) Major advances in the understanding of molecular mechanisms of cancer allow for the rational exploration of novel pharmacological agents directed toward tumor-specific targets. Signal transduction pathways, being central to cell growth and regulation, represent key targets for anticancer intervention. PKC signal transduction pathways play critical roles in the transformation and behavior of malignant cells. Separate phase I clinical trials, including metabolic and pharmacokinetic analyses, will be performed with Bryostatin-1 and UCN-01, novel agents which inhibit specific isoforms of the PKC signal transduction family of enzymes. To determine if PKC inhibition occurs after treatment with Bryostatin-1 (or UCN-01) in tumor cells and PBLs in vivo, fresh tumor samples and patient blood will be obtained and tested for alterations in the expression of PKC isoforms. To demonstrate the link between PKC and the malignant phenotype, these tumor and blood samples will be tested for alterations in the expression of matrix metalloproteinase, cyclin dependent kinase 1 and 2, and MAP kinase, biological markers downstream from PKC in the signal transduction pathway which may be uniquely altered in malignant cells. The data will be analysed for correlations which may exist between PKC isoform expression and downstream molecular changes, and to determine if peripheral blood changes accurately serve as markers for intra-tumoral changes. Phase II trials will be designed to confirm these molecular coffelations and to determine if correlations exist between the molecular changes and tumor response/time to disease progression. The translational in vivo analyses are critical to our understanding of the consequences of signal transduction modulation at the level of the tumor micro-environment. If successful, this work will identify and characterize a new target for the treatment of patients with solid tumors.
| Marshall, John L; Eisenberg, Steven G; Johnson, Michael D et al. (2004) A phase II trial of ISIS 3521 in patients with metastatic colorectal cancer. Clin Colorectal Cancer 4:268-74 |
| Marshall, John L; Bangalore, Neelesh; El-Ashry, Dorraya et al. (2002) Phase I study of prolonged infusion Bryostatin-1 in patients with advanced malignancies. Cancer Biol Ther 1:409-16 |
