DEVELOPMENT OF IGFBP-3 THERAPY IN MEN WITH PROSTATE CANCERIn preliminary data derived with this SPORE grant, we demonstrated interactions of IGFBP-3 withmitochondria! and nuclear apoptosis-related proteins and showed that IGFBP-3's action requires rapidinternalization, phosphorylation, and association with the multi-compartmental nuclear receptors RXRa andNur77 leading to both rapid induction of apoptosis pathways. Particularly, we described that the nucleo-mitochondrial translocation of Nur77 in response to IGFBP-3 treatment is a key event in the IGFBP-3cascade and could serve as a biomarkerfor IGFBP-3 responsiveness. Importantly, we have also shown thatthe in vivo administration of IGFBP-3 to xenograft bearing mice results in substantial tumor suppression andinhibition of angiogenesis and that the effects of IGFBP-3 in vivo are observed when given as a singletherapy, and are enhanced in combination with other agents. Our work has been instrumental in advancingthis field to its current state, and in this SPORE renewal we propose to further investigate the role of IGFBP-3 as a therapy for men with prostate cancer.
Our specific aims are to (1) Develop histopathology assays forIGFBP-3 pathway molecules in prostate cancer and evaluate of their role in determining disease prognosisand their ability to serve as surrogate tissue biomarkers of IGFBP-3 activity on prostate cancer in vivo, (e. g.Nur77 subcellular localization); and to determine, using the SPORE tissue array resource, if baseline intratumor staining levels of IGFBP-3, Nur77, and RXRa predict the clinical outcome of patients with prostatecancer. (2) Conduct a a Phase 1 b dose response neoadjuvant trial of IGFBP-3 in men with CaP. Theprimary goals of the study are to assess toxicity and to identify an active dose as defined by molecularinduction of apoptosis using assays that include those developed in Aim 1. Secondary goals will be to usegenomic and proteomic analyses to identify additional surrogate markers of treatment. (3) Optimize IGFBP-3treatment of prostate cancer in in vivo mouse models, prior to initiating a larger phase 2 study.
This Aim i s areverse translation that will build upon the preceding clinical study. Our goals are to identify drugs thatsynergize with IGFBP-3, such as IGF receptor inhibitors, EGF receptor antagonists and nutritional agentsincluding Pom X. Together, these efforts will serve to promote the development of rational IGFBP-3-relatedtherapies and tools to assess its efficacy in prostate cancer. As the first clinical trials targeting othercomponents of the IGF axis are already underway, we believe that IGFBP-3 will have additional tumorsuppressive effects given its IGF-dependent and -independent apoptosis-promoting properties. Ifsuccessful, our findings may provide new avenues for the treatment of this disease and pave the waytowards larger clinical studies involving IGFBP-3.
Showing the most recent 10 out of 339 publications
