Anna K.L. Reyners

Metformin: Taking away the candy for cancer?

Metformin is widely used in the treatment of diabetes mellitus type 2 where it reduces insulin resistance and diabetes-related morbidity and mortality. Population-based studies show that metformin treatment is associated with a dose-dependent reduction in cancer risk. The metformin treatment also increases complete pathological tumour response rates following neoadjuvant chemotherapy for breast cancer, suggesting a potential role as an anti-cancer drug. Diabetes mellitus type 2 is associated with insulin resistance, elevated insulin levels and an increased risk of cancer and cancer-related mortality. This increased risk may be explained by activation of the insulin- and insulin-like growth factor (IGF) signalling pathways and increased signalling through the oestrogen receptor. Reversal of these processes through reduction of insulin resistance by the oral anti-diabetic drug metformin is an attractive anti-cancer strategy. Metformin is an activator of AMP-activated protein kinase (AMPK) which inhibits protein synthesis and gluconeogenesis during cellular stress. The main downstream effect of AMPK activation is the inhibition of mammalian target of rapamycin (mTOR), a downstream effector of growth factor signalling. mTOR is frequently activated in malignant cells and is associated with resistance to anticancer drugs. Furthermore, metformin can induce cell cycle arrest and apoptosis and can reduce growth factor signalling. This review discusses the role of diabetes mellitus type 2 and insulin resistance in carcinogenesis, the preclinical rationale and potential mechanisms of metformins anti-cancer effect and the current and future clinical developments of metformin as a novel anti-cancer drug.

Expression of epidermal growth factor receptor (EGFR) and activated EGFR predict poor response to (chemo)radiation and survival in cervical cancer

Purpose: Activation of the epidermal growth factor receptor (EGFR) signaling pathway has been reported to induce resistance to (chemo)radiation in cancers, such as head and neck cancer, whereas EGFR-targeted agents in combination with (chemo)radiation seem to improve treatment efficacy. The aim of this study was to determine the relation between proteins involved in the EGFR pathway and response to (chemo)radiation and survival in a large, well-documented series of cervical cancer patients. Experimental Design: Pretreatment tissue samples of 375 consecutive International Federation of Gynecologists and Obstetricians stage Ib to IVa cervical cancer patients treated with (chemo)radiation between January 1980 and December 2006 were collected. Clinicopathologic and follow-up data were prospectively obtained during standard treatment and follow-up. Protein expression of EGFR, phosphorylated EGFR (pEGFR), PTEN, phosphorylated AKT, and phosphorylated extracellular signal-regulated kinase (pERK) was assessed by immunohistochemistry on tissue microarrays. Results: EGFR staining was present in 35.3%, pEGFR in 19.7%, PTEN in 34.1%, phosphorylated AKT in 4.1%, and pERK in 29.2% of tumors. pEGFR staining was related to PTEN (P = 0.001) and pERK staining (P = 0.004). EGFR staining was inversely related to PTEN (P = 0.011). In multivariate analysis, membranous staining of EGFR [hazard ratio (HR), 1.84; 95% confidence interval (95% CI), 1.20-2.82; P = 0.005] and cytoplasmic staining of pEGFR (HR, 1.71; 95% CI, 1.11-2.66; P = 0.016) were independent predictors of poor response to (chemo)radiation. Membranous EGFR staining also was an independent prognostic factor for poor disease-specific survival (HR, 1.54; 95% CI, 1.09-2.17; P = 0.014). Conclusions: EGFR and pEGFR immunostainings are frequently observed and independently associated with poor response to therapy and disease-specific survival in cervical cancer patients primarily treated by (chemo)radiation. Our data present the EGFR pathway as a promising therapeutic target in already ongoing clinical trials. (Clin Cancer Res 2009;15(23):7389–97)

Translating TRAIL-receptor targeting agents to the clinic

The extrinsic apoptotic pathway can be activated by the endogenous ligand TRAIL (Tumor Necrosis Factor (TNF)-Related Apoptosis-Inducing Ligand) by binding to the death receptors TRAIL-R1 and TRAIL-R2 on the cell surface. This pathway is currently evaluated as an anticancer treatment strategy. Both recombinant human TRAIL and several agonistic antibodies against TRAIL-R1 and R2 have been studied in single agent and combination studies and proved to be safe and well tolerated. In this article, the clinical studies published to date will be reviewed. Also, future perspectives and biomarker studies for selecting patients that will benefit from these agents will be discussed.

Polymorphisms in Endothelial Nitric Oxide Synthase (eNOS) and Vascular Endothelial Growth Factor (VEGF) Predict Sunitinib-Induced Hypertension

Hypertension is an important side effect of sunitinib treatment. In a retrospective study in 255 patients, single‐nucleotide polymorphisms (SNPs) in vascular endothelial growth factor A (VEGFA), vascular endothelial growth factor receptor (VEGFR)‐2, endothelin‐1 (ET‐1), and endothelium‐derived nitric oxide synthase (eNOS) were multivariately tested against hypertension grades and changes in systolic blood pressure (SBP), diastolic BP (DBP), and mean arterial BP (MAP). Next, the association between hypertension and survival in patients with metastatic renal cell cancer (mRCC) was studied. Greater elevations in SBP and MAP were associated with the presence of a haplotype in VEGFA (P = 0.014 and P = 0.036, respectively). The tendency to develop grade 3 hypertension was associated with this haplotype and also with a SNP in eNOS (P = 0.031 and P = 0.045, respectively). In mRCC patients, sunitinib‐induced hypertension was found to confer a survival benefit, with the mean overall survival being prolonged by 7.2 months (P = 0.035 and P = 0.026 for SBP and DBP elevations, respectively). Genetic polymorphisms in VEGFA and eNOS independently predict rise in BP and/or development of severe hypertension in sunitinib‐treated patients. Grade 3 hypertension was found to be an independent factor for overall survival in patients with mRCC.

Potentiation of a p53‐SLP vaccine by cyclophosphamide in ovarian cancer: A single‐arm phase II study

The purpose of the current phase II single‐arm clinical trial was to evaluate whether pretreatment with low‐dose cyclophosphamide improves immunogenicity of a p53‐synthetic long peptide (SLP) vaccine in patients with recurrent ovarian cancer. Patients with ovarian cancer with elevated serum levels of CA‐125 after primary treatment were immunized four times with the p53‐SLP vaccine. Each immunization was preceded by administration of 300 mg/m2 intravenous cyclophosphamide as a means to affect regulatory T cells (Tregs). Vaccine‐induced p53‐specific interferon‐gamma (IFN‐γ)‐producing T cells evaluated by IFN‐γ ELISPOT were observed in 90% (9/10) and 87.5% (7/8) of evaluable patients after two and four immunizations, respectively. Proliferative p53‐specific T cells, observed in 80.0% (8/10) and 62.5% (5/8) of patients, produced both T‐helper 1 and T‐helper‐2 cytokines. Cyclophosphamide induced neither a quantitative reduction of Tregs determined by CD4+FoxP3+ T cell levels nor a demonstrable qualitative difference in Treg function tested in vitro. Nonetheless, the number of vaccine‐induced p53‐specific IFN‐γ‐producing T cells was higher in our study compared to a study in which a similar patient group was treated with p53‐SLP monotherapy (p ≤ 0.012). Furthermore, the strong reduction in the number of circulating p53‐specific T cells observed previously after four immunizations was currently absent. Stable disease was observed in 20.0% (2/10) of patients, and the remainder of patients (80.0%) showed clinical, biochemical and/or radiographic evidence of progressive disease. The outcome of this phase II trial warrants new studies on the use of low‐dose cyclophosphamide to potentiate the immunogenicity of the p53‐SLP vaccine or other antitumor vaccines.

Molecular markers and clinical behavior of uterine carcinosarcomas: focus on the epithelial tumor component

Carcinosarcomas (malignant mixed Müllerian tumors) of the uterus are rare and aggressive malignancies consisting of an epithelial (carcinoma) and a mesenchymal (sarcoma) tumor component and are considered as metaplastic endometrial carcinomas. This study evaluated molecular characteristics and clinical behavior of uterine carcinosarcomas to improve treatment regimens in the future. Immunohistochemical expression of estrogen receptor-α and -β, progesterone receptor-A and -B, MLH1, MSH2, MSH6, PTEN (phosphatase and tensin homolog deleted on chromosome 10), p53, β-catenin and cyclin D1 was determined in 40 uterine carcinosarcomas. Immunostaining was compared between epithelial and mesenchymal tumor components. To determine the prognostic role of the epithelial component, clinicopathological data and survival were compared between patients with endometrioid and non-endometrioid epithelial tumor components. To determine prognosis of carcinosarcomas compared with high-risk endometrial carcinomas, clinicopathological characteristics and survival were compared between these patients. Hormone receptor expression occurred infrequently: estrogen receptor-α (8%) and -β (32%), progesterone receptor-A (0%) and -B (23%), next to β-catenin (4%) and cyclin D1 (7%). PTEN, MLH1, MSH2 and MSH6 mutations occurred in 39%, 33%, 22% and 21%, respectively (based on absent immunostaining). Overexpression of p53 was observed in 38%. Expression patterns of p53, MSH2 and MSH6 corresponded between epithelial and mesenchymal tumor components. In our cohort, the epithelial component caused the majority of metastases (72%) and vascular invasion (70%). Survival tended to be worse for patients with a non-endometrioid epithelial component compared with an endometrioid epithelial component (5-year survival: 26% and 55%, respectively). Survival was worse for patients with uterine carcinosarcomas compared with high-risk endometrial carcinomas (grade 3 endometrioid and non-endometrioid); 5-year survival rates: 42%, 77% and 57%, respectively. Our results support the monoclonal origin of uterine carcinosarcomas. The epithelial component determines prognosis by causing the majority of metastases and vascular invasion. To improve prognosis, treatment should focus on the epithelial tumor component of uterine carcinosarcomas.

Sexual functioning of cervical cancer survivors: A review with a female perspective

OBJECTIVE Sex is an important, often deteriorated, dimension of quality of life after cancer treatment. We conducted a systematic review on sexual functioning of cervical cancer survivors. METHODS Studies between January 1988 and April 2010 were rated on their internal validity. Results were analyzed focusing on four major categories of sexual functioning: desire, arousal, orgasm, pain. Comparisons were made between healthy controls versus cervical cancer survivors, survivors before versus after treatment and between different treatment modalities. RESULTS Twenty studies were included. Most studies showed no differences in the ability to achieve an orgasm. Cervical cancer survivors reported more dyspareunia than healthy controls and dyspareunia was more frequent and lasted longer after radiotherapy. Lack of lubrication was more frequent in cervical cancer survivors and a significant decrease in sexual interest and activity after treatment was found. CONCLUSION Cervical cancer survivors are at risk for sexual pain disorders, while sexual satisfaction (orgasm) is not impaired and radiotherapy negatively influenced sexual pain disorders. Health care providers should inform cervical cancer survivors about the possible risk of developing sexual pain disorders after cervical cancer treatment, especially after radiotherapy. As sexual satisfaction per se is not impaired, we suggest that prevention and treatment of sexual dysfunction should focus on painless and satisfactory sex instead of on resuming intercourse.

Internet-based support programs to alleviate psychosocial and physical symptoms in cancer patients: a literature analysis.

In this review the effect of internet-based support programs on psychosocial and physical symptoms resulting from cancer diagnosis and treatment is analyzed. Selection of studies was based on the following criteria: (non-)randomized controlled trials, performed in adult cancer patients, comparing quantitative psychosocial and/or physical outcomes of an internet-based support program with (a) comparison group(s). Literature search yielded 2032 studies of which 16 fulfilled the eligibility criteria. Three different internet-based support programs were identified: social support groups, online therapy for psychosocial/physical symptoms, and online systems integrating information, support, and coaching services. Outcomes improved by these programs in nine studies. Especially fatigue, social support, and distress improved, regardless of the program type. All online systems showed positive effects, mainly for social support and quality of life. This analysis indicates that internet-based support programs are effective in improving psychosocial and physical symptoms in cancer patients.

Do cancer and treatment type affect distress

We examined differences in distress levels and Distress Thermometer (DT) cutoff scores between different cancer types. The effect of socio‐demographic and illness‐related variables on distress was also examined.

Measurement of tumor VEGF-A levels with 89Zr-bevacizumab PET as an early biomarker for the antiangiogenic effect of everolimus treatment in an ovarian cancer xenograft model

Purpose: The mTOR pathway is frequently activated in ovarian cancers. mTOR inhibitors, such as everolimus, can reduce VEGF-A production by cancer cells. We investigated whether early everolimus treatment effects could be monitored by positron emission tomography (PET) with 89Zr-bevacizumab. Experimental Design: The effect of everolimus on VEGF-A secretion was determined in a panel of human ovarian cancer cell lines and in A2780luc+ ovarian cancer cells xenografted subcutaneously in BALB/c mice. Mice received daily 10 mg/kg everolimus intraperitoneally (i.p.) for 14 days. PET scans with the tracer 89Zr-labeled bevacizumab were conducted before and after treatment. Ex vivo 89Zr-bevacizumab biodistribution and correlative tissue analyses were conducted. Tumor VEGF-A levels were measured with ELISA and mean vascular density (MVD) was determined with immunohistochemistry. Results: Everolimus treatment reduced VEGF-A levels in the supernatant of all cell lines. Everolimus lowered 89Zr-bevacizumab tumor uptake by 21.7% ± 4.0% [mean standardized uptake value (SUVmean) 2.3 ± 0.2 vs. 2.9 ± 0.2, P < 0.01]. Ex vivo biodistribution also showed lower tracer uptake in the tumors of treated as compared with control animals (7.8 ± 0.8%ID/g vs. 14.0 ± 1.7%ID/g, P < 0.01), whereas no differences were observed for other tissues. This coincided with lower VEGF-A protein levels in tumor lysates in treated versus untreated tumors (P = 0.04) and reduced MVD (P < 0.01). Conclusion: Tumor VEGF-A levels are decreased by everolimus. 89Zr-bevacizumab PET could be used to monitor tumor VEGF-A levels as an early biomarker of the antiangiogenic effect of mTOR inhibitor therapy. Clin Cancer Res; 18(22); 6306–14. ©2012 AACR.