Effective therapies for acute leukemias have been developed incrementally, advanced by the development of agents with different mechanisms of action. Sapacitabine, the orally bioavailable form of CNDAC (2'-Ccyano- 2'-deoxy-1-/3-D-ara?>/no-pentofuranosyl- cytosine), is a potent cytosine nucleoside analogue with a novel mechanism of action. The design of CNDAC was based on the concept that once its triphosphate is incorporated into DMA, the addition of a subsequent deoxynucleotide would initiate 3-elimination, resulting in cleavage of the 3'-5'phosphodiester linkage and conversion of incorporated analogue to a chain-terminating nucleotide, CNddC. Clinically active in phase I studies, the mechanisms of action of sapacitabine are unique among therapeutic agents, as it causes a single strand nick in DMA that is terminated by a nucleotide that cannot be extended and is resistant to repair. Our hypothesis is that sapacitabine will elicit novel pharmacodynamic responses for detecting DMA damage, for repair of the lesions, and for activation of cell cycle checkpoints that will serve as biomarkers to guide clinical development of sapacitabine alone and in combination with targeted inhibitors of these pathways. We will conduct translational studies in primary leukemia cells in vitro and during therapy that will complement and extend ongoing laboratory investigations.
The specific aims for testing this hypothesis are: 1. Evaluate pharmacokinetics and pharmacodynamics of sapacitabine during phase l/ll clinical trials in patients with relapsed/refractory leukemias, 2. Characterize biomarkers for cellular responses to sapacitabine, 3. Formulate laboratory rationales for clinical translation of mechanism-based combinations of sapacitabine with small molecule inhibitors. The overall goal of our proposal is aimed at developing a thorough understanding of cellular responses to sapacitabine that will identify biomarkers that have prognostic value to optimize patient selection and schedules of administration in the clinic, and to provide rationales for combinations with agents targeted at inhibiting DMA damage sensors, DNA repair mechanisms, and dysregulating checkpoint controls. Lay abstract: We have identified a drug candidate that kills cancer cells in ways that are different from all other drugs. We have shown that it active treatment in humans with leukemia who have not responded to standard therapies, and propose laboratory and clinical studies that may increase its effectiveness at treating these and other cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA100632-07
Application #
7826871
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2009-05-01
Budget End
2010-04-30
Support Year
7
Fiscal Year
2009
Total Cost
$256,449
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Type
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Zhang, Hanghang; Pandey, Somnath; Travers, Meghan et al. (2018) Targeting CDK9 Reactivates Epigenetically Silenced Genes in Cancer. Cell 175:1244-1258.e26
Morita, Kiyomi; Kantarjian, Hagop M; Wang, Feng et al. (2018) Clearance of Somatic Mutations at Remission and the Risk of Relapse in Acute Myeloid Leukemia. J Clin Oncol 36:1788-1797
Fiorini, Elena; Santoni, Andrea; Colla, Simona (2018) Dysfunctional telomeres and hematological disorders. Differentiation 100:1-11
Cortes, Jorge; Perl, Alexander E; Döhner, Hartmut et al. (2018) Quizartinib, an FLT3 inhibitor, as monotherapy in patients with relapsed or refractory acute myeloid leukaemia: an open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol 19:889-903
Zhang, Weiguo; Ly, Charlie; Ishizawa, Jo et al. (2018) Combinatorial targeting of XPO1 and FLT3 exerts synergistic anti-leukemia effects through induction of differentiation and apoptosis in FLT3-mutated acute myeloid leukemias: from concept to clinical trial. Haematologica 103:1642-1653
Takahashi, Koichi; Wang, Feng; Morita, Kiyomi et al. (2018) Integrative genomic analysis of adult mixed phenotype acute leukemia delineates lineage associated molecular subtypes. Nat Commun 9:2670
Ishizawa, Jo; Nakamaru, Kenji; Seki, Takahiko et al. (2018) Predictive Gene Signatures Determine Tumor Sensitivity to MDM2 Inhibition. Cancer Res 78:2721-2731
Kayser, Sabine; Levis, Mark J (2018) Advances in targeted therapy for acute myeloid leukaemia. Br J Haematol 180:484-500
Xia, Fang; Ning, Jing; Huang, Xuelin (2018) Empirical Comparison of the Breslow Estimator and the Kalbfleisch Prentice Estimator for Survival Functions. J Biom Biostat 9:
Trujillo-Ocampo, Abel; Cho, Hyun-Woo; Herrmann, Amanda C et al. (2018) Rapid ex vivo expansion of highly enriched human invariant natural killer T cells via single antigenic stimulation for cell therapy to prevent graft-versus-host disease. Cytotherapy 20:1089-1101

Showing the most recent 10 out of 487 publications