Photo of Jose A. Halperin,  MD

Jose A. Halperin, MD

Harvard Medical School

Harvard Medical School
Phone: (617) 621-6136
Fax: (617) 621-6148


jose_halperin@hms.harvard.edu

Jose A. Halperin, MD

Harvard Medical School

EDUCATIONAL TITLES

  • Associate Professor, Medicine, Harvard Medical School

DF/HCC PROGRAM AFFILIATION

Research Abstract

My cancer research originated with the discovery of the anticancer effect of the anti-fungal drug clotrimazole (CLT). I found that CLT has a dual effect on intracellular calcium: it releases clacium from internal stores and closes restorative calcium influx. The resulting partial depletion of internal calcium activates the enzyme PKR, which phosphorylates and thereby inhibits eukaryotic initiation factor 2, the first step in mRNA translation initiation. In this manner, CLT inhibits translation initiation and synthesis of a subset of proteins that includes cyclin D1 and E, and stops cell cycle progression in the G1. My identification of the pharmacophore responsible for this anti-cancer effect of CLT has led to the rational design of analogs that are more potent and less toxic inhibitors of translation initiation.

My laboratory's most recent finding is that the n-3 unsaturated fatty acid EPA as well as thiazoinianones (TZDs) have anti-cancer effects that are mediated by inhibition of translation initiation in a manner almost identical to the effect of CLT. This is potentially important because epidemiological studies have shown that populations eating fish diets rich in EPA exhibit a very low incidence of cnacer, and the TZDs have already been tested in clinical trials for human cancers.

In summary, my cancer research has led to the uncovering of translation initiation as a valid target for anticancer drugs and to the discovery of new inhibitors of translation initiation soon to be tested in humans.

Publications

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  • Aktas BH, Bordelois P, Peker S, Merajver S, Halperin JA. Depletion of eIF2.GTP.Met-tRNAi translation initiation complex up-regulates BRCA1 expression in vitro and in vivo. 2015. PubMed
  • Papadopoulos E, Jenni S, Kabha E, Takrouri KJ, Yi T, Salvi N, Luna RE, Gavathiotis E, Mahalingam P, Arthanari H, Rodriguez-Mias R, Yefidoff-Freedman R, Aktas BH, Chorev M, Halperin JA, Wagner G. Structure of the eukaryotic translation initiation factor eIF4E in complex with 4EGI-1 reveals an allosteric mechanism for dissociating eIF4G. Proc Natl Acad Sci U S A 2014; 111:E3187-95. PubMed
  • Mahalingam P, Takrouri K, Chen T, Sahoo R, Papadopoulos E, Chen L, Wagner G, Aktas BH, Halperin JA, Chorev M. Synthesis of Rigidified eIF4E/eIF4G Inhibitor-1 (4EGI-1) Mimetic and Their in Vitro Characterization as Inhibitors of Protein-Protein Interaction. J Med Chem 2014. PubMed
  • Takrouri K, Chen T, Papadopoulos E, Sahoo R, Kabha E, Chen H, Cantel S, Wagner G, Halperin JA, Aktas BH, Chorev M. Structure-activity relationship study of 4EGI-1, small molecule eIF4E/eIF4G protein-protein interaction inhibitors. Eur J Med Chem 2014; 77:361-77. PubMed
  • Yefidoff-Freedman R, Chen T, Sahoo R, Chen L, Wagner G, Halperin JA, Aktas BH, Chorev M. 3-substituted indazoles as configurationally locked 4EGI-1 mimetics and inhibitors of the eIF4E/eIF4G interaction. Chembiochem 2014; 15:595-611. PubMed
  • Denoyelle S, Chen T, Yang H, Chen L, Zhang Y, Halperin JA, Aktas BH, Chorev M. Synthesis and SAR study of novel 3,3-diphenyl-1,3-dihydroindol-2-one derivatives as potent eIF2揃GTP揃Met-tRNAiMet ternary complex inhibitors. Eur J Med Chem 2013; 69:537-53. PubMed
  • Aktas BH, Qiao Y, Ozdelen E, Schubert R, Sevinc S, Harbinski F, Grubissich L, Singer S, Halperin JA. Small-Molecule targeting of translation initiation for cancer therapy. 2013; 4:1606-17. PubMed
  • Chen L, Aktas BH, Wang Y, He X, Sahoo R, Zhang N, Denoyelle S, Kabha E, Yang H, Freedman RY, Supko JG, Chorev M, Wagner G, Halperin JA. Tumor suppression by small molecule inhibitors of translation initiation. 2012; 3:869-81. PubMed
  • Hu W, Ge X, You T, Xu T, Zhang J, Wu G, Peng Z, Chorev M, Aktas BH, Halperin JA, Brown JR, Qin X. Human CD59 Inhibitor Sensitizes Rituximab-Resistant Lymphoma Cells to Complement-Mediated Cytolysis. Cancer Res 2011; 71:2298-307. PubMed
  • Wu G, Chen T, Shahsafaei A, Hu W, Bronson RT, Shi GP, Halperin JA, Aktas H, Qin X. Complement Regulator CD59 Protects Against Angiotensin II-Induced Abdominal Aortic Aneurysms in Mice. Circulation 2010; 121:1338-46. PubMed
  • Hu W, Yu Q, Hu N, Byrd D, Amet T, Shikuma C, Shiramizu B, Halperin JA, Qin X. A high-affinity inhibitor of human CD59 enhances complement-mediated virolysis of HIV-1: implications for treatment of HIV-1/AIDS. J Immunol 2009; 184:359-68. PubMed
  • Qin X,Hu W,Song W,Blair P,Wu G,Hu X,Song Y,Bauer S,Feelisch M,Leopold JA,Loscalzo J,Halperin JA. Balancing role of nitric oxide in complement-mediated activation of platelets from mCd59a and mCd59b double-knockout mice. Am J Hematol 2009; 84:221-7. PubMed
  • Wu G,Hu W,Shahsafaei A,Song W,Dobarro M,Sukhova GK,Bronson RR,Shi GP,Rother RP,Halperin JA,Qin X. Complement regulator CD59 protects against atherosclerosis by restricting the formation of complement membrane attack complex. Circ Res 2009; 104:550-8. PubMed
  • Qin X,Hu W,Song W,Grubissich L,Hu X,Wu G,Ferris S,Dobarro M,Halperin JA. Generation and phenotyping of mCd59a and mCd59b double-knockout mice. Am J Hematol 2008; 84:65-70. PubMed
  • Carganico S,Rovero P,Halperin JA,Papini AM,Chorev M. Building blocks for the synthesis of post-translationally modified glycated peptides and proteins. J Pept Sci 2008; 15:67-71. PubMed
  • Cantel S,Halperin JA,Chorev M,Scrima M,D'Ursi AM,Levy JJ,DiMarchi RD,Le Chevalier A,Rovero P,Papini AM. Side chain-to-side chain cyclization by intramolecular click reaction--building blocks, solid phase synthesis and conformational characterization. Adv Exp Med Biol 2009; 611:175-6. PubMed
  • Cantel S,Isaad Ale C,Scrima M,Levy JJ,DiMarchi RD,Rovero P,Halperin JA,D'Ursi AM,Papini AM,Chorev M. Synthesis and conformational analysis of a cyclic peptide obtained via i to i+4 intramolecular side-chain to side-chain azide-alkyne 1,3-dipolar cycloaddition. J Org Chem 2008; 73:5663-74. PubMed
  • Hu W, Ferris SP, Tweten RK, Wu G, Radaeva S, Gao B, Bronson RT, Halperin JA, Qin X. Rapid conditional targeted ablation of cells expressing human CD59 in transgenic mice by intermedilysin. Nat Med 2007; 14:98-103. PubMed
  • Hyberts SG, Heffron GJ, Tarragona NG, Solanky K, Edmonds KA, Luithardt H, Fejzo J, Chorev M, Aktas H, Colson K, Falchuk KH, Halperin JA, Wagner G. Ultrahigh-resolution (1)H-(13)C HSQC spectra of metabolite mixtures using nonlinear sampling and forward maximum entropy reconstruction. J Am Chem Soc 2007; 129:5108-16. PubMed
  • Moerke NJ, Aktas H, Chen H, Cantel S, Reibarkh MY, Fahmy A, Gross JD, Degterev A, Yuan J, Chorev M, Halperin JA, Wagner G. Small-molecule inhibition of the interaction between the translation initiation factors eIF4E and eIF4G. Cell 2007; 128:257-67. PubMed
  • Qin X, Dobarro M, Bedford SJ, Ferris S, Miranda PV, Song W, Bronson RT, Visconti PE, Halperin JA. Further characterization of reproductive abnormalities in mCd59b knockout mice: a potential new function of mCd59 in male reproduction. J Immunol 2005; 175:6294-302. PubMed
  • Halperin AC, Rigotti NA. US public universities' compliance with recommended tobacco-control policies. J Am Coll Health 2003; 51:181-8. PubMed
  • Palakurthi SS, Aktas H, Grubissich LM, Mortensen RM, Halperin JA. Anticancer effects of thiazolidinediones are independent of peroxisome proliferator-activated receptor gamma and mediated by inhibition of translation initiation. Cancer Res 2001; 61:6213-8. PubMed
  • Qin X, Miwa T, Aktas H, Gao M, Lee C, Qian YM, Morton CC, Shahsafaei A, Song WC, Halperin JA. Genomic structure, functional comparison, and tissue distribution of mouse Cd59a and Cd59b. Mamm Genome 2001; 12:582-9. PubMed
  • Qian YM, Qin X, Miwa T, Sun X, Halperin JA, Song WC. Identification and functional characterization of a new gene encoding the mouse terminal complement inhibitor CD59. J Immunol 2000; 165:2528-34. PubMed
  • Palakurthi SS, Fl. Inhibition of translation initiation mediates the anticancer effect of the n-3 polyunsaturated fatty acid eicosapentaenoic acid. Cancer Res 2000; 60:2919-25. PubMed
  • Acosta J, Hettinga J, Fl. Molecular basis for a link between complement and the vascular complications of diabetes. Proc Natl Acad Sci U S A 2000; 97:5450-5. PubMed
  • Aktas H, Fl. Depletion of intracellular Ca2+ stores, phosphorylation of eIF2alpha, and sustained inhibition of translation initiation mediate the anticancer effects of clotrimazole. Proc Natl Acad Sci U S A 1998; 95:8280-5. PubMed
  • Shen Y, Halperin JA, Benzaquen L, Lee CM. Characterization of neuronal cell death induced by complement activation. Brain Res Brain Res Protoc 1997; 1:186-94. PubMed
  • Acosta JA, Benzaquen LR, Goldstein DJ, Tosteson MT, Halperin JA. The transient pore formed by homologous terminal complement complexes functions as a bidirectional route for the transport of autocrine and paracrine signals across human cell membranes. Mol Med 1996; 2:755-65. PubMed
  • Benzaquen LR, Brugnara C, Byers HR, Gatton-Celli S, Halperin JA. Clotrimazole inhibits cell proliferation in vitro and in vivo. Nat Med 1995; 1:534-40. PubMed
  • Shen Y, Halperin JA, Lee CM. Complement-mediated neurotoxicity is regulated by homologous restriction. Brain Res 1995; 671:282-92. PubMed
  • Benzaquen LR, Nicholson-Weller A, Halperin JA. Terminal complement proteins C5b-9 release basic fibroblast growth factor and platelet-derived growth factor from endothelial cells. J Exp Med 1994; 179:985-92. PubMed
  • Berger HJ, Taratuska A, Smith TW, Halperin JA. Activated complement directly modifies the performance of isolated heart muscle cells from guinea pig and rat. Am J Physiol 1993; 265:H267-72. PubMed
  • Halperin JA, Taratuska A, Nicholson-Weller A. Terminal complement complex C5b-9 stimulates mitogenesis in 3T3 cells. J Clin Invest 1993; 91:1974-8. PubMed
  • Halperin JA, Taratuska A, Rynkiewicz M, Nicholson-Weller A. Transient changes in erythrocyte membrane permeability are induced by sublytic amounts of the complement membrane attack complex (C5b-9). Blood 1993; 81:200-5. PubMed
  • Nicholson-Weller A, Halperin JA. Membrane signaling by complement C5b-9, the membrane attack complex. Immunol Res 1993; 12:244-57. PubMed
  • Halperin JA, Cornelius F. A voltage-activated cation transport pathway associated with the sodium pump. Biochim Biophys Acta 1991; 1070:497-500. PubMed
  • Tosteson MT, Halperin JA, Kishi Y, Tosteson DC. Palytoxin induces an increase in the cation conductance of red cells. J Gen Physiol 1991; 98:969-85. PubMed
  • Halperin JA, Brugnara C, Van Ha T, Tosteson DC. Voltage-activated cation permeability in high-potassium but not low-potassium red blood cells. Am J Physiol 1990; 258:C1169-72. PubMed
  • Lorenzo AV, Taratuska A, Halperin JA. Suppression of cerebrospinal fluid (CSF) production by a Na+/K+ pump inhibitor extracted from human cerebrospinal fluid. Z Kinderchir 1989; 44 Suppl 1:24-6. PubMed
  • Halperin JA, Brugnara C, Tosteson MT, Van Ha T, Tosteson DC. Voltage-activated cation transport in human erythrocytes. Am J Physiol 1989; 257:C986-96. PubMed
  • Halperin JA, Brugnara C, Nicholson-Weller A. Ca2+-activated K+ efflux limits complement-mediated lysis of human erythrocytes. J Clin Invest 1989; 83:1466-71. PubMed
  • Halperin JA. Digitalis-like properties of an inhibitor of the Na+/K+ pump in human cerebrospinal fluid. J Neurol Sci 1989; 90:217-30. PubMed
  • Nicholson-Weller A, Halperin JA. Mechanisms by which the erythrocyte protects itself from complement damage. Prog Clin Biol Res 1988; 297:263-70; discussion 270-1. PubMed
  • Halperin JA, Nicholson-Weller A. Paroxysmal nocturnal hemoglobinuria. A complement-mediated disease. Complement Inflamm 1988; 6:65-72. PubMed
  • Halperin JA, Nicholson-Weller A, Brugnara C, Tosteson DC. Complement induces a transient increase in membrane permeability in unlysed erythrocytes. J Clin Invest 1988; 82:594-600. PubMed
  • Halperin JA, Riordan JF, Tosteson DC. Characteristics of an inhibitor of the Na+/K+ pump in human cerebrospinal fluid. J Biol Chem 1988; 263:646-51. PubMed
  • Halperin JA, Brugnara C, Kopin AS, Ingwall J, Tosteson DC. Properties of the Na+-K+ pump in human red cells with increased number of pump sites. J Clin Invest 1987; 80:128-37. PubMed
  • Halperin JA, Lobb RR. Effect of heparin-binding growth factors on monovalent cation transport in Balb/C 3T3 cells. Biochem Biophys Res Commun 1987; 144:115-22. PubMed
  • Halperin JA, Martin AM, Malave S. Increased digitalis-like activity in human cerebrospinal fluid after expansion of the extracellular fluid volume. Life Sci 1985; 37:561-6. PubMed
  • Halperín J, Schaeffer R, Galvez L, Malavé S. Ouabain-like activity in human cerebrospinal fluid. Proc Natl Acad Sci U S A 1983; 80:6101-4. PubMed
  • Goldstein DJ, Marante Perez DJ, Gunst JP, Halperin JA. Prostaglandin E1 inhibits acute cell dehydration thirst. Pharmacol Biochem Behav 1979; 10:895-8. PubMed
  • Goldstein DJ, Halperin JA. Mast cell histamine and cell dehydration thirst. Nature 1977; 267:250-2. PubMed
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