Translational Hematology & Oncology Research
The Department of Translational Hematology and Oncology Research (THOR) conducts cancer research to develop and make available novel diagnostic tools, targeted therapies and clinical trials for direct use in patient care.
Based on the most current scientific standards, THOR researchers apply advances in the laboratory to provide the highest level of care for patients.
An important part of the Taussig Cancer Institute research efforts, THOR is engaging a new generation of physician scientists to develop scientific advances and translational research that is internationally recognized.
Scientific Areas of Emphasis
- Cancer Genomics and Cytogenetics
- Cancer Stem Cell Biology
- Cancer Immunology and Tumor Surveillance
- Drug Design
- Cancer Pharmacology/Pharmacogenetics
- Signal Transduction
Department physician scientists are available for consultation regarding second or third opinion evaluations, participation in clinical trials and referrals to subspecialists. Some diseases targeted in the department’s research include but are not limited to the following:
- Acute Leukemia
- Bone Marrow Failure including:
- Aplastic Anemia
- Paroxysmal Nocturnal Hemoglobinuria
- Myelodysplastic Syndrome
- Large Granular Lymphocytic Leukemia
- Lung Cancer
- Multiple Myeloma
- Myeloproliferative Syndromes
- Ovarian Cancer
- Renal Cancer
The Department of Translational Hematology & Oncology Research has a substantial list of Journal Publications that help to further our research efforts. Follow the link below to view our most recent publications on PubMed.
Research News & Articles
2015 APR Annual Report
Translational Hematology & Oncology Research
- Dr. Saunthararajah completed phase I study of a novel pharmacologically rational oral non-cytotoxic epigenetic therapy in collaboration with other investigators. He has subsequently obtained funding for a phase II evaluation in pancreatic and lung cancer as well as myeloid and lymphoid neoplasia alone or in combination with immune check point inhibitors. The resultant trials will be performed nationally in a multicenter setting.
- Discovery of new familial leukemogenic mutations and a novel class of tumor suppressor genes, RNA helicases, in myeloid leukemias. This work was published in Cancer Cell. DDX41 mutations convey familiar predisposition to adult onset AML and acquisition of somatic bilallic DDX41 mutations. This discovery has already led to a proposal for a new AML category in WHO classification called "familial AML" including RUNX1, CEBPA, DDX41 and ETV6.
- Maciejewski, MD, PhD, collaborated with researchers from Harvard University (Dr. Weinstock) to discover mutations and clarify the mode of action of the novel tumor suppressor gene GPB1 published in Nature Medicine.
- Dr. Saunthararajah's invention showing means of resistance to the only drugs effective in MDS, DNMT1 depleting agents, was a feature in the Best of ASH.
- Dr. Maciejewski's program in aplastic anemia has contributed to the discovery of frequent clonal events in the otherwise considered benign aplastic anemia - a paradigm shifting discovery with regard to the understanding of the pathogenesis of this disease. This work has been reported in New England Journal of Medicine.
- Dr. Saunthararajah established rationale and completed phase I/II results of a novel non-cytotoxic therapy for MDS creating a new therapeutic paradigm for this disease. This work led by Dr. Saunthararajah was reported in Journal of Clinical Investigation.
- Dr. Saunthararajah has filed an invention disclosure for the first inhibitor of SWIF/SNF ATPase inhibitor, an entirely novel therapeutic concept and class of agents.
- Leukemia/MDS genomic initiative results. Next generation sequencing technology has been made available to TCI researchers and clinicians. The results of the large exome sequencing study have been presented at ASH and are under review in Nature Medicine.
- THOR Department received a multi-PI "LRI Centers of Excellence in CMML" grant.
- Dr. Saunthararajah presented Best of ASH abstract at the 2015 Annual ASH Meeting.
- Dr. Maciejewski has been appointed Chairman of the Myeloid Neoplasia Committee of the American Society of Hematology.
- Dr. Maciejewski has been appointed as a permanent member of the Molecular and Cellular Hematology Study Review Section of the National Institutes of Health.
- THOR has published high impact papers in top ranking journals: NEJM (1), Cancer Cell (1), Cell (1), Nat Med (1), JCI (1), J Exp Med (2).
- THOR has developed and obtained IRB approval for a STANDARD tissue collection/repository protocol available for use by Disease Programs throughout TCI.
- THOR Research Grants Administration Office submitted 35 initial proposals (~27 mil) for THOR and 20 proposals (~8 mil) for non-THOR TCI members in addition to managing grant requirements for CCCC p30 and NCTN and other ongoing collaborative projects.
Formation of AGING/LONGEVITY DRUG DEVELOPMENT CENTER. This new initiative is based on the theory that prevention/retardation of the aging process is a major contributor to delaying the occurrence of hematologic malignancies in the elderly. The center incorporates the skill of the drug development center and reaches across multiple departments within TCI and LRI.
Establishment of MEDICINAL CHEMISTRY CORE with 3 new faculty:
- Dr. Jim Phillips: Synthetic organic chemist
- Dr. Jha Babal: In silico chemist/structural biology
- Dr. Tom Radivoyevitch: Metabolomics/systems biologist
- Dr. Dan Lindner: Director, Animal Tumor Core
THOR has formed a close collaboration with Dr. Drew Adams (CCCC) from the High Throughput Testing Core to provide services to THOR members and LRI.
- Recruitment of Dr. Babal Jha PhD, Project Staff, to provide urgently needed expertise and services.
- Recruitment activities ongoing for 2 junior faculty candidates.
New Awards/Recent Funding:
- ASH Scholar Award - $600,000
- NIH KL2 Career Development Award - $480,000
- R01 HL128425 - $1,585,000
- R01 HL123904 - $2,058,580
- Evans Foundation MDS Discovery Grant - $900,000
Members of THOR received 5 VeloSano awards $100,000 (total of $500,000)
Members of THOR received 2 Scott Hamilton awards $100,000 (total $200,000)
- R01 12082538 - $1,981,250
- R01 submission - $1,981,250
- LLS TRP - $600,000
- LLS New Idea - $75,000
- R01 12079965 - $3,073,545
- LLS New Idea - $75,000
- LLS TRP - $600,000
- U01 CA210148-01 - $200,000
- R01 CA208182-01 - $1,981,250
- R01 CA138858-06A1 - $1,981,250
- U01 CA210148-01 - $175,000
- R01 subaward CWRU - $900,000
- R01 subaward Univ of Chicago - $475,000
- R01 subaward Univ of North Carolina - $264,000
- DOD subaward CWRU - $104,990
Current Grant Funding:
- R01 HL128425 - $1,585,000 (mentioned above under new funding)
- R01 HL123904 - $2,058,580 (mentioned above under new funding)
- Evans Foundation - $400,000 (mentioned above under new funding)
- LRI Centers of Excellence Grant - $900,000 (mentioned above under new funding)
- R01 Hl118281 - $1,507,000
- P30 CCCC - $60,350/yr
- CCCC Genomics Pilot Award - $103,025
- Celgene - $130,000
- AAMDSIF - $400,000
- R03 subaward Texas A&M - $50,000
- R01 subaward Cincinnati Childrens - $45,000
- DOD subaward UMKC - $140,000
- U01 HL117658 - $2,159,750
- CCCC Genomics Pilot Award - $100,000
- P30 CCCC - $60,350/yr
- Members of THOR have been very productive submitting grant proposals throughout the year: currently pending applications are:
- THOR Department has maintained an outstanding record of publications (see figure 1), national presentations and peer recognition. This record included 67 publications. Among them there were manuscripts published in, NEJM (1), Cancer Cell (1), Cell (1), JCI (1), Nat Med (1), JEM (2), Blood (2), Leukemia (13). Our department also scored 2 cover pages and 2 plenary papers in Blood. Included is a full listing of manuscripts published in journals:
- Saunthararajah Y, Sekeres M, Advani A, Mahfouz R, Durkin L, Radivoyevitch T, Englehaupt R, Juersivich J, Cooper K, Husseinzadeh H, Przychodzen B, Rump R, Reu F, Tiu R, Hamilton B, Hsi E, Kalaycio M, Maciejewski JP (2015). Evaluation of non-cytotoxic DNMT1-depleting treatment of myelodysplastic syndromes. J Clin Invest. Mar 2;125(3):1043-55.
- Polprasert CH, Schulze I, Sekeres MA, Makishima H, Przychodzen B, Hosono N. Padgett RP, Phillips JG, Clemente M, Dienes B, Du Y, Mukherjee S, Krug U, Klein HU, Berdel W, Yoshida K, Shiraishi Y, Chiba K, Ogawa S, Muller-Tidow C, Maciejewski JP (2015). Inherited and somatic defects in DDX41 in myeloid neoplasms. Cancer Cell. May 11; 27(5):658-70.
- Viny AD, Maciejewski JP (2015). High Rate of Both Hematopoietic and Solid Tumors Associated with Large Granular Lymphocyte Leukemia. Leuk Lymphoma. Feb;56(2):503-4.
- Patel B, Hirsch C, Clemente M, Sekeres M, Makishima H, Maciejewski JP (2015). Genetic and molecular characterization of myelodysplastic syndromes and related myeloid neoplasms. Int J Hematol. Mar;101(3):213-8.
- Molenaar RJ, Thota S, Nagata Y, Patel B, Clemente M, Hirsh C, Viny AD, Hosono N, Bleeker FE, Meggendorfer M, Alpermann T, Shiraishi Y, Chiba K, Tanaka H, van Noorden CJ, Radivoyevitch T, Carraway H, Makishima H, Miyano S, Sekeres MA, Ogawa S, Haferlach T, Maciejewski JP (2015). Clinical and biological implications of ancestral and non-ancestral IDH1 and IDH2 mutations in myeloid neoplasms. Leukemia. Nov;29(11):2134-42.
- Nazha A, Seastone D, Radivoyevitch T, Przychodzen B, Carraway HE, Patel BJ, Carew J, Makishima H, Sekeres MA, Maciejewski JP (2015). Genomic Patterns Associated with Hypoplastic Compared to Hyperplastic Myelodysplastic Syndromes. Haematologica. Nov;100(11):e434-7.
- Bilori B, Thota S, Clemente MJ, Patel B, Jerez A, Afable M, Maciejewski JP (2015). Tofacitinib as a novel salvage therapy for refractory T cell large granular lymphocytic leukemia. Leukemia. Dec;29(12):2427-9.
- Radivoyevitch T, Sachs RK, Gale RP, Molenaar RJ, Brenner DJ, Hill BT, Kalaycio ME, Carraway HE, Mukherjee S, Sekeres MA, Maciejewski JP (2015). Defining AML and MDS second cancer risk dynamics after diagnoses of first cancers treated or not with radiation. Leukemia. Sep 22. [Epub ahead of print]
- Kurtovic-Kozaric A, Przychodzen B, Singh J, Konarska MM, Clemente MJ, Otrock ZK, Nakashima M, Hsi ED, Yoshida K, Ogawa S, Boultwood J, Maciejewski JP, Padgett RA, Makishima H (2015). PRPF8 defects cause missplicing in myeloid malignancies. Leukemia. Jan;29(1):126-36.
- Yoda A, Adelmant G, Tamburini J, Chapuy B, Shindoh N, Yoda Y, Weigert O, Kopp N, Wu SC, Kim SS, Liu H, Tivey T, Christie AL, Elpek KG, Card J, Gritsman K, Gotlib J, Deininger MW, Makishima H, Turley SJ, Javidi-Sharifi N, Maciejewski JP, Jaiswal S, Ebert BL, Rodig SJ, Tyner JW, Marto JA, Weinstock DM, Lane AA (2015). Mutations in G protein ß subunits promote transformation and kinase inhibitor resistance. Nat Med. Jan;21(1):71-5.
- Nawrocki ST, Kelly KR, Smith PG, Keaton M, Carraway H, Sekeres MA, Maciejewski JP, Carew JS (2015). The NEDD8-activating enzyme inhibitor MLN4924 disrupts nucleotide metabolism and augments the efficacy of cytarabine. Clin Cancer Res. Jan 15;21(2):439-47.
- McGraw KL, Zhang LM, Rollison DE, Basiorka AA, Fulp W, Rawal B, Jerez A, Billingsley DL, Lin HY, Kurtin SE, Yoder S, Zhang Y, Guinta K, Mallo M, Solé F, Calasanz MJ, Cervera J, Such E, González T, Nevill TJ, Haferlach T, Smith AE, Kulasekararaj A, Mufti G, Karsan A, Maciejewski JP, Sokol L, Epling-Burnette PK, Wei S, List AF (2015). The relationship of TP53 R72P polymorphism to disease outcome and TP53 mutation in myelodysplastic syndromes. Blood Cancer J. Mar 13;5:e291.
- Nazha A, Seastone D, Keng M, Hobson S, Kalaycio M, Maciejewski JP, Sekeres MA (2015). The Revised International Prognostic Scoring System (IPSS-R) is not Predictive of Survival in Patients with Secondary Myelodysplastic Syndromes. Leuk Lymphoma. Dec;56(12):3437-9.
- Della Porta MG, Tuechler H, Malcovati L, Schanz J, Sanz G, Garcia-Manero G, Solé F, Bennett JM, Bowen D, Fenaux P, Dreyfus F, Kantarjian H, Kuendgen A, Levis A, Cermak J, Fonatsch C, Le Beau MM, Slovak ML, Krieger O, Luebbert M, Maciejewski JP, Magalhaes SM, Miyazaki Y, Pfeilstöcker M, Sekeres MA, Sperr WR, Stauder R, Tauro S, Valent P, Vallespi T, van de Loosdrecht AA, Germing U, Haase D, Greenberg PL, Cazzola M (2015). Validation of WHO classification-based Prognostic Scoring System (WPSS) for myelodysplastic syndromes and comparison with the revised International Prognostic Scoring System (IPSS-R). A study of the International Working Group for Prognosis in Myelodysplasia (IWG-PM). Leukemia. Jul;29(7):1502-13.
- Hobfoll SE, Gerhart JI, Zalta AK, Wells K, Maciejewski JP, Fung H (2015). Posttraumatic stress symptoms predict impaired neutrophil recovery in stem cell transplant recipients. Psychooncology. Nov;24(11):1529-35.
- Savona MR, Malcovati L, Komrokji R, Tiu RV, Mughal TI, Orazi A, Kiladjian JJ, Padron E, Solary E, Tibes R, Itzykson R, Cazzola M, Mesa R, Maciejewski JP, Fenaux P, Garcia-Manero G, Gerds A, Sanz G, Niemeyer CM, Cervantes F, Germing U, Cross NC, List AF; MDS/MPN International Working Group (2015). An international consortium proposal of uniform response criteria for myelodysplastic/myeloproliferative neoplasms (MDS/MPN) in adults. Blood. Mar 19;125(12):1857-65.
- Ornstein MC, Mukherjee S, Keng M, Elson P, Tiu RV, Saunthararajah Y, Maggiotto A, Schaub M, Banks D, Advani A, Kalaycio M, Maciejewski JP, Sekeres MA (2015). Impact of vancomycin-resistant enterococcal bacteremia on outcome during acute myeloid leukemia induction therapy. Leuk Lymphoma. Sep;56(9):2536-42.
- Ratajczak MZ, Borkowska S, Mierzejewska K, Kucia M, Mendek-Czajkowska E, Suszynska M, Sharma VA, Deptala A, Song W, Platzbecker U, Larratt L, Janowska-Wieczorek A, Maciejewski JP, and Ratajczak J (2015). Further evidence that paroxysmal nocturnal haemoglobinuria is a disorder of defective cell membrane lipid rafts. J. Cell Mol Med. Sep;19(9):2193-201.
- Yoshizato T, Dumitriu B, Hosokawa K, Makishima H, Yoshida K, Townsley D, Sato-Otsubo A, Sato Y, Liu D, Suzuki H, Wu CO, Shiraishi Y, Clemente MJ, Kataoka K, Shiozawa Y, Okuno Y, Chiba K, Tanaka H, Nagata Y, Katagiri T, Kon A, Sanada M, Scheinberg P, Miyano S, Maciejewski JP, Nakao S, Young NS, Ogawa S (2015). Somatic Mutations and Clonal Hematopoiesis in Aplastic Anemia. N Engl J Med. Jul 2;373(1):35-47.
- Dolatshad H, Pellagatti A, Fernandez-Mercado M, Yip BH, Malcovati L, Attwood M, Przychodzen B, Sahgal N, Kanapin AA, Lockstone H, Scifo L, Vandenberghe P, Papaemmanuil E, Smith CW, Campbell PJ, Ogawa S, Maciejewski JP, Cazzola M, Savage KI, Boultwood J (2015). Disruption of SF3B1 results in deregulated expression and splicing of key genes and pathways in myelodysplastic syndrome hematopoietic stem and progenitor cells. Leukemia. Aug;29(8):1798.
- Zeidan AM, Sekeres MA, Wang XF, Al Ali N, Garcia-Manero G, Steensma DP, Roboz G, Barnard J, Padron E, Dezern A, Maciejewski JP, List AF, Komrokji RS; MDS Clinical Research Consortium (2015). Comparing the prognostic value of risk stratifying models for patients with lower-risk myelodysplastic syndromes: Is one model better? Am J Hematol. Nov;90(11):1036-40.
- Dolatshad H, Pellagatti A, Fernandez-Mercado M, Yip BH, Malcovati L, Attwood M, Przychodzen B, Sahgal N, Kanapin AA, Lockstone H, Scifo L, Vandenberghe P, Papaemmanuil E, Smith CW, Campbell PJ, Ogawa S, Maciejewski JP, Cazzola M, Savage KI, Boultwood J (2015). Disruption of SF3B1 results in deregulated expression and splicing of key genes and pathways in myelodysplastic syndrome hematopoietic stem and progenitor cells. Leukemia. Aug;29(8):1798
- Sinyuk M, Alvarado AG, Nesmiyanov P, Shaw J, Mulkearns-Hubert EE, Eurich JT, Hale JS, Bogdanova A, Hitomi M, Maciejewski JP, Huang AY, Saunthararajah Y, Lathia JD (2015). Cx25 contributes to leukemia cell communication and chemosensitivity. Oncotarget. Oct 13;6(31):31508-21.
- Visconte V, Nawrocki ST, Espitia CM, Kelly KR, Possemato A, Beausoleil SA, Han Y, Carraway HE, Nazha A, Advani AS, Maciejewski JP, Sekeres MA, Carew JS (2015). Comprehensive quantitative proteomic profiling of the pharmacodynamic changes induced by MLN4924 in acute myeloid leukemia cells establishes rationale for its combination with azacitidine. Leukemia. Sep 15. [Epub ahead of print]
- Molenaar RJ, Botman D, Smits MA, Hira VV, van Lith SA, Stap J, Henneman P, Khurshed M, Lenting K, Mul AN, Dimitrakopoulou D, van Drunen CM, Hoebe RA, Radivoyevitch T, Wilmink JW, Maciejewski JP, Vandertop WP, Leenders WP, Bleeker FE, Van Noorden CJ (2015). Radioprotection of IDH1-mutated cancer cells by the IDH1-mutant inhibitor AGI-5198. Cancer Res. Nov 15;75(22):4790-802.
- Mughal TI, Cross NC, Padron E, Tiu RV, Savona M, Malcovati L, Tibes R, Komrokji RS, Kiladjian JJ, Garcia-Manero G, Orazi A, Mesa R, Maciejewski JP, Fenaux P, Itzykson R, Mufti G, Solary E, List AF (2015). An International MDS/MPN Working Group's perspective and recommendations on molecular pathogenesis, diagnosis and clinical characterization of myelodysplastic/myeloproliferative neoplasms. Haematologica. Sep;100(9):1117-30.
- Hurtado AM, Chen-Liang TH, Przychodzen B, Hamedi C, Muñoz-Ballester J, Dienes B, García-Malo MD, Antón AI, de Arriba F, Teruel-Montoya R, Ortuño FJ, Vicente V, Maciejewski JP, Jerez A (2015). Prognostic signature and clonality pattern of recurrently mutated genes in inactive chronic lymphocytic leukemia. Blood Cancer J. Aug 28;5:e342.
- Andersson E, Kuusanmäki H, Bortoluzzi S, Lagström S, Parsons A, Rajala H, van Adrichem A, Eldfors S, Olson T, Clemente MJ, Laasonen A, Ellonen P, Heckman C, Loughran TP, Maciejewski JP, Mustjoki S (2015). Activating somatic mutations outside the SH2-domain of STAT3 in LGL-leukemia. Leukemia. Sep 30. doi: 10.1038/leu.2015.263. [Epub ahead of print]
- McGraw KL, Cluzeau T, Sallman DA, Basiorka AA, Irvine BA, Zhang L, Epling-Burnette PK, Rollison DE, Mallo M, Sokol L, Solé F, Maciejewski JP, List AF (2015). TP53 and MDM2 single nucleotide polymorphisms influence survival in non-del(5q) myelodysplastic syndromes. Oncotarget. Oct 27;6(33):34437-45.
- Viny AD, Ott CJ, Spitzer B, Rivas M, Meydan C, Papalexi E, Yelin D, Shank K, Reyes J, Chiu A, Romin Y, Boyko V, Thota S, Maciejewski JP, Melnick A, Bradner JE, Levine RL (2015). Dose-dependent role of the cohesin complex in normal and malignant hematopoiesis. J Exp Med. Oct 19;212(11):1819-32.
- Okoye-Okafor UC, Bartholdy B, Cartier J, Gao EN, Pietrak B, Rendina AR, Rominger C, Quinn C, Smallwood A, Wiggall KJ, Reif AJ, Schmidt SJ, Qi H, Zhao H, Joberty G, Faelth-Savitski M, Bantscheff M, Drewes G, Duraiswami C, Brady P, Groy A, Narayanagari SR, Antony-Debre I, Mitchell K, Wang HR, Kao YR, Christopeit M, Carvajal L, Barreyro L, Paietta E, Makishima H, Will B, Concha N, Adams ND, Schwartz B, McCabe MT, Maciejewski JP, Verma A, Steidl U (2015). New IDH1 mutant inhibitors for treatment of acute myeloid leukemia. Nat Chem Biol. Nov;11(11):878-86.
- Varney ME, Niederkorn M, Konno H, Matsumura T, Gohda J, Yoshida N, Akiyama T, Christie S, Fang J, Miller D, Jerez A, Karsan A, Maciejewski JP, Meetei RA, Inoue JI, Starczynowski DT (2015). Loss of Tifab, a del(5q) MDS gene, alters hematopoiesis through derepression of Toll-like receptor-TRAF6 signaling. J Exp Med. Oct 19;212(11):1967-85.
- Ruffalo M, Husseinzadeh H, Makishima H, Przychodzen B, Ashkar M, Koyutürk M, Maciejewski JP, LaFramboise T (2015). Whole-exome sequencing enhances prognostic classification of myeloid malignancies. J Biomed Inform. Dec;58:104-13. doi: 10.1016/j.jbi.2015.10.003. Epub 2015 Oct 8.
- Visconte V, Tabarroki A, Hasrouni E, Maciejewski JP, Hsi ED, Tiu RV, Rogers HJ (2016). Molecular and phenotypic heterogeneity of refractory anemia with ring sideroblasts associated with marked thrombocytosis. Leuk Lymphoma. Jan;57(1):212-5.
- Vishwakarma BA, Nguyen N, Makishima H, Hosono N, Gudmundsson KO, Negi V, Oakley K, Han Y, Przychodzen B, Maciejewski JP, Du Y (2016). Runx1 repression by histone deacetylation is critical for Setbp1-induced mouse myeloid leukemia development. Leukemia. Jan;30(1):200-8.
- Makishima H, Yoshida K, Ruffalo R, Przychodzen B, LaFramboise T, Hosono H, Gómez-Seguí I, Husseinzadeh HD, Thota S, Clemente MJ, Shiraishi M, Sanada M, Nagata Y, Okuno Y, Sato Y, Saunthararajah Y, Sekeres MA, Shih L-Y, Ogawa S, Maciejewski JP. Landscape of somatic mutations in whole exomes of myelodysplastic syndromes and related myeloid neoplasms. Nat Med. 2015 (in revision).
- GFI1 as a novel prognostic and therapeutic factor for AML/MDS. Hönes JM, Botezatu L, Helness A, Vadnais C, Vassen L, Robert F, Hergenhan SM, Thivakaran A, Schütte J, Al-Matary YS, Lams RF, Fraszscak J, Makishima H, Radivoyevitch T, Przychodzen B, da Conceição Castro SV, Görgens A, Giebel B, Klein-Hitpass L, Lennartz K, Heuser M, Thiede C, Ehninger G, Dührsen U, Maciejewski J, Möröy T, Khandanpour C. Leukemia. 2016 Feb 5. doi: 10.1038/leu.2016.11. [Epub ahead of print]
- Hamilton BK, Visconte V, Jia X, Tabarroki A, Makishima H, Hasrouni E, Abounader D, Kalaycio M, Sekeres MA, Sobecks R, Duong Liu H, Bolwell B, Maciejewski JP, Copelan E, Tiu RV. Impact of allogeneic hematopoietic cell transplant in patients with myeloid neoplasms carrying spliceosomal mutations. Am J Hematol. [Epub ahead of print]
- Sakaguchi H, Muramatsu H, Okuno Y, Makishima H, Xu Y, Furukawa-Hibi Y, Wang X, Narita A, Yoshida K, Shiraishi Y, Doisaki S, Yoshida N, Hama A, Takahashi Y, Yamada K, Miyano S, Ogawa S, Maciejewski JP, Kojima S. Aberrant DNA Methylation Is Associated with a Poor Outcome in Juvenile Myelomonocytic Leukemia. PLoS One. 2015 Dec 31;10(12):e0145394.
- Miyano S, Ogawa S, Maciejewski JP, Kojima S. Aberrant DNA Methylation Is Associated with a Poor Outcome in Juvenile Myelomonocytic Leukemia. PLoS One. 2015 Dec 31;10(12):e0145394.
- Yard, B, Adams, DJ, Chie, EK, Tamayo, P, Battaglia, JS, Gopal, P, Rogacki, K, Pearson, B, Phillips, J, Cheah, J, Clemons, PA, Shamji, A, Peacock, CD, Schreiber, SL, Hammerman, PS, Abazeed, ME. A genetic basis for variation in the vulnerability of cancer to DNA damage. Nature Communications (in press).
- Yard, B, Chie, EK, Adams, DJ, Peacock, C, Abazeed, ME. Radiotherapy in the era of precision medicine. Semin Radiat Oncol (2015). 25(4):227-36.
- Banerjee, S., Li, G., Li, Y., Gaughan, C., Baskar, D., Parker, Y., Lindner, D. J., Weiss, S. R., and Silverman, R. H. (2015). RNase L is a Negative Regulator of Cell Migration, Oncotarget. (epublished
- Diaz, C. M., Mao, F. J., Barnard, J., Parker, Y., Zamanian-Daryoush, M., Pink, J. J., Finke, J. H., Rini, B. I., and Lindner, D. J. (2016) MEK inhibition abrogates sunitinib resistance in a renal cell carcinoma patient-derived xenograft model, Clin Cancer Res in press.
- Polprasert, C., Schulze, I., Sekeres, M. A., Makishima, H., Przychodzen, B., Hosono, N., Singh, J., Padgett, R. A., Gu, X., Phillips, J. G., Clemente, M., Parker, Y., Lindner, D. J., Dienes, B., Du, Y., Oakley, K., Nguyen, N., Mukherjee, S., Pabst, C., Godley, L. A., Churpek, J. E., Pollyea, D. A., Krug, U., Klein, H. U., Dugas, M., Berdel, W., Yoshida, K., Shiraishi, Y., Chiba, K., Tanaka, H., Miyano, S., Ogawa, S., Muller-Tidow, C., and Maciejewski, J. P. (2015) Inherited and somatic defects in DDX41 in myeloid neoplasms, Cancer cell 27, 609-611.
- 4. Pore, D., Bodo, J., Danda, A., Yan, D., Phillips, J., Lindner, D. J., Hill, B., Smith, M., Hsi, E., and Gupta, N. (2015) Identification of Ezrin-Radixin-Moesin proteins as novel regulators of pathogenic B cell receptor signaling and tumor growth in diffuse large B cell lymphoma Leukemia 29, 1857-1867.
- Baker, D. P., Virata, C., Boccia, A., Lindner, D. J., English, N., Pathan, N., Brickelmaier, M., Hu, X., Gardner, J. L., Scripps, T., Bennett, D., and Joseph, I. (2015) Anti-tumor activity of peginterferon beta-1a in murine xenograft model of human melanoma, International J. of Cancer.
- Lindner, D. J. (2014) Animal models and the tumor microenvironment, Seminars in Oncology 41, 146-155.
- Eswarappa, S. M., Potdar, A. A., Koch, W. J., Fan, Y., Vasu, K., Lindner, D., Willard, B., Graham, L. M., DiCorleto, P. E., and Fox, P. L. (2014) Programmed Translational Readthrough Generates Antiangiogenic VEGF-Ax, Cell 157, 1605-1618.
- Mah WC, Thurnherr T, Chow PK, Chung AY, Ooi LL, Toh HC, Teh BT, Saunthararajah Y, Lee CG. Correction: Methylation Profiles Reveal Distinct Subgroup of Hepatocellular Carcinoma Patients with Poor Prognosis. PLoS One. 2016 Jan11;11(1):e0146690.
- Sohal DP, Rini BI, Khorana AA, Dreicer R, Abraham J, Procop GW, Saunthararajah Y, Pennell NA, Stevenson JP, Pelley R, Estfan B, Shepard D, Funchain P, Elson P, Adelstein DJ, Bolwell BJ. Prospective Clinical Study of Precision Oncology in Solid Tumors. J Natl Cancer Inst. 2015 Nov 9;108(3).
- Sinyuk M, Alvarado AG, Nesmiyanov P, Shaw J, Mulkearns-Hubert EE, Eurich JT, Hale JS, Bogdanova A, Hitomi M, Maciejewski J, Huang AY, Saunthararajah Y, Lathia JD. Cx25 contributes to leukemia cell communication and chemosensitivity. Oncotarget. 2015 Oct 13;6(31):31508-21.
- Crabb JW, Hu B, Crabb JS, Triozzi P, Saunthararajah Y, Tubbs R, Singh AD. iTRAQ Quantitative Proteomic Comparison of Metastatic and Non-Metastatic Uveal Melanoma Tumors. PLoS One. 2015 Aug 25;10(8):e0135543.
- Cui S, Lim KC, Shi L, Lee M, Jearawiriyapaisarn N, Myers G, Campbell A, Harro D, Iwase S, Trievel RC, Rivers A, DeSimone J, Lavelle D, Saunthararajah Y, Engel JD. The LSD1 inhibitor RN-1 induces fetal hemoglobin synthesis and reduces disease pathology in sickle cell mice. Blood. 2015 Jul 16;126(3):386-96.
- Saunthararajah Y. Targets of opportunity for precision medicine. Blood. 2015 May 14;125(20):3041-2.
- Polprasert C, Schulze I, Sekeres MA, Makishima H, Przychodzen B, Hosono N, Singh J, Padgett RA, Gu X, Phillips JG, Clemente M, Parker Y, Lindner D, Dienes B, Jankowsky E, Saunthararajah Y, Du Y, Oakley K, Nguyen N, Mukherjee S, Pabst C, Godley LA, Churpek JE, Pollyea DA, Krug U, Berdel WE, Klein HU, Dugas M, Shiraishi Y, Chiba K, Tanaka H, Miyano S, Yoshida K, Ogawa S, Müller-Tidow C, Maciejewski JP. Inherited and Somatic Defects in DDX41 in Myeloid Neoplasms. Cancer Cell. 2015 May 11;27(5):658-70.
- Saunthararajah Y, Sekeres M, Advani A, Mahfouz R, Durkin L, Radivoyevitch T, Englehaupt R, Juersivich J, Cooper K, Husseinzadeh H, Przychodzen B, Rump M, Hobson S, Earl M, Sobecks R, Dean R, Reu F, Tiu R, Hamilton B, Copelan E, Lichtin A, Hsi E, Kalaycio M, Maciejewski J. Evaluation of noncytotoxic DNMT1-depleting therapy in patients with myelodysplastic syndromes. J Clin Invest. 2015 Mar 2;125(3):1043-55.
- Ornstein MC, Mukherjee S, Keng M, Elson P, Tiu RV, Saunthararajah Y, Maggiotto A, Schaub M, Banks D, Advani A, Kalaycio M, Maciejewski JP, Sekeres MA. Impact of vancomycin-resistant enterococcal bacteremia on outcome during acute myeloid leukemia induction therapy. Leuk Lymphoma. 2015;56(9):2536-42.
- Visconte V, Tabarroki A, Zhang L, Parker Y, Hasrouni E, Mahfouz R, Isono K, Koseki H, Sekeres MA, Saunthararajah Y, Barnard J, Lindner D, Rogers HJ, Tiu RV. Splicing factor 3b subunit 1 (Sf3b1) haploinsufficient mice display features of low risk Myelodysplastic syndromes with ring sideroblasts. J Hematol Oncol. 2014 Dec 7;7:89.
- Minca EC, Tubbs RR, Portier BP, Wang Z, Lanigan C, Aronow ME, Triozzi PL, Singh A, Cook JR, Saunthararajah Y, Plesec TP, Schoenfield L, Cawich V, Sulpizio S, Schultz RA. Genomic microarray analysis on formalin-fixed paraffin-embedded material for uveal melanoma prognostication. Cancer Genet. 2014 Jul-Aug;207(7-8):306-15.
- Mah WC, Thurnherr T, Chow PK, Chung AY, Ooi LL, Toh HC, Teh BT, Saunthararajah Y, Lee CG. Methylation profiles reveal distinct subgroup of hepatocellular carcinoma patients with poor prognosis. PLoS One. 2014 Aug 5;9(8):e104158.
- Uchida N, Hsieh MM, Platner C, Saunthararajah Y, Tisdale JF. Decitabine suspends human CD34+ cell differentiation and proliferation during lentiviral transduction. PLoS One. 2014 Aug 4;9(8):e104022.
- Egusa S, Ebrahem Q, Mahfouz RZ, Saunthararajah Y. Ligand exchange on gold nanoparticles for drug delivery and enhanced therapeutic index evaluated in acute myeloid leukemia models. Exp Biol Med (Maywood). 2014 May 30;239(7):853-861.
- Visconte V, Avishai N, Mahfouz R, Tabarroki A, Cowen J, Sharghi-Moshtaghin R, Hitomi M, Rogers HJ, Hasrouni E, Phillips J, Sekeres MA, Heuer AH, Saunthararajah Y, Barnard J, Tiu RV. Distinct iron architecture in SF3B1-mutant myelodysplastic syndrome patients is linked to an SLC25A37 splice variant with a retained intron. Leukemia. 2015 Jan;29(1):188-95.
- Thornbrougha JM, Jha BK, Yount B, Elliott R, Li Y, Goldstein SA, Sims AC, Baric RC, Silverman RH and Weiss SR. Middle east respiratory syndrome coronavirus NS4b protein inhibits host ribonuclease l activation. MBio. 2016 Feb in press.
- Sui B, Huang J, Jha BK, Yin P, Zhou M, Fu ZF, Silverman RH, Weiss SR, Peng G, Zhao L. Crystal structure of the mouse hepatitis virus ns2 phosphodiesterase domain that antagonizes RNase L activation. J Gen Virol. 2016 Jan 12. doi: 10.1099/jgv.0.000395.
- Ogden KM, Hu L, Jha BK, Sankaran B, Weiss SR, Silverman RH, Patton JT, Prasad BV. Structural basis for 2'-5'-oligoadenylate binding and enzyme activity of a viral RNase L antagonist. J Virol. 2015 Jul;89(13):6633-45.
- Liu P, Liu J, Jiang WQ, Carew JS, Ogasawara M, Pelicano H, Croce C, Estrov Z, Xu R, Keating MJ, and Huang P. Elimination of chronic lymphocytic leukemia cells in stromal microenvironment by targeting CPT with an anti-angina drug perhexiline. (2016) Oncogene (in press)
- Klionsky D,…Carew JS,…Zughaier SM. Guidelines for the use and interpretation of assays (3rd edition). (2016) Autophagy 12:1-222.
- Visconte V, Nawrocki ST, Espitia CM, Kelly KR, Possemato A, Beausoleil SA, Han Y, Carraway HE, Nazha A, Advani AS, Maciejewski JP, Sekeres MA, and Carew JS. Comprehensive quantitative proteomic profiling of the pharmacodynamics changes induced by MLN4924 in acute myeloid leukemia cells establishes rationale for its combination with azacytidine. (2015) Leukemia (epub ahead of print)
- Kelly KR, Espitia CM, Zhao W, Wendlandt E, Tricot G, Zhan F, Carew JS, and Nawrocki ST. Junctional adhesion molecule-A is overexpressed in advanced multiple myeloma and determines response to reolysin. (2015) Oncotarget 6:41275-89.
- Nazha A, Seastone D, Radivoyevitch T, Dienes B, Przychodzen B, Carraway H, Patel B, Carew J, Makishima H, Sekeres M, Maciejewski JP. Genomic patterns associated with hyoplastic compared to hyper/normoblastic myelodysplastic syndromes. (2015) Haematologica 100:434-7.
- Carew JS, Espitia CM, Zhao W, Mita MM, Mita AC, and Nawrocki ST. Targeting survivin inhibits renal cell carcinoma progression and enhances the activity of temsirolimus. (2015) Mol Cancer Ther 14:1404-13.
- Nawrocki ST, Kelly KR, Smith PG, Keaton M, Carraway H, Sekeres M, Maciejewski J, and Carew JS. The NEDD8-activating enzyme inhibitor MLN4924 disrupts nucleotide metabolism and augments the efficacy of cytarabine. (2015) Clin Cancer Res 21:439-47.
- Vatolin S, Phillips JG, Jha BK, Govindgari S, Hu J, Grabowski D, Parker Y, Lindner DJ, Zhong F, Distelhorst CW, Smith MR, Cotta C, Xu Y, Chilakala S, Kuang RR, Tall S, Reu, FJ. Discovery of a Novel Protein Disulfide Isomerase Inhibiting Compound with In Vivo Activity against Myeloma by an Assay that Models Liver, Kidney and Bone Marrow. Revision submitted to Cancer Research.
- Bistulfi G, Affronti HC, Foster BA, Karasik E, Gillard B, Morrison C, Mohler J, Phillips JG, Smiraglia DJ. The essential role of methylthioadenosine phosphorylase in prostate cancer. Accepted for Oncotarget Jan 24, 2016
- Yard B, Adams DJ, Chie EK, Tamayo P, Battaglia JS, Gopal P, Rogacki K, Pearson B, Phillips JG, Cheah J, Clemons PA, Shamji A, Peacock CD, Schreiber SL, Hammerman PS, Abazeed ME. A genetic basis for variation in the vulnerability of cancer to DNA damage. Nature Communications (in press). Accepted for publication in Nature Communications with minor revisions
- Carew JS, Espitia CM, Zhao W, Han Y, Visconte V, Phillips JG, Nawrocki, ST. ROC-325: a novel inhibitor of autophagy with single agent in vivo anticancer activity. *Resubmitted for review to Autophagy
- Zhong B, Vatolin S, Idippily ND, Lama R, Alhadad LA, Reu FJ, Su B. Structural optimization of non-nucleoside DNA methyltransferase inhibitor as anti-cancer agent. Bioorg Med Chem Lett. 2016 Jan 9. [Epub ahead of print]
- Hong S, Valent J, Rybicki L, Abounader D, Bolwell B, Dean R, Gerds AT, Jagadeesh D, Hamilton BK, Hill B, Kalaycio ME, Pohlman B, Reu F, Samaras C, Sobecks R, Majhail NS, Liu HD. Outcomes of autologous hematopoietic cell transplantation in primary amyloidosis after bortezomib-based induction therapy. Bone Marrow Transplant. 2016 Jan 4. [Epub ahead of print].
- Lavik AR, Zhong F, Chang MJ, Greenberg E, Choudhary Y, Smith MR, McColl KS, Pink J, Reu FJ, Matsuyama S, Distelhorst CW. A synthetic peptide targeting the BH4 domain of Bcl-2 induces apoptosis in multiple myeloma and follicular lymphoma cells alone or in combination with agents targeting the BH3-binding pocket of Bcl-2. Oncotarget. 2015 6:27388-402.
- Li Y, Zheng Y, Li T, Wang Q, Qian J, Lu Y, Zhang M, Bi E, Yang M, Reu F, Yi Q, Cai Z. Chemokines CCL2, 3, 14 stimulate macrophage bone marrow homing, proliferation, and polarization in multiple myeloma. Oncotarget. 2015 Sep 15;6(27):24218-29.
- Saunthararajah Y, Sekeres M, Advani A, Mahfouz R, Durkin L, Radivoyevitch T, Englehaupt R, Juersivich J, Cooper K, Husseinzadeh H, Przychodzen B, Rump M, Hobson S, Earl M, Sobecks R, Dean R, Reu F, Tiu R, Hamilton B, Copelan E, Lichtin A, Hsi E, Kalaycio M, Maciejewski J. Evaluation of noncytotoxic DNMT1-depleting therapy in patients with myelodysplastic syndromes. J Clin Invest. 2015 125:1043-55
Our research focuses on identifying the genomic abnormalities which give rise to therapeutic resistance in cancers and using this information to develop personalized therapies in a new strategy of biologically-guided treatment. As a Radiation Oncologist with training in radiation science, genomics, and cellular and molecular biology, Dr. Abazeed uses his experience in both patient care and basic science to develop a clinically relevant research program to study cancers and to translate laboratory discoveries into potential improvements in clinical care. The goal of our efforts, through a highly integrative and collaborative research program, is to nominate therapeutic targets in cancer and to motivate an evolution in the use of therapy from a generic approach to one in which therapies are selected based on the molecular alterations identified in a patient’s tumor. This approach allows us to enhance efficacy and limit toxicity in the context of a new approach of precision therapy. We have recently developed a large body of data annotating the radiogenomic landscape of cancer and we are focused on studying recently discovered genomic alterations in order to better understand and therapeutically target cancers.
The main focus of our research is novel target discovery and small molecule therapeutic development against myeloid malignancies and hematological disorders. We are heavily invested in understanding the fundamental mechanism of the gain of survival function in cancer cells upon therapeutic treatment. We study cellular innate immunity and transcriptional reprogramming in cancer cells upon treatment with DNA damaging agents. We use structure guided small molecule design and synthesis to target oncogenic factors responsible for aberrant activation of cell survival. We use various state-of-the-art techniques in structural biology, biochemistry and molecular biology to tease out the detailed mechanism of cancer cell survival. Our long term goal is to develop a new generation of therapeutics against myeloid malignancies and hematological disorders.
We have an interest in inositol polyphosphate kinases, their enzymatic products, and the pathways by which they affect cell growth and apoptosis. Ongoing studies with IP6K2 knockout mice suggest that they are predisposed to development of head and neck carcinoma.
We are also utilizing a genetic approach to identify genes that may alter the phenotype of myelodysplastic syndrome and resultant bone marrow failure syndrome. Another focus of the laboratory is tumor induced angiogenesis. Utilizing murine models, we have shown that myeloid derived suppressor cells are early promoters of angiogenesis in renal cell carcinoma.
Our laboratory investigates pathogenesis of several hematopoietic disorders including aplastic anemia, paroxysmal nocturnal hemoglobinuria, myelodysplastic syndrome and chronic and acute myeloid malignancies. The research areas include stem cell biology, molecular pathogenesis of malignant transformation including mutations and DNA damage and immune mechanisms of hematopoietic suppression leading to deficient blood cell production. We apply high density DNA arrays, methylation arrays, high throughput sequencing, flow cytometry and various cell culture systems. All research projects are highly translational and have a goal to identify diagnostic and therapeutic targets in patients.
The McCrae laboratory focuses on vascular cell biology in pathologic disorders through study of endothelial cells in vitro and in vivo. We are primarily interested in two areas. One is the antiphospholipid syndrome (APS), a clinical disorder characterized by thrombosis and recurrent fetal loss. “Antiphospholipid” antibodies are actually not directed against phospholipid, but a phospholipid binding protein, β¬2-glycoprotein I (β2GPI).
We have shown that β2GPI binds to endothelial cells through cell surface annexin A2 (AII) and that cross linking of AII-bound β2GPI by bivalent anti-β2GPI antibodies leads to activation of endothelial cells; our focus is to define the mechanisms by which β2GPI/AII cross-linking leads to transmission of a transmembrane signal. We have also observed increased numbers of endothelial cell and platelet-derived microparticles in plasma of patients with APS.
Our other major interest is in the role of kininogen, a member of the intrinsic coagulation pathway, in regulation of angiogenesis. Upon cleavage, high molecular weight kininogen (HK) is converted to cleaved kininogen (HKa) with the release of bradykinin (BK). We have observed that HKa causes rapid apoptosis of proliferating endothelial cells, and inhibits angiogenesis. We have produced a kininogen deficient mouse, which displays a pro-angiogenic phenotype, and are exploring the mechanisms underlying this phenotype, which contrasts with other animal models of kininogen deficiency. Microarray studies suggest altered expression of a number of genes in tumors from kininogen deficient mice.
Clinical Focus: Genitourinary Cancers (e.g., Bladder, Prostate, Urethra, Kidney)
Research Mission: To improve outcomes and minimize treatment related toxicity through a better understanding of the interaction between radiation, the tumor environment, and the epigenome.
Research Overview: Cancer is fundamentally a genetic and epigenetic disease characterized by pervasive genomic disorganization. Epigenetic therapies are poised to change the landscape of cancer treatment and we have a unique opportunity in Radiation Oncology to harness these breakthroughs. In my laboratory we are interested in addressing two areas of clinical need in radiation oncology: 1) the utilization of epigenetic therapies (e.g., DNA methylation inhibitors, bromodomain inhibitors, HDAC inhibitors) and global modifiers of epigenetic programs (e.g., Methyl-CpG binding Proteins, Steroid hormone inhibitors) to enhance the efficacy of radiation therapy and 2) the need for reliable epigenetic biomarkers of disease burden, response to radiation therapy, early relapse, risk of radiation related normal tissue injury, and the underlying biology that distinguishes indolent from lethal phenotypes.
Our laboratory’s primary disease focuses include myelodysplastic syndromes, chronic and acute myeloid malignancies, myeloproliferative syndromes, multiple myeloma, and B-cell lymphomas. Our laboratory provides medicinal chemistry expertise. Working collaboratively with the principal investigators in the department of Translational Hematology and Oncology Research, our efforts are focused on using relevant biomarkers discovered within the department to develop more rationally designed small-molecule drugs. Present investigations involve the design and synthesis of LSD1 inhibitors, RNA helicase inhibitors, selective spliceosomal inhibitors, and ubiquitin transfer facilitators.
The goal of our young laboratory is to exploit epigenetic principles for the treatment of cancer in general and cancers of the antibody producing cells (multiple myeloma and related diseases) in particular. We use high throughput screening to identify molecules that selectively reactivate relevant tumor suppressor genes or silence oncogenes, followed by in vitro and in vivo preclinical drug development before translation into clinical study in multiple myeloma. Additionally we want to define the optimal use of already clinically available epigenetic drugs for the treatment of multiple myeloma, like in a clinical trial that uses azacitidine and measures DNA demethylation and tumor suppressor gene re-expression in bone marrow myeloma cells.
A major objective of our work is to develop therapy that selectively destroys malignant cells while sparing normal stem cells. To this end, our work covers a number of aspects: one aspect focuses on understanding the mechanisms by which malignant stem cells self-renew, and finding differences between malignant self-renewal and normal stem cell self-renewal. Another aspect focuses on identifying and developing drug-able compounds that target identified differences between normal and malignant self-renewal. A final aspect studies the pharmacologic properties and considerations of proposed agents to enable the clinical trials for selective malignant stem cell destruction. The other major objective of our efforts is to develop more effective methods for pharmacologic reactivation of fetal hemoglobin expression as a treatment for sickle cell disease and beta-thalassemia.
Clinical Focus: Sarcoma
Research Mission: To understand how cancers acquire resistance to targeted biological agents and radiation and to harness this knowledge to design better therapeutic strategies for our patients.
Research Overview: Cancer is a complex disease that is an aberration of our own tissues, but it still obeys fundamental biological rules. Our greatest challenge in the clinic is the emergence of resistance to our therapies, a process which is governed by Darwinian evolution. Using a suite of mathematical and experimental models, my laboratory seeks to deconvolute the complexity of the evolutionary process into fundamental principles. We aim to use this knowledge to then curtail the evolutionary process to increase the efficacy of targeted therapies and radiation. This same knowledge can be further harnessed to understand the differences in disease progression and therapy response on a personalized basis, so that the right treatment can be given to the right patient at the right time.
Research Administrative Coordinator
THOR Primary Investigators
- James Philips, PhD
- Fred Reu, MD
- Yogen Saunthararajah, MD
THOR Secondary Investigators
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