The primarily research focus of the Lazo Laboratory is on the mechanism of action and of resistance to novel and existing anticancer agents, particularly natural products, and on the fundamental biological role of protein tyrosine phosphatases.
We are currently studying small molecules that disrupt the interactions of the oncoprotein c-Myc with its partner Max to determine their usefulness as anticancer agents. We have developed a human tumor stem cell model that permits the interrogation of chemical libraries and small interference RNA libraries to identify compounds and pathways that control the survival of tumor stem cells. Similarly, we are studying small molecules and intracellular pathways that mitigate or enhance the toxic effects of radiation. Some of the high throughput approaches we use are broadly applicable to other pathological conditions including neurodegenerative diseases, such as Alzheimer’s, and neglected diseases, such as leishmaniasis.
A second major research project focuses on investigating how protein tyrosine phosphatases, such as mitogen-activated protein kinase phosphatases, Cdc25, and phosphatase of regenerating liver, control cell proliferation, migration, invasion, and survival using both molecular biological and pharmacological approaches and on applying chemical biological methodologies to the discovery of new chemical probes and potential therapeutics. We currently have developed the first phosphatase of regenerating liver knock out mouse model to investigate the role of this unique protein in tumorigenesis. We have discovered several potent and specific small molecule inhibitors of these protein phosphatases and are investigating their pharmacological properties.
Nakashima, M., and Lazo, J.S. Phosphatase of Regenerating Liver-1 promotes cell migration and invasion and regulates filamentous actin dynamics. J. Pharmacol. Exp. Ther. 334:627-33. 2010.
Guiguemde WA, Shelat AA, Bouck D, Duffy S, Crowther GJ, Davis PH, Smithson DC, Connelly M, Clark J, Zhu F, Jiménez-Díaz MB, Martinez MS, Wilson EB, Tripathi AK, Gut J, Sharlow ER, Bathurst I, El Mazouni F, Fowble JW, Forquer I, McGinley PL, Castro S, Angulo-Barturen I, Ferrer S, Rosenthal PJ, Derisi JL, Sullivan DJ, Lazo JS, Roos DS, Riscoe MK, Phillips MA, Rathod PK, Van Voorhis WC, Avery VM, Guy RK. Chemical genetics of Plasmodium falciparum. Nature. 465:311-315, 2010.
Thaker, N.G., Zhang, F., McDonald, P.R., Shun, T.Y., Lewen, M.D., Pollack, I.F., and Lazo, J.S. Identification of survival genes in human glioblastoma cells using siRNA screening. Mol Pharmacol. 76:1246-1255, 2009.
Molina, G., Vogt, A., Bakan, A., Dai, W., Queiroz de Oliveira, P., Smithgall, T., Bahar, I., Lazo, J.S., Day, B.W. and Tsang, MI. An allosteric inhibitor of Dusp6, identified by a transgenic zebrafish chemical screen, expands cardiac progenitors and heart size. Nature Chem Biol. 5: 680-687, 2009.
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