Abstract C243: Activity of BTK and HDAC inhibitors alone and in combination in a mouse model of non-small cell lung cancer.

Abstract

Abstract Background: The effectiveness of two drugs, a Bruton's Tyrosine Kinase inhibitor (BTKi: ibrutinib, PCI-32765) and a histone deacetylase inhibitor (HDACi: abexinostat, PCI-24781), was tested on a mouse model for non-small lung cancer (NSCLC). The Grg1 mouse model is a transgenic mouse line that overexpresses the Groucho-related gene (Grg1; TLE1 in humans) and develops tumors that resemble human non-small cell lung cancer. The tumors initiate at 1 month of age, progress to bronchioalveolar carcinoma, and continue to invasive adenocarcinoma by 8 months. Both abexinostat and ibrutinib have shown promising activity as single agents in hematologic malignancies in the clinic. In this model, abexinostat was tested to determine if it was effective against the Grg1/HDAC function in lung tumor growth. Ibrutinib was tested to determine if this drug had activity in vivo in solid tumors, and if so further determine the mechanism of action. Lastly, it was of interest to determine if the combination of these agents with possibly different mechanism would be more or less active compared to the single agents. Methods: Mice were treated with the drugs or vehicle in two therapeutic settings: early intervention, starting at 2 months or late intervention starting at 5 months of age. In both cases, the drugs were administered for 4 weeks, 5 days per week. Following treatment, mice were sacrificed and visible tumors on the lung surface were counted using a dissecting microscope. In addition, the left lobe was used for histological analysis and the number of tumors in 5 um sections over two levels of 100 um was determined. Tumors in the sections were counted and tumor diameter was measured. Results: In the 3 month old cohort (Figure 1), the average number of surface visible tumors in untreated mice was 5.9 (n=10), BTKi-treated mice was 2.6 (n=8), HDACi-treated mice was 2.9 (n=9), and BTKi and HDACi-treated mice was 1.4 (n=11). In the serial sections the number of tumors in untreated mice was 5, BTKi-treated was 2, HDACi-treated was 3 and BTKi and HDACi-treated was 3 (n=4 for all groups). In the 6 month old cohort, the average number per mice of surface visible tumors in untreated mice was variable and ranged from 0 to 13 tumors. However the number of large tumors (over 1 mm) was higher for the untreated mice than the treated mice (untreated: 1.0; BTKi-treated: 0.2, HDACi-treated: 0.2, BTKi and HDACi treated: 0.2; n=5 for all groups). Pharmacodynamic analysis of the tumors showed histone acetylation in abexinostat-treated tumors, but did not reveal BTK expression or occupancy with a fluorescent-labeled probe. However, significant differences were observed in immune-cell infiltration in the large tumors. While the large control tumors exhibited areas of necrotic cell death, HDACi-treated tumors had larger areas of tumor cell death as well as apoptotic macrophages whereas BTKi-treated tumors had few or no infiltrating live or apoptotic macrophages. Conclusions: NSCLC tumors and others solid tumors that over-express Grg1 may respond to treatment with HDACi or BTKi by different mechanisms; the combination is more active than either agent alone. Interestingly, even solid tumors, such as lung cancer, may respond to immunomodulatory drugs such as BTK inhibitors by modulating infiltrating immune cells. Abexinostat and ibrutinib thus may have potential as a combination for treating solid tumors. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C243. Citation Format: Corrinne G. Lobe, Michael J. Allain, Wenyi Yang, Mint Sirisawad, Sriram Balasubramanian. Activity of BTK and HDAC inhibitors alone and in combination in a mouse model of non-small cell lung cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C243.