James Eshleman Jr., MD, PhD

Professional Titles

• Associate Director, Molecular Diagnostics Laboratory

Primary Academic Title

Professor of Pathology

Background

Centers and Institutes

Sidney Kimmel Comprehensive Cancer Center

Additional Academic Titles

Professor of Oncology

Research Interests

Genetic instability, Molecular diagnosis of cancer, Pancreatic cancer genetics and chemosensitivity

Research Summary

Pancreatic cancers: genetics of sporadic and familial pancreatic cancer.  In collaboration with the Vogelstein/Kinzler lab, in 2008 we reported exome sequencing for 24 pancreatic cancers, where we confirmed identified genes in another 92 cancers. In Jones 2009, we identified that the partner and localizer of BRCA2 (PALB2) was a familial pancreatic cancer predisposition gene.  Using gene mutations in primary cancers and their metastases, we clocked the progression of pancreatic cancer to demonstrate that metastasis is a late event, occurring after 17 years of growth in the primary site.  Finally, in Norris et al, we reported a new method of mutagenesis in pancreatic cancer.
 
For the past 8 years, we have developed a new method to kill cancer based on genetics.  Specifically, we target somatic mutations using CRISPR-Cas9 to induce double-strand breaks in cancer cells.  Because these mutations do not exist in the patients' normal cells, they are not affected.
 
Novel molecular pathology tools. We wrote software to simulate pyrosequencing (Chen et al), and developed a method (haplotype counting) to overcome the error rate of next-generation sequencing (Debeljak et al).

PubMed - Publications

http://www.ncbi.nlm.nih.gov/pubmed/?term=Eshleman+J%2C+Hopkins

Selected Publications

• Eshleman JR, Lang EZ, Bowerfind GK, Parsons R, Vogelstein B, Willson JKV, Veigl M, Sedwick WD, and Markowitz S. Increased mutation rate at the hprt locus accompanies microsatellite instability in colon cancer. Oncogene. 1995; 10:33-7.

• Cui Y, Brosnan JA, Blackford A, Sur S, Hruban RH, Kinzler KW, Vogelstein B, Maitra A, Diaz LA, Iacobuzio-Donahue CA, and Eshleman JR. Genetically defined subsets of human pancreatic cancer demonstrate unique in vitro chemosensitivity. Clinical Cancer Research, 2012;18:6519-30. [PMC3513499].

• Dudley JC, Lin MT, Le DT, Eshleman JR.  Microsatellite instability as a biomarker for PD-1 blockade.  Clin Cancer Res. 2016 Feb 15;22(4):813-20.

• Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Kamiyama H, Jimeno A, Hong SM, Fu B, Lin MT, Calhoun ES, Kamiyama M, Walter K, Nikolskaya T, Nikolsky Y, Hartigan J, Smith DR, Hidalgo M, Leach SD, Klein AP, Jaffee EM, Goggins M, Maitra A, Iacobuzio-Donahue C, Eshleman JR, Kern SE, Hruban RH, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, and Kinzler KW. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science. 2008; 321:1801-6. [PMC2848990].

• Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, Lu S, Kemberling H, Wilt C, Luber BS, Wong F, Azad NS, Rucki AA, Laheru D, Donehower R, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Greten TF, Duffy AG, Ciombor KK, Eyring AD, Lam BH, Joe A, Kang SP, Holdhoff M, Danilova L, Cope L, Meyer C, Zhou S, Goldberg RM, Armstrong DK, Bever KM, Fader AN, Taube J, Housseau F, Spetzler D, Xiao N, Pardoll DM, Papadopoulos N, Kinzler KW, Eshleman JR, Vogelstein B, Anders RA, Diaz LA Jr. Mismatch-repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017 July; 357: 409-413.

Graduate Program Affiliations

• Pathobiology, Cellular and Molecular Medicine