RANDOM PEPTIDE DRUG DEVELOPMENT

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The central focus of project 29 is to develop growth-inhibitory peptides for the treatment of cancer using the random synthetic peptide library synthesis and testing technology ("Selective process") originally conceived of by this project's leaders. This new technology (which can use natural and/or unnatural amino acids) will be used to identify novel peptide ligands which bind with high affinity to 1 of 3 specific molecular targets: (1) cell-surface Ig in B-cell non-Hodgkin's lymphoma (NHL), (2) the enzyme matrilysin (MMP-7), implicated in tumor cell invasion, and (3) the enzyme phosphatidylinositol phospholipase C(PtdInsPLc, PLC), implicated in intracellular signalling after growth factor interaction with tumor cells. High affinity peptides binding to cell-surface Ig from human B-cell lymphomas will be tested for immunotherapeutic growth-inhibitory properties first in preclinical human lymphoma models in vitro and in SCID mice using either unlabeled or radioiodinated techniques. Success in these models will be lead to the subsequent clinical development of patient Cancer Center through project 19. Synthesis of specific random peptides which bind MMP-7 with high affinity and which also inhibit the function of this tumor-secreted enzyme will be scaled up for preclinical testing in vitro and in animal models for tumor cell invasion and for adjuvant therapy of cancer. Identification of specific random peptides which inhibit PLC enzyme activity will be followed with testing in cellular systems to determine whether the peptide leads can inhibit intracellular signalling after growth factor stimulation of tumor cells. Lead peptide inhibitors for PLC will also be tested in relevant human tumor models in SCID mice. Success in these enzyme-inhibition models will lead to selection of candidate peptides for formal pharmaceutical development via industrial collaborators. Phase I/II studies of successful enzyme inhibitors with antitumor activity in animal models would be conducted via project 19 after approval of IND's by the FDA.