1. Preclinical drug development dual MAPK and PI3K-Akt pathway inhibition in pancreatic cancer and identification of escape pathways Aim: - To evaluate the efficacy of combined MEK and PI3K inhibition in a preclinical model of pancreas cancer - To map escape pathways of tumor resistance following prolonged MEK and PI3K inhibitor treatment - To develop a reliable predictor (gene signature) for this strategy by correlating the underlying genotype to pathway activation and response to dual pathway inhibition Rationale: There is a very sound rationale for the combination of small molecule MEK and PI3K inhibitors in pancreatic cancer (PDAC): - The PI3K-Akt pathway is upregulated in PDAC in about 60% of cases due to direct activation of the p85 PI3K subunit by activated Kras. Using a combination of MEK and PI3K inhibition, the major outflow and escape pathway of activated Kras signaling (KRAS most common oncogene in PDAC) is inhibited - The PI3K-Akt pathway is also activated by abnormal EGFR signaling in 20% of cases in PDAC Methods: The NCI/Surgery Branch has a panel of greater than 50 pancreatic cancer cell lines available. These include cell lines from primary and metastatic tumors. In the majority of cases, the underlying genotype with respect to KRAS, CDKN2A, PTEN, TP53, Smad4, and TGFRII mutation status in these lines is known, and can be correlated with growth inhibition observed in the in vitro cell line model. Anti-proliferation and apoptotic activity of MEK and PI3K inhibition will be studied with a triplex (viable + dead + apoptotic) assay which reads - cell death - cell survival - apoptotic cells Two examples of growth inhibition curves in pancreatic cancer cell lines using a MEK inhibitor in sensitive and resistant cell lines to MEK inhibition are shown: ASUC Animal Protocol (SB-211) entitled In vivo platform for translational genotype-directed drug development in pancreatic cancer and other upper GI malignancies allows the creation of xenografts from resected pancreatic tumors from patients of the Surgery Branch and collaborating institutions. In vivo activity of growth inhibition in the cell model will be confirmed in vivo in a xenograft model by: - Inhibition of tumor growth at primary site (pancreas) - Inhibition of metastasis using consecutive in vivo imaging It is anticipated that the above findings will be translated into a phase II clinical trial where pancreas cancer patients will be treated, based on the genetic profile or their tumors predicting response to MEK inhibition and presence of escape pathways, with a combination of MEK and PI3K. 2. The Impact of the Tumor Environment on the Efficacy of Anticancer Therapy in Ductal Adenocarcinoma of the Pancreas Aim: - To evaluate if targeted therapy against the tumor microenvironment in PDAC improves drug delivery and efficacy of anti-cancer therapy Rationale: Recent studies, including reports from the Surgery Branch/NCI have shown that treating the microenvironment can dramatically increase the efficacy of other anticancer therapy in PDAC. Treatment with the anti-microenvironment sonic hedgehog inhibitor IPI-926 improved antitumor efficacy of gemcitabine in a transgenic mouse model of PDAC. These data suggest that the dense, desmoplastic microenvironement prevents gemcitabine, the commonly used chemotherapy agent against pancreas cancer, to reach the actual cancer cells to exercise a meaningful antitumor effect. The objective of this study is to evaluate the impact of different treatment strategies against the microenvironment on the efficacy of antitumor cancer therapy in PDAC in different transgenic mouse models simulating the most common genetic backgrounds of human PDAC. Methods: The role of the microenvironent cannot be studied in an in vitro cell system. To evaluate the complex interactions of the various cellular components, the tumor micro-vasculature, and the extracellular matrix of the tumor microenvironment as possible targets for novel treatment strategies in PDAC requires an in vivo model: The transgenic/knockout mice who develop pancreatic cancer are well-established models for studying possible modulators of carcinogenesis. These models contain conditional knock-in mutations of the Kras oncogene which is present in greater than 85% of PDAC in combination with knock-outs of the common tumor suppressor genes CDKN2A and Smad4 which are lost in greater than 50% of PDAC. These genetically engineered mouse models resemble the human genomic landscape of PDAC which is driven by alterations in one of these genes in greater than 95% of cases: Pdx-cre;LSL-KrasG12D;LSL-p53R172H Pdx-cre;LSLKrasG12D;Ink4a/Arflox/lox Pdx-cre;LSL-KrasG12D;Ink4a/Arflox/lox;Smad4lox/lox The efficacy of the following five anti-PDAC treatments/strategies: 1. Control (normal saline) 2. Gemcitabine 3. MEK inhibition 4. Combined MEK PI3K inhibition 5. Cycline-dependent kinase inhibition after treatment of the microenviroment with the following compounds / small molecule: 7. Sonic hedgehog inhibitor 8. Sunitinib and lenolidomide and metronomic cisplatin 9. Inhibitors of the platelet-derived growth factor receptor (PDGFR) or the vascular endothelial growth factor receptor 10. Tumor necrosis factor alpha 11. Rituximab and Toll cell receptor (TLR-9) agonist 12. Integrin inhibitor Study endpoint: Tumor growth and tumor growth inhibition will be evaluated by in vivo infrared imaging. Functional imaging will be complemented by formal anatomical cross-sectional imaging with CT and MR in the Mouse Imaging Facility (MIF) of the CCR/NCI to assess impact of the various strategies targeting the microenvironment on tumor development and progression. Ultimate endpoint for analysis of the different groups is overall survival of the tumor-bearing mice. 3. Role of functional, non-coding regions in the pancreas cancer genome in cancer development and progression Aim: - To evaluate regulatory units of known cancer genes for somatic mutations and their contribution to tumor initiation and progression Rationale: For many pathways involved in carcinogenesis in pancreas cancer the exact cause of its activation/dysregulation is not known. For example, while EGFR/HER2 signaling is abnormally activated in greater than 60 % of pancreatic cancers, in many cases no activating somatic mutations, gene amplifications, or other abnormal inputs from collateral signaling has beenidentified. This observation raises the possibility that in PDAC essential growth and proliferation pathways are dysregulated because of alterations in the promoter / functional non-coding regions of important oncogenes. Methods: The project involves a large-scale sequencing effort using second generation whole genome sequencing on the Illumina platform. The project is performed within an NCI collaboration with Complete Genomics, Inc, and will start with three samples of matched tumor and normal. The regulatory regions (promoter regions to -4,000bp upstream) of the most pertinent cancer genes (PI3K, EGFR, Kras, Braf in PDAC) are screened for the presence of somatic mutations / genomic alterations suggesting altered function (e.g. altered known binding sites of transcription factors). Mutated promoter sequence(s) suggesting altered function (e.g. gain of function because of altered transcription initiation) will be cloned into a reporter plasmid, and tested in vitro with respect to their impact on cell growth and proliferation. Identifying alterations in regulatory regions as cancer-promoting and driving events in pancreas can [summary truncated at 7800 characters]

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