PEGYLATED PROLACTIN RECEPTOR ANTAGONISTS AS CANCER DRUGS

Effective management of human cancers of the breast and other prolactin-responsive tissues (e.g., prostate) is the long-term goal of this research. The first phase of this study involves the design, synthesis and in vitro testing of polymer conjugates of a novel mutein of human prolactin (hPRL) that appears to be more selective as an antagonist than those previously tested. This antagonist (PRLA), developed and provided by Charles L. Brooks, contains a deletion that interferes with the positive cooperative interactions between the two receptor-binding sites on hPRL. PRLA binds to the receptor, but inhibits the intramolecular signal transduction pathway involving phosphorylation of Janus kinase (JAK) and signal transducer and activator of transcription (STAT) proteins. Polymer conjugates of PRLA will be synthesized containing 1-3 strands of linear or branched poly(ethylene glycols) (PEGs) of various molecular weights (10-60 kDa), linked by various chemistries. The optimal conjugates will have long half-lives in the circulation, high affinity for hPRL receptors, minimal agonist activity and minimal immunogenicity. Conjugates will be tested on human breast cancer cells in culture and grown as xenografs in immunocompromised mice. Tumor growth or shrinkage will be monitored non-invasively, using tumors derived from cells transfected to contain luciferase, in collaboration with Robert S. Negrin.