ABOUT THE RESEARCHER

OVERVIEW

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 ATP-binding cassette, sub-family B, member 5 (ABCB5) in normal tissue-specific stem cells and malignant cancer stem cells.

Stem Cell Therapeutics

 Dr. Frank's 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 - in press; Kiritsis et al. JCI Insight 2021 - in press). 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.

Cancer Stem Cell-Targeted Therapeutic Strategies

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.

BACKGROUND

Markus Frank is Associate Professor of Pediatrics and of Dermatology at Harvard Medical School, Associate Physician in the Renal Division at Brigham and Women's Hospital, a member of the Stem Cell Program at Boston Children's Hospital, and Co-Leader of the Harvard Stem Cell Institute Skin Program. Dr. Frank received a Bachelor’s degree in Biochemical Sciences from Harvard College and an M.D. degree from the University of Heidelberg School of Medicine, Germany. He completed a residency in Internal Medicine at Albert Einstein College of Medicine in New York and a fellowship in Nephrology at Brigham and Women's Hospital, followed by research training in transplant immunology at Brigham and Women's Hospital and Boston Children's Hospital. He is an elected member of the American Society for Clinical Investigation (ASCI).

PUBLICATIONS

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  1. Clinical trial of ABCB5+ mesenchymal stem cells for recessive dystrophic epidermolysis bullosa. JCI Insight. 2021 Nov 22; 6(22). View abstract
  2. Angiogenin Released from ABCB5+ Stromal Precursors Improves Healing of Diabetic Wounds by Promoting Angiogenesis. J Invest Dermatol. 2021 Nov 19. View abstract
  3. Allogeneic ABCB5+ mesenchymal stem cells for treatment-refractory chronic venous ulcers: a phase I/IIa clinical trial. JID Innov. 2022 Jan; 2(1). View abstract
  4. High expression of SARS-CoV2 viral entry-related proteins in human limbal stem cells. Ocul Surf. 2021 Oct 13. View abstract
  5. Human iPS cells engender corneal epithelial stem cells with holoclone-forming capabilities. iScience. 2021 Jun 25; 24(6):102688. View abstract
  6. Process development and safety evaluation of ABCB5+ limbal stem cells as advanced-therapy medicinal product to treat limbal stem cell deficiency. Stem Cell Res Ther. 2021 03 19; 12(1):194. View abstract
  7. ABCB5+ dermal mesenchymal stromal cells with favorable skin homing and local immunomodulation for recessive dystrophic epidermolysis bullosa treatment. Stem Cells. 2021 Jul; 39(7):897-903. View abstract
  8. Clinical Implications of Colorectal Cancer Stem Cells in the Age of Single-Cell Omics and Targeted Therapies. Gastroenterology. 2021 05; 160(6):1947-1960. View abstract
  9. Process data of allogeneic ex vivo-expanded ABCB5+ mesenchymal stromal cells for human use: off-the-shelf GMP-manufactured donor-independent ATMP. Stem Cell Res Ther. 2020 11 16; 11(1):482. View abstract
  10. Ex vivo-expanded highly pure ABCB5+ mesenchymal stromal cells as Good Manufacturing Practice-compliant autologous advanced therapy medicinal product for clinical use: process validation and first in-human data. Cytotherapy. 2021 02; 23(2):165-175. View abstract
  11. Targeting the ABC transporter ABCB5 sensitizes glioblastoma to temozolomide-induced apoptosis through a cell-cycle checkpoint regulation mechanism. J Biol Chem. 2020 05 29; 295(22):7774-7788. View abstract
  12. Loss of the Epigenetic Mark 5-hmC in Psoriasis: Implications for Epidermal Stem Cell Dysregulation. J Invest Dermatol. 2020 06; 140(6):1266-1275.e3. View abstract
  13. PD-L1 Expression on Circulating Tumor Cells May Be Predictive of Response to Pembrolizumab in Advanced Melanoma: Results from a Pilot Study. Oncologist. 2019 Dec 05. View abstract
  14. PD-L1 Expression on Circulating Tumor Cells May Be Predictive of Response to Pembrolizumab in Advanced Melanoma: Results from a Pilot Study. Oncologist. 2020 03; 25(3):e520-e527. View abstract
  15. Investigation of factors associated with ABCB5-positive limbal stem cell isolation yields from human donors. Ocul Surf. 2020 01; 18(1):114-120. View abstract
  16. Newly Defined ATP-Binding Cassette Subfamily B Member 5 Positive Dermal Mesenchymal Stem Cells Promote Healing of Chronic Iron-Overload Wounds via Secretion of Interleukin-1 Receptor Antagonist. Stem Cells. 2019 08; 37(8):1057-1074. View abstract
  17. In vivo safety profile and biodistribution of GMP-manufactured human skin-derived ABCB5-positive mesenchymal stromal cells for use in clinical trials. Cytotherapy. 2019 05; 21(5):546-560. View abstract
  18. Immunomagnetic-Enriched Subpopulations of Melanoma Circulating Tumour Cells (CTCs) Exhibit Distinct Transcriptome Profiles. Cancers (Basel). 2019 Jan 30; 11(2). View abstract
  19. ATP-binding cassette member B5 (ABCB5) promotes tumor cell invasiveness in human colorectal cancer. J Biol Chem. 2018 07 13; 293(28):11166-11178. View abstract
  20. Repairing the corneal epithelium using limbal stem cells or alternative cell-based therapies. Expert Opin Biol Ther. 2018 05; 18(5):505-513. View abstract
  21. Limbal stem cells: identity, developmental origin, and therapeutic potential. Wiley Interdiscip Rev Dev Biol. 2018 03; 7(2). View abstract
  22. Rapid generation of Col7a1-/- mouse model of recessive dystrophic epidermolysis bullosa and partial rescue via immunosuppressive dermal mesenchymal stem cells. Lab Invest. 2017 10; 97(10):1218-1224. View abstract
  23. Isolation and detection of circulating tumour cells from metastatic melanoma patients using a slanted spiral microfluidic device. Oncotarget. 2017 Jun 27. View abstract
  24. Isolation and detection of circulating tumour cells from metastatic melanoma patients using a slanted spiral microfluidic device. Oncotarget. 2017 Sep 15; 8(40):67355-67368. View abstract
  25. Expression of Cell-Surface Marker ABCB5 Causes Characteristic Modifications of Glucose, Amino Acid and Phospholipid Metabolism in the G3361 Melanoma-Initiating Cell Line. PLoS One. 2016; 11(8):e0161803. View abstract
  26. Suppression of Neutrophil-Mediated Tissue Damage-A Novel Skill of Mesenchymal Stem Cells. Stem Cells. 2016 09; 34(9):2393-406. View abstract
  27. ABCB5-Targeted Chemoresistance Reversal Inhibits Merkel Cell Carcinoma Growth. J Invest Dermatol. 2016 Apr; 136(4):838-846. View abstract
  28. Effects of Malignant Melanoma Initiating Cells on T-Cell Activation. Methods Mol Biol. 2016 Jan 20. View abstract
  29. Isolation of Circulating Melanoma Cells. Methods Mol Biol. 2015 Sep 29. View abstract
  30. Melanoma Cell-Intrinsic PD-1 Receptor Functions Promote Tumor Growth. Cell. 2015 Sep 10; 162(6):1242-56. View abstract
  31. ABCB5 Identifies Immunoregulatory Dermal Cells. Cell Rep. 2015 Sep 08; 12(10):1564-74. View abstract
  32. Circulating Melanoma Cell Subpopulations: Their Heterogeneity and Differential Responses to Treatment. J Invest Dermatol. 2015 Aug; 135(8):2040-2048. View abstract
  33. Expression of Multidrug Resistance Transporter ABCB5 in a Murine Model of Human Conjunctival Melanoma. Ocul Oncol Pathol. 2015 Apr; 1(3):182-189. View abstract
  34. Restoring the cornea from limbal stem cells. Regen Med. 2015; 10(1):1-4. View abstract
  35. Nestin depletion induces melanoma matrix metalloproteinases and invasion. Lab Invest. 2014 Dec; 94(12):1382-95. View abstract
  36. ABCB5 is a limbal stem cell gene required for corneal development and repair. Nature. 2014 Jul 17; 511(7509):353-7. View abstract
  37. ABCB5 maintains melanoma-initiating cells through a proinflammatory cytokine signaling circuit. Cancer Res. 2014 Aug 01; 74(15):4196-207. View abstract
  38. The multidrug-resistance transporter ABCB5 is expressed in human placenta. Int J Gynecol Pathol. 2014 Jan; 33(1):45-51. View abstract
  39. Stem cells and targeted approaches to melanoma cure. Mol Aspects Med. 2014 Oct; 39:33-49. View abstract
  40. Genetically determined ABCB5 functionality correlates with pigmentation phenotype and melanoma risk. Biochem Biophys Res Commun. 2013 Jul 05; 436(3):536-42. View abstract
  41. Markers of circulating tumour cells in the peripheral blood of patients with melanoma correlate with disease recurrence and progression. Br J Dermatol. 2013 Jan; 168(1):85-92. View abstract
  42. Synergy of photoacoustic and fluorescence flow cytometry of circulating cells with negative and positive contrasts. J Biophotonics. 2013 May; 6(5):425-34. View abstract
  43. Metabolic inhibition of galectin-1-binding carbohydrates accentuates antitumor immunity. J Invest Dermatol. 2012 Feb; 132(2):410-20. View abstract
  44. ABCB5 identifies a therapy-refractory tumor cell population in colorectal cancer patients. Cancer Res. 2011 Aug 01; 71(15):5307-16. View abstract
  45. Colorectal Cancer Stem Cells: Biology and Therapeutic Implications. Curr Colorectal Cancer Rep. 2011 Jun; 7(2):128-135. View abstract
  46. The pro-apoptotic protein Bim is a microRNA target in kidney progenitors. J Am Soc Nephrol. 2011 Jun; 22(6):1053-63. View abstract
  47. SOX2 and nestin expression in human melanoma: an immunohistochemical and experimental study. Exp Dermatol. 2011 Apr; 20(4):339-45. View abstract
  48. VEGFR-1 expressed by malignant melanoma-initiating cells is required for tumor growth. Cancer Res. 2011 Feb 15; 71(4):1474-85. View abstract
  49. Isolation of tumorigenic circulating melanoma cells. Biochem Biophys Res Commun. 2010 Nov 26; 402(4):711-7. View abstract
  50. The in vitro spheroid melanoma cell culture assay: cues on tumor initiation? J Invest Dermatol. 2010 Jul; 130(7):1769-71. View abstract
  51. A novel in vivo regulatory role of P-glycoprotein in alloimmunity. Biochem Biophys Res Commun. 2010 Apr 09; 394(3):646-52. View abstract
  52. Tumor initiation in human malignant melanoma and potential cancer therapies. Anticancer Agents Med Chem. 2010 Feb; 10(2):131-6. View abstract
  53. Modulation of T-cell activation by malignant melanoma initiating cells. Cancer Res. 2010 Jan 15; 70(2):697-708. View abstract
  54. The therapeutic promise of the cancer stem cell concept. J Clin Invest. 2010 Jan; 120(1):41-50. View abstract
  55. A gene encoding a multidrug-resistance human P-glycoprotein homologue on chromosome 7p15-2 and uses thereof. 2009. View abstract
  56. Identification and targeting of cancer stem cells. Bioessays. 2009 Oct; 31(10):1038-49. View abstract
  57. Antitumor immunity and cancer stem cells. Ann N Y Acad Sci. 2009 Sep; 1176:154-69. View abstract
  58. ABCB5 gene amplification in human leukemia cells. Leuk Res. 2009 Oct; 33(10):1303-5. View abstract
  59. Identifizierung tumorinitiierender Zellen im Pankreaskarzinom: Untersuchung zur Bedeutung des MDR-Gens ABCB5. 126. Kongress der Deutschen Gesellschaft für Chirurgie, 28.04. - 01.05.2009, München. 2009; DOI: 10.3205/09dgch095. View abstract
  60. Tumour-Promoting Vasculogenic Channels of Cancer Stem Cell Origin. 7th World Congress on Melanoma, May 12 -16 2009, Vienna, Austria. 2009; 191. View abstract
  61. Inhibition of T cell activation by melanoma stem cells. 7th World Congress on Melanoma, May 12 -16 2009, Vienna, Austria. 2009; 191-192. View abstract
  62. Detection and Quantification of Circulating Melanoma Cells. 7th World Congress on Melanoma, May 12 -16 2009, Vienna, Austria. 2009; 123. View abstract
  63. Melanoma vasculogenesis driven by cancer stem cells. Proceedings of the American Association for Cancer Research 100th Annual Meeting 2009, Denver, Colorado. 2009; 50(April 2009):759 (Abstract #3131). View abstract
  64. Cancer stem cell-mediated immunomodulation in human malignant melanoma. Proceedings of the American Association for Cancer Research 100th Annual Meeting 2009, Denver, Colorado. 2009; 50(April 2009):765 (Abstract #3164). View abstract
  65. Solid tumor stem cells – implications for cancer therapy. Regulatory Networks in Stem Cells. 2009. View abstract
  66. The effects of tamoxifen on immunity. Curr Med Chem. 2009; 16(24):3076-80. View abstract
  67. Solid tumor stem cells – implications for cancer therapy. Regulatory Networks in Stem Cells (V.K. Rajasekhar and M.C. Vemuri, Editors.). 2009; 527-543. View abstract
  68. Gene encoding a multidrug resistance human P-glycoprotein homologue on chromosome 7p15-21 and uses thereof. 2008. View abstract
  69. Gene encoding a multidrug-resistance human P-glycoprotein homologue on chromosome 7p15-2 and uses thereof. 2008. View abstract
  70. Therapeutic and diagnostic methods relating to cancer stem cells. 2008. View abstract
  71. Identification of cells initiating human melanomas. International Investigative Dermatology 2008 Meeting. 2008; Kyoto, Japan May 14-17 2008. View abstract
  72. Identification of cells initiating human melanomas. AACR Annual Meeting 2008. 2008; San Diego, CA, USA April 12-16. View abstract
  73. Cancer stem cells and human malignant melanoma. Pigment Cell Melanoma Res. 2008 Feb; 21(1):39-55. View abstract
  74. Identification of cells initiating human melanomas. Nature. 2008 Jan 17; 451(7176):345-9. View abstract
  75. ABCB5 positive mesenchymal stem cells as immunomodulators. 2007. View abstract
  76. Targeting ABCB5 for cancer therapy. 2007. View abstract
  77. P-glycoprotein functions as a differentiation switch in antigen presenting cell maturation. Am J Transplant. 2006 Dec; 6(12):2884-93. View abstract
  78. Regulation of myogenic progenitor proliferation in human fetal skeletal muscle by BMP4 and its antagonist Gremlin. J Cell Biol. 2006 Oct 09; 175(1):99-110. View abstract
  79. Investigation of multidrug resistance in cultured human renal cell carcinoma cells by 31P-NMR spectroscopy and treatment survival assays. MAGMA. 2005 Jul; 18(3):144-61. View abstract
  80. ABCB5-mediated doxorubicin transport and chemoresistance in human malignant melanoma. Cancer Res. 2005 May 15; 65(10):4320-33. View abstract
  81. A gene encoding a multidrug resistance human P-glycoprotein homologue on chromosome 7p15-21 and uses thereof. 2005. View abstract
  82. CD40-induced transcriptional activation of vascular endothelial growth factor involves a 68-bp region of the promoter containing a CpG island. Am J Physiol Renal Physiol. 2004 Sep; 287(3):F512-20. View abstract
  83. Immunomodulatory functions of mesenchymal stem cells. Lancet. 2004 May 01; 363(9419):1411-2. View abstract
  84. Regulation of progenitor cell fusion by ABCB5 P-glycoprotein, a novel human ATP-binding cassette transporter. J Biol Chem. 2003 Nov 21; 278(47):47156-65. View abstract
  85. P-glycoprotein--a novel therapeutic target for immunomodulation in clinical transplantation and autoimmunity? Curr Drug Targets. 2003 Aug; 4(6):469-76. View abstract
  86. P-glycoprotein and alloimmune T-cell activation. Clin Appl Immunol Rev. 2003 Jul; 4(1):3-14. View abstract
  87. Specific MDR1 P-glycoprotein blockade inhibits human alloimmune T cell activation in vitro. J Immunol. 2001 Feb 15; 166(4):2451-9. View abstract
  88. Monoclonal Antibody Targeting of Adhesion Molecules. Current and Future Immunosuppressive Therapies Following Transplantation. 2001; 249-263. View abstract
  89. Tolerance: is it time to move to the clinic?. Current and Future Immunosuppressive Therapies Following Transplantation. 2001; 293-313. View abstract
  90. Interferon alpha2b differentially affects proliferation of two human renal cell carcinoma cell lines differing in the P-glycoprotein-associated multidrug-resistant phenotype. J Cancer Res Clin Oncol. 1999; 125(2):117-20. View abstract
  91. [Reversible esophageal dysfunction as a side effect of levodopa]. Bildgebung. 1996 Mar; 63(1):48-50. View abstract
  92. 31P-NMR-spektroskopische Studien zur Multidrug-Resistenz des menschlichen Nierenzellkarzinoms [Doctoral Dissertation]. 1995. View abstract