Oral Cancer

Dr. Chan’s interests in cancer research started with studies in the diversity of the autoantibody responses in cancer during his tenure at the Scripps Research Institute, La Jolla, CA. His laboratory cloned many autoantigens, including CIP2A (or p90), which was identified later as a highly important inhibitor of PP2A in oral cancer through collaboration with Dr. Jukka Westermarck in Finland (Cell. 2007; 130:51-62).

Since joining the University of Florida, his lab has worked on head and neck and oral cancers. In 2018, 51,540 new cases and 10,030 deaths from oral cavity and pharynx cancer were expected in the United States. In Florida, cancer of the oral cavity and pharynx is one of two cancers (other being cancer of the cervix) that have both higher incidence and mortality rates than the national average. There is clearly a need to improve the diagnosis and treatment of oral cancer as it represents a significant burden to society.

MolCa Grapic Abstract

The lab has a record of accomplishment in the analysis of oral tumors. They have shown that high expression of miR-21 is a major factor related to the poor prognosis of patients, and that miR-7 and miR-21 are both upregulated in oral cancer and negatively regulate the tumor suppressor gene RECK (J Biol Chem. 2012; 287:29261-72). On the other hand, miR-375 is a key tumor suppressor miRNA that is underexpressed in oral cancer. The lab has demonstrated that miR-375 regulates a number of important genes, including CIP2A, E6AP, 14-3-3ζ, and HPV viral proteins E6 and E7 (Mol Cancer. 2014; 13:80). More importantly, they have established and published a mouse model of oral cancer that can be used to test for efficacy of therapies (Genes Chromosomes Cancer. 2010; 49:549-59). miR-375 is clearly a prominent tumor suppressor miRNA in oral cancer (Mol Biol Cell. 2013; 24:1638-48, S1-7) as well as in other cancers (Cancer Lett. 2018; 438:126-32). More interestingly, miR-375 has been identified as a biomarker for malignant transformation in oral lesions (Oral Surg Oral Med Oral Pathol Oral Radiol. 2016; 122:743-52.e1).

 

CAR-T Therapy schematicThe current focus is the development of chimeric antigen receptor-T cell (CAR-T)-based immunotherapy for oral cancer and an in vitro demonstration of feasibility was published last year (Oral Oncol. 2018; 78:145-50). There is ongoing testing of anti-CD70 CAR-T in a mouse xenograft model using human tumor cells implanted into the flank of NSG mice, which are genetically designed to be immunodeficient and able to accept these tumors. Additional tumor models have been developed using tumor cells injected into the tongue to examine the effect of CAR-T cell delivery in different tumor environments.

This work is supported in part by funding from the Andrew J. Semesco Foundation, Ocala, FL.

Publications

Harrandah AM, Mora RA, and Chan EKL. Emerging microRNAs in cancer diagnosis, progression, and immune surveillance. Cancer Lett. 2018; 438:126-132.

Park YP, Jin L, Bennett KB, Wang D, Fredenburg KM, Tseng JE, Chang LJ, Huang J, and Chan EKL. CD70 as a target for chimeric antigen receptor T cells in head and neck squamous cell carcinoma. Oral Oncol. 2018; 78:145-150.

Harrandah, A., Fitzpatrick, S.G., Smith, M.H., Wang, D., Cohen, D.M., and Chan, E.K. MicroRNA-375 as a Biomarker for Malignant Transformation in Oral Lesions. Oral Surg Oral Med Oral Pathol Oral Radiol. 2016; 122(6):743-752.e1.

Jung, H.M., Benarroch, Y., and Chan, E.K. Anti-cancer drugs reactivate tumor suppressor miR-375 expression in tongue cancer cells. J Cell Biochem. 2015; 116:836-43.

Libório-Kimura, T.N., Jung, H.M., and Chan, E.K. miR-494 represses HOXA10 expression and inhibits cell proliferation in oral cancer. Oral Oncol. 2015; 51:151-7.

Jung, H.M., Phillips, B.L., and Chan, E.K. miR-375 activates p21 and suppresses telomerase activity by coordinately regulating HPV E6/E7, E6AP, CIP2A, and 14-3-3ζ. Mol Cancer. 2014; 13:80.

Jung, H.M., Patel, R.S., Phillips, B.L., Wang, H., Cohen, D.M., Reinhold, W.C., Chang, L.J., Yang, L.J., and Chan, E.K. Tumor suppressor miR-375 regulates MYC expression via repression of CIP2A coding sequence through multiple miRNA-mRNA interaction. Mol Biol Cell. 2013; 24:1638-48.

Jung, H.M., Phillips, B.L., Patel, R.S., Cohen, D.M., Jakymiw, A., Kong, W.W., Cheng, J.Q., and Chan, E.K. Keratinization-associated miR-7 and miR-21 regulate tumor suppressor reversion-inducing-cysteine-rich protein with kazal motifs (RECK) in oral cancer. J Biol Chem. 2012; 287:29261-72.

Patel, R.S., Jakymiw, A., Yao, B., Pauley, B.A., Carcamo, W.C., Katz, J., Cheng, J.Q., and Chan, E.K. High resolution of microRNA signatures in human whole saliva. Arch. Oral Biol. 2011; 56:1506-13.

Jakymiw A, Patel RS, Deming N, Bhattacharyya I, Shah P, Lamont RJ, Stewart CM, Cohen DM, and Chan EKL. Overexpression of dicer as a result of reduced let-7 MicroRNA levels contributes to increased cell proliferation of oral cancer cells. Genes Chromosomes Cancer. 2010; 49:549-59.