Abstract LB-225: MLN8237 (aurora A inhibitor) plus vincristine plus rituximab is curative in mice bearing aggressive B-cell non-Hodgkin's lymphoma
Authors: Mahadevan Daruka , Cooke Laurence S. , Stejskal Amy , Persky Daniel O. , Miller Thomas P. , Qi Wenqing 
Published: June 2012

Majority of B-cell non-Hodgkin's lymphoma (B-NHL) are not curative with current chemo-immunotherapy. Targeting synergistic mechanisms within the context of the hallmarks of cancer with minimal toxicity may yield novel effective therapies for aggressive B-NHL. Auroras (A and B) are mitotic serine-thronine kinases involved in high fidelity cell division. Aberrant over-expression of Auroras is oncogenic leading to genetic instability, polyploidy and tumor progression. Over-expression of Auroras promote resistance to microtubule targeting agents (MTAs) such as taxanes and vincas. Inhibition of Auroras with siRNA knockdown or a small molecule inhibitor [MLN8237] leads to enhanced sensitivity of cancer cells to MTAs. We demonstrated in vitro [5–10 nM] and in vivo [Granta-519 mantle cell lymphoma (MCL) mouse xenograft model] additivity when MLN8237 [M] (Aurora A inhibitor) is combined with docetaxel [D] leading to mitotic catastrophe in B-NHL. Tumors harvested from MCL SCID mice xenografts treated with M+D showed central necrosis, an adjacent layer of apoptosis (cleaved caspase-3) and a peripheral rim of proliferation (Ki-67+) despite tumor volumes &gt;60% smaller compared to single agent therapy (p=0.05). We hypothesized that addition of rituximab [R] targeting proliferation (CD20) to M+D would be additive-synergistic in B-NHL. Cell culture modeling showed combining R with M+D was additive and in a MCL mouse xenograft model resulted in a tumor growth inhibition (TGI) of ∼85% versus ∼25% [M+R] and ∼62% [M+D] (p=0.001) over control, respectively. Overall survival of &gt;40 days with increased apoptosis (cleaved caspase 3) and decreased proliferation (Ki-67) was observed with M+D+R. We next hypothesized that microtubule de-polymerization with vincristine (V) would be more effective in synergizing with MLN8237 than a microtubule polymerizing agent [D]. Cell culture modeling indicated that M+V+R is superior to M+D+R therapy. In a SCID mouse MCL (Granta-519) xenograft model tumors continue to grow with M+R but at a reduced rate and volume (∼25–30% TGI). However, mice treated with M+V had tumor regression and disappearance for 3 weeks but then relapsed with tumor growth (∼50% TGI). In contrast, mice treated with M+V+R showed tumor regression and complete responses with no relapse 90 days post-treatment (p=0.0001). Tumors harvested from control, M+R (end of treatment) and M+V (at relapse) are under evaluation by gene expression profiling for mechanism(s) of resistance and response with confirmatory qPCR, IHC and Western blotting. Biomarker analyses for pHisH3, pAurora A, p53, Ki-67 and cleaved caspase-3 by IHC correlates well with response to therapy (M+R and M+V) compared to control (p=0.01). The M+V+R triple therapy combination for B-NHL to overcome or prevent the emergence of doublet (M+R or M+V) mediated drug resistance warrants evaluation in early phase clinical trials.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-225. doi:10.1158/1538-7445.AM2011-LB-225