Department Name

Steven N. Hochwald M.D.

RESEARCH INTERESTS: Focal adhesion kinase and insulin-like growth factor receptor-1 interactions in pancreatic cancer cell signaling and survival

The proposed research focuses on cancer of the exocrine pancreas, which continues to be a major unsolved health problem in the United States. Due to difficulty in early diagnosis, the aggressiveness of established pancreatic cancer, and the lack of effective systemic therapies, fewer than 5% of patients with adenocarcinoma of the pancreas will survive five years after diagnosis. This research project examines the role of inhibition of FAK and IGF-1R on cell signaling and survival. FAK and IGF-1R are tyrosine kinases whose overexpression occurs in a number of human malignancies including pancreatic cancer. FAK has been reported to be an important survival signal for tumor cells to resist apoptosis as well as a promoter of tumor invasion and metastasis. Downregulation of FAK expression by introduction of anti-sense oligonucleotides or the dominant negative C-terminal part of FAK leads to cell detachment and apoptosis in transformed cells.
The insulin-like growth factor system efficiently signals cells to grow, differentiate and survive. One central determinant in the prevention of cell death is the IGF-1R. Signal transduction through this receptor leads to intracellular phosphorylation of substrates resulting in the activation of several signaling pathways including Akt and MAP kinases. Therefore, the hypothesis that will be tested is whether activated IGF-1R and FAK physically interact and synergize as important survival signals in human pancreatic adenocarcinoma cells. Studies outlined will seek to elucidate the mechanism of interaction between FAK and IGF-1R in human pancreatic adenocarcinoma cells and to determine if inhibition of both FAK and IGF-1R simultaneously will more efficiently inhibit cell proliferation and migration and potentiate cell detachment and apoptosis. FAK and IGF-1R expression will be inhibited with multiple approaches including siRNA and expression of dominant negative forms of FAK and IGF-1R as well as with the use of small molecule kinase inhibitors of IGF-1R. Results are expected to illuminate novel, therapeutic molecular targets in the treatment of pancreatic cancer which is refractory to conventional cytotoxic therapy, including chemotherapy and radiation treatment.

CURRENT--

University of Florida Department of Surgery Career Development Award
Role: PI
Anti-neoplastic efficacy of FAK and/or IGF-1R tyrosine kinase inhibition in human pancreatic cancer xenografts
Dates: 7/1/05-6/30/06
 

NCI R21CA098741-01
Role: Investigator, 2% effort
Alternative estrogen therapy for colon cancer prevention
Dates: 7/1/03-6/30/05 (no cost extension to 6/30/06)
 

Ortho Biotech Clinical Affairs, LLC
Role: Co-PI
Placebo-controlled pilot study to assess the post-operative administration of Epoetin alpha on patients undergoing abdominal or pelvic surgery for malignancy
Dates: 11/01/05-11/01/06
 

PENDING--

Lustgarten Foundation for Pancreatic Cancer Research
Role: Co-PI
Comprehensive molecular characterization of benign and malignant pancreatic cystic tumors
Dates: 01/01/06-12/31/06
Total costs: $100,000

NCI-K08 -- resubmitted-- scored 150, funding levels yet to be determined
Role: PI
FAK and IGF-1R interactions in pancreatic cancer survival
Dates: 4/01/06-3/31/11
Total costs: $593,925

PRIOR--

Aventis Pharmaceuticals
Role: PI
A phase II trial of neoadjuvant irinotecan and docetaxel chemotherapy followed by surgery in patients with gastric cancer
Dates: 9/1/01-12/1/04
Total costs: $37,467

Florida Biomedical Research Program
Role: PI
Role of Nuclear Factor kB in the chemotherapy and radioresistance of gastrointestinal cancer
Dates: 7/1/01-12/31/04
Total costs: $470,419

Other trials as local Principal Investigator at the University of Florida

ACOSOG Z9000 A Phase II Study of Adjuvant ST1571 (Gleevec TM) therapy in Patients Following Completely Resected High-risk Primary Gastrointestinal Stromal Tumor (GIST)

ACOSOG Z9001 A Phase III Randomized Double-blind Study of Adjuvant ST1571 (Gleevec TM) Versus Placebo in Patients Following the Resection of Primary Gastrointestinal Stromal Tumor (GIST)

ACOSOG Z0190 A Prospective Study of the Prognostic Significance of Microsatellite Instability in Patients with Early Age-of-Onset Colorectal Cancer

ACOSOG Z0531 A Phase II study of adjuvant interferon based chemoradiation for resected pancreatic head adenocarcinoma

Protocol CSTI5721BUS227 Gastrointestinal Stromal Tumor (GIST) Registry Protocol reGISTry

PUBLICATIONS:

1. Li, J., Minnich, D, Brank, A, Camp, E.R., MacKay, S.L.D, Hochwald, S.N . Enhanced sensitivity to chemotherapy in esophageal cancer through inhibition of NF-kappaB. J. Surg Research, 2005, Dec 7.

2.  Zee, SY, Hochwald S.N. , Conlon KC, Brennan, MF, Klimstra, DS. Pleomorphic pancreatic endocrine neoplasms: A variant commonly confused with adenocarcinoma. Am J Surg Pathol (2005); 29: 1194-1200.

3.  Mendenhall, WM, Zlotecki, RA, Hochwald S.N., Hemming AW, Grobmyer SR, Cance, WG. Retroperitoneal soft tissue sarcoma. Cancer (2005), 104(4) :669-675.

4.  Zlotecki, R.A., Katz, T.S., Morris, C.G., Lind, D.S., Hochwald, S.N. Adjuvant radiation therapy for resectable retroperitoneal soft tissue sarcoma: The University of Florida Experience. Am J Clin Oncol (2005); 28: 310-316.

5.  Mendenhall, W.M., Zlotecki, R.A., Morris, C.G., Hochwald, S.N., Scarborough, M.T. Aggressive Fibromatosis. Am J Clin Oncol (2005); 28: 211-15.

6.  Camp, E.R., Hochwald, S.N., Liu, C. FAP with simultaneous duodenal polyposis and carcinoid tumor. J Surg Oncol (2004); 15: 187-190.

7.  Mendenhall, W.M., Amos, E.H., Rout, W.R., Zlotecki, R.A., Hochwald, S.N., Cance, W.G. Adjuvant postoperative radiotherapy for colon cancer. Cancer (2004); 101: 1338-44.

8.  Camp, E.R., Li, J., Minnich, J., Brank, A., Moldawer, L.L., MacKay, S.L.D., Hochwald, S.N. Inducible NF-kappaB activation contributes to chemotherapy resistance in gastric cancer. J Am Coll Surg (2004); 199 (2): 249-258.

9.  Voboril, R, Hochwald, S.N., Li, J., Brank, A., Weberova, J., Wessels, F., Moldawer, LL, Camp, ER, MacKay, S.L. Inhibition of NF-kappaB augments sensitivity to 5-fluorouracil/folinic acid in colon cancer.  J surg Res (2004)  aug: 120(2): 178-88.

10.  Newlin, H.E., Zlotecki, R.A., Morris, C.G., Hochwald, S.N., Riggs, C.E., Mendenhall, W.M. Squamous cell carcinoma of the anal margin. J Surg Oncol (2004); 86 (2); 55-62.

11.  Hemming, A.W., Reed, A.I., Howard, R.J., Fujita, S., Hochwald, S.N ., Caridi, J.G., Hawkins, I.F. Vauthey, J.N. Preoperative portal vein embolization for extended hepatectomy. Ann Surg. (2003); 237 (5); 686-693.

12.  Minter, R.M., Reith J., Hochwald S.N.  Metastatic dermatofibrosarcoma protuberans with fibrosarcomatous change resulting in pancreaticoduodenectomy. J Surg Oncol (2003); 82: 201-208.

13.  Hochwald, S.N., Lind, D.S., Malaty, J., Copeland, E.M., Moldawer, L.L., MacKay, S.L.D. Anti-neoplastic therapy in colorectal cancer through proteasome inhibition. American Surgeon (2003); 69; 15-23.

14.  Feezor, R.J., Kasraeian A., Copeland, E.M., Schell, S.R., Hochwald, S.N., Cendan, J., Drane, W., Mastin S., Wilkinson, E., Lind, D.S. Sequential dermal-peritumoral radiocolloid injection for sentinel node biopsy for breast cancer: The University of Florida experience. American Surgeon (2002); 68 (8); 684-688.

15. Hochwald, S.N., Zee, S., Conlon, K.C., Colleoni, R., Louie, O., Brennan, M.F., Klimstra, D.S. Prognostic factors in pancreatic endocrine neoplasms: An analysis of 136 cases with a proposal for low grade and intermediate grade groups. J Clin Oncol (2002); 20 (11); 2633-2642.

Book chapters and invited manuscripts  

1. Hochwald, S.N., Heslin, M. Amino acid concentrations in cancer cachexia. In: Protein and amino acid metabolism in cancer cachexia. Brennan, M.F., Pisters, P.W.T, Eds. (1996); 73-82.

2. Newman, E., Hochwald, S.N. Regional amino acid studies in cancer cachexia. In: Protein and amino acid metabolism in cancer cachexia. Brennan, M.F., Pisters, P.W.T., Eds. (1996); 93-111.

3. Hochwald, S.N., Burt, M. Gluconeogenic blockade. In: Protein and amino acid metabolism in cancer cachexia. Brennan, M.F., Pisters, P.W.T., Eds. (1996); 171-185.

4. Hochwald, S.N., Coit, D.G. Role of elective lymph node dissection in melanoma. Seminars in Surg Oncol (1998); 14; 276-282.

5. Hochwald, S.N., Conlon, K.C., Brennan, M.F. Nonfunctional pancreatic islet cell tumors. In: Surgical Endocrinology. Doherty, G.M., Skogseid, B., Eds. (2000); 361-373.

6. Hochwald, S.N., Conlon, K.C. Neuroendocrine pancreatic cancer. In: Clinical Challenges in Hepatobiliary and Pancreatic Surgery. Poston, G.J., Blumgart, L.H., Eds., (2002).

7. Hochwald, S.N., Fong, Y. Ablative technique for liver metastases. In: Colorectal Cancer: A Clinical Guide to Therapy. Bleiberg, H., Kemeny, N., Rougier, Ph., Wilke, H.J., Eds. (2002); 339-352.

8. Feezor, R.J., Copeland, E.M., Hochwald, S.N.  Significance of micrometastases in colorectal cancer. Ann Surg Oncol. (2002); 9 (10): 944-953.

9. Camp, E.R., Hochwald, S.N. Gastroduodenal Procedures. In: ACS Surgery: Principles & Practice. Souba WW, Fink, MP, Jurkovish, GJ, Kaiser, LR, Pearce, WH, Pemberton, JH, Soper, NJ, Eds (2004); 421-436.

10. Hochwald, S.N., Bloom, D., Golubovskaya, V., Cance W. Fundamentals of Cancer Biology and Molecular Therapeutics; in press, 2005.