Our laboratory has used in vivo phage display (1) to demonstrate how the vascular endothelium of organs is modified in a tissue-specific manner, and (2) to prove that the development of cancer is accompanied by specific abnormalities in the cells that form tumor-associated blood vessels. From previous work in an IRB- approved protocol involving phage-display screening with a random library injected intravenously into an irreversibly injured patient, a homing peptide was isolated from post-injection prostate biopsies. The selected sequence mimicked a motif of interleukin 11 (IL-11), and it in fact was bound to IL-11 receptor alpha (IL- 11 R). Subsequent studies, including an extensive immunohistochemical analysis of primary and metastatic prostate cancer samples, showed increased expression of IL-1 IR during disease progression, particularly in bone metastases. The seminal observation that the vasculature of human prostate cancer selectively binds a small peptide motif via IL-11R raises many potential directions for both basic and translational research. In particular, it engenders the novel hypothesis that IL-11R-mediated signaling is biologically important in the progression of prostate cancer to a lethal phenotype;and, that understanding how this expression is regulated-particularty in relation to progression to a castrate-resistant state-will provide novel and relevant insights into the biology of human prostate cancer. The discovery of this prostate-homing peptide also suggests the use of novel imaging and therapeutic agents based on the selective binding. We have chosen to pursue aggressively a therapeutic application: we have produced an agent, BMTP-11 (Bone Metastasis Targeting Peptide-11), in which the selected peptide motif is combined with the mitochondrial disrupting, and therefore apoptosis-inducing moiety. The most important translational research issues in this context are: 1) Does BMTP-11 selectively distribute to prostate cancer in human patients, 2) How is IL-11R expression regulated, because this information is important for the selection of patients and the modulation of effective BMTP-11 treatment, and 3) What are the toxicities of this agent, and how can they be mechanistically understood and thereby mitigated. The following Specific Aimis state our priorities relevant to these questions. We will (i) Study the induction and activity of IL-11 and the IL-11Ra within the tumor microenvironment during prostate cancer progression;(ii) Determine the stimuli mediating up-regulation and activation ofthe IL-11Ra. Potential interplay linking IL-11, IL-11R and castrate-resistant tumor growth will be investigated;and (iii) Develop pre-clinical and clinical assays to evaluate BMTP-11 activity in patients.

Public Health Relevance

Metastatic, castration-resistant prostate cancer continues to be a lethal disease phenotype, with median survival time of about 18 months and accounting for over 28,000 deaths annually in the United States. There is a pressing need for new approaches. Targeting the bone compartment can alter the natural history of the disease. BMTP-11 is especially attractive because it may be capable of selectively delivering an apoptosis- inducing agent by means of ligand-directed targeting of bone metastases.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA140388-05
Application #
8541600
Study Section
Special Emphasis Panel (ZCA1-RPRB-7)
Project Start
Project End
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
5
Fiscal Year
2013
Total Cost
$229,889
Indirect Cost
$77,415
Name
University of Texas MD Anderson Cancer Center
Department
Type
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Zhang, Tao; Tseng, Chieh; Zhang, Yan et al. (2016) CXCL1 mediates obesity-associated adipose stromal cell trafficking and function in the tumour microenvironment. Nat Commun 7:11674
Sun, Sheng; Sun, Le; Zhou, Xi et al. (2016) Phosphorylation-Dependent Activation of the ESCRT Function of ALIX in Cytokinetic Abscission and Retroviral Budding. Dev Cell 36:331-43
Hosoya, Hitomi; Dobroff, Andrey S; Driessen, Wouter H P et al. (2016) Integrated nanotechnology platform for tumor-targeted multimodal imaging and therapeutic cargo release. Proc Natl Acad Sci U S A 113:1877-82
Maity, Sankar N; Titus, Mark A; Gyftaki, Revekka et al. (2016) Targeting of CYP17A1 Lyase by VT-464 Inhibits Adrenal and Intratumoral Androgen Biosynthesis and Tumor Growth of Castration Resistant Prostate Cancer. Sci Rep 6:35354
Saha, Achinto; Blando, Jorge; Fernandez, Irina et al. (2016) Linneg Sca-1high CD49fhigh prostate cancer cells derived from the Hi-Myc mouse model are tumor-initiating cells with basal-epithelial characteristics and differentiation potential in vitro and in vivo. Oncotarget 7:25194-207
Han, Ying; Rand, Kristin A; Hazelett, Dennis J et al. (2016) Prostate Cancer Susceptibility in Men of African Ancestry at 8q24. J Natl Cancer Inst 108:
Varkaris, Andreas; Corn, Paul G; Parikh, Nila U et al. (2016) Integrating Murine and Clinical Trials with Cabozantinib to Understand Roles of MET and VEGFR2 as Targets for Growth Inhibition of Prostate Cancer. Clin Cancer Res 22:107-21
Fong, Eliza L S; Wan, Xinhai; Yang, Jun et al. (2016) A 3D in vitro model of patient-derived prostate cancer xenograft for controlled interrogation of in vivo tumor-stromal interactions. Biomaterials 77:164-72
Weiderhold, Kimberly N; Fadri-Moskwik, Maria; Pan, Jing et al. (2016) Dynamic Phosphorylation of NudC by Aurora B in Cytokinesis. PLoS One 11:e0153455
Qiao, Yuanyuan; Feng, Felix Y; Wang, Yugang et al. (2016) Mechanistic Support for Combined MET and AR Blockade in Castration-Resistant Prostate Cancer. Neoplasia 18:1-9

Showing the most recent 10 out of 167 publications