) ABCB5 can be therapeutically targeted to inhibit tumor growth (e.g., Schatton et al. Nature 2008, cover article). These findings established for the first time proof-of-principle for the potential therapeutic utility of the cancer stem cell concept, and hence have had broad and far-reaching impact on the cancer stem cell field by providing the key rationale for the development and clinical translation of cancer stem cell- targeted therapeutic strategies. Therefore, efforts are currently underway in his laboratory, with biopharmaceutical collaboration (Rheacell), to generate fully human high-affinity ABCB5 monoclonal antibodies for further clinical development as cancer stem cell-targeted drug candidates.
Moreover, Dr. Frank's laboratory has identified normal tissue-specific immunoregulatory ABCB5-positive adult stem cells (human and mouse) and revealed their differentiation potential and therapeutic capacity as a transplantable cell source for novel applications in tissue engineering, in a first example of constructing a fully functional human tissue from molecularly defined adult stem cells (Ksander et al. Nature 2014). As a result of these discoveries, advanced clinical-stage efforts are now underway to translate ABCB5+ dermal mesenchymal stem cell (DMSC)- and ABCB5+ limbal stem cell (LSC)-based strategies to novel EMA- and/or FDA-approved allogeneic stem cell-based clinical therapies for multiple disorders of aberrant immune activation and tissue regeneration, with initial successful results for improvement of wound healing in chronic venous ulcer (CVU) disease patients (Kerstan et al. Cytotherapy 2021; Kerstan et al. JID Innovations 2022) and, upon systemic allo-transplantation, of reduced disease activity in recessive dystrophic epidermolysis bullosa (RDEB) patients (Kiritsi et al. JCI Insight 2021) now already available, with pivotal FDA- and EMA-approved phase III human clinical trials in RDEB (NCT05838092, NCT05464381) and therapy-resistant CVU (NCT06489028) recently initiated nationally and internationally and ongoing. Of note, allogeneic ABCB5+ DMSCs (AMESANAR®) have already obtained national drug regulatory authorization for CVU therapy in Germany by Germany’s Federal Institute for Vaccines and Biomedicines (License No. PEI.A.12060.01.1, Paul-Ehrlich-Institut). This underlines Dr. Frank's considerable expertise in bringing innovative stem cell-targeted therapeutics to the clinic and demonstrates the promise, impact and high translational potential of his laboratory’s current and planned future stem cell-focused research activities in diverse areas of investigation and application, including cancer therapeutics, immune diseases, stem cell dysfunction, and aging-associated disorders.
