iSPIN iCorp Training

SUMMARY High risk types of human papillomavirusesHPVare responsible for virtually all cases of human cervicalcarcinomaas well as an increasing number of other malignancies including those of the head and neckanus and vulvaUnfortunatelygood treatment options for late stage HPVmalignancies are not currently availablein large part because the virus encodes a proteinEwhich disables cellular apoptotic pathways by accelerating the degradation of molecules such as FADDcaspaseand pThis makes it difficult to eliminate HPVcancer cells using conventional inducers of apoptosisTo overcome this obstacleour laboratory has identified several small molecules that block the binding between Eand partners such as caspaseand E APAccording to our working modelthe use of such molecules in a combinatorial manner will greatly increase the effectiveness of standard radioand chemotherapeutic treatmentsBoth in vitro binding data and cellular data from our laboratory provide strong data in support of this working modeland it is now time to test our approach in an in vivo contextThe overall objective of this current applicationthereforeis to move our exciting in vitro and cellular observations into a mouse xenograft modelWe will do this by combining spinacineour bestmolecular candidatewith two potential therapeutic agentsTRAILa biologicand cisplatina more conventional chemotherapeuticasking whether either of these combinations can reduce or eliminate the growth of HPVtumorsof either cervical or head and neck originin a nude mouse modelIn particularwe willDetermine the toxicity of spinacine in miceWe will assess the toxicity of spinacine in micedefining the maximumtolerated dose and identifying the optimum dose with which to carry out experiments designed to test its efficacyandEvaluate the ability of spinacine to synergize with TRAILand or chemo based therapies toreduce or eliminate HPVtumor growthWe will assess the ability of spinacine to synergize with hrTRAIL and or the DNA damaging drug cisplatin to inhibit tumor growth in a xenograft modelAt the conclusion of this workwe will haveDetermined the toxicity of the Einhibiting molecule spinacine in miceandEvaluated the effectiveness of combining spinacine with TRAILand cisplatin based treatments in an animal modelThis work has the potential to save the lives of thousands of patients suffering from HPV associated malignancies