Training
B.A., University of Vermont, Zoology 1987
Ph.D., University of Vermont, Cell Biology/ Pharmacology, 1994
Postdoctoral Associate, University of Arizona, 1995-1997
Postdoctoral Associate, Moffitt Cancer Center, 1997-1999

Research Interests
Dr. Hazlehurst's laboratory research interests are in the area of delineating mechanisms of de-novo drug resistance associated with anthracyclines and anthracenediones. Anthracylines and anthracenediones, remain a mainstay for the treatment of many tumor types including AML and multiple myeloma. The mechanism of action of these drugs involves intercalation between DNA base pairs resulting in the covalent trapping of topoisomerase (topo) II. Although most patients enter a remission following induction chemotherapy with these agents, the presence of minimal residual disease (MRD) results in recurrent disease, which is often, is resistant to most forms of therapy. We propose that the tumor microenvironment directly impacts failure to eliminate MRD following chemotherapy and facilitates the emergence of clinical drug resistance. Resistance to this class of drugs includes quantitative and qualitative changes in topo II, overexpression of drug transporters such as BCRP and Pgp, and defects in the apoptotic machinery. However, drug resistant mechanisms traditionally have been identified in unicellular acquired drug resistant models and it is unclear if these mechanisms contribute to MRD. Recently, we showed that cell adhesion mediated by b1 integrins confers resistance to anthracenediones and anthracyclines. Moreover, drug resistance correlated with reduced drug-induced DNA damage and alterations in the pool of Topo IIb as measured by a decrease in salt extractability of the enzyme. Currently, we are determining whether post-translational modifications such as sumoylation, phosphorylation or ribosylation of topo II contribute to adhesion-mediated alterations in the nuclear trafficking of topo IIb and decreased drug-induced DNA damage. The second focus of our laboratory is determining the role of topo IIb in mediating the repair of interstrand DNA crosslinks induced by crosslinking agents. We recently showed that cells lines, which contain reduced levels of topo IIb are hypersensitive to crosslinking agents. We are currently investigating whether topo IIb is an active participant in the fanconi anemia/BRCA1 DNA repair pathway.

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Selected Publications
1. Krapcho A.P, Maresch MJ, Hacker MP, Hazlehurst L et al. Anthracene-9-10-Diones and aza bioiosteres as anititumor agents. Current Medicinal Chemistry 2:803-824, 1995.

2. Hazlehurst LA, Krapcho AP and Hacker MP: Correlation of DNA reactivity and cytotoxicity of a new class of anticancer agents: aza-anthracenediones. Cancer Letters 91(1):115-24, 1995.
Hazlehurst LA, Krapcho AP, and Hacker MP: Comparison of aza-anthracenedione-induced DNA damage and cytotoxicity in experimental tumor cells. Biochemical Pharmacology 50:1087-94, 1995.

3. Hazlehurst LA, Foley NE, Guzman-Gleason MC, Hacker MP, Cress AE, Greenberger LW, DeJong MC and Dalton WS. Multiple mechanisms confer drug resistance to mitoxantrone in the human 8226 myeloma cell line. Cancer Research 59: 1021-1028, 1999.

4. Hazlehurst LA, Damiano JS, Buyuksal I., Pledger WJ and Dalton WS. Adhesion to fibronectin via b1 integrins regulates p27kip1 levels and contributes to cell adhesion mediated drug resistance (CAM-DR) Oncogene: 19:4319-4327,2000.

5. Hazlehurst, LA, Valkov N., Wisner L., Storey JA, Boulware D, Sullivan DM, Dalton WS. Reduction in drug-induced DNA double strand-breaks associated with b1 integrin-mediated adhesion correlates with drug resistance in U937 leukemia cells Blood 98:1897-903, 2001.

6. Hazlehurst LA and Dalton WS. Mechanisms associated with Cell Adhesion Mediated Drug Resistance (CAM-DR) in hematopoietic malignancies. Cancer and Metastasis Reviews 20:43-50, 2001.

7. Hazlehurst LA, Landowski TH, Dalton WS: The role of the microenvironment in mediating drug resistance Oncogene, 22:7396-402, 2003.

8. Hazlehurst LA , Enkemann SA, Bean CA, Argilagos RF, Painter J, Shain KH, Saporta S, Boulware L, Moscinski M, Alsina M Dalton, WS. Genotypic and phenotypic comparisons of de-novo and acquired melphalan resistance in an isogenic multiple myeloma cell line model. Cancer Research 63:7900-7906, 2003.

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Cancer Biology Ph.D. Program
H. Lee Moffitt Cancer Center, MRC-4 East
12902 Magnolia Drive
Tampa, Florida 33612
Phone: 813-745-6876
E-mail: CancerPHD@moffitt.org
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