Matrix metalloproteinase inhibitors: past lessons and future prospects in breast cancer

The matrix metalloproteinases (MMPs) play a central role in invasion and metastasis. However, despite striking activity in preclinical models, the clinical development of the matrix metalloproteinase inhibitors (MMPIs) has been difficult. The results of important phase III trials are now emerging and it is therefore opportune to review the current state of the MMPIs. In this article the evidence for the role of MMPs in the progression of breast cancer, the development of the MMPIs and the recent phase III results are discussed. Despite the problems encountered it is hoped that the MMPIs may yet provide another mechanism for the long-term control of micrometastatic disease. Furthermore, important lessons can be learnt from their development that are relevant to the development of other biological agents

Lack of telomerase gene expression in alternative lengthening of telomere cells is associated with chromatin remodeling of the hTR and hTERT gene promoters

The presence of active telomere maintenance mechanisms in immortal cells allows the bypass of senescence by maintaining telomere length. In most immortal cell lines and tumors, telomere maintenance is attributable to telomerase reactivation. However, a number of immortal cell lines and tumors can achieve telomere maintenance in the absence of detectable telomerase activity by the alternative lengthening of telomere (ALT) mechanism. Epigenetic mechanisms have been implicated in the regulation of telomerase expression. We show that specific modifications within the chromatin environment of the hTR and hTERT promoters correlate with expression of hTR and hTERT in ALT, normal and telomerasepositive tumor cell lines. Lack of expression of hTR and hTERT in ALT cell lines is associated with histone H3 and H4 hypoacetylation and methylation of Lys(9) histone H3. Conversely, hTR and hTERT expression in telomerase-positive cell lines is associated with hyperacetylation of H3 and H4 and methylation of Lys(4) H3. Methylation of Lys(20) H4 was not linked to gene expression but instead was specific to the hTR and hTERT promoters of ALT cells. This may provide an insight into the differences between ALT and telomerase-positive cells as well as a novel marker for the ALT phenotype. Treatment of normal and ALT cells with 5-azadeoxycytidine in combination with Trichostatin A caused chromatin remodeling of both promoters and reactivation of hTR and hTERT expression in ALT and normal cell lines. This data establishes a definite link between the chromatin environment of the telomerase gene promoters and transcriptional activit

Telomerase-Directed Molecular Therapeutics

The management of malignant disease remains one of the most challenging areas of modern medicine. The lifetime risk of developing cancer in the western world is estimated to be as high as 1 in 3. Traditionally, surgery, chemotherapy and radiotherapy have been the primary choice of treatment for patients with malignant tumours. Despite advances in the use and development of conventional cytotoxic agents, the cure rate remains disappointing in most patients with advanced disease of the common solid tumours. Consequently, the development of novel anti-cancer therapies is a high priority in cancer medicine. In recent years, a new generation of cancer therapies has emerged, based on a growing understanding of the molecular events that contribute to malignant transformation. A major difference between normal and cancer cells is the ability of cancer cells to multiply in an unrestricted and ungoverned fashion. In this context, there is considerable interest in elucidating the mechanisms that allow this unrestricted proliferation and that ultimately result in immortal cancer cells. It is now clear that the enzyme telomerase confers immortality on cells in most types of cancer. With the cancer cell reliant on telomerase for its survival, telomerase represents an extremely attractive mechanism-based target for the development of new cancer therapeutics

Telomerase-specific suicide gene therapy vectors expressing bacterial nitroreductase sensitize human cancer cells to the pro-drug CB1954

Telomerase activation is considered to be a critical step in cancer progression due to its role in cellular immortalization. The prevalence of telomerase expression in human cancers makes it an attractive candidate for new mechanism-based targets for cancer therapy. The selective killing of cancer cells can be achieved by gene-directed enzyme pro-drug therapy (GDEPT). In this study we have tested the feasibility of using the transcriptional regulatory sequences from the hTERT and hTR genes to regulate expression of the bacterial nitroreductase enzyme in combination with the pro-drug CB1954 in a suicide gene therapy strategy. hTERT and hTR promoter activity was compared in a panel of 10 cell lines and showed a wide distribution in activity; low activity was observed in normal cells and telomerase-negative immortal ALT cell lines, with up to 300-fold higher activity observed in telomerase positive cancer lines. Placing the nitroreductase gene under the control of the telomerase gene promoters sensitized cancer cells in tissue culture to the pro-drug CB1954 and promoter activity was predictive of sensitization to the pro-drug (2-20-fold sensitization), with cell death restricted to lines exhibiting high levels of promoter activity. The in vivo relevance of these data was tested using two xenograft models (C33a and GLC4 cells). Significant tumour reduction was seen with both telomerase promoters and the promoter-specific patterns of sensitization observed in tissue culture were retained in xenograft models. Thus, telomerase-specific suicide gene therapy vectors expressing bacterial nitroreductase sensitize human cancer cells to the pro-drug CB1954

Randomized phase II study of decitabine in combination with carboplatin compared with carboplatin alone in patients with recurrent advanced ovarian cancer

Background: Experimental and clinical data (Gifford et al, Clin Cancer Res. 2004) indicate the potential importance of methylation in mediating resistance to carboplatin in ovarian cancer. A previous phase I trial (Appleton et al, J Clin Oncol. 2007) established the feasibility of combining carboplatin with the demethylating agent decitabine on a day 1 + 8 q4 weekly (w) schedule and PD data provided evidence of target cell demethylation. Methods: Patients (pt) with ovarian cancer relapsing 6-12 months following first line treatment were randomised to receive either 6 cycles of carboplatin AUC 6 q4 w (Arm A), or 90 mg/m2 decitabine as a 6 hour infusion on day 1 and carboplatin AUC 6 on day 8 q4 w (Arm B). The primary endpoint was response rate. An interim analysis was planned after 11 patients were enrolled into Arm B. Results: 29 pt were enrolled. After the first 4 pt had been treated (at 90 mg/m2 decitabine) the frequency of dose delays due to neutropenia was considered unacceptable, and therefore the starting dose of decitabine was reduced to 45 mg/m2 for the subsequent 11 pt. 7 out of 14 pt in Arm A completed 6 cycles compared with 0 of 11 in Arm B (at 45 mg/m2 decitabine). Grade 2/3 hypersensitivity reactions were more common in Arm B than Arm A (64% vs. 21%), as were prolonged treatment delays due to neutropenia (36% vs. 10%). At the interim analysis, in the 11 pt treated with 45mg/m2 (Arm B), there were no RECIST responses, while 2 pt had short-lived CA125 responses (59 and 63 days). In contrast 6 of 14 patients in Arm A had RECIST responses consistent with the expected efficacy of carboplatin in this population. Conclusions: The lack of efficacy, as well as the difficulties in treatment delivery in Arm B, led the project team to conclude that the study should be closed. With this dose and schedule, decitabine is ineffective in reversing carboplatin resistance. Further investigations are ongoing to understand (a) the apparent increased incidence of hypersensitivity and (b) the trend towards reduced efficacy in Arm B

Therapeutic modulation of epigenetic drivers of drug resistance in ovarian cancer

Epigenetic changes in tumours are associated not only with cancer development and progression, but also with resistance to chemotherapy. Aberrant DNA methylation at CpG islands and associated epigenetic silencing are observed during the acquisition of drug resistance. However, it remains unclear whether all of the observed changes are drivers of drug resistance, causally associated with response of tumours to chemotherapy, or are passenger events representing chance DNA methylation changes. Systematic approaches that link DNA methylation and expression with chemosensitivity will be required to identify key drivers. Such drivers will be important prognostic or predicitive biomarkers, both to existing chemotherapies, but also to epigenetic therapies used to modulate drug resistance

Gynecologic Cancer InterGroup (GCIG) Consensus Review for Uterine Serous Carcinoma

Biological, physical and clinical aspects of cancer treatment with ionising radiatio

Gynecologic Cancer InterGroup (GCIG) Consensus Review for Uterine and Ovarian Carcinosarcoma

Biological, physical and clinical aspects of cancer treatment with ionising radiatio

Does body mass index affect progression-free or overall survival in patients with ovarian cancer? Results from SCOTROC I trial

Background: Previous studies have indicated an association between obesity and poor survival in several tumour types, including ovarian cancer. We sought to test the hypothesis that obesity reduces survival in a large, well-characterised and relatively homogeneous cohort of ovarian cancer patients. Patients and methods: The relationship between body mass index (BMI) and overall survival (OS) and progression-free survival (PFS) in 1067 patients participating in the Scottish Randomised Trial in Ovarian Cancer I trial was assessed. All patients received first-line carboplatin/taxane chemotherapy. The dose of carboplatin was determined by a measured glomerular filtration rate (GFR), ensuring accurate dosing in all categories of BMI and the dose of taxane was not capped. Patients were assigned to one of four categories: underweight (BMI < 18.5), ideal weight (BMI 18.5-24.9), overweight (BMI 25-29.9) or obese (BMI >= 30). Results: There were neither statistically significant differences in PFS or OS between these four groups nor were there any differences in taxane or carboplatin dose intensity. Furthermore, there was no association between BMI and tumour stage or grade at presentation, or completeness of debulking surgery. Conclusions: Obese patients with epithelial ovarian cancer do not have a poorer prognosis, provided that they receive optimal doses of chemotherapy based on measured GFR and actual body weight