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Combined In vivo Effect of A12, a Type 1 Insulin-Like Growth Factor Receptor Antibody, and Docetaxel against Prostate Cancer Tumors

Authors' Affiliations: ¹ Department of Medicine, University of Washington; ² Veterans Affairs Puget Sound Health Care System; ³ Fred Hutchinson Cancer Research Center; ⁴ Departments of Urology and Immunology, University of Washington, Seattle, Washington; and ⁵ ImClone Systems, New York, New York

Requests for reprints: Jennifer D. Wu, Department of Medicine, University of Washington, Box 359625, Seattle, WA 98104. Phone: 206-341-5349; Fax: 206-341-5302; E-mail: wuj{at}u.washington.edu.

Purpose: A human type 1 insulin-like growth factor receptor antibody (A12) has been shown to effectively inhibit human xenograft tumor growth, including androgen-dependent and androgen-independent prostate tumors. Docetaxel, either as a single agent or combined with others, has shown a survival benefit in prostate cancer patients. Based on these data, we investigated the combined in vivo effect of A12 and docetaxel on human androgen-independent and osseous prostate tumor growth.

Experimental Design: To study human androgen-independent prostate cancer model, LuCaP35V tumors were implanted s.c. into castrated severe combined immunodeficient mice. When tumors reached about 100 mm³, animals were treated with vehicle control docetaxel (10 or 20 mg/kg) and docetaxel in combination with A12 (40 µg/kg) for 4 weeks. To study human osseous prostate cancer model, LuCaP 23.1 tumors were implanted intratibiae. When serum prostate-specific antigen reached 5 to 10 ng/mL, treatments were initiated.

Results: A12 markedly augmented the inhibition of docetaxel on tumor growth. When docetaxel is combined with A12, the inhibition of tumor growth continued after treatment cessation, which was associated with continued apoptosis and decreased proliferation of tumor cells. Gene expression profiles indicated that the posttreatment suppression of tumor growth may be due to enhanced negative regulation of cell cycle progression– and/or cell survival–associated genes, some of which have been shown to induce resistance to docetaxel.

Conclusions: Our findings suggest that targeting type 1 insulin-like growth factor receptor can enhance the therapeutic effect of docetaxel on advanced prostate cancer. Our findings also suggest a potential mechanism to improve the treatment efficacy of docetaxel in prostate cancer.

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