Bone mimetic environments support engineering, propagation, and analysis of therapeutic response of patient-derived cells, ex vivo and in vivo.

Bone metastases are the most common milestone in the lethal progression of prostate cancer and prominent in a substantial portion of renal malignancies. Interactions between cancer and bone host cells have emerged as drivers of both disease progression and therapeutic resistance. To best understand these central host-epithelial cell interactions, biologically relevant preclinical models are required.

Targeting prostate tumor low-molecular weight tyrosine phosphatase for oxidation-sensitizing therapy.

Protein tyrosine phosphatases (PTPs) play major roles in cancer and are emerging as therapeutic targets. Recent reports suggest low-molecular weight PTP (LMPTP)-encoded by the gene-is overexpressed in prostate tumors. We found up-regulated in human prostate tumors and expression inversely correlated with overall survival.

Enhancing Ra Treatment Efficacy by Anti-1 Integrin Targeting.

Ra is an α-emitter approved for the treatment of bone metastatic prostate cancer (PCa), which exerts direct cytotoxicity toward PCa cells near the bone interface, whereas cells positioned in the core respond poorly because of short α-particle penetrance. β1 integrin (β1I) interference has been shown to increase radiosensitivity and significantly enhance external-beam radiation efficiency. We hypothesized that targeting β1I would improve Ra outcome.

Computational modeling identifies multitargeted kinase inhibitors as effective therapies for metastatic, castration-resistant prostate cancer.

Castration-resistant prostate cancer (CRPC) is an advanced subtype of prostate cancer with limited therapeutic options. Here, we applied a systems-based modeling approach called kinome regularization (KiR) to identify multitargeted kinase inhibitors (KIs) that abrogate CRPC growth. Two predicted KIs, PP121 and SC-1, suppressed CRPC growth in two-dimensional in vitro experiments and in vivo subcutaneous xenografts.

Engineered bone for probing organotypic growth and therapy response of prostate cancer tumoroids in vitro.

Mechanistic analysis of metastatic prostate cancer (PCa) biology and therapy response critically depends upon clinically relevant three-dimensional (3D) bone-like, organotypic culture. We here combine an engineered bone-mimetic environment (BME) with longitudinal microscopy to test the growth and therapy response of 3D PCa tumoroids. Besides promoting both tumor-cell autonomous and microenvironment-dependent growth in PCa cell lines and patient-derived xenograft cells, the BME enables in vivo-like tumor cell response to therapy, and reveals bone stroma dependent resistance to chemotherapy and BME-targeted localization and induction of cytoxicity by Radium-223.

Radium 223-Mediated Zonal Cytotoxicity of Prostate Cancer in Bone.

Background: Bone-targeting radiotherapy with Radium-223 (Rad-223), a radioisotope emitting genotoxic alpha-radiation with limited tissue penetrance (∼100 µm), prolongs the survival of patients with metastatic prostate cancer (PCa). Confoundingly, the clinical response to Rad-223 is often followed by detrimental relapse and progression, and whether Rad-223 causes tumor-cell directed cytotoxicity in vivo remains unclear. We hypothesized that limited radiation penetrance in situ defines outcome.