Research Abstract
Dr. Frank's 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.
His laboratory has cloned and characterized a novel human P-glycoprotein family member, ABCB5, which regulates maintenance and differentiation of normal tissue-specific stem cells with therapeutic capacity as a transplantable cell source for immunomodulation (Schatton et al. Cell Reports 2015) and tissue regeneration, as shown, for example, in a first report of constructing a fully functional human tissue (cornea) from molecularly defined adult stem cells (Ksander et al. Nature 2014). As a result of these discoveries, advanced EMA- and/or FDA-approved human clinical trials are currently underway to translate ABCB5+ dermal mesenchymal stem cell (DMSC)- and ABCB5+ limbal stem cell (LSC)-based strategies to novel therapies for multiple disorders of aberrant immune activation and tissue regeneration (ClinicalTrials.gov Identifiers: NCT04971161 – chronic venous ulcer disease (CVU); NCT03549299 – limbal stem cell deficiency (LSCD); NCT03529877 – recessive dystrophic epidermolysis bullosa (RDEB)), with initial successful clinical results in cutaneous wound healing and RDEB now already available (Kerstan et al. JID Innovations 2021; Kiritsi et al. JCI Insight 2021). Additionally, Germany’s Federal Institute for Vaccines and Biomedicines (Paul-Ehrlich-Institut) recently granted national approval for allogeneic ABCB5+ DMSCs (AMESANAR®) as an Advanced Therapy Medicinal Product (ATMP) for treatment of chronic wounds in patients with chronic venous insufficiency.
Dr. Frank's laboratory has also shown that ABCB5 serves as a multidrug resistance transporter in cancer stem cells of several human malignancies, including malignant melanoma, colorectal cancer and glioblastoma, conferring resistance to chemotherapy. Specifically, his laboratory's 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, colorectal cancer and glioblastoma patients and serves as a prognostic marker of disease progression or recurrence; and 3) ABCB5 can be therapeutically targeted to inhibit tumor growth (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 provided a key rationale for the development and clinical translation of cancer stem cell- targeted therapeutic strategies. Therefore, efforts are currently underway to further develop fully human high-affinity ABCB5 monoclonal antibodies as novel cancer stem cell-targeted drug candidates for clinical therapy.
