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The Aurora kinases are a family of serine/threonine kinases that mediate essential functions in cell division. Aurora A depletion results in accumulation of cells in the G2/M phase and apoptosis. Inhibition of Aurora B/C results in abnormal cell division, polyploidy, resulting in apoptosis, therefore, Aurora kinases present an attractive target for chemotherapy. Cells treated with aurora inhibitors enter mitosis with normal kinetics but fail to undergo cytokinesis due to mitotic spindle checkpoint disruption. ABT-348 is a novel adenosine triphosphate (ATP)-competitive inhibitor of Aurora A, Aurora B, and Aurora C (Enzyme IC50 A=116, B=5, C= 1 nM) and a potent inhibitor of all members of the VEGF and PDGF family of receptor tyrosine kinases (RTKs). Despite significant advances in the epidemiological, genetic and biological understanding of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), the basic therapeutic approach has not substantially changed for the last 10-15 years, so most patients still die of this disease. Here we demonstrate profound in vivo efficacy (with regressions) of ABT-348 in both AML (MV-4-11, FLT3 mutant expressing the internal tandem duplication with constitutive kinase activation) and MDS (SKM-1) xenograft models. MV-4-11 tumor-bearing SCID mice were treated at 6.25, 12.5 and 25 mg/kg/day, p.o., q7d x 3 (%TGI ratios on day 30 were 80, 86 and 94%, respectively). SKM-1 tumor-bearing SCID mice were treated at 6.25, 12.5 and 25 mg/kg/day, p.o., q7d x 3 (% tumor growth inhibition or TGI ratios on day 30 were 38, 59 and 80%, respectively). In addition, ABT-348 provided additive effects when combined with cytarabine, decitabine or doxorubicin compared to cytotoxic monotherapies. The treatments were well tolerated with no animal health concerns observed indicating the feasibility of ABT-348 combination strategies in the clinic. Currently ABT-348 is being evaluated (monotherapy and in combination with cytotoxic therapies) in the HL-60 acute promyelocytic leukemia xenograft model in vivo. Dose/scheduling studies for combination therapies in the SKM-1 and HL-60 xenografts are ongoing. Pharmacokinetic/pharmacodynamic biomarker analyses in these xenograft models were evaluated using phospho-H3 (an Aurora B substrate, proliferation) and cleaved caspase-3 (apoptosis) by IHC at various timepoints post single dose (1/2 hr to 5 days). A general decrease in proliferation and increase in apoptosis consistent with the mechanism of action was observed which coincided with the potent in vivo efficacy in xenograft models. Overall, ABT-348 is a potent, oral Aurora kinase inhibitor, demonstrating robust in antitumor activity in AML and MDS xenograft models with a good safety profile that warrants investigation in the clinic. ABT-348 is currently undergoing Phase I clinical trials in advanced hematologic malignancies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 858. doi:1538-7445.AM2012-858

The Aurora kinases are a family of serine/threonine kinases that mediate multiple essential functions in cell division. Aurora A depletion results in accumulation of cells in the G2/M phase and apoptosis. Inhibition of Aurora B/C results in abnormal cell division, polyploidy, followed by apoptosis, therefore, Aurora kinases present an attractive target for chemotherapy. Cells treated with aurora inhibitors enter mitosis with normal kinetics but fail to undergo cytokinesis due to a disruption of the mitotic spindle checkpoint. ABT-348 is a novel adenosine triphosphate (ATP)-competitive inhibitor of Aurora A, Aurora B, and Aurora C (Enzyme IC50 A=116, B=5, C= 1 nM) and a potent inhibitor of all members of the VEGF and PDGF family of receptor tyrosine kinases (RTK). Here we demonstrate profound in vivo efficacy (with regressions) in a broad spectrum of histological types (breast, colon, NSCLC, HNSCC, melanoma, ovarian, pancreatic, prostate, leukemia, lymphoma and renal; 50–94% TGI, tumor growth inhibition). The treatment was well tolerated with no animal health concerns observed. In addition, ABT-348 was also efficacious in tumor xenografts overexpressing P-gp and provided significant in vivo efficacy in comparison to competitor compounds in colon, NSCLC and ovarian xenograft models. Various dosing schemes to achieve optimal efficacy (IV, OMP and PO) were investigated. The anti-tumor efficacy of ABT-348 was not affected by the route of administration. Similar efficacy was achieved by IV, OMP or PO administration, once weekly in a dose-dependent manner. Pharmacokinetic/pharmacodynamic biomarker analysis in select tumor xenograft models were evaluated by phospho-H3 (an Aurora B substrate, proliferation marker) and cleaved caspase-3 (apoptosis marker) by IHC at various timepoints post single dose (6 hr to 9 days). Significant levels of ABT-348 were detected in the plasma and tumor. A general decrease in proliferation and increase in apoptosis consistent with the mechanism of action was observed and coincide with the potent in vivo efficacy in xenograft models. Overall, ABT-348 is a potent, oral Aurora kinase inhibitor, demonstrating robust in vitro and in vivo antitumor activity with a good safety profile that warrants investigation in the clinic. ABT-348, is currently undergoing Phase I clinical trials in both solid and hematologic malignancies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B231.

PARP's role in DNA damage recognition/repair makes PARP inhibition an attractive cancer therapeutic target. Veliparib (ABT-888) is a potent PARP inhibitor with excellent oral bioavailability that readily crosses the blood-brain barrier and is currently in Phase 2 clinical trials. Veliparib has shown significant ability to potentiate multiple DNA damaging agents (cisplatin, carboplatin, cyclophosphamide, irinotecan, radiation and temozolomide) in a spectrum of tumors from multiple histological types. In studies using cytotoxic combinations with veliparib (cisplatin, cyclophosphamide, TMZ) there was a marked increase in efficacy over cytotoxic monotherapies, especially in the MX-1 breast model. Since DNA repair deficiencies (e.g. HR-defective) are known to render cells very sensitive to PARP inhibition, we genotyped the MX-1 breast line and found it to be HR-deficient. Subsequent studies with both the MX-1 (BRCA1-deleted and BRCA2-mutated breast line) and the Capan-1 (BRCA2-deficient pancreatic cancer cell line), showed that veliparib (25 mg/kg/day, p.o., b.i.d.×5) demonstrated enhancement of TMZ (50 mg/kg/day, p.o., q.d.×5) activity, with regressions compared to TMZ alone (81–97% TGI, tumor growth inhibition). Continuous dosing at 4×-8× higher doses (100 and 200 mg/kg/day, p.o., b.i.d.×21) demonstrated a significant single agent, dose-responsive activity (26–87% TGI). Similar results were observed with single agent veliparib treatment of BRCA isogenic cell lines in vitro. Further, the combination treatment of veliparib (100 and 200 mg/kg/day, p.o., b.i.d.×21) with carboplatin, carbotaxol, radiation, gemcar, cyclophosphamide, topotecan and TMZ also demonstrated a measurable advantage over either veliparib or cytotoxic agent alone. Both high dose single agent veliparib and the cytotoxic combination therapy were well tolerated and there were no observable animal health concerns; this indicated the feasibility of using the single agent and cytotoxic combination regimen in the clinic. Analysis of tumors for the reduction of PAR after veliparib treatment demonstrated a correlative and significant reduction by western blot indicating the ability of veliparib to inhibit PARP activity in vivo. Altogether, our studies show the strong activity of veliparib as a single agent in BRCA-deficient xenografts as well as the enhanced activity and tolerability of veliparib in combination with various cytotoxic agents. These results warrant investigation of single agent therapy and cytotoxic combination regimens in BRCA-deficient patients to further the clinical development of veliparib. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B62.