DLBCL

AACR 2017 poster 4295/4 – AZ’5576 demonstrates in vitro and in vivo activity in preclinical models of ABC Diffuse Large B-Cell Lymphoma

At the American Association for Cancer Research (AACR) annual meeting in Washington, DC, USA, on Tuesday 4th April, a poster session titled “Cell Death in Cancer” took place.

One of the posters on display (4295 / 4) was titled “AZ’5576, a selective CDK9 inhibitor, demonstrates in vitro and in vivo activity in diverse preclinical models of non-Hodgkin lymphoma” by Justin Cidado from AstraZeneca, Waltham, MA, and colleagues.

AZ’5576 is an oral, highly selective inhibitor of CDK9. Using cell potency and magnitude of caspase activation to define sensitivity, the group previously found that AZ’5576 shows broad in vitro and in vivo activity in Acute Myeloid Leukemia (AML) and Multiple Myeloma (MM). The data presented includes their expanded scope encompassing Non-Hodgkin Lymphomas (NHLs).

Key Highlights:
  • In vitro screening assays found approximately half (19/35) of NHL cell lines undergo cell death in response to AZ’5576, demonstrating a potency <520nM and a maximum caspase activation >55% after 6 hours of treatment
  • Combining AZ’5576 with acalabrutinib (BTK inhibitor) enhanced cell death versus that observed with either agent alone in BTK inhibitor-sensitive ABC-DLBCL cell lines
  • In a mouse xenograft model of ABC-DLBCL cell line OCILY10, significant anti-tumor activity was associated with rapid reduction of pSer2-RNAPII levels, loss of MCL-1 and MYC, after intermittent dosing of AZ’5576
  • In the OCILY10 xenograft model, AZ’5576 plus acalabrutinib in vivo drove tumors into regression (Tumor Growth Inhibition [TGI] with combination = 199%) compared to partial TGI from either single agent (AZ’5576 TGI =79%; acalabrutinib TGI = 58%)
  • In aggressive Eµ-Myc transgenic mouse model of B-Cell Lymphoma, administration of AZ’5576 resulted in a >50-day increase in median overall survival in vivo

The poster was concluded by stating that these data indicate that inhibition of CDK9 has therapeutic potential in NHL, either as monotherapy or in combination with BTK inhibition.

Reference:
  1. Cidado J. et al. AZ’5576, a selective CDK9 inhibitor, demonstrates in vitro and in vivo activity in diverse preclinical models of non-Hodgkin lymphoma [Poster]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; 2017. Poster nr [4295 / 4].