Abstract
Abstract Epidemiological and laboratory based studies suggest that the growth hormone/insulin-like growth factor I (GH/IGF-I) axis is positively correlated with a variety of different cancer types. In recent years, our research team has developed animal models to explore the role of GH signaling in carcinogenesis. These include rat and mouse models of mammary, prostate and colon cancer in which the GH receptor is knocked out, antagonized or GH itself is knocked out. In all of these models, we observed a significant (50% or more) disruption in carcinogenesis when GH signaling is impaired compared to normal controls. Our initial studies demonstrated that carcinogenesis can be effectively inhibited by the disruption of GH signaling in animals lacking genes for wild-type GH or the GH receptor. These findings are consistent with a recent report by Guevara-Aguirre and colleagues (Sci Transl Med 3: 70ra13, 2011) who found that a population lacking a functional GH receptor (Laron syndrome) were cancer free except for one patient whose ovarian cancer did not recur after chemotherapy. A control cohort of relatives suffered a 20% mortality rate from cancer. The response of the Laron patient's tumor to chemotherapy inspired us to hypothesize that the lack of GH signaling may render a tumor more vulnerable to conventional chemotherapy. To test this hypothesis, we treated 6 Spontaneous Dwarf rats (SDR) with GH (150 μg/kg twice daily) beginning at 3 weeks of age; 6 control rats received vehicle injections. At 4 weeks of age, all rats were exposed to a single injection of the mammary carcinogen N-methyl-N-nitrosourea (50 mg/kg). Once a rat developed a mammary tumor of 1cm in diameter, GH or vehicle injections were halted and doxorubicin (1.25 mg/kg; 6 injections over 2 weeks) treatments began. The dose of doxorubicin that was chosen was lower than that normally used to induce regression in this model. We observed that tumor growth in wild-type rats was stopped and remained static during treatment with doxorubicin. In contrast, the tumors of SDR rats, lacking GH, all regressed in response to doxorubicin treatment (p < 0.005). These data suggest that disrupting GH signaling may enhance the efficacy of conventional anticancer chemotherapy. Pegvisomant, a GH antagonist approved by the FDA for the treatment of acromegaly, or one of several investigational drugs currently under study for the disruption of IGF-I signaling, may serve to translate the findings presented here to the clinic to improve current cancer therapy regimens. This work was supported by NIH grant R01-CA099904. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 949. doi:1538-7445.AM2012-949
Published Version
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