Mechanisms Regulating Reversal of Premalignancy and Threapuetic Sensitivity

Georgetown University, Washington DC

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Abstract

1 Our long-range research goal is to translate molecular definition of cancer pathophysiology into more 2 effective therapy. The project goal is development of relevant tissue culture and mouse models to study 3 pathogenesis of different histological types of salivary tumor and perform preclinical testing of potential 4 therapeutics. Specific aims: 1. Utilize an established conditional genetically engineered mouse model of 5 submandibular salivary cancer to further define molecular signatures at different stages of salivary gland 6 cancer progression and determine if disease-relevant molecular signatures and response to therapeutics in 7 vivo are maintained in two types of in vitro culture. 2. Use human tissue samples of parotid, submandibular and 8 minor salivary glands obtained from de-identified surgical specimens to establish a living bio-bank (a panel of 9 cell cultures) from normal, benign, invasive cancer and metastatic human salivary gland tissue using 10 conditional reprogramming to evaluate potential therapeutic response in vitro and in xenograft models and 11 establish molecular signatures of disease. The significance of the proposal is that it answers the stated FOA, 12 e.g. provide molecular signatures of salivary gland tumors and develop relevant mouse models to study 13 pathogenesis and perform preclinical testing. The major innovation in the project is the utilization of a novel 14 system for conditionally reprogramming normal, preneoplastic and malignant epithelial cells developed by 15 project co-investigators that permit us to readily generate human material representative of different cancer 16 types for determining molecular signatures and preclinical testing. We are relatively unique in that we already 17 have molecularly characterized a conditional mouse model of submandibular salivary gland cancer in which 18 expression of the initiating oncogene can be turned off to study molecular determinants of cancer progression 19 independent from the initiating oncogene. The methodology is a logical sequence of experiments utilizing 20 material from both mouse models and human primary disease material for determination of molecular 21 signatures and testing of potential therapeutics while evaluating a unique system for reprogramming epithelial 22 cells that can be used for expanding small numbers of primary cells and may have future clinical utility for 23 determining optimal therapies for uncommon cancers or otherwise challenging clinical cases. Expected 24 outcomes are an adequately powered test of the utility of conditionally reprogrammed cells for determining 25 response to potential therapeutics and molecular signature testing using a well-characterized mouse model 26 and establishment and evaluation of a panel cell cultures of different types of human salivary tumors for further 27 use in preclinical testing and determination of molecular signatures. The results will effect other research 28 areas by establishing caveats for the use of similar experimental approaches for the characterization (both 29 therapeutically and by molecular signature) of other epithelial cancer types and pave the way for cost-effective 30 and timely approaches for predicting in vivo chemotherapy sensitivity. 1