Program: Oral and Poster Abstracts
Session: 616. Acute Myeloid Leukemia: Novel Therapy, excluding Transplantation: Poster I
Methods: We used an ex vivo drug sensitivity assay to determine the activity of APTO-253, JQ1, and quizartinib across increasing concentrations of each agent up to 10 μM. Combinations were tested at fixed, equimolar ratios over the same concentration range. After a 3-day ex vivo culture, cell viability was assessed using a colorimetric tetrazolium-based MTS assay, and IC50 values were calculated. RNA-Seq was performed on AML specimens to permit investigation of correlations of drug sensitivity with gene expression levels.
Results: We evaluated specimens from 177 patients with a variety of hematologic malignancy diagnoses (80 AML, 72 CLL, 25 MDS/MPN). The highest frequency of APTO-253 sensitivity occurred in AML, with 43/80 (54%) samples exhibiting an IC50 <1 μM. At this cutoff, 25/72 (35%) CLL samples and 3/25 (12%) MDS/MPN samples were sensitive to APTO-253. The average expression of KLF4 mRNA was 2-fold lower among AML samples with an IC50 <1 µM compared to those with IC50 >1 µM (p=0.07). Approximately 65% (56/87) of cases tested with a combination of APTO-253 and JQ1 showed the combination IC50 to be at least 2-fold lower than the IC50 of either agent alone. This enhanced efficacy of APTO-253 with JQ1 was observed across all 3 hematologic malignancies tested, whereas quizartinib enhancement of APTO-253 sensitivity was confined to AML (14/38, or 37% showed reduced IC50).
Conclusions: These results support the potential of KLF4 as an important and frequently dysregulated master transcription factor in AML and suggest that the KLF4 inducer APTO-253 is effective at killing tumor cells in a majority of AML samples. The data also indicate activity of APTO-253 in other hematologic malignancies, namely CLL. Expression level of KLF4 may be one component of a biomarker for prediction of APTO-253 efficacy; a more extensive global gene expression signature analysis is under way. Finally, these data have identified prominent interaction of APTO-253 with the BET bromodomain inhibitor JQ1, as well as AML-restricted interaction of APTO-253 with the FLT3 inhibitor quizartinib, suggesting these classes of drugs as potential combination partners for APTO-253.
Disclosures: Rice: Aptose Biosciences: Employment , Equity Ownership , Membership on an entity’s Board of Directors or advisory committees . Howell: Aptose Biosciences: Consultancy , Equity Ownership ; Angstrom: Equity Ownership , Membership on an entity’s Board of Directors or advisory committees ; Abeoda: Equity Ownership , Membership on an entity’s Board of Directors or advisory committees ; InhibRx: Equity Ownership . Vellanki: Aptose Biosciences: Employment , Equity Ownership . Druker: Oncotide Pharmaceuticals: Research Funding ; Sage Bionetworks: Research Funding ; Fred Hutchinson Cancer Research Center: Research Funding ; Bristol-Myers Squibb: Research Funding ; Novartis Pharmaceuticals: Research Funding ; Henry Stewart Talks: Patents & Royalties ; McGraw Hill: Patents & Royalties ; Leukemia & Lymphoma Society: Membership on an entity’s Board of Directors or advisory committees , Research Funding ; Blueprint Medicines: Consultancy , Equity Ownership , Membership on an entity’s Board of Directors or advisory committees ; Oregon Health & Science University: Patents & Royalties ; MolecularMD: Consultancy , Equity Ownership , Membership on an entity’s Board of Directors or advisory committees ; Gilead Sciences: Consultancy , Membership on an entity’s Board of Directors or advisory committees ; ARIAD: Research Funding ; AstraZeneca: Consultancy ; Aptose Therapeutics, Inc (formerly Lorus): Consultancy , Equity Ownership , Membership on an entity’s Board of Directors or advisory committees ; CTI Biosciences: Consultancy , Equity Ownership , Membership on an entity’s Board of Directors or advisory committees ; Millipore: Patents & Royalties ; Roche TCRC, Inc.: Consultancy , Membership on an entity’s Board of Directors or advisory committees ; Cylene Pharmaceuticals: Consultancy , Equity Ownership , Membership on an entity’s Board of Directors or advisory committees . Tyner: Incyte: Research Funding ; Janssen Pharmaceuticals: Research Funding ; Constellation Pharmaceuticals: Research Funding ; Array Biopharma: Research Funding ; Aptose Biosciences: Research Funding .
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