Abstract B112: Synergistic anti-lymphoma activity of ibrutinib and dual mTORC1/2 inhibitors in diffuse large B cell lymphoma is maintained in vivo on an intermittent schedule
Authors: Proia Theresa , Deng Nanhua , Polanska Urzsula , Lawson Deborah , Sah Vasu , San Martin Maryann , Reimer Corinne , Cosulich Sabina 
Published: May 2016

Abstract
Diffuse large B cell lymphoma (DLBCL) is the most common type of aggressive non Hodgkins lymphoma. The Activated B-Cell (ABC) subtype of DLBCL is driven by chronic active BCR signaling and remains the most difficult to treat. Resistant ABC-DLBCL occurs in as many as 40% of patients following treatment with R-CHOP. To identify additional treatment options, we performed a combination screen in DLBCL cell lines using a panel of drugs known to target survival and proliferation pathways in DLBCL, and uncovered a drug combination with highly synergistic activity that included the BTK inhibitor, ibrutinib, with the dual mTORC1/2 inhibitor, AZD2014. Ibrutinib is known to have activity in ABC-DLBCL; in a recent Phase I/II clinical trial of relapsed/refractory ABC-DLBCL, ibrutinib treatment resulted in 55% response rate in patients with B cell receptor mutations (Wilson et al, Nature Medicine 2015). In ABC-DLBCL cell lines, combination of AZD2014 with ibrutinib resulted in cell death, induction of cleaved caspase 3, and potent inhibition of c-myc and p-4EBP1. In vivo, combination of ibrutinib with AZD2014 was well tolerated and resulted in potent anti-tumor activity in OCI-Ly10 that was greater than either agent alone, with greater than 100% tumor growth inhibition as well as synergistic inhibition of p-4EBP1 (Ezell et al, Oncotarget 2014). This work was evaluated using a continuous daily dosing schedule of AZD2014 and ibrutinib. More recently, both continuous and intermittent dosing schedules (2 days on, 5 off) have been explored in patients with other solid tumours and was found to be better tolerated. We evaluated an intermittent schedule of AZD2014 in our preclinical ABC-DLBCL model, OCI-Ly10, in combination with ibrutinib and demonstrated that the synergistic combination activity was maintained, with 60% regression compared to only 36% regression with the daily dosing schedule combination. In addition to p-4EBP1 inhibition, we also observed synergistic inhibition of p-pRAS40, p-AKT, p-NDRG1, c-myc, survivin and HMGSC1. Ongoing preclinical work is focused on understanding whether more significant suppression of relevant pathways was achieved with intermittent compared to continuous dosing. Collectively, our data support a rationale for combining BTK and dual mTORC1/2 inhibitors for an effective and alternative treatment option in ABC-DLBCL.
Citation Format: Theresa Proia, Nanhua Deng, Urzsula Polanska, Deborah Lawson, Vasu Sah, Maryann San Martin, Corinne Reimer, Sabina Cosulich. Synergistic anti-lymphoma activity of ibrutinib and dual mTORC1/2 inhibitors in diffuse large B cell lymphoma is maintained in vivo on an intermittent schedule. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B112.