Boris A. Hadaschik

Clusterin knockdown using the antisense oligonucleotide OGX-011 re-sensitizes docetaxel-refractory prostate cancer PC-3 cells to chemotherapy

To characterize changes in secretory clusterin (sCLU) expression in prostate cancer cells after treatment with docetaxel and to determine whether sCLU knockdown can re‐introduce chemosensitivity in a docetaxel‐resistant, androgen‐independent human prostate cancer model.

Paclitaxel incorporated in hydrophobically derivatized hyperbranched polyglycerols for intravesical bladder cancer therapy

To develop paclitaxel incorporated into unimolecular micelles based on hydrophobically derivatized hyperbranched polyglycerols (dHPGs) for use as mucoadhesive intravesical agents against non‐muscle‐invasive bladder cancer.

Targeting prostate cancer with HTI-286, a synthetic analog of the marine sponge product hemiasterlin

Therapeutic resistance is the underlying cause for most cancer deaths and a major problem associated with treatment of metastatic prostate cancer. HTI‐286, a fully synthetic analog of the natural tripeptide hemiasterlin, inhibits tubulin polymerization and circumvents transport‐based resistance to taxanes. In our study, we evaluated its inhibitory effects on human prostate cancer growth in vitro and in different in vivo models. Androgen‐dependent and androgen‐independent prostate cancer cell lines including a docetaxel‐refractory PC‐3 subline (PC‐3dR) were treated with HTI‐286. Transcriptional profiling was carried out to screen for changes in gene expression induced by HTI‐286 and compared to docetaxel. In vivo, nude mice with established PC‐3 or PC‐3dR xenografts were given HTI‐286 intravenously. Additionally, mice bearing hormone‐sensitive LNCaP tumors were treated with castration in combination with early or delayed HTI‐286 therapy. In all cell lines tested, HTI‐286 was a potent inhibitor of proliferation and induced marked increases in apoptosis. Despite similar transcriptomic changes regarding cell death and cell cycle regulating genes after exposure to HTI‐286 or docetaxel, array analysis revealed distinct molecular signatures for both compounds. Invivo, HTI‐286 significantly inhibited growth of PC‐3 and LNCaP xenografts and retained potency in PC‐3dR tumors. Simultaneous castration plus HTI‐286 therapy was superior to sequential treatment in the LNCaP model. In conclusion, HTI‐286 showed strong antitumor activity both in androgen‐dependent and androgen‐ independent tumors and may be a promising agent in second‐ line treatment strategies for patients suffering from docetaxel‐ refractory prostate cancer.

Intravesikale Therapie nicht muskelinvasiver Blasentumoren mit onkolytischen Vesikular-Stomatitisviren

Patients with high-risk bladder cancer who do not respond to bacillus Calmette-Guerin (BCG) immunotherapy represent a significant therapeutic challenge. The addition of interferon to BCG has recently evolved as a second-line treatment option; however, many high-grade tumors are nonresponsive to interferon. Thus, replication-competent oncolytic vesicular stomatitis viruses (VSV) that selectively target interferon-refractory tumors are promising intravesical agents. In vitro, wild-type VSV as well as a mutant variant (AV3) that has an impaired ability to shut down innate immunity preferentially killed undifferentiated, interferon-nonresponsive bladder cancer cells. Testing of these viruses in an orthotopic murine model of high-grade bladder cancer, which we have recently validated, revealed that both AV3 and wild-type VSV significantly inhibited orthotopic tumor growth. Despite the use of immunocompromised nude mice, there was no evidence of toxicity. In conclusion, VSV instillation therapy demonstrated strong antitumor activity and safety in an orthotopic model of high-risk disease. These findings provide preclinical proof-of-principle for the intravesical use of VSV, especially in interferon-refractory patients.

Intravesikale Therapie nicht muskelinvasiver Blasentumoren mit onkolytischen Vesikular-Stomatitisviren@@@Oncolytic vesicular stomatitis viruses as intravesical agents against non-muscle-invasive bladder cancer

Patients with high-risk bladder cancer who do not respond to bacillus Calmette-Guerin (BCG) immunotherapy represent a significant therapeutic challenge. The addition of interferon to BCG has recently evolved as a second-line treatment option; however, many high-grade tumors are nonresponsive to interferon. Thus, replication-competent oncolytic vesicular stomatitis viruses (VSV) that selectively target interferon-refractory tumors are promising intravesical agents. In vitro, wild-type VSV as well as a mutant variant (AV3) that has an impaired ability to shut down innate immunity preferentially killed undifferentiated, interferon-nonresponsive bladder cancer cells. Testing of these viruses in an orthotopic murine model of high-grade bladder cancer, which we have recently validated, revealed that both AV3 and wild-type VSV significantly inhibited orthotopic tumor growth. Despite the use of immunocompromised nude mice, there was no evidence of toxicity. In conclusion, VSV instillation therapy demonstrated strong antitumor activity and safety in an orthotopic model of high-risk disease. These findings provide preclinical proof-of-principle for the intravesical use of VSV, especially in interferon-refractory patients.