Preclinical Assessment of Response to Cetuximab and Combination Treatment with [18F]ICMT-11 and [18F]FLT PET Imaging


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Kathrin Heinzmann1,Quang-De Nguyen1,Diana Brickute1,Chris Barnes1,Steve Stribbling1,Eric Aboagye1
1Imperial College London

Abstract

Background

Non-small cell lung cancer (NSCLC) is characterized by high incidence and mortality rates, and rapid emergence of resistance against commonly used chemotherapeutics. Because EGFR is overexpressed in 65% to 100% of NSCLC cases, therapeutics were developed that block EGFR. Cetuximab has been demonstrated having anti-tumour activity in NSCLC experimental models and combination treatments (i.e. gemcitabine) can increase its efficacy (Butts et al., JCO 2007). In the present study, we have explored the use of Positron Emission Tomography (PET) imaging of apoptosis and proliferation to annotate early response to cetuximab and combination treatment in two tumour models, one sensitive and one insensitive to cetuximab.

Method

NSCLC H1975 tumour-bearing mice were treated with either vehicle, cetuximab (one dose or two doses) and/or gemcitabine. HCT116 tumour-bearing mice were treated with either vehicle or two doses of cetuximab. The mice were then submitted to [18F]ICMT-11 or [18F]FLT PET imaging on day 3. PET acquisitions were performed on a GENISYS4 (Sofie Biosciences). After the imaging, tumours were excised and evaluated using IHC and western blot. A second cohort of mice was treated identically and measured by caliper for 14 days.

Results

Retention of both tracers in H1975 tumours was sensitive to cetuximab and change in [18F]FLT imaging (max: 2-fold) was concurrent with a decrease in expression levels of EGFR (2-fold) and markers for proliferation (i.e. %Ki67: 4-fold). Interestingly, we found that one dose of cetuximab (10mg/kg) is insufficient to induce apoptosis but sufficient to effect proliferation as detected by studying tumour growth delay and PET imaging in H1975 tumours. Combination of cetuximab with gemcitabine had no significant effect on [18F]ICMT-11 and [18F]FLT imaging and marginal effects on tumour growth delay. No treatment-induced modulation of the imaging tracers was detected in the cetuximab-insensitive model (HCT116).

Conclusion

[18F]ICMT-11 and [18F]FLT are both valuable tools to assess cetuximab sensitivity.