Acute Myeloid Leukemia- How can we fix it?

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1 Acute Myeloid Leukemia- ow can we fix it? Jeffrey W. Taub, M.D. Division of ematology/ncology Children s ospital of Michigan Wayne State University School of Medicine Detroit, Michigan

2 Proliferation of immature forms of white blood cells whose development into mature white blood cells is blocked. Symptoms related to infiltration of the bone marrow with production of normal bone marrow cells: neutropenia (low levels of granulocytes/neutrophils, anemia (low red blood cells) and thrombocytopenia (low platelets). What is Leukemia?

3 Subclasses of Leukemia Acute Lymphoblastic Leukemia (ALL) Acute Myeloid Leukemia (AML) Subtypes M0-M7 [Cure: 20-50%] 500 pediatric cases/year in the U.S. Most common acute leukemia in adults. AML is treated with short but intensive chemotherapy and frequently stem cell transplants are considered part of the front line treatment along with chemotherapy. ALL AML

4 Strategies to Improve AML Treatments Identify subgroups which have a good prognosis. Down syndrome Identify selective drugs which may have a broad range of activity against multiple cancers (including leukemia). istone deacetylase inhibitors (panobinostat) Develop or synthesize new selective drugs by combining the essential/key structures of chemotherapy drugs. istone deacetylase inhibitors + wee1 Kinase inhibitor.

5 Down Syndrome Acute Myeloid Leukemia (DS-AML) Children with Down syndrome (DS) have a fold higher risk of developing leukemia (both ALL and AML) compared to children without DS. Clinical and biological features of DS-AML are unique including: i) pre-leukemia condition, the transient myeloproliferative disorder (TMD) diagnosed in ~25% of DS newborns which resolves spontaneously. ~20-30% of patients will subsequently develop DS-AML before the age of 4 years. ii) 500-fold increased risk of developing the AML subtype, acute megakaryocytic leukemia (AMKL).

6 Children s ncology Group CG AAML0431: Study Entry < 4 years of age at diagnosis Induction I CI-TAD + IT AraC The Treatment of Down Syndrome Children with Acute Myeloid Leukemia and Myelodysplastic Syndrome Under the Age of 4 Years Jeffrey Taub Protocol Chair Induction II Capizzi II Course Induction III CI-TAD + IT AraC Induction IV CI-TAD Intensification I VP/Ara-C Intensification II VP/Ara-C BMA/MRD Follow-Up BMA = Bone Marrow Aspirate. MRD = Minimal Residual Disease CI-TAD: Continuous Infusion Cytarabine (AraC)/Daunorubicin + 6-Thioguanine CR = Complete Response PR = Partial Response RD = Refractory Diease Capizzi II: Cytarabine (AraC)/L-asparaginase VP/Ara-C: Etoposide/Cytarabine (AraC) IT AraC: Intrathecal Cytarabine

7 verall Survival S: 92.7% = Years from Study Entry 1 Event Free Survival EFS:90% = Years from Study Entry

8 Why does DS-AML have very high cure rates? A I II III IV V VI GATA1 Chr Xp terminus Zinc finger domain C-terminus Ara-U Ara-UMP chromosome 21 FG-1 f Cf GATC(A/T)GATA(A/G) GATA1 (50kDa) Ara-C dcyd CDA dck Ara-C dctp dttp dck dcyd Ara-CMP dcmp dump TS dcmpda dcmpda Ara-CTP dctp Reduced folate/ S-adenosylmethioine pathways DA B trisomy 21 ormal megakaryocyte and erythroid cell development I II III IV V VI mutated GATA1 FG-1 Zinc finger domain C-terminus f Cf GATA1s (40kDa) GATC(A/T)GATA(A/G) Acute megakaryocytic leukemia transformation dttp CBS

9 ew Drugs Frequently drugs in development or approved by the FDA for one specific cancer, may be beneficial for other cancers. istone deacetylase inhibitors are a new category of chemotherapy drugs which have multiple different mechanisms which can kill cancer cells. Panobinostat is a newly approved drug by the FDA for treating multiple myeloma.

10 Control Panobinostat Cytarabine Combination Day 11 Day 18 RAD51 BRCA1 CK1 β-actin Bone Marrow C P Day 24 Day 32 Median Radiance p/s/cm²/sr (x10 7 ) Vehicle Panobinostat Ara-C Combination Time (Days) verall Survival Probability 100 Vehicle (=10) Panobinostat (=8) 80 Ara-C (=10) 60 Combination (=8) Time (Days)

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12 Designing ew Drugs The active structure of chemotherapy drugs can be altered/modified by medicinal chemists to try and improve their activity and/or reduce side effects.

13 Chemical structures of panobinostat, vorinostat, MK-1775 and the designed hybrid (dual-acting) drugs A: modifications on 4-(4-Methyl piperazino) aniline MK-1775 Panobinostat Linker B: modofications on 2-(6-Bromopyridin-2- yl)-2-propanol Linker Cap Vorinostat Linker Zinc binding group n n n=0 or 1 C n=1 to 7 D E F 1' 4' 5' n n=1 to 7

14 Proposed synthesis of target compounds 9-12 MeS mcpba Me 2 S Amine 3,4,5 R TP Amine or TP 3 2 Cl n( 2 C) TP then + (C 2 )n n= or (C 2 )n n=1-7 12

15 Acknowledgments CM/KCI/WSU Dr. Yubin Ge Dr. Larry Matherly Dr. Alan Dombkowski Dr. J. Timothy Caldwell Dr. Zhihui Qin olly Edwards Steven Buck akland University Dr. Gerard Madlambayan