Amanda L. Jackson

Emerging therapies: angiogenesis inhibitors for ovarian cancer

Introduction: Patients with epithelial ovarian cancer (EOC) have a high rate of recurrence, and overall survival remains at ∼ 25%. There is a need for new treatments that can increase progression free survival and quality of life. Recent clinical trials focus on angiogenesis, VEGFs, and tyrosine kinase inhibitors that play a role in recurrence, metastasis, and ascites in EOC. Areas covered: This review summarizes clinical rationale, mechanisms of action, and clinical data for angiogenesis inhibitors under evaluation in Phase II and III trials for EOC. Anti-angiogenesis agents reviewed in this paper include aflibercept, bevacizumab, cediranib, fosbretabulin, imatinib, nintedanib, pazopanib, saracatinib, sorafenib, sunitinib, and trebananib. Expert opinion: These agents have particular rationale for potential use in EOC due to the molecular changes associated with EOC tumorigenesis, namely a significant increase in angiogenic activity. Due to the costs and toxicities associated with anti-angiogenics, biomarker or molecular signature selection strategy for patients who will most benefit would be ideal but no such strategy has been validated to date.

Extremes in body mass index affect overall survival in women with cervical cancer

OBJECTIVE To examine the effect of BMI on pathologic findings, cancer recurrence and survival in cervical cancer patients. METHODS A retrospective cohort study of cervical cancer patients treated from July 2000 to March 2013 was performed. BMI was calculated, and patients were classified by BMI. The primary outcome was overall survival (OS). Secondary outcomes included stage, histopathology, disease-specific survival (DSS) and recurrence free survival (RFS). Kaplan-Meier survival curves were generated and compared using Cox proportional hazard ratios. RESULTS Of 632 eligible patients, 24 (4%) were underweight, 191 (30%) were normal weight, 417 (66%) were overweight/obese. There was no difference in age (p=0.91), stage at presentation (p=0.91), grade (p=0.46), or histology (p=0.76) between weight categories. There were fewer White patients in the underweight (54%) and overweight/obese (58%) groups compared to the normal weight (71%) group (p=0.04). After controlling for prognostic factors, underweight and overweight/obese patients had worse median RFS than normal weight patients (7.6 v 25.0months, p=0.01 and 20.3 v 25.0months, p=0.03). Underweight patients also had worse OS (10.4 v 28.4months, p=0.031) and DSS (13.8 v 28.4months, p=0.04) compared to normal weight patients. Overweight/obese patients had worse OS than normal weight patients (22.2 v 28.4months, p=0.03) and a trend toward worse DSS (21.9 v 28.4months, p=0.09). CONCLUSION Both extremes of weight (underweight and overweight/obesity) were associated with worse survival in patients with cervical cancer. Optimizing weight in cervical cancer patients may improve outcomes in these patients.

Phenformin has anti-tumorigenic effects in human ovarian cancer cells and in an orthotopic mouse model of serous ovarian cancer

Obesity and diabetes have been associated with increased risk and worse outcomes in ovarian cancer (OC). The biguanide metformin is used in the treatment of type 2 diabetes and is also believed to have anti-tumorigenic benefits. Metformin is highly hydrophilic and requires organic cation transporters (OCTs) for entry into human cells. Phenformin, another biguanide, was taken off the market due to an increased risk of lactic acidosis over metformin. However, phenformin is not reliant on transporters for cell entry; and thus, may have increased potency as both an anti-diabetic and anti-tumorigenic agent than metformin. Thus, our goal was to evaluate the effect of phenformin on established OC cell lines, primary cultures of human OC cells and in an orthotopic mouse model of high grade serous OC. In three OC cell lines, phenformin significantly inhibited cellular proliferation, induced cell cycle G1 arrest and apoptosis, caused cellular stress, inhibited adhesion and invasion, and activation of AMPK and inhibition of the mTOR pathway. Phenformin also exerted anti-proliferative effects in seven primary cell cultures of human OC. Lastly, phenformin inhibited tumor growth in an orthotopic mouse model of serous OC, coincident with decreased Ki-67 staining and phosphorylated-S6 expression and increased expression of caspase 3 and phosphorylated-AMPK. Our findings demonstrate that phenformin has anti-tumorigenic effects in OC as previously demonstrated by metformin but it is yet to be determined if it is superior to metformin for the potential treatment of this disease.

Dual inhibition of glycolysis and glutaminolysis as a therapeutic strategy in the treatment of ovarian cancer

Cancer cell metabolism is required to support the biosynthetic demands of cell growth and cell division, and to maintain reduction oxidaton (redox) homeostasis. This study was designed to test the effects of glucose and glutamine on ovarian cancer cell growth and explore the inter-relationship between glycolysis and glutaminolysis. The SKOV3, IGROV-1 and Hey ovarian cancer cell lines were assayed for glucose, pyruvate and glutamine dependence by analyzing cytotoxicity, cell cycle progression, apoptosis and ATP production. As determined by MTT assay, glucose stimulated cell growth while the combination of glucose, glutamine and pyruvate resulted in the greatest stimulation of cell proliferation. Furthermore, 2-deoxy-glucose (2-DG) and 3-bromopyruvate (3-BP) induced apoptosis, caused G1 phase cell cycle arrest and reduced glycolytic activity. Moreover, 2-DG in combination with a low dose of aminooxyacetate (AOA) synergistically increased the sensitivity to 2-DG in the inhibition of cell growth in the ovarian cancer cell lines. These studies suggest that dual inhibition of glycolysis and glutaminolysis may be a promising therapeutic strategy for the treatment of ovarian cancer.Cancer cell metabolism is required to support the biosynthetic demands of cell growth and cell division, and to maintain reduction oxidaton (redox) homeostasis. This study was designed to test the effects of glucose and glutamine on ovarian cancer cell growth and explore the inter-relationship between glycolysis and glutaminolysis. The SKOV3, IGROV-1 and Hey ovarian cancer cell lines were assayed for glucose, pyruvate and glutamine dependence by analyzing cytotoxicity, cell cycle progression, apoptosis and ATP production. As determined by MTT assay, glucose stimulated cell growth while the combination of glucose, glutamine and pyruvate resulted in the greatest stimulation of cell proliferation. Furthermore, 2-deoxy-glucose (2-DG) and 3-bromopyruvate (3-BP) induced apoptosis, caused G1 phase cell cycle arrest and reduced glycolytic activity. Moreover, 2-DG in combination with a low dose of aminooxyacetate (AOA) synergistically increased the sensitivity to 2-DG in the inhibition of cell growth in the ovarian cancer cell lines. These studies suggest that dual inhibition of glycolysis and glutaminolysis may be a promising therapeutic strategy for the treatment of ovarian cancer.