Aggresome disruption: a novel strategy to enhance bortezomib-induced apoptosis in pancreatic cancer cells.

The proteasome inhibitor bortezomib (formerly known as PS-341) recently received Food and Drug Administration approval for the treatment of multiple myeloma, and its activity is currently being evaluated in solid tumors. Bortezomib triggers apoptosis in pancreatic cancer cells, but the mechanisms involved have not been fully elucidated. Here, we show that pancreatic cancer cells exposed to bortezomib formed aggregates of ubiquitin-conjugated proteins ("aggresomes") in vitro and in vivo. Bortezomib-induced aggresome formation was determined to be cytoprotective and could be disrupted using histone deacetylase (HDAC) 6 small interfering RNA or chemical HDAC inhibitors, which resulted in endoplasmic reticulum stress and synergistic levels of apoptosis in vitro and in an orthotopic pancreatic cancer xenograft model in vivo. Interestingly, bortezomib did not induce aggresome formation in immortalized normal human pancreatic epithelial cells in vitro or in murine pancreatic epithelial cells in vivo. In addition, these cells did not undergo apoptosis following treatment with bortezomib, suberoylanilide hydroxamic acid, or the combination, showing tumor selectivity. Taken together, our study shows that inhibition of aggresome formation can strongly potentiate the efficacy of bortezomib and provides the foundation for clinical trials of bortezomib in combination with HDAC inhibitors for the treatment of pancreatic cancer.

Bortezomib sensitizes pancreatic cancer cells to endoplasmic reticulum stress-mediated apoptosis.

Bortezomib (PS-341, Velcade) is a potent and selective inhibitor of the proteasome that is currently under investigation for the treatment of solid malignancies. We have shown previously that bortezomib has activity in pancreatic cancer models and that the drug induces endoplasmic reticulum (ER) stress but also suppresses the unfolded protein response (UPR). Because the UPR is an important cytoprotective mechanism, we hypothesized that bortezomib would sensitize pancreatic cancer cells to ER stress-mediated apoptosis. Here, we show that bortezomib promotes apoptosis triggered by classic ER stress inducers (tunicamycin and thapsigargin) via a c-Jun NH(2)-terminal kinase (JNK)-dependent mechanism. We also show that cisplatin stimulates ER stress and interacts with bortezomib to increase ER dilation, intracellular Ca(2+) levels, and cell death. Importantly, combined therapy with bortezomib plus cisplatin induced JNK activation and apoptosis in orthotopic pancreatic tumors resulting in a reduction in tumor burden. Taken together, our data establish that bortezomib sensitizes pancreatic cancer cells to ER stress-induced apoptosis and show that bortezomib strongly enhances the anticancer activity of cisplatin.

Port-site metastasis: the influence of biology.

OBJECTIVE: Several surgical and technical mechanisms have been proposed for the development of port-site metastasis, but the influence of tumor and host biologic factors has not been emphasized. We present a case of a pelvic chordoma that metastasized to a prior laparoscopic radical nephrectomy port-site. METHODS: A 62-year-old woman underwent laparoscopic radical nephrectomy (LRN) for a pT1b grade 3 renal cell carcinoma, followed 6 weeks later by resection of a sacral chordoma. The incisions and areas of dissection for the two procedures were discontinuous. RESULTS: Eight months following the LRN she developed a nodule in one of the laparoscopic port-sites. The port-site metastasis was treated with wide surgical resection, which was confirmed as metastatic chordoma on histologic examination. CONCLUSION: Based on the chronological sequence and physical distance between surgical sites, only biological factors could have contributed to this port-site metastasis. This unusual case highlights the important role that tumor and host biologic mechanisms play in the development of port-site metastasis.

Integrating basic science and clinical research in bladder cancer: update from the first bladder Specialized Program of Research Excellence (SPORE).

PURPOSE OF REVIEW: To review the progress of the genitourinary SPORE (Specialized Program of Research Excellence) in bladder cancer. RECENT FINDINGS: The optimal management of bladder cancer depends on the accurate assessment of the biological potential of the disease. Methotrexate, vincristine, adriamycin and cisplatin (M-VAC) chemotherapy has been the standard of therapy for over a decade. However, there has been no improvement in patient survival. Encouraging preclinical data have resulted in the rapid translation of epidermal growth factor receptor antagonists into the clinic. However, phase I and II single-agent clinical trials in head and neck, lung, and colon cancer failed to match the hope generated by laboratory investigations since only a minority of patients seemed to benefit from this approach. Nonetheless, recent data revealed that non-small-cell lung cancer tumors that responded to single-agent Iressa possessed activating epidermal growth factor receptor mutations. These findings have generated refound interest for epidermal growth factor receptor-dependent tumors that are identified by molecular and pharmacodynamic approaches prior to or early in the course of therapy. SUMMARY: Targeted therapy against epidermal growth factor receptor has become one of the primary focuses of the genitourinary SPORE in bladder cancer. The SPORE grant scheme is designed to encourage rapid development of new and innovative cancer research in areas of high priority, in this case bladder cancer. The SPORE has facilitated the advancement of novel epidermal growth factor receptor-targeted therapy, such as the monoclonal antibody IMC-225 and the tyrosine kinase inhibitor ZD1839 (Iressa), from the laboratory to clinical trials. The integration of these new biological agents in combination with chemotherapy, in order to abrogate the progression of advanced bladder cancer, is the prime directive of our current phase II Iressa/docetaxel trial.

Is bladder biopsy necessary at three or six months post BCG therapy?

The standard of practice set by the SWOG investigation of BCG therapy for superficial bladder cancer has been to evaluate response at 3 months with cystoscopy and bladder biopsy. This study is to determine if all patients require a biopsy post therapy at 3 or 6 months. We reviewed the charts of 43 patients who had received a 6-weekly course of BCG (Connaught strain) for high grade or recurrent Ta, T1, or Tis transitional cell carcinoma of the bladder. The patients with Ta recurrent, T1 or Tis disease received maintenance therapy. All patients were followed through 6 months. At 3 months, 32/43 patients had negative cystoscopies. All 32 patients had corresponding negative biopsies. Eight patients had visible papillary tumors, while three patients had erythematous lesions, which were biopsy negative. At 6 months, eight different patients had visible lesions on cystoscopy that were biopsy proven superficial bladder cancer. The positive predictive value at 3 and 6 months post BCG therapy was 72.6% and 100%, respectively. The false positive rate was 7% at the 3-month checkpoint. Bladder biopsy is not necessary at the 3 or 6 month period following BCG therapy in the face of negative cystoscopic findings.

Initial report of bladder carcinoma following combined bladder-drained pancreas and kidney transplantation.

Although long-term survival of a functional allograft requiring long-term immunosuppressive therapy is responsible for higher incidence of non-urothelial cancers in renal allograft recipients than in normal population, the incidence of bladder cancer is uncommon and carcinoma of the bladder in the setting of combined kidney-pancreas transplantation has not been reported to date. We herein report a case of poorly differentiated invasive adeno-squamous cell carcinoma of the bladder following renal and bladder-drained pancreatic transplantation in a 44-yr-old lady with long-standing insulin dependent diabetes mellitus, which necessitated radical extirpation. Management implications are reviewed.