This revised proposal has as an objective the development of a novel therapy for well-differentiated oral squamous carcinoma based on targeting the expression of an endoplasmic reticulum resident protein that is uniquely expressed on the cell surface of well-differentiated carcinomas. Well-differentiated oral squamous cell carcinomas like other well-differentiated carcinomas are difficult to treat because of their low mitotic indices and proliferation rates. However, these well- differentiated neoplasms are known to possess and express an endoplasmic reticulum (ER) collagen chaperone, Hsp47. Although Hsp47 specifically binds procollagen in the ER, in malignancy the protein escapes ER retention to be expressed on the cell surface. We hypothesize that the specific peptide binding characteristics of this protein and unique location in malignancy provides a marker that may serve as a target to which drugs or contrast agents may be directed for chemotherapy or imaging. This hypothesis will be tested through the accomplishment of three specific aims. These include: (1) Expand the repertoire of Hsp47-binding peptides by utilizing random peptide libraries and two-hybrid screening of random displayed peptides with Hsp47 as a bait protein; (2) Determine the availability and fate of Hsp47 binding peptides on the cell surface of epidermoid carcinoma cells in culture and in solid tumors; and (3). Determine the efficacy of Hsp47-binding peptides and Hsp47 monoclonal antibodies in homing chemotherapeutic drugs to tumor sites in oral squamous carcinoma xenografts. To accomplish these aims we have assembled a collaborative team of pathologists, molecular biologists, oncologists, and experts in developmental therapeutics that encompass the University of Maryland's Schools of Dentistry, Medicine and The Greenbaum Cancer Center. The ultimate success of this proposal will be determined by the impact that such an approach has on reducing the morbidity and mortality of oral cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
3R01DE013118-02S1
Application #
6464745
Study Section
Oral Biology and Medicine Subcommittee 1 (OBM)
Program Officer
Shirazi, Yasaman
Project Start
2000-04-01
Project End
2003-03-31
Budget Start
2001-06-01
Budget End
2002-03-31
Support Year
2
Fiscal Year
2001
Total Cost
$58,410
Indirect Cost
Name
University of Maryland Baltimore
Department
Dentistry
Type
Schools of Dentistry
DUNS #
003255213
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Nikitakis, Nikolaos G; Scheper, Mark A; Papanikolaou, Vasileios S et al. (2009) The oncogenic effects of constitutive Stat3 signaling in salivary gland cancer cells are mediated by survivin and modulated by the NSAID sulindac. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 107:826-36
Nikitakis, Nikolaos G; Scheper, Mark A; Papanikolaou, Vasileios S et al. (2009) Immunohistochemical expression of the oncogenic molecules active Stat3 and survivin in benign and malignant salivary gland tumors. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 107:837-43
Scheper, M A; Nikitakis, N G; Sauk, J J (2007) Survivin is a downstream target and effector of sulindac-sensitive oncogenic Stat3 signalling in head and neck cancer. Int J Oral Maxillofac Surg 36:632-9
Scheper, Mark A; Nikitakis, Nikolaos G; Chaisuparat, Risa et al. (2007) Sulindac induces apoptosis and inhibits tumor growth in vivo in head and neck squamous cell carcinoma. Neoplasia 9:192-9
Hebert, Carla; Norris, Kathleen; Parashar, Pallavi et al. (2006) Hypoxia-inducible factor-1alpha polymorphisms and TSC1/2 mutations are complementary in head and neck cancers. Mol Cancer 5:3
Scheper, Mark A; Sauk, John J; Nikitakis, Nikolaos G (2006) COX-independent antineoplastic effects of sulindac in oral cancer are mediated by survivin down-regulation. Anticancer Res 26:4103-13
Nan, Anjan; Ghandehari, Hamidreza; Hebert, Carla et al. (2005) Water-soluble polymers for targeted drug delivery to human squamous carcinoma of head and neck. J Drug Target 13:189-97
Siavash, H; Nikitakis, N G; Sauk, J J (2004) Abrogation of IL-6-mediated JAK signalling by the cyclopentenone prostaglandin 15d-PGJ(2) in oral squamous carcinoma cells. Br J Cancer 91:1074-80
Nikitakis, N G; Siavash, H; Sauk, J J (2004) Targeting the STAT pathway in head and neck cancer: recent advances and future prospects. Curr Cancer Drug Targets 4:637-51
Siavash, Hessam; Nikitakis, Nikolaos G; Sauk, John J (2004) Targeting of epidermal growth factor receptor by cyclopentenone prostaglandin 15-Deoxy-Delta12,14-prostaglandin J2 in human oral squamous carcinoma cells. Cancer Lett 211:97-103

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