DLBCL|FL

AACR 2017 poster 1358/9 – PAMs present as a novel therapeutic strategy for Follicular Small Cell Cleaved Lymphoma and Diffuse Large B-Cell Lymphoma

This year’s American Association for Cancer Research (AACR) annual meeting took place on 1–5 April in Washington, DC, USA. The program committee Chair was Kornelia Polyak, MD, PhD, from the Dana-Farber Cancer Institute, Boston, Massachusetts.

On Monday 3rd April, a poster (1358 / 9) by Asfar S. Azmi, from Wayne State University, Detroit, MI, et al. titled “p21 activated kinase 4 (pak4) as a novel therapeutic target for Non-Hodgkin's Lymphoma” was presented.

The group analyzed the effect of newly developed p21-Activated Kinase 4 (PAK4) Allosteric Modulators (PAMs) on proliferation of NHL cells both in vitro and in vivo. WSU-FSCCL (representing Follicular Small Cell Cleaved Lymphoma) and WSU-DLCL2 (DLBCL) were administered with increasing concentrations of the Pan-PAK inhibitor PF-3758309, or different PAM analogs (KPT-7523, KPT-7189, KPT-9037, KPT-9274, or KPT-7010 [inactive]), in the presence or absence of CHOP (used at IC25) for 72 hrs. Subcutaneous and disseminated xenograft models of NHL were also used to determine the toxicity and efficacy of PAMs.

Key Highlights:
  • PAM monotherapy shows anti-proliferative activity in NHL cell lines; IC50 was 50nM and 250nM for WSU-FSCCL and WSU-DLCL2, respectively
  • Statistically significant dose-dependent difference in apoptosis induction in NHL cell lines treated with PAMs versus vehicle control
  • PAMs decreased total p-PAK4 and downstream signaling proteins involved in proliferation and apoptosis
  • In R-CHOP combination studies, superior viability suppression, amplified apoptosis, and concurrent down-regulation of PAK4 signaling pathway proteins were observed versus any single agent alone
  • KPT-9274 was well tolerated and showed remarkable anti-tumor activity in WSU-DLCL2 sub-cutaneous xenograft in mice (P < 0.01 at 140mg/kg/bid for 4 weeks with no loss in body weight)
  • Residual tumors analysis demonstrated suppression of PAK4 signaling pathways
  • Single agent and R-CHOP combination efficacy is currently being evaluated in subcutaneous and systemic WSU-FSCCL and in primary patient derived xenografts in mice

The poster was concluded by the authors by stating that this is the first study exploring the role of PAK4 in DLBCL and FSCCL. Their data supports PAK4 as a potential therapeutic strategy for NHL, as a monotherapy or combined with chemotherapy such as CHOP.

Reference:
  1. Azmi A.S. et al. p21 activated kinase 4 (pak4) as a novel therapeutic target for non-hodgkin's 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 [1358 / 9].