Determinants of Response to Type 1 Insulin-Like Growth Factor Inhibition in Prost

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We have shown that targeted therapy to the type 1 insulin-like growth factor receptor (IGF-IR) is very effective in decreasing tumor size in preclinical models of prostate cancer (CaP). It is also clear from phase 1 trials that human monoclonal antibodies (hmab) to the IGF-IR are well tolerated. We also show that the efficacy of IGF-IR hmabs are dependent on the clinical stage of tumor e.g. AD vs. Al and alterations in components of the IGF-IR signaling pathway. Therefore, as we proceed with.our clinical trials, there is an urgent need for basic and preclinical data to guide these trials forward. The hypothesis of this proposal is: the effectiveness of targeting the IGF-IR in treating CaP depends on the status of the androgen responsiveness of the tumor and the integrity of the IGF-IR signaling pathway in the cancer. This hypothesis is addressed by the following aims: Aim 1. Determine mechanisms of resistance to IGF-IR targeted therapy by the human monoclonal antibody A12. This aim will use the 27 unique human prostate cancer xenografts available in the Biospecimen Core as well as our preclinical finding of the significant synergy between castration and IGF-IR inhibition. Aim 2. Analysis of the functional interactions of the AR on IGF-IR gene expression as a determinant of response to A12 in CaP. This aim will define the mechanism of androgen regulation of the IGF-IR . Aim 3. Determine the potential of tumors that remain dormant following treatment with castration plus A12 to re-initiate tumor growth. This aim will define the mechanisms and characteristics of those CaP that remain dormant after combination therapy with castration and IGF-IR inhibition. Aim 4. Determine how the protease activity of TMPRSS2 influences IGF signaling and the response to A12. As an interaction with Project 2, this further develops the effects of TMPRSS2 cleavage of IGFBPs -3 and -5. Aim 5. Role of androgens and IGF in establishing the survival and growth of dormant CaP cells in an osseous site. This interaction with Project 1 will determine the role of IGF-IR inhibition on DTCs. The long term goals are to define the characteristics for our clinical trials targettting IGF-IR to succeed. RELEVANCE (See instructions); IGF-IR inhibition will become part of the clinical armementarium for tretament of prostate cancer. Project 3 will define the appropriate setting for the most efficacious clinical use of this targeted therapy.