Last Updated: 3/25/2009

Clinical Interests

Tumor hypoxia as it relates to therapy.

Research Interests
My research is focused on tumor hypoxia and its relationship to therapy resistance and overall tumor aggressiveness. A key tool for the studies is our immunochemical assay for tissue hypoxia. The assay was invented in my laboratory and translated from the lab to the clinic in the Department of Radiation Oncology in collaboration with my physician colleague, Dr. Mahesh Varia. Early work involved key collaborators at the College of Veterinary Medicine at North Carolina State University and, at NPI, Incorporated a small company that has worked with me to provide the hypoxia marker on a scale suitable for clinical use. Our hypoxia marker technique is now being used as an investigational tool in laboratories and clinics in the US, Canada, Europe and Asia.

Tumor hypoxia is associated with chemo- and radiotherapy resistance but also with overall tumor aggressiveness independent of treatment protocol. Aggressiveness is manifested by an increased probability of regional invasion and distant spread. The mechanisms underlying therapy resistance are fairly well understood but the mechanisms underlying tumor aggressiveness are not yet clear. Our marker approach has opened up new ways of addressing the question.

My own studies concentrate on the relationship of tumor hypoxia to oxygen regulated protein expression in cervix and head and neck squamous cell carcinomas and in breast carcinomas on the basis that proteins such as VEGF and metallothionein could contribute to both therapy resistance and tumor aggressiveness. It was during these studies that we made the important discovery that the majority of hypoxic cells express a cell marker for differentiation. We have now shown that AP-1 dependent markers for differentiation are oxygen regulated proteins. This has major implications for understanding gene expression in human tumors and the impact that this has on cancer therapy and diagnosis.

Recent Accomplishments and Honors
1. A major accomplishment of the past few years has been the translation of my immunohistochemical hypoxia marker assay into clinical use. It involved carrying out preclinical testing in the clinical setting of the Veterinary Hospital at North Carolina State University; obtaining funding for clinical studies; making the marker available on a large scale for clinical use; obtaining FDA IND clearance; testing the marker for clinical efficacy and safety; and, providing the marker to clinical investigators in Canada and Europe for independent validation of the assay. Well over 800 patients are now in clinical trials around the world.

2. In a pilot collaborative study with Dutch investigators, the hypoxia marker predicted for outcome for patients receiving radiation therapy and, in addition, demonstrated that an intervention designed to remove tumor hypoxia during radiation treatment actually achieved its goal (Kaanders et al, 2002). A multicenter prospective trial designed to test the result of the pilot study was opened for analysis in 2008.

3. We have discovered that the majority of hypoxic cells in squamous cell carcinomas express a marker for terminal differentiation and have demonstrated how this affects the expression of oxygen regulated proteins in these tumors. This discovery is of fundamental importance to understanding the control of gene expression in squamous cell carcinomas. It also has treatment planning implications for conventional radiation treatment and more novel approaches such as gene therapy.

4. I served as Principal Investigator for a multicenter, international clinical test of the relationship between hypoxia marking binding and oxygen electrode measurements of hypoxia in squamous cell carcinomas of the uterine cervix (Nordsmark et al, 2003 and 2006). The results have raised interesting questions about the relationship between these two ways of measuring tissue hypoxia and their relationship to prognosis (Nordsmark et al 2006).

5. In the last five years, I have authored or co-authored 29 peer-reviewed manuscripts in which our hypoxia marker has been used to investigate the role of hypoxia in tumor therapy; tumor biology including endogenous hypoxia markers; bone remodeling; wound healing; embryogenesis; hepatic pathology; renal pathology; pancreatic pathology; and, therapy resistance of tuberculosis bacteria in lung.

Publications
Hypoxia and vascular endothelial growth factor protein expression in human tumors. Raleigh, JA, Calkins-Adams, DP, Rinker, LH, Ballenger, CA, Weissler, MC, Fowler, Jr, WC, Novotny, DB and Varia, MA. Cancer Res. 58: 3765-3768, 1998.

A clinical study of hypoxia and metallothionein protein expression in squamous cell carcinomas. Raleigh, JA, Chou, S-C, Calkins-Adams, DP, Ballenger, CA, Rinker, LH, Novotny, DB, and Varia, MA. Cl. Cancer Res. 6: 855-862, 2000.

Pimonidazole binding and tumor vascularity predict for treatment outcome in head and neck cancer. Kaanders JH, Wijffels KI, Marres HA, Ljungkvist AS, Pop LA, van den Hoogen FJ, de Wilde PC, Bussink J, Raleigh JA and van der Kogel AJ. Cancer Res. 62: 7066-7074, 2002.

GLUT-1 and CAIX as intrinsic markers of hypoxia in carcinoma of the cervix. Relationship to pimonidazole binding. Airley RE, Loncaster J, Raleigh J, Harris AL, Davidson SE, Hunter RD, Catharine M L West CML and Stratford IJ. Int. J. Cancer, 104: 85-91, 2003.

Measurements of hypoxia using pimonidazole and polarographic oxygen-sensitive electrodes in human cervix carcinomas.
Nordsmark M, Loncaster J, Aquino-Parsons C, Chou S-C, Ladekarl M, Havsteen H, Lindegaard JC, Davidson SE, Varia M, West C, Hunter R, Overgaard J and Raleigh JA. Radiother. Oncol. 67: 35-44, 2003.

Hypoxia and differentiation in squamous cell carcinomas of the uterine cervix: pimonidazole and involucrin. Azuma, Y, Chou, S-C, Lininger, R, Murphy, BJ, Varia, MA and Raleigh, JA. Cl. Cancer Res. 9: 4944-4952, 2003.

Evidence that involucrin, a marker for differentiation, is oxygen regulated in human squamous cell carcinomas. Chou S-C, Azuma Y, Varia MA and Raleigh JA. Br. J. Cancer 90: 728-735, 2004.

Erythropoietin and erythropoietin receptor expression in head and neck cancer: relationship to tumor hypoxia. Arcasoy, M. O., Amin, K., Chou, S. C., Haroon, Z. A., Varia, M., and Raleigh, J. A. Clin Cancer Res, 11: 20-27, 2005.

Hypoxic cell turnover in different solid tumor lines. Int J Radiat Oncol Biol Phys, 62: 1157-1168, 2005. Ljungkvist, A.S., Bussink, J., Kaanders, J. H., Rijken, P. F., Begg, A. C., Raleigh, J. A., and van der Kogel, A. J.

Comparison between pimonidazole binding, oxygen electrode measurements, and expression of endogenous hypoxia markers in cancer of the uterine cervix. Cytometry B Clin Cytom, 70: 45-55. 2006. Jankovic, B., Aquino-Parsons, C., Raleigh, J. A., Stanbridge, E. J., Durand, R. E., Banath, J. P., Macphail, S. H., and Olive, P. L.

A comparison of oral and intravenous pimonidazole in canine tumors using intravenous CCI-103F as a control hypoxia marker. Int J Radiat Oncol Biol Phys, 64: 592-602, 2006. Kleiter, M. M., Thrall, D. E., Malarkey, D. E., Ji, X., Lee, D. Y., Chou, S. C., and Raleigh, J. A.

The prognostic value of pimonidazole & tumour pO2 in human cervix carcinomas after radiation therapy: A prospective international multi-center study. Radiother Oncol. 80: 123-131, 2006. Nordsmark, M., Loncaster, J., Aquino-Parsons, C., Chou, S-C., Gebski, V., West, C., Lindegaard, J.C., Havsteen, H., Davidson, S.E., Hunter, R., Raleigh, J.A. and Overgaard, J.

Pimonidazole labelling and response to fractionated irradiation of five human squamous cell carcinoma (hSCC) cell lines in nude mice: the need for a multivariate approach in biomarker studies. Radiother Oncol. 81:122-129, 2006. Yaromina, A., Zips, D., Thames, H.D., Eicheler, W., Krause, M., Rosner, A., Haase, M., Petersen, C., Raleigh, J.A., Quennet, V., Walenta, S., Müller-Klieser,W. and Baumann, M.

Tuberculous granulomas are hypoxic in guinea pigs, rabbits, and non-human primates. Infect Immun, 76(6): 2333-2340, 2008. Via, L. E., Lin, P. L., Ray, S. M., Carrillo, J., Allen, S. S., Eum, S. Y., Taylor, K., Klein, E., Manujantha, U., Gonzales, J., Lee, E. G., Park, S. K., Raleigh, J. A., Cho, S. N., McMurray, D. N., Flynn, J. L., and Barry, C. E., 3rd.

E-mail: james_raleigh@med.unc.edu
Telephone: (919) 260 6398
FAX: (919) 933 9216
Address: Radiation Oncology, UNC School of Medicine CB# 7512 Chapel Hill, NC 27599-7512
URL: http://www.hypoxyprobe.com

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