DEVELOPMENT OF IGFBP-3 THERAPY IN MEN WITH PROSTATE CANCER In preliminary data derived with this SPORE grant, we demonstrated interactions of IGFBP-3 with mitochondria! and nuclear apoptosis-related proteins and showed that IGFBP-3's action requires rapid internalization, phosphorylation, and association with the multi-compartmental nuclear receptors RXRa and Nur77 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-3 cascade and could serve as a biomarkerfor IGFBP-3 responsiveness. Importantly, we have also shown that the in vivo administration of IGFBP-3 to xenograft bearing mice results in substantial tumor suppression and inhibition of angiogenesis and that the effects of IGFBP-3 in vivo are observed when given as a single therapy, and are enhanced in combination with other agents. Our work has been instrumental in advancing this 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 for IGFBP-3 pathway molecules in prostate cancer and evaluate of their role in determining disease prognosis and 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 intra tumor staining levels of IGFBP-3, Nur77, and RXRa predict the clinical outcome of patients with prostate cancer. (2) Conduct a a Phase 1 b dose response neoadjuvant trial of IGFBP-3 in men with CaP. The primary goals of the study are to assess toxicity and to identify an active dose as defined by molecular induction of apoptosis using assays that include those developed in Aim 1. Secondary goals will be to use genomic and proteomic analyses to identify additional surrogate markers of treatment. (3) Optimize IGFBP-3 treatment of prostate cancer in in vivo mouse models, prior to initiating a larger phase 2 study.
This Aim i s a reverse translation that will build upon the preceding clinical study. Our goals are to identify drugs that synergize with IGFBP-3, such as IGF receptor inhibitors, EGF receptor antagonists and nutritional agents including Pom X. Together, these efforts will serve to promote the development of rational IGFBP-3-related therapies and tools to assess its efficacy in prostate cancer. As the first clinical trials targeting other components of the IGF axis are already underway, we believe that IGFBP-3 will have additional tumor suppressive effects given its IGF-dependent and -independent apoptosis-promoting properties. If successful, our findings may provide new avenues for the treatment of this disease and pave the way towards larger clinical studies involving IGFBP-3.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA092131-09
Application #
8094357
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
9
Fiscal Year
2010
Total Cost
$206,509
Indirect Cost
Name
University of California Los Angeles
Department
Type
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Nagarajan, Mahesh B; Raman, Steven S; Lo, Pechin et al. (2018) Building a high-resolution T2-weighted MR-based probabilistic model of tumor occurrence in the prostate. Abdom Radiol (NY) 43:2487-2496
Calais, Jeremie; Fendler, Wolfgang P; Eiber, Matthias et al. (2018) Impact of 68Ga-PSMA-11 PET/CT on the Management of Prostate Cancer Patients with Biochemical Recurrence. J Nucl Med 59:434-441
Vidal, Adriana C; Howard, Lauren E; de Hoedt, Amanda et al. (2018) Neutrophil, lymphocyte and platelet counts, and risk of prostate cancer outcomes in white and black men: results from the SEARCH database. Cancer Causes Control 29:581-588
Vidal, Adriana C; Howard, Lauren E; de Hoedt, Amanda et al. (2018) Obese patients with castration-resistant prostate cancer may be at a lower risk of all-cause mortality: results from the Shared Equal Access Regional Cancer Hospital (SEARCH) database. BJU Int 122:76-82
Jelinek, David; Flores, Aimee; Uebelhoer, Melanie et al. (2018) Mapping Metabolism: Monitoring Lactate Dehydrogenase Activity Directly in Tissue. J Vis Exp :
Lee, John K; Bangayan, Nathanael J; Chai, Timothy et al. (2018) Systemic surfaceome profiling identifies target antigens for immune-based therapy in subtypes of advanced prostate cancer. Proc Natl Acad Sci U S A 115:E4473-E4482
Mitra, Mithun; Lee, Ha Neul; Coller, Hilary A (2018) Determining Genome-wide Transcript Decay Rates in Proliferating and Quiescent Human Fibroblasts. J Vis Exp :
Zou, Yongkang; Qi, Zhi; Guo, Weilong et al. (2018) Cotargeting the Cell-Intrinsic and Microenvironment Pathways of Prostate Cancer by PI3K?/?/? Inhibitor BAY1082439. Mol Cancer Ther 17:2091-2099
Henning, Susanne M; Galet, Colette; Gollapudi, Kiran et al. (2018) Phase II prospective randomized trial of weight loss prior to radical prostatectomy. Prostate Cancer Prostatic Dis 21:212-220
Miller, Eric T; Salmasi, Amirali; Reiter, Robert E (2018) Anatomic and Molecular Imaging in Prostate Cancer. Cold Spring Harb Perspect Med 8:

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