hemiasterlin and Urinary-Bladder-Neoplasms

HTI-286 is a fully synthetic analogue of the natural tripeptide hemiasterlin that inhibits tubulin polymerization and has strong cytotoxic potential. In this study, we evaluate the inhibitory effects of HTI-286 on human bladder cancer growth, both in vitro and as an intravesical agent in an orthotopic murine model.. Various bladder cancer cell lines were treated with HTI-286 and mitomycin C (MMC) in vitro. Human KU-7 bladder tumor cells that stably express firefly luciferase were inoculated in female nude mice by intravesical instillation and quantified using bioluminescence imaging. Mice with established KU-7-luc tumors were given HTI-286 or MMC intravesically twice a week for 2 h. Pharmacokinetic data was obtained using high-performance liquid chromatography-mass spectrometry analyses.. In vitro, HTI-286 was a potent inhibitor of proliferation in all tested cell lines and induced marked increases in apoptosis of KU-7-luc cells even after brief exposure. In vivo, HTI-286 significantly delayed cancer growth of bladder tumors in a dose-dependent fashion. HTI-286, at a concentration of 0.2 mg/mL, had comparable strong cytotoxicity as 2.0 mg/mL of MMC. The estimated systemic bioavailability of intravesically given HTI-286 was 1.5% to 2.1% of the initial dose.. Intravesical HTI-286 instillation therapy showed promising antitumor activity and minimal toxicity in an orthotopic mouse model of high-grade bladder cancer. These findings provide preclinical proof-of-principle for HTI-286 as an intravesical therapy for nonmuscle-invasive bladder cancer and warrant further evaluation of efficacy and safety in early-phase clinical trials.

Topics: Administration, Intravesical; Animals; Antibiotics, Antineoplastic; Apoptosis; Cell Cycle; Cell Proliferation; Drug Therapy, Combination; Female; Humans; Luminescence; Mice; Mice, Nude; Mitomycin; Oligopeptides; Tumor Cells, Cultured; Urinary Bladder Neoplasms; Xenograft Model Antitumor Assays

Although cisplatin-based neoadjuvant chemotherapy (NAC) improves survival of unselected patients with muscle-invasive bladder cancer (MIBC), only a minority responds to therapy and chemoresistance remains a major challenge in this disease setting.. To investigate the clinical significance of oncofetal chondroitin sulfate (ofCS) glycosaminoglycan chains in cisplatin-resistant MIBC and to evaluate these as targets for second-line therapy.. An ofCS-binding recombinant VAR2CSA protein derived from the malaria parasite Plasmodium falciparum (rVAR2) was used as an in situ, in vitro, and in vivo ofCS-targeting reagent in cisplatin-resistant MIBC. The ofCS expression landscape was analyzed in two independent cohorts of matched pre- and post-NAC-treated MIBC patients.. An rVAR2 protein armed with cytotoxic hemiasterlin compounds (rVAR2 drug conjugate [VDC] 886) was evaluated as a novel therapeutic strategy in a xenograft model of cisplatin-resistant MIBC.. Antineoplastic effects of targeting ofCS.. In situ, ofCS was significantly overexpressed in residual tumors after NAC in two independent patient cohorts (p<0.02). Global gene-expression profiling and biochemical analysis of primary tumors and cell lines revealed syndican-1 and chondroitin sulfate proteoglycan 4 as ofCS-modified proteoglycans in MIBC. In vitro, ofCS was expressed on all MIBC cell lines tested, and VDC886 eliminated these cells in the low-nanomolar IC. Targeting ofCS provides a promising second-line treatment strategy in cisplatin-resistant MIBC.. Cisplatin-resistant bladder cancer overexpresses particular sugar chains compared with chemotherapy-naïve bladder cancer. Using a recombinant protein from the malaria parasite Plasmodium falciparum, we can target these sugar chains, and our results showed a significant antitumor effect in cisplatin-resistant bladder cancer. This novel treatment paradigm provides therapeutic access to bladder cancers not responding to cisplatin.

Topics: Animals; Antigens, Protozoan; Antineoplastic Agents; Biomarkers, Tumor; British Columbia; Cell Death; Cell Line, Tumor; Chondroitin Sulfates; Cisplatin; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Europe; Gene Expression Regulation, Neoplastic; Humans; Inhibitory Concentration 50; Kaplan-Meier Estimate; Mice; Oligopeptides; Time Factors; Treatment Outcome; Tumor Burden; Urinary Bladder Neoplasms; Xenograft Model Antitumor Assays