Faculty Publications

Objective. To determine the activity and pharmacodynamics (PD) of bortezomib in platinum-sensitive epithelial ovarian or primary peritoneal cancer (EOC/PPC). Patients and methods. Eligible women with recurrent EOC/PPC progressing between 6 and 12 months after initial chemotherapy were treated with bortezomib on days 1, 4, 8, and 11 [1.5 (cohort I) and 1.3 (cohort II) mg/m(2)/dose]. Patients must have had initial chemotherapy only. Response Evaluation Criteria in Solid Tumors (RECIST) was assessed by computed tomography (CT) scan every 2 cycles. 20S proteasome activity was quantified in three pre-treatment and a 1-hour post-treatment (cycle one, day 1) whole blood lysates. Results. Initially, 26 evaluable patients were treated at the 1.5 mg/m2/dose level. Objective response rate was 3.8% (1/26), a partial response. An additional 10 patients (38.5%) had stable disease. Given concerns that treatment discontinuations due to toxicity limited drug exposure/activity a second Cohort of 29 evaluable patients was accrued at 1.3 mg/m(2)/dose. The 1.3 mg/m(2)/dose regimen is currently approved as an indication for multiple myeloma and mantle cell lymphoma. Treatment was more tolerable, although objective responses remained low at 6.9% (2/29, partial responses). Second stage accrual was not warranted at either dose. Bortezomib effectively inhibited 20S proteasome activity in whole blood lysates between 37 and 92% in 24/25 (96%) patients in cohort I, and 14-84% in 27/28 (96%) patients in cohort II who provided satisfactory pre- and post-treatment specimens for testing. Conclusion. Bortezomib has minimal activity as a single-agent in the treatment of recurrent platinum-sensitive EOC/PPC. Treatment with bortezomib at 1.5 mg/m(2)/dose was not feasible in this patient population due to excess toxicity. Bortezomib was well tolerated at 1.3 mg/m(2)/dose. (C) 2009 Elsevier Inc. All rights reserved.

The majority of patients who present with epithelial ovarian cancer respond well to the initial treatment, but will ultimately experience a recurrence of their disease. Chemotherapy can palliate symptoms of disease recurrence, and there is some evidence that it also can improve survival. Recurrent ovarian carcinoma is divided into two subsets of patients: those with platinum-sensitive disease and those with platinum-resistant disease. Management for these two groups has diverged in the last few years, as evidence accrues that the response to treatment and duration of treatment-free interval after completion of front-line therapy impacts the prognosis and the treatment choice for these patients. Recent randomized trials have demonstrated a benefit for platinum combination re-treatment in patients with platinum-sensitive disease. Additionally, there are multiple single-agent trials evaluating novel agents for patients with platinum-resistant as well as platinum-sensitive disease. This review will discuss the role of chemotherapy in recurrent disease, describe the various agents used in this setting, and touch on the role of biologic agents in recurrent epithelial ovarian carcinoma.

OBJECTIVES: To determine the proportion of patients with tumor response, the proportion who survived progression-free for at least 6 months (progression-free survival >or= 6 months), and the frequency and severity of toxicities of patients with recurrent squamous cell carcinoma of the uterine cervix treated with erlotinib. METHODS: This was a multicenter, open-label, single-arm trial evaluating the toxicity and efficacy of oral erlotinib at an initial dosage of 150 mg daily until progressive disease or adverse effects prohibited further therapy. RESULTS: Twenty-eight patients with squamous cell carcinoma were enrolled onto this trial. Twenty-five patients were evaluable. There were no objective responses, with 4 (16%) patients achieving stable disease; only 1 patient had a progression-free survival of 6 months (4%) or more. The 1-sided 90% confidence interval for response was 0.0% to 8.8%. The 2-sided 90% confidence interval for the proportion of patients surviving progression-free for at least 6 months is 0.2% to 17.6%. Erlotinib was well tolerated, with the most common drug-related adverse events being gastrointestinal toxicities, fatigue, and rash. CONCLUSIONS: Erlotinib is inactive as monotherapy in patients with recurrent squamous cell carcinoma of the uterine cervix.

BACKGROUND: Imatinib mesylate (Gleevec, Novartis, Basel, Switzerland) is a small-molecule tyrosine kinase inhibitor with activity against ABL, BCR-ABL, c-KIT, and PDGFR alpha. Several clinical trials have evaluated the efficacy and safety of imatinib in patients with ovarian carcinoma who have persistent or recurrent disease following front-line platinum/taxane based chemotherapy. However, there is limited pre-clinical and clinical data on the molecular targets and action of imatinib in ovarian cancer. MATERIALS AND METHODS: Human ovarian cancer cells (A2780) were treated with imatinib mesylate for either 6 or 24 h. We employed a 2D (two-dimensional) gel electrophoresis and mass spectrometry-based proteomics approach to identify protein expression patterns and signaling pathways that were altered in response to imatinib. Cells were analyzed for PDGFR alpha and AKT expression, which were then correlated with imatinib sensitivity. RESULTS: Using 2D gel electrophoresis of overlapping pH ranges from pH 4 to 11, about 4,000 protein spots could be analyzed reproducibly. Proteins whose levels changed between twofold to 30 fold were grouped according to whether changes were in the same direction at both time points of treatment with respect to the control, or changed their levels only at one of the time points. CONCLUSION: Differentially regulated proteins following imatinib treatment of A2780 cells involved the regulation of actin cytoskeleton, metabolic pathways, cell cycle, cell proliferation, apoptosis, cell junctions, and signal transduction. Thus, exposure of cells to imatinib produces complex changes in the cell that require further investigation.

PURPOSE This phase II trial assessed the activity and tolerability of an oral dose of imatinib mesylate 400 mg twice daily in patients with recurrent or persistent epithelial ovarian or primary peritoneal carcinoma. The association between the expression of certain markers and clinical outcome was investigated. PATIENTS AND METHODS Primary measure of clinical efficacy was progression-free survival (PFS) at 6 months. Mutational analysis of KIT, immunohistochemistry (IHC) and enzyme-linked immunosorbent assay for markers (KIT, platelet-derived growth factor [PDGF] receptor [-R], AKT2, phosphorylated AKT [p-AKT], stem cell factor [SCF], and PDGF) were performed. Results Fifty-six eligible patients were evaluated. Nine patients were progression free for at least 6 months including one complete responder. The median PFS and survival were 2 and 16 months, respectively. The most common grade 3 and 4 toxicities were neutropenia, GI, dermatologic effects, pain, and electrolyte disturbances. At least one target of imatinib (KIT, PDGFR-alpha, or PDGFR-beta) was expressed in all tumors, and most tumors expressed all three receptors. Higher expression of p-AKT and PDGFR-beta were associated with shorter PFS, and higher IHC scores (% immunopositive cells x staining intensity) of SCF and p-AKT were associated with decreased overall survival. No sequence mutations were detected in the KIT gene. Higher pretreatment plasma concentrations of PDGF-AB, PDGF-BB, and vascular endothelial growth factor (VEGF) were individually associated with shorter PFS and survival. CONCLUSION Imatinib mesylate was well tolerated but had minimal single-agent activity in patients with recurrent ovarian or primary peritoneal carcinoma. No marker was identified that would predict activity of imatinib; however, tumor p-AKT and plasma VEGF levels were associated with poor outcome.

Although platinum chemotherapeutic agents such as carboplatin, cisplatin, and oxaliplatin are used to treat a broad range of malignant diseases, their efficacy in most cancers is limited by the development of resistance. There are multiple factors that contribute to platinum resistance but alterations of DNA repair processes have been known for some time to be important in mediating resistance. Recently acquired knowledge has provided insight into the molecular mechanisms of DNA repair pathways and their effect on response to chemotherapy. This review will discuss the most important DNA repair pathways known to be involved in the platinum response, i.e., nucleotide excision repair (NER) and mismatch repair (MMR), and will briefly touch on the role of BRCA in DNA repair. The therapeutic implications of alterations in DNA repair which affect response to platinum in the treatment of patients with malignant disease, such as excision repair cross-complementation group 1 (ERCC1) deficiency and mismatch repair deficiency, will be reviewed.

PURPOSE: mTOR (mammalian target of rapamycin) plays a central role in regulating cell growth and cell cycle progression and is regarded as a promising therapeutic target. We examined whether mTOR inhibition by RAD001 (everolimus) is therapeutically efficacious in the treatment of ovarian cancer as a single agent and in combination with cisplatin. EXPERIMENTAL DESIGN: Using four human ovarian cancer cell lines, we determined the effect of RAD001 by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, Western blot, and apoptosis assays. We evaluated the association between phospho-AKT/mTOR activity and RAD001 sensitivity. We also determined the effect of RAD001 on tumor growth and malignancy using mice inoculated with human ovarian cancer cells. RESULTS: RAD001 markedly inhibited cell proliferation of human ovarian carcinoma cells with high AKT activity (OVCAR10 and SKOV-3), but the effect was minimal in cells with low AKT activity (OVCAR4 and OVCAR5). Sensitivity to RAD001 was independent of p53 expression. RAD001 inhibited the phosphorylation of downstream 4E-BP1 and p70S6 kinase and attenuated the expression of Myc. RAD001 also attenuated the expression of HIF-1alpha and vascular endothelial growth factor, important factors in angiogenesis and tumor invasiveness. RAD001 enhanced cisplatin-induced apoptosis in cells with high AKT/mTOR activity, with minimal effect in cells with low AKT-mTOR activity. Mouse xenografts of SKOV-3 cells revealed that RAD001 inhibits tumor growth, angiogenesis, and i.p. dissemination and ascites production and prolongs survival. Moreover, treatment with RAD001 significantly enhanced the therapeutic efficacy of cisplatin in vivo. CONCLUSION: These results indicate that RAD001 could have therapeutic efficacy in human ovarian cancers with hyperactivated AKT/mTOR signaling.

BACKGROUND. Radioimmunotherapy with radiolabeled monoclonal antibodies to CD20 produces a high response rate in patients with recurring non-Hodgkin lymphoma (NHL), but the durability of those remissions is not well defined. METHODS. Data on patients with recurring NHL treated with yttrium Y 90 ibritumomab tiuxetan in 4 clinical trials were reviewed to identify patients with a long-term response, defined as a time to progression of 12 months or longer. RESULTS. Long-term responses were seen in 37% (78/211) of patients. At a median follow-up of 53.5 months (range, 12.7-88.9) the median duration of response was 28.1 months and the median time to progression was 29.3 months. A third of these patients had been treated with at least 3 previous therapies, and 37% of them had not responded to their last therapy. The findings in patients with follicular lymphoma (n = 59) were similar to those in the overall population of long-term responders. The estimated overall survival at 5 years was 53% for all patients treated with Y-90 ibritumomab tiuxetan and 81% for long-term responders. CONCLUSIONS. A single dose of Y-90 ibritumomab tiuxetan can produce durable responses and prolonged overall survival in a substantial number of patients in whom previous therapies have failed.

Despite an aggressive approach of surgical cytoreduction and adjuvant combination chemotherapy, ovarian cancer mortality remains a significant problem. We are entering a new era of cancer therapeutics in which targeted therapies offer the potential for improvement in long-term disease control with fewer toxicities. The greatest success of targeted therapy to date in the setting of epithelial ovarian carcinoma has come from angiogenesis inhibition. This review will focus on the role of angiogenesis in normal ovarian function as well as in ovarian carcinoma development and disease progression. Current knowledge about the molecular pathways involved in angiogenesis and various approaches to angiogenesis inhibition in the treatment of ovarian cancer are discussed. Current data regarding the role of bevacizumab and other novel agents in the treatment of ovarian carcinoma are summarized.

Background: Proprotein convertases (PCs) are serine proteases that after restricted proteolysis activate many proteins that play a crucial role in cancer such as metalloproteinases, growth factors and growth factor receptors, adhesion molecules, and angiogenic factors. Although the expression of several PCs is increased in many tumors, their expression in primary ovarian tumors has not been studied in detail. We sought to determine if there was an association between the expression of the ubiquitously expressed PCs, furin, PACE-4, PC-5 and PC-7, and ovarian tumor progression. Methods: We assessed their expression by RT-PCR, Real-time PCR, Western blot, and immunohistochemistry using cells derived from normal human ovarian surface epithelium (HOSE) and cancer cell lines as well as ovarian epithelial cancer specimens (45 RT-PCR/Real-time PCR, and 120 archival specimens for Immunohistochemistry). Results: We found that furin expression was restricted to the cancer cell lines!

Although significant improvements in standard therapy for ovarian carcinoma have been made over the past decade, current treatment is limited by the development of resistance to cytotoxic chemotherapy, and most women ultimately die of the disease. New knowledge of the biology of ovarian cancer has led to the identification of potential molecular targets that are differentially expressed in normal cells versus cancer cells, and advances in pharmacology have led to the development of novel agents that work differently from traditional cytotoxic chemotherapy by exploiting these targets. Many of these agents are being evaluated in clinical trials. This article discusses molecular targets that are important in ovarian carcinoma, including angiogenesis, tyrosine kinases, mitogen-activated protein kinases, and phosphatidylinositol-like kinases such as mammalian target of rapamycin, and the proteosome. This article reviews novel non-cytotoxic agents that target these pathways and are currently being evaluated in ovarian carcinoma treatment.