Abstract 1322: Novel CDK4/6 inhibitors provide robust antitumor activity in a murine model of luminal breast cancer

Abstract

Abstract Introduction: Selective CDK4/6 inhibitors have emerged as attractive antineoplastic agents due to the importance of CDK4/6 activity in regulating cell proliferation. We have identified a series of orally available, potent and selective dual CDK4/6 inhibitors (G1T100182, G1T100183, G1T101551). Preclinical characterization of these compounds indicates that they inhibit CDK4 and CDK6 with an IC50 of 0.7-1.0 nM and 5-6 nM, respectively. In Rb competent tumor cells, these compounds potently inhibit Rb phosphorylation resulting in a G1 arrest. Here we assess the in vivo efficacy of these compounds in a genetically engineered mouse model of luminal breast cancer. Methods: MMTV-Neu mice were housed and therapeutic response assessed in the UNC Lineberger Comprehensive Cancer Center's Mouse Phase I Unit (MP1U). Compounds were supplied by G1 Therapeutics, Inc. Tumors were serially assessed weekly using caliper measurements. Therapeutic intervention began once tumors reached 40-64mm3 and continued for 28 consecutive days. Tumor volume was calculated using the formula ((Width2) x Length)/2). All compounds were administered orally via medicated diets. RECIST criteria were used to assess objective response rates. Results: Significant objective responses were noted in mice treated with G1T100182, G1T100183, G1T101551. Treatments produced modest reversible myelosuppression, but where otherwise well tolerated with no other clinical signs of toxicity or deaths associated with toxicity. A linear regression t-test was used to determine statistical significance of tumor volume changes over time. All treatment cohorts demonstrated statistically significant improvement when compared to un-treated mice; G1T100182, p<0.0001; G1T100183, p=0.0001; G1T101551, p<0.0001. Conclusions: In summary, we have identified a series of orally active, potent, and selective small molecule inhibitors of CDK4/6 that may provide therapeutic benefit to cancer patients with tumors that have functional Rb protein. Complete ResponsePartial ResponseStable DiseaseProgressive DiseaseORR % (CR+PR+SD/PD)Mean % Change in Tumor VolNo Treatment00090 (0/9)500G1T1001821510100 (7/0)-70G1T100183141185 (6/1)-67G1T1015511250100 (8/0)-40 Citation Format: Patrick J. Roberts, David B. Darr, John E. Bisi, Jay C. Strum. Novel CDK4/6 inhibitors provide robust antitumor activity in a murine model of luminal breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1322. doi:10.1158/1538-7445.AM2014-1322