INJURY-RELATED MORPHOGENIC PATHWAY SIGNALING AND HEPATOCARCINOGENESIS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Aim #1: Extend analysis of a small animal model to prove/disprove if (and why) changes in the activity of two morphogenic signaling pathways (Hedgehog (Hh) and Wnt) cause HCC to emerge and/or metastasize. a) Based on ongoing work and publications from other labs, we know that mice homozygous for a targeted deletion in mdr2 (mdr2-/-) have evidence of ongoing liver injury at as young as 2-weeks of age, which leads to sustained activation of at least one morphogenic signaling pathway (Hh) and culminates in liver cirrhosis and the outgrowth of HCC at around 1-year of age. Therefore, we will treat 4 groups of at least 4 mice each with a minimum age of 1 year. The 1st group will receive an inhibitor to the Hh pathway; the 2nd will be given an inhibitor to the Wnt pathway, which we also have in our possession ,and have successfully used to induce regression of colon cancer xenografts. The final 2 groups will be controls. All injections will be intraperitoneal, given daily for 3 weeks. Prior to treatment, we will MRI each group to characterize size, number, and location of tumors (including presence or absence of metastases). We will re-MRI the mice at treatment conclusion to evaluate for treatment effect prior to sacrifice. MRI imaging is central and critical to the study's success. As indicated in Aim 2, the overall goal is the development of potential treatments to use in human patients with HCC or felt to be at high risk for HCC. MRI is crucial in its translational relevance to how human patients receiving these treatments would be intervally evaluated for treatment effect. b) The work proposed in (a) will be repeated in cirrhotic mice who have yet to develop HCC. We will treat mice <1 year (prior to emergence of HCC) with the above-mentioned morphogenic pathway inhibitors or vehicle control. Mice will undergo MRI imaging prior to initiation of treatment to ensure they do not have tumor and again at conclusion of treatment to assess tumor prevention. Work on this aim will not begin until work proposed in a) is completed and therefore this proposal for collaboration is primarily directed to the work listed in a). The goal of this aim is to determine the safety and efficacy of two morphogenic pathway inhibitors as chemopreventive agents and/or treatments for HCC. Aim #2: Apply knowledge gained in Aim #1 to determine if morphogenic pathway activity-dependent carcinogenic mechanisms are conserved across species and therefore serve as potential targets for development of novel HCC biomarkers or treatments. Work in this aim will take place on human biopsy specimens from patients with various stages of fibrosis and/or HCC. The success of Aim #1 is necessary for our ability to complete this Aim as the availability of human samples is very limited and the work proposed to take place under this Aim (microarray analysis, QRT-PCR, and immunohistochemistry) is very time consuming and costly. The goal of this study as a whole is to provide a compelling rationale for expedited clinical trials for new treatments of HCC in patients who already have tumor or in those felt to be high risk for the development of HCC.