Yogen  Saunthararajah,  MB, BCh

Yogen Saunthararajah, MB, BCh

Staff

Lerner Research Institute, 9500 Euclid Avenue, Cleveland, Ohio 44195
Phone: (216) 444-8170

 

We focus on characterizing and exploiting a fundamental and common distinction between normal and malignant self-replication, that enables selective termination of malignant but not normal self-replication even in cancers which have inactivated p53 and are resistant to chemotherapy. We identify rational molecular targets for this non-toxic oncotherapy paradigm and develop small molecule drugs to engage these targets. The same treatments can moreover trigger immune-recognition of cancers (convert tumors from ‘cold’ to ‘hot’) while sparing immune-effectors, and are therefore a rational platform for increasing the spectrum of responses to immune checkpoint blockade. An important co-focus of the Saunthararajah group is non-cytotoxic epigenetic induction of fetal hemoglobin, for sustainable, life-long disease modification of the beta-hemoglobinopathies.


Gu X, Saunthararajah Y. Cytoplasmic dislocation of NPM1 and PU.1 in NPM1-mutated leukaemia is obscured by paraformaldehyde fixation. Br J Haematol. 2020 May;189(3):578-581. doi: 10.1111/bjh.16545. Epub 2020 Feb 29. PubMed PMID: 32112392.

Awada H, Mahfouz RZ, Kishtagari A, Kuzmanovic T, Durrani J, Kerr CM, Patel BJ, Visconte V, Radivoyevitch T, Lichtin A, Carraway HE, Maciejewski JP, Saunthararajah Y. Extended experience with a non-cytotoxic DNMT1-targeting regimen of decitabine to treat myeloid malignancies. Br J Haematol. 2020 Mar;188(6):924-929. doi: 10.1111/bjh.16281. Epub 2019 Nov 17. PubMed PMID: 31736067; PubMed Central PMCID: PMC7154732.

Sergeeva O, Kepe V, Zhang Y, Miller-Atkins GA, Keynon JD, Iyer R, Sexton S, Awadallah A, Xin W, Saunthararajah Y, Chan ER, Lee Z. [(18)F] Clofarabine for PET Imaging of Hepatocellular Carcinoma. Cancers (Basel). 2019 Nov 7;11(11). pii: E1748. doi: 10.3390/cancers11111748. PubMed PMID: 31703407; PubMed Central PMCID: PMC6896045.

Saunthararajah Y. Targeting sickle cell disease root-cause pathophysiology with small molecules. Haematologica. 2019 Sep;104(9):1720-1730. doi: 10.3324/haematol.2018.207530. Epub 2019 Aug 8. Review. PubMed PMID: 31399526; PubMed Central PMCID: PMC6717594.

Velcheti V, Wong KK, Saunthararajah Y. EZH2 Inhibitors: Take It EZy, It Is All About Context. Cancer Discov. 2019 Apr;9(4):472-475. doi:10.1158/2159-8290.CD-19-0090. PubMed PMID: 30936220.

Banerjee S, Gusho E, Gaughan C, Dong B, Gu X, Holvey-Bates E, Talukdar M, Li Y, Weiss SR, Sicheri F, Saunthararajah Y, Stark GR, Silverman RH. OAS-RNase L innate immune pathway mediates the cytotoxicity of a DNA-demethylating drug. Proc Natl Acad Sci U S A. 2019 Mar 12;116(11):5071-5076. doi: 10.1073/pnas.1815071116. Epub 2019 Feb 27. PubMed PMID: 30814222; PubMed Central PMCID: PMC6421468.

Enane FO, Saunthararajah Y, Korc M. Differentiation therapy and the mechanisms that terminate cancer cell proliferation without harming normal cells. Cell Death Dis. 2018 Sep 6;9(9):912. doi: 10.1038/s41419-018-0919-9. PubMed PMID: 30190481; PubMed Central PMCID: PMC6127320.

Gu X, Ebrahem Q, Mahfouz RZ, Hasipek M, Enane F, Radivoyevitch T, Rapin N, Przychodzen B, Hu Z, Balusu R, Cotta CV, Wald D, Argueta C, Landesman Y, Martelli MP, Falini B, Carraway H, Porse BT, Maciejewski J, Jha BK, Saunthararajah Y. Leukemogenic nucleophosmin mutation disrupts the transcription factor hub that regulates granulomonocytic fates. J Clin Invest. 2018 Oct 1;128(10):4260-4279. doi: 10.1172/JCI97117. Epub 2018 Jul 17. PubMed PMID: 30015632; PubMed Central PMCID: PMC6159976.

Velcheti V, Schrump D, Saunthararajah Y. Ultimate Precision: Targeting Cancer but Not Normal Self-replication. Am Soc Clin Oncol Educ Book. 2018 May 23;38:950-963. doi: 10.1200/EDBK_199753. Review. PubMed PMID: 30231326.

Lavelle D, Engel JD, Saunthararajah Y. Fetal Hemoglobin Induction by Epigenetic Drugs. Semin Hematol. 2018 Apr;55(2):60-67. doi: 10.1053/j.seminhematol.2018.04.008. Epub 2018 Apr 22. Review. PubMed PMID: 29958562; PubMed Central PMCID: PMC6029722.

Saleh MFM, Saunthararajah Y. Severe pyoderma gangrenosum caused by myelodysplastic syndrome successfully treated with decitabine administered by a noncytotoxic regimen. Clin Case Rep. 2017 Oct 31;5(12):2025-2027. doi:10.1002/ccr3.1221. eCollection 2017 Dec. PubMed PMID: 29225849; PubMed Central PMCID: PMC5715603. 

Enane FO, Shuen WH, Gu X, Quteba E, Przychodzen B, Makishima H, Bodo J, Ng J, Chee CL, Ba R, Seng Koh L, Lim J, Cheong R, Teo M, Hu Z, Ng KP, Maciejewski J, Radivoyevitch T, Chung A, Ooi LL, Tan YM, Cheow PC, Chow P, Chan CY, Lim KH, Yerian L, Hsi E, Toh HC, Saunthararajah Y. GATA4 loss of function in liver cancer impedes precursor to hepatocyte transition. J Clin Invest. 2017 Sep 1;127(9):3527-3542. doi: 10.1172/JCI93488. Epub 2017 Jul 31. PubMed PMID: 28758902; PubMed Central PMCID: PMC5669578.

Molokie R, Lavelle D, Gowhari M, Pacini M, Krauz L, Hassan J, Ibanez V, Ruiz MA, Ng KP, Woost P, Radivoyevitch T, Pacelli D, Fada S, Rump M, Hsieh M, Tisdale JF, Jacobberger J, Phelps M, Engel JD, Saraf S, Hsu LL, Gordeuk V, DeSimone J, Saunthararajah Y. Oral tetrahydrouridine and decitabine for non-cytotoxic epigenetic gene regulation in sickle cell disease: A randomized phase 1 study. PLoS Med. 2017 Sep 7;14(9):e1002382. doi:10.1371/journal.pmed.1002382. eCollection 2017 Sep. PubMed PMID: 28880867; PubMed Central PMCID: MC5589090.

Daifuku R, Hu Z, Saunthararajah Y. 5-aza-2',2'-Difluoro Deoxycytidine (NUC013): A Novel Nucleoside DNA Methyl Transferase Inhibitor and Ribonucleotide Reductase Inhibitor for the Treatment of Cancer. Pharmaceuticals (Basel). 2017 Jul 20;10(3). pii: E65. doi:10.3390/ph10030065. PubMed PMID: 28726739; PubMed Central PMCID: PMC5620609.

Gu X, Hu Z, Ebrahem Q, Crabb JS, Mahfouz RZ, Radivoyevitch T, Crabb JW, Saunthararajah Y. Runx1 regulation of Pu.1 corepressor/coactivator exchange identifies specific molecular targets for leukemia differentiation therapy. Biol Chem. 2014 May 23;289(21):14881-95. doi: 10.1074/jbc.M114.562447. Epub 2014 Apr 2. PubMed PMID: 24695740; PubMed Central PMCID: PMC4031539.

Mahfouz RZ, Jankowska A, Ebrahem Q, Gu X, Visconte V, Tabarroki A, Terse P, Covey J, Chan K, Ling Y, Engelke KJ, Sekeres MA, Tiu R, Maciejewski J, Radivoyevitch T, Saunthararajah Y. Increased CDA expression/activity in males contributes to decreased cytidine analog half-life and likely contributes to worse outcomes with 5-azacytidine or decitabine therapy. Clin Cancer Res. 2013 Feb 15;19(4):938-48. doi: 10.1158/1078-0432.CCR-12-1722. Epub 2013 Jan 3. PubMed PMID: 23287564; PubMed Central PMCID: PMC3577958.

Hu Z, Gu X, Baraoidan K, Ibanez V, Sharma A, Kadkol S, Munker R, Ackerman S, Nucifora G, Saunthararajah Y. RUNX1 regulates corepressor interactions of PU.1. Blood. 2011 Jun 16;117(24):6498-508. doi: 10.1182/blood-2010-10-312512. Epub 2011 Apr 25. PubMed PMID: 21518930; PubMed Central PMCID: PMC3123020.

Ng KP, Ebrahem Q, Negrotto S, Mahfouz RZ, Link KA, Hu Z, Gu X, Advani A, Kalaycio M, Sobecks R, Sekeres M, Copelan E, Radivoyevitch T, Maciejewski J, Mulloy JC, Saunthararajah Y. p53 independent epigenetic-differentiation treatment in xenotransplant models of acute myeloid leukemia. Leukemia. 2011 Nov;25(11):1739-50. doi: 10.1038/leu.2011.159. Epub 2011 Jun 24. PubMed PMID: 21701495; PubMed Central PMCID: PMC3668642.

Hu Z, Negrotto S, Gu X, Mahfouz R, Ng KP, Ebrahem Q, Copelan E, Singh H, Maciejewski JP, Saunthararajah Y. Decitabine maintains hematopoietic precursor self-renewal by preventing repression of stem cell genes by a differentiation-inducing stimulus. Mol Cancer Ther. 2010 Jun;9(6):1536-43. doi: 10.1158/1535-7163.MCT-10-0191. Epub 2010 May 25. PubMed PMID: 20501800; PubMed Central PMCID: PMC2884053.

Saunthararajah Y. Decitabine and sickle cell disease: molecular therapy for a molecular disease. Pediatr Hematol Oncol. 2007 Oct-Nov;24(7):465-8. PubMed PMID: 17786782.


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