Program: Oral and Poster Abstracts
Session: 616. Acute Myeloid Leukemia: Novel Therapy, excluding Transplantation: Poster I
Our in vitro and in vivo data support the clinical potential of a novel orally bioavailable inhibitor of CDK9, CDKI-73, as an effective therapy for MLL-AML patients. CDKI-73 is a potent inhibitor of CDK9 (Ki 3.5nM)1 and has been shown to induce down-regulation of MCL1, and cell death of Chronic Lymphocytic Leukemia (CLL) B-cells2 and Ovarian Cancer (OvCa) cells3 with nanomolar potency. At doses that are highly toxic for tumour cells, CDKI-73 shows limited toxicity for normal T- and B- Lymphocytes, Bone Marrow Mononuclear cells (BMMNC) and normal colony forming cells (CFC) from the BMMNC fraction. CDKI-73 has many favorable properties also making it an excellent clinical candidate for AML when compared to other CDK9i; in particular, CDKI-73 is (i) unique in its spectrum of inhibition, including targeting CDK6 (IC50 = 0.038 µM; a critical kinase for MLL-AML4), and is (ii) orally bioavailable (F = 56%)2, facilitating sustained in vivo target inhibition.
Here we present data showing that in MLL-AML cell lines, CDKI-73 induces growth suppression and apoptosis associated with rapid loss of Myc and MCL1, and activation of PARP. In primary AML patient samples treated with 200nM CDKI-73, we have observed a similar decrease in MCL1 protein levels, with increased 7AAD uptake and Annexin-V staining, consistent with apoptotic cell death.
Using a subcutaneous MV4;11 nude mouse xenograft model, we have shown that oral dosing of CDKI-73 (100 mg/kg once every 3 days for 18 days) resulted in a high level of anti-tumour efficacy (p<0.0001 compared to vehicle-treated mice), with minimal toxicity. Moreover, for an established MLL-AML patient-derived xenograft (PDX) generated in NOD/SCID-IL2RG-/- (NSG) mice we also observed significant inhibition of human AML in peripheral blood (p<0.0001), BM (p<0.05) and spleen (p<0.001) with administration of CDKI-73 at 75 mg/kg every 3 days for 15 days. In both models CDKI-73 was well-tolerated at these doses, consistent with our published and preliminary data showing differential effects of CDKI-73 on tumour versus normal cell populations.
Given this data, our priority now is to establish the effectiveness of CDKI-73 across a larger panel of primary MLL-AML samples, in further patient derived AML xenografts, and as a combination treatment with AML chemotherapy.
REFERENCES:
1. Shao H, Shi S, et al. (2013). J Med Chem. 56(3):640-59.
2. Walsby E, Pratt G, et al. (2014). Oncotarget. 5(2):375-85.
3. Lam F, Abbas AY, et al. (2014). Oncotarget. 5(17):7691-704.
4. Placke T, Faber K, et al. (2014). Blood. 124(1):13-23.
Disclosures: No relevant conflicts of interest to declare.
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