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Restoring the cancer cell’s ability to respond to apoptotic signalling and to ignore proliferative signals are promising strategies for treatment. The cytokine, TNF related apoptosis-inducing ligand (TRAIL) is a very promising anti-cancer agent, as it induces apoptotic death in only cancerous cells, but not in normal, non-transformed cells. However, when TRAIL binds to its two apoptosis-inducing receptors, death receptor 4 (DR4) and DR5, parallel to the apoptotic signal, an inflammatory, pro-survival signal, mediated by nuclear factor-kappa B (NF-kB), is also generated which can counteract the apoptotic signal. This is often the cause of TRAIL resistance of tumours and a significant contributor to metastases. Our previous studies using computational design have identified peptides to prevent the recruitment of TRAF2 to TRADD to the DR4/DR5 receptors and thus prevent DR4/DR5-mediated NF-kB activation. We believe that these TRADD-TRAF2 interaction inhibitors would uncouple the apoptotic signalling from the pro-survival signalling induced by TRAIL in tumour cells without causing toxic side effects in non-cancerous cells. Also, these TRADD-TYRAF2 interaction inhibitors used in combination with TRAIL could eliminate/reduce the risk of tumour metastasis induced by NF-kB activation. The objective of this study is to evaluate the potency and specificity of these peptides to block DR4/DR5-mediated NF-kB activation and assess their anti-cancer efficacy in in vivo xenograft models
A major aim of anti-tumour therapies is to inhibit growth and induce death of tumour cells without affecting normal cells. In this regard, the so called death ligand/death receptor family, present in most of the cells in our body are of interest since they regulate both cell death and cell proliferation. One TNF family member, TRAIL, is of particular interest since it selectively induces death of tumour cells without affecting normal cells. TRAIL and TRAIL-specific antibodies are being investigated as anti-cancer agents in phase I and II clinical trials with promising results. However, one drawback to their efficacy is that TRAIL can also initiate an inflammatory response in the tumour cell, depressing the death signal and promoting tumour cell survival. Using a computational design strategy, we have designed specific drugs that can prevent the inflammatory/anti-death signal and thus guarantee tumour cell killing by TRAIL. This proposal will test these drugs for their efficiency. The drugs will be tested on colon carcinoma and pancreatic cancer cells followed by pre-clinical, xenograft models.
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