This K24 application has supported my career development in patient oriented research and mentoring. The original grant focused on clinical studies using new agents which putatively target epigenetically-mediated aberrant gene transcription in cancer. These included a Phase I study of a novel combination of the DNA methyltransferase inhibitor 5-azacytidine (5AC) with an oral histone deacetylase (HDAC) inhibitor entinostat in patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML);a randomized Phase II trial of two schedules of the HDAC inhibitor vorinostat in patients with relapsed or high risk AML;and a national US Leukemia Intergroup randomized Phase II trial (E1905) comparing the 5AC/entinostat combination to 5AC alone for the treatment of MDS, chronic myelomonocytic leukemia, and AML with trilineage dysplasia (MDS-associated, AML-TLD). Together with intensive correlative laboratory science aimed at dissecting the mechanisms by which these """"""""epigenetically targeted"""""""" drugs exert their clinical activity, these studies have been fertile ground for intensive mentoring of pre- and post-doctoral trainees in biologically-driven drug development. This renewal application requests an additional five years of funding to continue my development in patient oriented research and mentoring as I continue to build integrated programs in epigenetically targeted drug development in hematologic malignancies at Johns Hopkins and nationally, and increase my abilities and reach as a mentor to more junior faculty at Hopkins and at other institutions. The research in which mentees will be involved includes the correlative science associated with E1905, which is the first major trial to critically assess the clinical benefit of the addition of an HDAC inhibitor to a DNA methyltransferase inhibitor. These combinations have been developed based on in vitro data demonstrating synergistic re-expression of genes silenced through methylation of cytosines in gene promoters. The correlative studies focus on identifying alterations and signatures in the DNA methylome upon treatment, which correlate with clinical response to 5AC/entinostat.
The second aim will compare clinical outcomes when entinostat is given in a sequential manner (following 5AC) rather than the current overlapping schedule.
The third aim will examine to what extent epigenetic modifications differ when the HDAC inhibitor is given concomitantly with the DNMT inhibitor versus sequential administration
Drugs which target aberrant transcription in cancer through modification of epigenetic marks demonstrate marked activity in myeloid leukemias;however the mechanism by which these drugs improve clinical outcome remains uncertain. Understanding the mechanism underlying clinically activity is critical for development of better drugs, and for the effective development of epigenetically-targeted strategies in other more common cancers.
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|Podoltsev, Nikolai A; Stahl, Maximilian; Zeidan, Amer M et al. (2016) Selecting initial treatment of acute myeloid leukaemia in older adults. Blood Rev :|
|Ball, Brian; Zeidan, Amer; Gore, Steven D et al. (2016) Hypomethylating agent combination strategies in myelodysplastic syndromes: hopes and shortcomings. Leuk Lymphoma :1-15|
|Kim, Tae Kon; Xu, Mina L; Podoltsev, Nikolai A et al. (2016) Single agent blinatumumab as frontline therapy for an 85-year-old patient with B cell precursor acute lymphoblastic leukemia. Ann Hematol 95:1895-8|
|Zeidan, Amer M; Wang, Rong; Gross, Cary P et al. (2016) Modest improvement in survival of patients with refractory anemia with excess blasts in the hypomethylating agents era in the United States. Leuk Lymphoma :1-4|
|Prebet, Thomas; Sun, Zhuoxin; Ketterling, Rhett P et al. (2016) Azacitidine with or without Entinostat for the treatment of therapy-related myeloid neoplasm: further results of the E1905 North American Leukemia Intergroup study. Br J Haematol 172:384-91|
|Zeidan, A M; Sekeres, M A; Garcia-Manero, G et al. (2016) Comparison of risk stratification tools in predicting outcomes of patients with higher-risk myelodysplastic syndromes treated with azanucleosides. Leukemia 30:649-57|
|Pine, Alexander B; Lee, Eun-Ju; Sekeres, Mikkael et al. (2016) Wide variations in blood product transfusion practices among providers who care for patients with acute leukemia in the United States. Transfusion :|
|Wang, Rong; Zeidan, Amer M; Yu, James B et al. (2016) Myelodysplastic Syndromes and Acute Myeloid Leukemia After Radiotherapy for Prostate Cancer: A Population-Based Study. Prostate :|
|Fletcher, Sean A; Cronin, Angel M; Zeidan, Amer M et al. (2016) Intensity of end-of-life care for patients with myelodysplastic syndromes: Findings from a large national database. Cancer 122:1209-15|
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