Our Science

Clemens Krepler, M.D.

Clemens Krepler, M.D.

  • Research Assistant Professor, Molecular and Cellular Oncogenesis Program
  • 215-898-0002, Office
Summary

Clemens Krepler is a dermatologist specializing in cutaneous oncology, focusing on translational melanoma research and personalized medicine.

He received his medical degree from the University of Vienna, Vienna, Austria where he then spent two years of post-graduate training at the Department of Clinical Pharmacology.  He was co-investigator on clinical trials testing bcl-2 antisense oligonucleotides in advanced melanoma patients. In addition to this, he was part of the molecular biology program focusing on novel melanoma therapies. He then transitioned into a dermatology residency with a special focus on dermato-oncology, gaining in-depth experience of all aspects of melanoma clinical care, from initial diagnosis and surgery to systemic therapies and palliative care, both on the ward and in the outpatient clinic. After receiving his specialist degree in dermatology, he joined the Wistar Institute in 2009 as a visiting scientist on a Max Kade fellowship.

His initial studies in the Herlyn lab were concentrated on novel targeted therapies in melanoma using 3D spheroid and in vivo xenograft transplantation models. He then focused on building the PDX (patient-derived xenografts) infrastructure managing a small but experienced team. PDX models are established without intermediate adaptation to in vitro growth from both MAPK inhibitor-naïve and -relapsed patients. Thus, PDX models resemble the original tumors closely in tissue architecture, genotype, and heterogeneity; the relapsed patient-derived samples phenocopy the patient’s resistance whereas the naïve samples show initial tumor regression, often followed by relapse. Ongoing Projects are focusing on i. Characterization of the PDX bank (n~300), ii. Testing of novel compounds and combinations in relapsed PDX in vivo, and iii. Screening for novel targeted agent combinations. These three projects allow Dr. Krepler and his team to study melanoma as it is found in patients and focus on a personalized approach to the treatment of this highly heterogeneous disease. They expect that these studies will lead to novel biomarker signatures of response for subgroups of melanoma patients, and improvements in therapeutic combinations. Dr. Krepler’s overarching goal is to translate melanoma research into effective therapies for patients.

Selected Publications

1 - Wacheck V, Krepler C, Strommer S, Heere-Ress E, Klem R, Pehamberger H, Eichler H-GG, Jansen B. Antitumor effect of G3139 Bcl-2 antisense oligonucleotide is independent of its immune stimulation by CpG motifs in SCID mice. Antisense Nucleic Acid Drug Dev. 2002;12(6):359-67. PMID: 12568310
2 - Allen M, Pratscher B, Roka F, Krepler C, Wacheck V, Schöfer C, Pehamberger H, Müller M, Lucas T. Loss of novel mda-7 splice variant (mda-7s) expression is associated with metastatic melanoma. J Invest Derm. 2004;123(3):583-8. PMID: 15304100
3 - Krepler C, Certa U, Wacheck V, Jansen B, Wolff K, Pehamberger H. Pegylated and conventional interferon-alpha induce comparable transcriptional responses and inhibition of tumor growth in a human melanoma SCID mouse xenotransplantation model. J Invest Derm. 2004;123(4):664-9. PMID: 15373770
4 - Krepler C, Wacheck V, Strommer S, Hartmann G, Polterauer P, Wolff K, Pehamberger H, Jansen B. CpG oligonucleotides elicit antitumor responses in a human melanoma NOD/SCID xenotransplantation model. J Invest Derm. 2004;122(2):387-91.
5 - Allen M, Pratscher B, Krepler C, Frei K, Schöfer C, Pehamberger H, Müller M, Lucas T. Alternative splicing of IL-24 in melanocytes by deletion of exons 3 and 5. Int J Immunogenet. 2005;32(6):375-8. PMID: 16313301
6 - Wagner S, Krepler C, Allwardt D, Latzka J, Strommer S, Scheiner O, Pehamberger H, Wiedermann U, Hafner C, Breiteneder H. Reduction of human melanoma tumor growth in severe combined immunodeficient mice by passive transfer of antibodies induced by a high molecular weight melanoma-associated antigen mimotope vaccine. Clin Cancer Res. 2008;14(24):8178-83. PMID: 19088033
7 - John JK, Paraiso KH, Rebecca VW, Cantini LP, Abel EV, Pagano N, Meggers E, Mathew R, Krepler C, Izumi V, Fang B, Koomen JM, Messina JL, Herlyn M, Smalley KS. GSK3β inhibition blocks melanoma cell/host interactions by downregulating N-cadherin expression and decreasing FAK phosphorylation. The J Invest Derm. 2012;132(12):2818-27. PMID: 22810307
8 - Schayowitz A, Bertenshaw G, Jeffries E, Schatz T, Cotton J, Villanueva J, Herlyn M, Krepler C, Vultur A, Xu W, Yu GH, Schuchter L, Clark DP. Functional profiling of live melanoma samples using a novel automated platform. PLoS One. 2012;7(12):e52760. PMID: 23285177; PMCID: PMC3532357
9 - Desai BM, Villanueva J, Nguyen TT, Lioni M, Xiao M, Kong J, Krepler C, Vultur A, Flaherty KT, Nathanson KL, Smalley KS, Herlyn M. The anti-melanoma activity of dinaciclib, a cyclin-dependent kinase inhibitor, is dependent on p53 signaling. PLoS One. 2013;8(3):e59588. PMID: 23527225; PMCID: PMC3601112
10 - Krepler C, Chunduru SK, Halloran MB, He X, Xiao M, Vultur A, Villanueva J, Mitsuuchi Y, Neiman EM, Benetatos C, Nathanson KL, Amaravadi RK, Pehamberger H, McKinlay M, Herlyn M. The novel SMAC mimetic birinapant exhibits potent activity against human melanoma cells. Clin Cancer Res. 2013;19. PMID: 23403634; PMCID: PMC3618495
11 - Roesch A, Vultur A, Bogeski I, Wang H, Zimmermann KM, Speicher D, Korbel C, Laschke MW, Gimotty PA, Philipp SE, Krause E, Patzold S, Villanueva J, Krepler C, Fukunaga-Kalabis M, Hoth M, Bastian BC, Vogt T, Herlyn M. Overcoming intrinsic multidrug resistance in melanoma by blocking the mitochondrial respiratory chain of slow-cycling JARID1B(high) cells. Cancer Cell. 2013;23(6):811-25. PMID: 23764003; PMCID: PMC3810180
12 - Villanueva J, Infante JR, Krepler C, Reyes-Uribe P, Samanta M, Chen HY, Li B, Swoboda RK, Wilson M, Vultur A, Fukunaba-Kalabis M, Wubbenhorst B, Chen TY, Liu Q, Sproesser K, DeMarini DJ, Gilmer TM, Martin AM, Marmorstein R, Schultz DC, Speicher DW, Karakousis GC, Xu W, Amaravadi RK, Xu X, Schuchter LM, Herlyn M, Nathanson KL. Concurrent MEK2 mutation and BRAF amplification confer resistance to BRAF and MEK inhibitors in melanoma. Cell Rep. 2013;4(6):1090-9. PMID: 24055054
13 - Vultur A, Villanueva J, Krepler C, Rajan G, Chen Q, Xiao M, Li L, Gimotty PA, Wilson M, Hayden J, Keeney F, Nathanson KL, Herlyn M. MEK inhibition affects STAT3 signaling and invasion in human melanoma cell lines. Oncogene. 2014 Apr 3;33(14):1850-61. Epub 2013 Apr 29. PMID: 23624919
14 - Mirkina I, Hadzijusufovic E, Krepler C, Mikula M, Mechtcheriakova D, Strommer S, Stella A, Jensen-Jarolim E, Holler C, Wacheck V, Pehamberger H, Valent P. Phenotyping of human melanoma cells reveals a unique composition of receptor targets and a subpopulation co-expressing ErbB4, EPO-R and NGF-R. PLoS One. 2014;9(1):e84417. PMID: 24489649; PMCID: PMC3906015
15 - Menon D, Das S, Krepler C, Vultur A, Rinner B, Schauer S, Kashofer K, Wagner K, Rad EB, Haass N, Soyer P, Gabrielli B, Somasundaram R, Hoefler G, Herlyn M, Schaider H. A Stress Induced Early Innate Response Causes Multi-Drug Tolerance in Melanoma. Oncogene, 2014 Nov 24. doi: 10.1038/onc.2014.372. [Epub ahead of print].
16 - Wang T, Xiao M, Ge Y, Krepler C, Xu X, Zhang G, Azuma R, S, Liu Q, Li L, Amaravadi R, Xu W, Karakousis G, Schuchter L, Halloran M, Herlyn M, Kaufman RE. BRAF inhibition stimulates melanoma-associated macrophages to drive tumor growth. Clinical Cancer Research, in press.