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.
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.
|Luo, Yong; Azad, Abul Kalam; Karanika, Styliani et al. (2017) Enzalutamide and CXCR7 inhibitor Combination Treatment Suppresses Cell Growth and Angiogenic Signaling in Castration-Resistant Prostate Cancer Models. Int J Cancer :|
|Lin, Song-Chang; Lee, Yu-Chen; Yu, Guoyu et al. (2017) Endothelial-to-Osteoblast Conversion Generates Osteoblastic Metastasis of Prostate Cancer. Dev Cell 41:467-480.e3|
|Gao, Jianjun; Ward, John F; Pettaway, Curtis A et al. (2017) VISTA is an inhibitory immune checkpoint that is increased after ipilimumab therapy in patients with prostate cancer. Nat Med 23:551-555|
|Yu, Kai-Jie; Li, Jeffrey K; Lee, Yu-Chen et al. (2017) Cabozantinib-induced osteoblast secretome promotes survival and migration of metastatic prostate cancer cells in bone. Oncotarget 8:74987-75006|
|Tu, Huakang; Gu, Jian; Meng, Qing H et al. (2017) Low serum testosterone is associated with tumor aggressiveness and poor prognosis in prostate cancer. Oncol Lett 13:1949-1957|
|Gökce, Mehmet I; Wang, Xuemei; Frost, Jacqueline et al. (2017) Informed decision making before prostate-specific antigen screening: Initial results using the American Cancer Society (ACS) Decision Aid (DA) among medically underserved men. Cancer 123:583-591|
|Karanika, Styliani; Karantanos, Theodoros; Li, Likun et al. (2017) Targeting DNA Damage Response in Prostate Cancer by Inhibiting Androgen Receptor-CDC6-ATR-Chk1 Signaling. Cell Rep 18:1970-1981|
|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|
|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|
|Subudhi, Sumit K; Aparicio, Ana; Gao, Jianjun et al. (2016) Clonal expansion of CD8 T cells in the systemic circulation precedes development of ipilimumab-induced toxicities. Proc Natl Acad Sci U S A 113:11919-11924|
Showing the most recent 10 out of 198 publications