Maintenance therapy in ovarian cancer: Molecular basis and therapeutic approach

Abstract

Abstract. Ovarian cancer has the highest mortality rate among gynaecological tumours despite the fact that the majority of patients with advanced disease achieve complete remission after first-line surgery and chemotherapy. Unfortunately, disease recurrence occurs in the majority of patients and second-line treatments are not curative. Clearly, the persistence of dormant and drug-resistant cells after front-line treatments results in the inability to cure the disease. The identification of cancer-initiating cells or cancer stem cells as key players in the development of recurrence has opened up a novel field of research aimed at identifying additional innovative therapeutic approaches. Strategies of maintenance therapy to extend the survival of patients have been studied, but to date no overall survival benefit has been detected. Currently, numerous clinical trials have just been completed or are ongoing involving patients achieving a complete clinical response after first-line chemotherapy in order to evaluate the efficacy of different therapeutic approaches in terms of disease-free survival and overall survival. At the 2010 ASCO meeting, the first positive results of a phase iii clinical trial in this setting were presented: bevacizumab (15 mg/kg i.v. every 21 days) added to first-line chemotherapy and continued for an additional 15 cycles was found to prolong progression-free survival of 3.8 months in comparison to 6 cycles of chemotherapy alone or only 6 cycles of chemotherapy plus bevacizumab. In addition, positive results were announced for a second phase iii trial testing bevacizumab in the same setting, but at half dose. The final assessment of the overall clinical benefit and the approval of bevacizumab in maintenance therapy by regulatory agencies is expected to be positive, as are the final results of abagovomab phase III trial MIMOSA, another antibody-based therapy tested as a maintenance treatment for advanced ovarian cancer patients. Encouraging preliminary results confirming the safety profile and the immunogenic activity of abagovomab were presented at the last ASCO meeting. The final results are expected to be released in the first half of 2011.

OC125, M11 and OV197 Epitopes Are Not Uniformly Distributed in the Tandem-Repeat Region of CA125 and Require the Entire SEA Domain

“…The antigenic properties of CA125 are also considered for therapeutic approaches against ovarian cancer. Indeed, anti-CA125 mAbs were evaluated as radionuclide or cytotoxin conjugated [20,37], as anti-idiotype antibody in order to mime the OC125 epitope and to elicit an antitumor immune response [12,19], or as immunoglobulins to induce an antibody-dependent cellular cytotoxicity [3].…”

Protein tyrosine phosphatase receptor type R (PTPRR) antagonizes the Wnt signaling pathway in ovarian cancer by dephosphorylating and inactivating β-catenin

“…Ovarian cancer is one of the deadliest malignant tumors and the fifth-leading cause of cancer-related death in women from the United States (1,2). Over the last 2 decades, advances have greatly improved cancer therapy; however, the survival rate of women with ovarian cancer has barely changed (3)(4)(5). Thus, further research is needed to understand how different molecular pathways contribute to tumorigenesis of ovarian cancer and to discover potential therapeutic targets.…”

“…In the current study, using a shRNA-based biochemical screen, we determined that protein tyrosine phosphatase PTPRR, 4 which is down-regulated in ovarian cancers, is responsible for tyrosine dephosphorylation of ␤-catenin on residue 142. Ectopic expression of PTPRR decreases tyrosine phosphorylation of ␤-catenin, inhibits the ␤-catenin-mediated transcriptional activation of downstream target genes, and significantly delays ovarian cancer cell proliferation both in vitro and in vivo.…”

FER-mediated phosphorylation and PIK3R2 recruitment on IRS4 promotes AKT activation and tumorigenesis in ovarian cancer cells

“…The lack of a genetically engineered mouse model for ovarian cancer significantly delays the entire process of ovarian cancer research. In particular, the molecular mechanisms of ovarian tumor progression and metastasis are not well understood, key factors severely restricting the overall survival from ovarian cancer ( Binaschi et al, 2011 ). Consequently, there is an urgent need and enormous translational potential in revealing the molecular mechanisms regulating the initiation and progression of ovarian cancers.…”