Cancers involving the liver are responsible for over one million deaths a year. At present, liver resection represents the only potentially curative treatment. However, in the majority of patients, tumor recurs, because microscopic disease remain undetected at the time of liver resection. This R01 is one of four submissions in an Interactive Research Project Grants. Using shared resources, including animal models, central isotope facility, Positron Emission Tomography (PET) facility, Magnetic Resonance (MR) facility, and patients, these grants seek to improve survival of patients with liver cancer. The current submission examines the cellular alterations underlying liver regeneration and the resultant biological determinants for the optional timing of adjuvant therapy after resection of tumors. In experimental models, the liver regenerative process stimulates growth of residual tumor. Adjuvant chemotherapy or oncolytic viral therapy strives to eradicate microscopic residual tumor. Theoretically, early adjuvant therapy is desirable. However, clinicians are reluctant to institute adjuvant therapy within four weeks after liver resection for fear that such therapy may detrimentally alter liver regeneration. In the previous grant study period, we showed that characteristic changes in cellular phospholipids and high energy phosphates can be detected by MR spectroscopy in animals and be used as a surrogate marker for liver recovery in planning of safe adjuvant therapy. We further demonstrated that such characteristic MR spectroscopic changes can be detected in man. Non-invasive measure of DNA synthesis by 124I-IUDR PET scanning was also validated in animals and used to predict safe administration not only of chemotherapy but also of 125I-IUDR as anti-tumor therapy. Two new advances that are reaching clinical testing and utilization are 1) pre-operative unilateral portal vein embolization as a means of producing contralateral liver hypertrophy to extend the possibilities of resective therapy, and 2) oncolytic viral therapies that also exploit cell proliferation for tumor targeting. In the current proposal, we seek to extend our MR spectroscopy observations to study of liver and tumor metabolism after portal vein embolization in order to characterize hepatocyte alterations during regeneration without the confounding issues of major surgery, but more importantly to determine if tumor proliferation is enhanced in man during regeneration. We also seek to determine if MR or PET can be used to determine tumor sensitivity and liver toxicity in response to viral oncolytic therapy. Finally, the use of 124I-IUDR PET validated in animals as a non-invasive measure of DNA synthesis in the previous grant period will be extended to a human trial. Thus, the specific goals of this application are to determine the comparative cellular proliferative rates of hepatocyte versus residual tumor after liver resection, to determine if these changes in proliferative rates can be determined non-invasively in vivo, with the hope that an adjuvant strategy exploiting the differential changes in tumor and hepatocyte proliferation may provide the basis for future therapy in man.
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