Poster Presentation 25th Lorne Cancer Conference 2013

Harnessing the tumour adaptive response to hypoxia to identify novel combinations of the vascular disrupting agent BNC105 with targeted therapeutics. (#216)

Daniel J Inglis 1 , Lavranos C Tina , Beaumont M Donna , Annabell F Leske , Chloe K Brown , Gabriel Kremmidiotis
  1. Bionomics Ltd, Thebarton, SA, Australia

BNC105 is a Vascular Disrupting Agent (VDA) that exerts anti-cancer activity through selective shut-down of tumour blood vessels. A single dose of BNC105 causes a very high degree of hypoxia and necrosis 24hrs post treatment in rodent tumour models. Tumour recovery from the hypoxic stress occurs by day 2 post-treatment. We have conducted immunohistochemical analysis to identify the molecular basis driving this tumour recovery.

Using the mouse renal cancer orthotopic tumour model RENCA, BNC105 causes significant vascular shutdown within the tumour followed by activation of proteins involved in tumour adaptive responses to hypoxia. Similar observations were recorded from BNC105 treated mice bearing tumours of the human renal cancer cell lines Caki-1 (VHL wild type) and A-498 (VHL mutant). These observations led us to investigate the potential therapeutic benefit of combining BNC105 with agents inhibiting the function of proteins being upregulated as a result of BNC105 induced hypoxia.

These responses included phosphorylation of mTOR and 4EBP1. Rapamycin was used to inhibit mTOR signalling. Tumour growth inhibition with Rapamycin alone was 18% and BNC105 alone 12%. The Rapamycin + BNC105 combination treatment resulted in statistically significant (p<0.05) 47% tumour growth inhibition compared to the monotherapies.

Futhermore, upregulation of PERK and phosphorylation of eIF2a, reflected ER stress caused by accumulation of unfolded proteins and activation of the Unfolded protein Response (UPR). We hypothesised that concurrent inhibition of the proteasome with Bortezomib will increase cell stress resulting in increased tumour necrosis. Treatment of RENCA tumours with BNC105 + Bortezomib resulted in increased tumour necrosis compared to animals treated with Bortezomib or BNC105 alone. This suggests that the tumour is more susceptible to these agents when in combination.

These data demonstrate that BNC105 can be combined with therapies targeting tumour adaptive responses to hypoxia to yield greater anti-tumour efficacy.