David J. Riese, Ph.D. Associate Professor of Medicinal Chemistry and Molecular Pharmacology Phone: (765) 494-6091 Fax: (765) 496-3601 E-mail: driese@purdue.edu Full directory listing

Specialization: ErbB Receptor Signal Transduction in Human Malignancies

Education

Research: ErbB Receptor Signal Transduction in Human Malignancies

OVERVIEW - Our group studies the Epidermal Growth Factor (EGF) family of peptide hormones and their receptors, the ErbB family of receptor tyrosine kinases. This network plays a significant role in regulating the proliferation and differentiation of epithelial cells. Moreover, deregulated signaling by this network is a causative event in many human tumors, and contributes to increased tumor cell invasiveness, metastatic potential, and chemoresistance. Consequently, our group studies this signaling network with the ultimate goal being the development of novel cancer diagnostic and treatment strategies.

ERBB4 AND EPITHELIAL TUMORS - ErbB4 expression is lost in many epithelial tumors, suggesting that ErbB4 is a tumor suppressor in these tissues. Indeed, a constitutively active, ligand independent ErbB4 mutant inhibits colony formation on plastic by human breast, pancreatic, and prostate tumor cell lines [1,6]. However, other data indicate that ErbB4 is coupled to tumor cell proliferation, motility, and invasiveness. We are using various expression systems, analytical approaches, ErbB4 ligands, and ErbB4 mutants to characterize ErbB4 coupling to tumor suppression and malignant phenotypes. We are focused on deciphering the mechanisms by which ErbB4 can be coupled to these divergent responses [6,7,12,14].

EGF FAMILY HORMONES - In collaboration with Mark Lemmon (University of Pennsylvania), Stephen Ethier (Wayne State University), John Foley (Indiana University), Anne Lykkesfeldt (Danish Cancer Institute), Claudio Aguilar (Purdue University) and Robert Hammer (Louisiana State University), we are identifying factors that regulate the affinity, potency, and efficacy of EGF family hormones [2,3,4,8,11,13,14,17,18,19,21]. We are interested in elucidating the roles that EGFR and its ligands play in tumor cell colonization of the bone. We are also interested in elucidating the structural features of EGF family hormones that are responsible for differences in affinity, potency, and efficacy. Recently we have discovered that some EGF family hormones can antagonize the activity of other EGF family hormones and that single amino acid substitutions can be sufficient to change an agonist to an antagonist and vice versa. Thus, these studies have the potential to yield new cancer therapies.

TARGETED TUMOR IMAGING AGENTS - In collaboration with Henry VanBrocklin (UCSF) and Julie Sutcliffe-Golden (UC-Davis), we are investigating EGFR ligands as possible functional targeted tumor imaging agents. EGFR ligands under investigation include small molecule inhibitors, oligopeptides, and EGF family hormones and hormone mutants [5]. Such agents have the potential to selectively image aggressive primary tumors and their metastases.

EGFR MUTANTS AND LUNG CANCER - In collaboration with Jeffrey Settleman and Daniel Haber (Harvard Medical School), we are investigating the mechanisms by which EGFR mutants contribute to chemosensitive and chemoresistance in non-small-cell lung carcinoma (NSCLC) [9,10,15]. We are focusing on the role that EGFR heterodimerization with other ErbB receptors may play in these processes.

EGFR AS SIGNAL INTEGRATOR - In collaboration with Val Watts and Julia Chester (Purdue University), we are investigating whether EGFR mediates the effects of dopamine and alcohol on breast cells [16,20]. Such studies may elucidate the mechanisms by which Parkinson's disease patients and individuals suffering from alcoholism exhibit an elevated risk of developing breast cancer. Such studies may also result in strategies for managing this risk.

Teaching

MCMP 44000 - Pathophysiology - Spring Semester
MCMP 51400 - Advanced Medicinal Analysis - Spring Semester
MCMP 57000 - Basic Principles of Chemical Action on Biological Systems - Fall Semester

Honors and Credentials

Predoctoral Fellowship, Howard Hughes Medical Institute (1988-93)
Postdoctoral Fellowship, Department of Defense Breast Cancer Research Program (1994-97)
Henry W. Heine Award for Excellence in Undergraduate Teaching, Purdue School of Pharmacy (2000)
Career Development Award, Department of Defense Breast Cancer Research Program (2000-04)
New Investigator Award, Department of Defense Prostate Cancer Research Program (2002-05)

Grants

"Regulation of ErbB4 Signaling by Neuregulin Isoforms", NIH R01CA114209
08/01/2006 - 07/31/2011, Principal Investigator.

"Gefitinib-Sensitive EGF Receptor Mutants In Lung Cancer", NIH R01CA115830
06/01/2005 - 05/31/2010, co-Investigator (Jeffrey Settleman, Harvard, PI).

Administration and Committee Work

Editorial Advisory Board, Biochemical Journal
Editorial Board, Breast Cancer - Targets and Therapy
Executive Committee and co-Program Leader, Purdue University Center for Cancer Research

Representative Publication

1. EE Williams, LJ Trout, RM Gallo, SE Pitfield, DJ Penington, I Bryant, and DJ Riese II. A constitutively-active ErbB4 mutant inhibits drug-resistant colony formation by the DU-145 and PC-3 human prostate tumor cell lines. Cancer Lett 192: 67-74 (2003). PMID: 12637154.

2. SS Hobbs, EM Cameron, RP Hammer, ATD Le, RM Gallo, EN Blommel, SL Coffing, and DJ Riese II. Five carboxyl-terminal residues of Neuregulin2 are critical for atimulation of signaling by the ErbB4 receptor tyrosine kinase. Oncogene 23: 883-894 (2004). PMID: 14661053.

3. JL Gilmore and DJ Riese II. secErbB4-26/549 antagonizes ligand-induced ErbB4 tyrosine phosphorylation. Oncol Res 14: 589-602 (2004). PMID: 15667000.

4. SS Hobbs, RM Gallo, and DJ Riese II. Phe45 of NRG2beta is critical for the affinity of NRG2beta for ErbB4 and for potent stimulation of ErbB4 signaling by NRG2beta. Growth Factors 23: 273-283 (2005). PMID: 16338790.

5. HF VanBrocklin, JK Lim, SL Coffing, DL Hom, K Negash, MY Ono, SM Hanrahan, SE Taylor, JL Gilmore, I Bryant, and DJ Riese II. Anilino-dialkoxyquinazolines: Screening epidermal growth factor receptor tyrosine kinase inhibitors for potential tumor imaging probes. J Med Chem 48: 7445-7456 (2005). PMID: 16279804.

6. SE Pitfield, I Bryant, DJ Penington, G Park, and DJ Riese II. Phosphorylation of ErbB4 on tyrosine 1056 is critical for ErbB4 coupling to inhibition of colony formation by human mammary cell lines. Oncol Res 16: 179-193 (2006). PMID: 17120616.

7. RM Gallo, I Bryant, R Fry, EE Williams, and DJ Riese II. Phosphorylation of ErbB4 on Tyr1056 is critical for inhibition of colony formation by prostate tumor cell lines. Biochem Biophys Res Com 349: 372-382 (2006). PMID: 16934755.

8. JL Gilmore, RM Gallo, and DJ Riese II. The EGFR-S442F mutant displays increased affinity for Neuregulin2beta and agonist-independent coupling to downstream signaling events. Biochem J 396: 79-88 (2006). PMID: 16445385.

9. N Godin-Heymann, I Bryant, MN Rivera, L Ulkus, DW Bell, DJ Riese II, J Settleman, and DA Haber. Oncogenic activity of EGFR kinase mutant alleles is enhanced by the T790M drug resistance mutation. Cancer Res 67: 7319-7326 (2007). PMID: 17671201.

10. DJ Riese II, RM Gallo, and J Settleman. Mutational Activation of ErbB Receptor Tyrosine Kinases: Insights Into Mechanisms of Signal Transduction and Tumorigenesis. Bioessays 26: 558-565 (2007). PMID: 17508401.

11. KJ Wilson, CP Mill, EM Cameron, SS Hobbs, RP Hammer, and DJ Riese II. Interconversion of Neuregulin2 full and partial agonists for ErbB4. Biochem Biophys Res Com 364: 351-357 (2007). PMID: 17945187.

12. RM Gallo and DJ Riese II. The antibody sc-33040-R fails to specifically recognize phosphorylation of ErbB4 on tyrosine 1056. Growth Factors 25: 329-333 (2007). PMID: 18236211.

13. JL Gilmore, JA Scott, Z Bouizar, A Robling, SE Pitfield, DJ Riese II, and J Foley. Amphiregulin-EGFR signaling regulates PTHrP gene expression in breast cancer cells. Breast Cancer Res Treat 110: 496-505 (2008). PMID: 17882547.

14. T Frogne, RV Benjaminsen, K Sonne-Hansen, BS Sorensen, E Nexo, A-V Laenkholm, LM Rasmussen, DJ Riese II, P de Cremoux, J Stenvang, and AE Lykkesfeldt. Activation of ErbB3, EGFR, and Erk is essential for growth of human breast cancer cell lines with acquired resistance to fulvestrant. Breast Cancer Res Treat 114: 263-275 (2009). PMID 18409071.

15. SM Rothenberg, JA Engelman, S Le, DJ Riese II, DA Haber, and J Settleman. Modeling oncogene addiction with RNA interference. Proc Natl Acad Sci USA 105: 12480-12484 (2008). PMID: 18711136.

16. JA Przybyla, JP Cueva, BR Chemel, KJ Hsu, DJ Riese II, JD McCorvy, JA Chester, DE Nichols, and VJ Watts. Comparison of the enantiomers of (+/-)-doxanthrine, a high efficacy full dopamine D1 receptor agonist, and a reversal of enantioselectivity at D1 versus alpha2C adrenergic receptors. Eur Neuropsychopharmacol 19: 138-146 (2009). PMID: 19028082.

17. KJ Wilson, JL Gilmore, J Foley, MA Lemmon, and DJ Riese II. Functional selectivity of EGF Family Peptide Growth Factors: Implications for Cancer. Pharmacol Ther 122: 1-8 (2009). PMID: 19135477.

18. NE Willmarth, A Baillo, ML Dziubinski, K Wilson, DJ Riese II, and SP Ethier. Altered EGFR localization and degradation in human breast cancer cells with an amphiregulin/EGFR autocrine loop. Cell Signal 21: 212-219 (2009). PMID: 18951974.

19. JL Gilmore, RM Gonterman, K Menon, G Lorch, DJ Riese II, A Robling, and J Foley. Reconstitution of amphiregulin-EGFR signaling in lung squamous carcinomas activates PTHrP gene expression and cancer-mediated diseases of the bone. Mol Cancer Res 7: 1714-1728 (2009). PMID: 19825997.

20. CP Mill, J Chester, and DJ Riese II. The epidermal growth factor receptor may couple moderate alcohol consumption to increased breast cancer risk. Breast Cancer - Targets and Therapy 1: 31-38 (2009).

21. BG Coon, D Mukherjee, CB Hanna, DJ Riese II, M Lowe, and RC Aguilar. Lowe syndrome patient fibroblasts display Ocr11-specific cell migration defects that cannot be rescued by the homologous Inpp5b phosphatase. Hum Mol Gen 18: 4478-4491 (2009). PMID: 19700499.

Curriculum Vitae

Click here for a full CV for David J. Riese. (an Adobe Acrobat file)