Justin Summy, Ph.D.

Principal Investigator
Cancer Signaling Laboratory

Lab Members
Justin Summy, PhD    Principal Investigator

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 Biography

Dr. Summy received his Bachelor of Arts in Biology from West Virginia University in 1996. Dr. Summy was awarded his PhD in Microbiology and Immunology from the West Virginia University Health Sciences Center in 2001. Dr. Summy carried out his graduate studies in the laboratory of Dr. Daniel Flynn. His research there was focused on uncovering the roles of the modular functional domains in dictating specificity in signaling between the Src family tyrosine kinases c-Src and c-Yes. Dr. Summy received his post-doctoral training at the University of Texas MD Anderson Cancer Center. Dr. Summy trained in the laboratory of Dr. Gary Gallick in the Department of Cancer Biology. During his time at MD Anderson Cancer Center, Dr. Summy conducted research into the role of c-Src in pancreatic cancer signaling and biology and the use of Src family kinase inhibitors as anti-tumor and anti-metastatic agents in pre-clinical models. After completing his post-doctoral fellowship, Dr. Summy moved on to a faculty position at the MD Anderson Cancer Center Orlando. Dr. Summy is currently pursuing research into the role of c-Src and its signaling partners in pancreatic cancer metastasis and evaluating how they may best be utilized as anti-cancer targets.

Research Summary

My laboratory research is focused on signal transduction pathways regulating the tumorigenesis and metastatic progression of human pancreatic cancer cells. Pancreatic cancer is one of the deadliest human malignancies, with over 95% of diagnosed patients succumbing within five years. The majority of pancreatic cancer deaths are caused by metastatic dissemination of the primary tumor, most commonly to the liver, regional lymph nodes, lungs, and peritoneum. The only curative treatment for pancreatic cancer is surgical resection; however, the efficacy of surgery is limited by tumor stage at initial diagnosis. The rapid progression of pancreatic cancer, coupled with the lack of distinctive symptoms makes it extremely difficult to diagnose at an early stage. The current standard of care for treatment of pancreatic cancer patients is the nucleoside analog gemcitabine; however, the rapid emergence of gemcitabine resistance greatly limits the therapeutic efficacy of this drug. The need for new strategies to combat pancreatic cancer is increasingly evident. Understanding the biology of pancreatic cancer will be of fundamental importance for improving treatment strategies.

Protein tyrosine kinases are attractive therapeutic targets, as they are often upregulated in expression or activity in cancer cells, and they regulate many of the cellular functions that are required for tumor progression and metastasis. However, protein tyrosine phosphatases, which remove phosphate groups from substrate tyrosines, play an equally important role in governing the activity of signaling pathways regulated by tyrosine phosphorylation. While they often act as ???negative regulators??? of oncogenic signaling pathways, phosphatases also frequently perform signal promoting functions. The SH2-domain containing protein tyrosine phosphatase SHP-2 is an example of a phosphatase that functions primarily in promoting cellular signaling pathways. We hypothesize that inhibition of both a tyrosine kinase and a signal-promoting tyrosine phosphatase may improve anti-tumor and/or anti-metastasis effects in comparison to inhibition of either individually.

We are studying the phosphatase/kinase pair of SHP-2 and the non-receptor tyrosine kinase c-Src. While recent studies have revealed an important role for c-Src in pancreatic cancer cell biology in cell culture in vitro and tumor progression in animal models, the role of SHP-2 in this disease is poorly characterized. Through the use of small molecule inhibitors and RNAi-mediated knockdown of gene expression, we are evaluating the importance of SHP-2 for biological processes associated with tumorigenicity and metastasis, including proliferation, survival, adhesion, invasion, and metastasis, as well as the role of SHP-2 in signal transduction pathways that regulate these important features of cancer cell biology. We will also compare the effects of SHP-2 ablation to the effects of c-Src inhibition and dual SHP-2/c-Src inhibition on in vitro biological markers of tumorigenicity and characterize the roles of SHP-2 and c-Src in signaling pathways governing these processes. We are additionally examining the effects of SHP-2 downregulation on pancreatic cancer tumorigenesis and metastasis, individually and in the context of RNAi-mediated c-Src inhibition, in an orthotopic nude mouse model. Finally, we are investigating the regulation of SHP-2 and c-Src activity in pancreatic cancer cells, including the mutual regulatory effects these proteins may exert on each other.

Selected Publications

Kuchma MH, Komanski CB, Colon J, Teblum A, Masunov AE, Alvarado B, Babu S, Seal S, Summy J, Baker CH: Phosphate ester hydrolysis of biologically relevant molecules by cerium oxide nanoparticles. Nanomedicine 2010, 6:738-744.

Connelly SF, Isley BA, Baker CH, Gallick GE, Summy JM: Loss of tyrosine phosphatase-dependent inhibition promotes activation of tyrosine kinase c-Src in detached pancreatic cells. Mol Carcinog 2010, 49:1007-1021.

Zhang J, Park SI, Artime MC, Summy JM, Shah AN, Bomser JA, Dorfleutner A, Flynn DC, Gallick GE: AFAP-110 is overexpressed in prostate cancer and contributes to tumorigenic growth by regulating focal contacts. J Clin Invest 2007, 117:2962-2973.

Shah AN, Summy JM, Zhang J, Park SI, Parikh NU, Gallick GE: Development and characterization of gemcitabine-resistant pancreatic tumor cells. Ann Surg Oncol 2007, 14:3629-3637.

Trevino JG, Summy JM, Lesslie DP, Parikh NU, Hong DS, Lee FY, Donato NJ, Abbruzzese JL, Baker CH, Gallick GE: Inhibition of SRC expression and activity inhibits tumor progression and metastasis of human pancreatic adenocarcinoma cells in an orthotopic nude mouse model. Am J Pathol 2006, 168:962-972.

Trevino JG, Summy JM, Gallick GE: SRC inhibitors as potential therapeutic agents for human cancers. Mini Rev Med Chem 2006, 6:681-687.

Trevino JG, Gray MJ, Nawrocki ST, Summy JM, Lesslie DP, Evans DB, Sawyer TK, Shakespeare WC, Watowich SS, Chiao PJ, et al: Src activation of Stat3 is an independent requirement from NF-kappaB activation for constitutive IL-8 expression in human pancreatic adenocarcinoma cells. Angiogenesis 2006, 9:101-110.

Summy JM, Gallick GE: Treatment for advanced tumors: SRC reclaims center stage. Clin Cancer Res 2006, 12:1398-1401.

Lesslie DP, Summy JM, Parikh NU, Fan F, Trevino JG, Sawyer TK, Metcalf CA, Shakespeare WC, Hicklin DJ, Ellis LM, Gallick GE: Vascular endothelial growth factor receptor-1 mediates migration of human colorectal carcinoma cells by activation of Src family kinases. Br J Cancer 2006, 94:1710-1717.

Baker CH, Trevino JG, Summy JM, Zhang F, Caron A, Nesbit M, Gallick GE, Fidler IJ: Inhibition of PDGFR phosphorylation and Src and Akt activity by GN963 leads to therapy of human pancreatic cancer growing orthotopically in nude mice. Int J Oncol 2006, 29:125-138.

Trevino JG, Summy JM, Gray MJ, Nilsson MB, Lesslie DP, Baker CH, Gallick GE: Expression and activity of SRC regulate interleukin-8 expression in pancreatic adenocarcinoma cells: implications for angiogenesis. Cancer Res 2005, 65:7214-7222.

Summy JM, Trevino JG, Lesslie DP, Baker CH, Shakespeare WC, Wang Y, Sundaramoorthi R, Metcalf CA, 3rd, Keats JA, Sawyer TK, Gallick GE: AP23846, a novel and highly potent Src family kinase inhibitor, reduces vascular endothelial growth factor and interleukin-8 expression in human solid tumor cell lines and abrogates downstream angiogenic processes. Mol Cancer Ther 2005, 4:1900-1911.

Summy JM, Trevino JG, Baker CH, Gallick GE: c-Src regulates constitutive and EGF-mediated VEGF expression in pancreatic tumor cells through activation of phosphatidyl inositol-3 kinase and p38 MAPK. Pancreas 2005, 31:263-274.

Camp ER, Summy J, Bauer TW, Liu W, Gallick GE, Ellis LM: Molecular mechanisms of resistance to therapies targeting the epidermal growth factor receptor. Clin Cancer Res 2005, 11:397-405.

Cabioglu N, Summy J, Miller C, Parikh NU, Sahin AA, Tuzlali S, Pumiglia K, Gallick GE, Price JE: CXCL-12/stromal cell-derived factor-1alpha transactivates HER2-neu in breast cancer cells by a novel pathway involving Src kinase activation. Cancer Res 2005, 65:6493-6497.

Summy JM, Sudol M, Eck MJ, Monteiro AN, Gatesman A, Flynn DC: Specificity in signaling by c-Yes. Front Biosci 2003, 8:s185-205.

Summy JM, Qian Y, Jiang BH, Guappone-Koay A, Gatesman A, Shi X, Flynn DC: The SH4-Unique-SH3-SH2 domains dictate specificity in signaling that differentiate c-Yes from c-Src. J Cell Sci 2003, 116:2585-2598.

Summy JM, Gallick GE: Src family kinases in tumor progression and metastasis. Cancer Metastasis Rev 2003, 22:337-358.

Windham TC, Parikh NU, Siwak DR, Summy JM, McConkey DJ, Kraker AJ, Gallick GE: Src activation regulates anoikis in human colon tumor cell lines. Oncogene 2002, 21:7797-7807.

Qian Y, Baisden JM, Cherezova L, Summy JM, Guappone-Koay A, Shi X, Mast T, Pustula J, Zot HG, Mazloum N, et al: PKC phosphorylation increases the ability of AFAP-110 to cross-link actin filaments. Mol Biol Cell 2002, 13:2311-2322.

Summy JM, Guappone AC, Sudol M, Flynn DC: The SH3 and SH2 domains are capable of directing specificity in protein interactions between the non-receptor tyrosine kinases cSrc and cYes. Oncogene 2000, 19:155-160.

Hoey JG, Summy J, Flynn DC: Chimeric constructs containing the SH4/Unique domains of cYes can restrict the ability of Src(527F) to upregulate heme oxygenase-1 expression efficiently. Cell Signal 2000, 12:691-701.

Qian Y, Guappone AC, Baisden JM, Hill MW, Summy JM, Flynn DC: Monoclonal antibodies directed against AFAP-110 recognize species-specific and conserved epitopes. Hybridoma 1999, 18:167-175.