Poster Presentation 27th Lorne Cancer Conference 2015

Effect of EGFR-targeted and metabolic inhibitor combination therapy in sarcomas (#322)

Reichelle Yeo 1 , Pierre J. Dilda 1 , Jia-Lin Yang 1
  1. Prince of Wales Clinical School, University of New South Wales, Sydney, New South Wales, Australia

Currently, EGFR-targeted treatment of sarcoma, a malignant tumour, has limited effect on survival outcome of the disease1. PENAO, an anti-tumour metabolic compound produced in our laboratory is currently in clinical trials treating various solid tumours, however it has yet to be tested on sarcoma.

Aims: i) Determine the characteristics of PENAO as a single agent and in combination with gefitinib on sarcoma cell proliferation, ii) identify induced cell death mechanisms iii) assess the impact of the treatments on sarcoma cell metabolism.

Methods: Effects of PENAO and gefitinib treatments as single agents and combination on sarcoma cell proliferation were determined using a real-time cell analyser2. The combination parameters of the two drugs were determined by MTT end-point proliferation assay3, followed by CalcuSyn software analysis4. Cell death mechanisms were investigated by flow cytometry (Annexin-V/Propidium Iodide staining)5 and western blots (cPARP and LC3B detection). Mitochondrial respiration and glycolysis were measured by a real-time metabolic analyser.

Results: PENAO monotherapy induced anti-proliferation (IC50: 1.1 – 7.3μM) in 6 soft tissue (449B, 778, GCT, HT1080, SW872, SW982) and 6 osteosarcoma (143B, HOS, MG-63, Saos-2, SJSA, U2-OS) cells lines. The combined treatment had synergistic effects on cell proliferation (CI: 0.52 – 0.73), enhanced cell death and perturbed mitochondrial function of selected soft tissue and osteo-sarcomas cell lines.

Conclusion: Sarcoma cells were sensitive to PENAO and gefitinib combination, as it synergistically induced anti-proliferation, enhanced apoptosis and perturbed tumour metabolism. Our study supports further in vivo studies and may have immediate impact in translating therapeutic research to clinical trials.

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