Takaomi SANDA

Targeted molecular therapy has yielded remarkable outcomes in certain cancers, but specific therapeutic targets remain elusive for many others. The primary focus of our laboratory is to understand the transcription factor abnormalities as therapeutic targets in cancer/leukemia, particularly T-cell acute lymphoblastic leukemia (T-ALL). The most frequent genetic abnormality in T-ALL is the dysregulation of transcription factor genes. We previously identified the “core transcriptional regulatory circuits” controlled by the oncogenic transcription factor TAL1 in T-ALL. This work establishes that T-ALL cells possess the same general motifs of transcriptional circuitry that were identified earlier in stem cells. Our laboratory will develop a novel means to target these oncogenic mechanisms in T-ALL cells through combining cancer genomics with functional genetics and bioinformatics.

As a physician scientist, I am particularly motivated by work that has the potential to improve public health, by advancing understanding of cancer for the eventual development of improved therapeutics. I hope to translate the knowledge gained from the experimental studies into effective therapy. My long-term goal is to improve cancer cure rates by developing novel therapeutics. To meet this challenge, I have been studying T-cell acute lymphoblastic leukemia (T-ALL) and other lymphoid malignancies.

T-ALL is a malignant disorder resulting from the leukemic transformation of T-cell precursors and is one of the most common forms of cancer in children and also found in adults. The most frequent genetic abnormality in T-ALL is the dysregulation of transcription factor genes, including aberrant expressions of TAL1, HOX11 and HOX11L2, and activating mutations of NOTCH1. However, those factors are generally difficult to target with small-molecules. Therefore, further advances in treatment outcome will require an improved knowledge of T-ALL.

“Core regulatory circuits” – We previously reported that the oncogenic transcription factor TAL1 and its regulatory partners (GATA3. RUNX1 and MYB) form a stem cell-like transcriptional circuitry in T-ALL cells. This discovery is significant, because it showed, for the first time, that cancer/leukemia cells possess the same general transcriptional network motifs that control the pluripotency and self-renewal of stem cells. Hence, we hypothesize that this regulatory structure we identified in T-ALL cells is likely required for the initiation or maintenance of malignant T-cells (“core regulatory circuits”).

Alteration of transcriptional regulatory program – Importantly, TAL1 is normally expressed in hematopoietic stem cells and regulates genes required for stem cell function, but it is silenced during T-cell development. Ectopic expression of TAL1 in immature thymocytes causes T-ALL. Hence, we think that TAL1 blocks the expression of genes that are normally required for T-cell differentiation and instead reactivates stem cell genes in malignant T-cells (“hijacking the stemness”), thus altering the transcriptional program in developing thymocytes. Such imbalance between T-cell differentiation and stem cell machineries would be the critical mechanism in T-ALL.

In our laboratory, we will elucidate the oncogenic mechanisms induced by the TAL1 complex in T-ALL cells and develop a novel means to target this machinery through combining cancer genomics with functional genetics and bioinformatics. We utilize the zebrafish model for functional analysis in vivo. Success in the projects will not only validate the therapeutic approach outlined above, but should also generate a series of highly effective, first-in-class small-molecule inhibitors for future clinical testing. The knowledge gleaned from this work could well extend to other leukemia/cancer in which an oncogenic transcription factor controls the core transcriptional machinery.

Selected Publications:

  1. Liau WS, Tan SH, Ngoc PC, Wang CQ, Tergaonkar V, Feng H, Gong Z, Osato M, Look AT, Sanda T. Aberrant activation of the GIMAP enhancer by oncogenic transcription factors in T-cell acute lymphoblastic leukemia. Leukemia, 2017, Jan 27.
  2. Liau WS, Ngoc PC, Sanda T. Roles of the RUNX1 Enhancer in Normal Hematopoiesis and Leukemogenesis (review article). Adv Exp Med Biol. 2017;962:139-147.
  3. Akahane K, Sanda T, Mansour MR, Radimerski T, DeAngelo DJ, Weinstock DM, Look AT. HSP90 inhibition leads to degradation of the TYK2 kinase and apoptotic cell death in T-cell acute lymphoblastic leukemia. Leukemia, 2016 Jan;30(1):219-28.
  4. Tan SH, Yam AW, Lawton LN, Wong RW, Young RA, Look AT, Sanda T. TRIB2 reinforces the oncogenic transcriptional program controlled by the TAL1 complex in T-cell acute lymphoblastic leukemia. Leukemia, 2016 Apr;30(4):959-62.
  5. Mansour MR, Abraham BJ, Anders L, Berezovskaya A, Gutierrez A, Durbin AD, Etchin J, Lawton L, Sallan SE, Silverman LB, Loh ML, Hunger SP, Sanda T, Young RA, Look AT. Oncogene regulation. An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element. Science, 2014 Dec 12;346(6215):1373-7.
  6. Kwiatkowski N, Zhang T, Rahl PB, Abraham BJ, Reddy J, Ficarro SB, Dastur A, Amzallag A, Ramaswamy S, Tesar B, Jenkins CR, Hannett NM, McMillin D, Sanda T, Sim T, Kim ND, Look AT, Mitsiades C, Weng AP, Brown JR, Benes CH, Marto JA, Young RA, Gray NS. Targeting transcriptional dependencies in cancer using a covalent CDK7 inhibitor. Nature, 2014 Jul 31;511(7511):616-20.
  7. Mansour MR, Sanda T, Lawton LN, Li X, Kreslavsky T, Novina CD, Brand M, Gutierrez A, Kelliher MA, Jamieson CH, von Boehmer H, Young RA, Look AT. The TAL1 complex targets the FBXW7 tumor suppressor by activating miR-223 in human T cell acute lymphoblastic leukemia. J Exp Med, 2013 Jul 29;210(8):1545-57.
  8. Sanda T, Tyner JW, Gutierrez A, Ngo VN, Glover J, Chang BH, Yost A, Ma X, Fleischman AG, Zhou W, Yang Y, Kleppe M, Ahn Y, Tatarek J, Kelliher MA, Neuberg DS, Levine RL, Moriggl R, Müller M, Gray NS, Jamieson CHM, Weng AP, Staudt LM, Druker BJ, Look AT. TYK2-STAT1-BCL2 Pathway Dependence in T-Cell Acute Lymphoblastic Leukemia, Cancer Discovery, 2013 May;3(5):564-77.
  9. Choi YJ, Li X, Hydbring P, Sanda T, Stefano J, Christie AL, Signoretti S, Look AT, Kung AL, von Boehmer H, Sicinski P. The requirement for cyclin d function in tumor maintenance. Cancer Cell, 2012 Oct 16; 22(4):438-51.
  10. Sanda T, Lawton LN, Barrasa MI, Fan ZP, Kohlhammer H, Gutierrez A, Ma W, Tatarek J, Ahn Y, Kelliher MA, Jamieson CHM, Staudt LM, Young RA, and Look AT. Core transcriptional regulatory circuit controlled by the TAL1 complex in human T-cell acute lymphoblastic leukemia. Cancer Cell, 2012 Aug 14;22(2):209-21.
  11. Sanda T, Li X, Gutierrez A, Ahn Y, Neuberg DS, O’Neil J, Strack PR, Winter CG, Winter SS, Larson RS, von Boehmer H & Look AT. Interconnecting Molecular Pathways in the Pathogenesis and Drug Sensitivity of T-cell Acute Lymphoblastic Leukemia, Blood, 2010 Mar 4;115(9):1735-45.
  12. *George RE, *Sanda T (co-first author), *Hanna M, Fröhling S, Luther W 2nd, Zhang J, Ahn Y, Zhou W, London WB, McGrady P, Xue L, Zozulya S, Gregor VE, Webb TR, Gray NS, Gilliland DG, Diller L, Greulich H, Morris SW, Meyerson M, Look AT.. Activating mutations in ALK provide a therapeutic target in neuroblastoma. Nature, 2008 Oct 16;455(7215):975-8.
Name Takaomi SANDA
Affiliations Principal Investigator, Cancer Science Institute of Singapore, NUS
Assistant Professor, Department of Medicine, Yong Loo Lin School of Medicine, NUS
Email takaomi_sanda[at]nus.edu.sg

Education

Institute Degree (if applicable) Year(s)
Nagoya City University Medical School, Nagoya, Japan MD 2000
Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan Ph.D. 2006

Professional Experience

Principal Investigator, Cancer Science Institute of Singapore, NUS 2013 – Present
Assistant Professor, Department of Medicine, Yong Loo Lin School of Medicine, NUS 2013 – Present
Instructor, Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 2010 – 2013
Research Fellow, Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 2006 – 2010
Resident, Hematology and Oncology, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan 2002 – 2003
Resident, Internal Medicine, Nagoya City University Hospital, Nagoya, Japan 2000 – 2002

TAN Shi Hao

PhD
Research Fellow
shihao_tan[at]nus.edu.sg

Identification and characterization of novel therapeutic targets involved in T-cell acute lymphoblastic leukemia.

TAN Tze King

PhD
Research Fellow
csittk[at]nus.edu.sg

Novel therapeutics targeting the core regulatory circuits in human T-cell acute lymphoblastic leukemia.

Stella AMANDA

Research Assistant
csisa[at]nus.edu.sg

Identification and characterization of novel therapeutic targets involved in T-cell acute lymphoblastic leukemia.

Carla BERTULFO

Research Assistant

Identification and characterization of novel therapeutic targets involved in T-cell acute lymphoblastic leukemia.

CHAN Allison Si-Yu

Research Assistant

Identification and characterization of novel therapeutic targets involved in T-cell acute lymphoblastic leukemia.

Wei Zhong LEONG

Research Assistant

Identification and characterization of novel therapeutic targets involved in T-cell acute lymphoblastic leukemia.

Regina WONG Wan Ju

Research Assistant

Identification and characterization of novel therapeutic targets involved in T-cell acute lymphoblastic leukemia.

Zulfaqar ALI

Laboratory Executive
csimza[at]nus.edu.sg

Identification and characterization of novel therapeutic targets involved in T-cell acute lymphoblastic leukemia.

WANG Lu

PhD Student

Identification and characterization of novel therapeutic targets involved in T-cell acute lymphoblastic leukemia.

ZHANG Chujing

PhD Student

Identification and characterization of novel therapeutic targets involved in T-cell acute lymphoblastic leukemia.

Singapore National Research Foundation (NRF)
Fellowship
2013
U.S. National Institute of Health (NIH)/National Cancer
Institute (NCI), K99 Award
2011