The objective of this program is to make a dominant negative variant of Insulin-like Growth Factor-I (IGF-I) that interferes with the growth and proliferation of IGF-I dependent tumor cells. Therapeutics aimed at specific molecular targets hold immense potential for treating cancer and other diseases. As more is learned about the molecular mechanisms of disease, more of these drugs will become available. In the cancer arena, molecular targets such as the HER family of receptor Tyrosine Kinases (and especially EGFR and HER2) and VEGFR are particularly attractive targets. Small molecule therapeutics that interfere with kinase domains and monoclonal antibodies that interact with the extra-cellular domains have been approved and are having some success in the clinic. One well-recognized target for molecular therapeutics remains un-assailed: Insulin-like Growth Factor-I Receptor (IGF-IR). IGF-IR has been shown to play an important role during cancer progression and the multistage process of metastasis, including cell adhesion, cellular migration, invasion, angiogenesis and metastatic growth. Despite many attempts to produce both small molecule and monoclonal antibody-based antagonists, no one has yet overcome the problem of cross reactivity with the very closely related insulin receptor (IR). One molecule that can bind preferentially to IGF-IR rather than IR is the IGF-IR cognate ligand, IGF-I. Our goal is to produce a dominant negative variant of IGF-I that binds to IGF-IR on the surface of tumor cells, does not initiate signal transduction, blocks the binding of the authentic ligand and does not bind to IR. The potential of this Dominant Negative Ligand approach was clinically validated with the approval of Somavert, an engineered form of human growth hormone used to treat acromegaly. We have successfully produced variants of Epidermal Growth Factor (EGF) that antagonize EGFR-dependent tumor growth. Our approach to this problem is based on a rational protein (re)design strategy, facilitated by a structural and sequence analysis of IGF-I, Insulin and their receptors. We plan to ablate one of the IGF-I binding surfaces, while enhancing binding at the other site. In this fashion, the ligand will bind to the receptor, block binding by the authentic ligand, and lock the receptor in the inactive form. ? ? ?
