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Preclinical Studies and Early Drug Development: In Vitro and In Vivo Assays and Models

Individualizing therapy using direct xenografting of pancreas cancers: a multi-modality approach

Johns Hopkins University, Baltimore, MD

Abstract

B2

While there are many new agents entering clinical development, often there is no information on biomarkers that may predict the activity of these drugs, and there is very little data to prioritize which agents should be administered to a given patient. We have generated a cohort of 30 pancreatic cancer xenografts by implanting tumor materials from surgical specimens in nude mice. Molecular studies show that a) these tumors maintain the genetic features of the originator cancer; b) tumors represent the heterogeneity of pancreatic cancer well and c) features do not changed over time. We have used this retrospective platform to explore the activity of a set of over 20 anticancer agents including inhibitors of tubulin, MAPK, EGFR, mTOR, PLK1, src kinase, Ras oncogene, angiogenesis, heat shock protein 90 and hedgehog pathway inhibitors using a methodology similar to a two stage phase II clinical trial. All agents are tested against 10 xenografts. Those inactive are not explored further. Active agents are tested against the full set of tumors. For active agents, we have characterized the tumors for potential strategies and biormarkers that may predict activity using both a target-focus approach as well as general profiling approach. We have taken a step forward in the individualization of therapy, and are following a three-fold approach. First, we are developing predictive markers for these therapies, such as the correlation between MAPT expression and sensitivity to a new family of BPU analogs. Second, we are developing ex vivo assays applicable to fine-needle aspiration (FNA) tumor tissue, that allow exposing briefly the tumor cells to the drug and testing whether they are sensitive before the individual patient is even treated; examples of this are ex vivo assays for EGFR and PLK1 inhibitors. The 30-case xenograft bank has demonstrated to be a powerful tool, as each case represents an individual subject, and the ex vivo assays can be validated after testing the whole cohort. Thirdly, we are conducting a clinical trial where patients give permission to prospectively xenograft and perpetuate resected pancreas cancer specimens. While the patients receive adjuvant therapy, their tumors are treated as xenografts on mice with a panel of approved anticancer agents; in those cases where the patient develops disease progression we are utilizing the growth inhibition information to guide his/her therapy in the advanced setting. This ultimately corresponds to the clinical validation of the xenograft platform. Examples of newly discovered and developed predictive factors and ex vivo assays, and an update on the clinical trial will be presented. This multi-direction approach towards the individualization of therapy is needed given that the increasing abundance of anticancer agents has little impact on those diseases where few lines of treatment can be realistically administered, such as pancreas cancer.