Complete excision of cancer is guided by histologic assessment of surgical margins. Molecular detection of margins could allow for a better cure rate. Unfortunately, no marker is sensitive enough to be used reliably in a clinical setting. We have determined that the proto-oncogene eIF4E is overexpressed in 100% of HNSCC. A single institutional study showed that eIF4E overexpression in histologically tumor-free surgical margins results in a significant decrease in disease free interval compared to patients with eIF4E-negative margins. We will test our hypothesis that eIF4E overexpression in tumor-free surgical margins is an independent predictor of recurrence in a multi-institutional trial. We will use samples collected in an ongoing ECOG trial by Dr. Koch's group from Johns Hopkins, who are currently analyzing margins for p53 mutations, to determine if overexpression of eIF4E in these margins is a significant predictor of recurrence. Activation of eIF4E results in increased translation of mRNAs such as cyclin D1, associated with tumor progression. We have shown increased activation of eIF4E in margins of HNSCC patients over-expressing eIF4E is associated with elevation of cyclin D1.The activated mammalian target of rapamycin, mTOR, phosphorylates 4E-BP 1 releasing bound eIF4E to stimulate cap-dependent translation. Hence inhibition of mTOR by rapamycin will inhibit phosphorylation of 4E-BP 1 and sequester eIF4E with 4E-BP 1 decreasing translation of mRNAs involved in tumor progression. To determine if CCI-779 a rapamycin analogue can potentially be used as adjuvant therapy for patients with eIF4E-positive margins, we will confirm in a definitive study if phospho-4E-BP1 and cyclin D1 are overexpressed in eIF4E positive margins indicating increased activity of eIF4E. We will then elucidate the anti-tumorigenic properties of CCI-779 on HNSCC cell lines with varying eIF4E levels in vitro and in vivo, in a model of minimal residual disease. We will also determine if these effects are a result of inhibition of mTOR by studying the effects of CCI-779 on the amount of 4E-BP1 associated with eIF4E and its effects on the expression of cyclin D 1. If our hypotheses were proven, our long-term goal would be to conduct a clinical trial with CCI-779 as adjuvant therapy, for eIF4E-positive margin patients to possibly decrease recurrence rates.
