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Ovarian cancer is the deadliest gynecologic cancer in the United States. Advances in conventional chemotherapy have improved the median survival in patients with ovarian cancer over the last two decades. These advances include taxane/platinum-based chemotherapy, intraperitoneal delivery of chemotherapy, dose-dense chemotherapy, and the availability of novel agents such as bevacizumab. Unfortunately, the overall survival remains poor and there is a need for new therapeutic paradigms. One of the biggest challenges in treating ovarian cancer is the development of platinum resistance which eventually occurs in 90% of ovarian cancer patients. Further research is needed to understand how molecular pathways contribute to the development of agents.
Almost 10 years ago, a new classification was proposed that separated ovarian cancers into type I and II tumors. Type I tumors were low grade; some (endometrioid, mucinous, and clear cell types) harbored mutations in KRAS, BRAF, and PTEN with microsatellite instability. Type II tumors included high-grade serous and carcinosarcoma, which frequently contain mutations in p53, BRCA1, and BRCA2. Integrated genomic analysis of ovarian cancer in several hundred tumors, further delineated four transcriptional subtypes, and identified somatic mutations in NF1, CDK12, BRCA1, and BRCA2. Importantly, homologous recombination repair of DNA damage is defective in roughly 50% of high grade serous cancer and NOTCH and FOXM1 signaling are implicated in the pathophysiology of serous tumors. Now that prevalent type-associated underlying genetic signatures have been identified, the foundations have been laid upon which personalized medicine should be built over the next decade.
The molecularly targeted treatment has emerged consequent to our improved understanding of the underlying biology of ovarian cancer. The knowledge about genetic mutations in ovarian cancer is leading to the assessment of mutation-focused, mechanism-based treatment. The convergences of the PI3K/AKT signaling pathway on mTOR and their importance in ovarian cancer have led to the assessment of inhibitors of both signaling components. Published data with mTOR inhibitors have not been encouraging and are associated with the class-specific effects of hyperglycemia and hyperlipidemia. Several PI3 kinase inhibitors are also in early clinical development. However, these inhibitors are also associated with class-related diarrhoea and other toxic effects making these drugs difficult to develop. MEK/ERK mitogen-activated proliferation kinase (MAPK), which is commonly activated in ovarian cancer, is downstream of PI3K/AKT and RAS/RAF and other major pathways. Selemetinib, a selective MAPK inhibitor, was examined for activity in recurrent low-grade serous ovarian cancer, yielding a median PFS of 11 months. However, no association was reported between KRAS, BRAF, or RAS protein mutations and outcome.
In addition to gene mutation-targeted therapeutics, angiogenesis and cell proliferation share many common ligands, which should be targeted. These include the PDGFs, FGFs, and HGF/c-Met. Several agents that target these molecules are in the clinic and are likely to have some activity; the major problem in their development is the elucidation of predictive biomarkers. Creative Biogene, as a leading biotechnology company, is able to offer various ovarian cancer pathway related products including stable cell lines, viral particles and clones for your drug discovery projects.