Showing papers by "Paul Ellis published in 2012"
TL;DR: The biology of TNBC at the pathologic and the molecular levels is discussed and the role of systemic therapies and the results of the first phase III clinical trial evaluating the addition of iniparib are elaborate.
Abstract: Triple-negative breast cancer (TNBC) accounts for 15% to 20% of breast cancers. It is a heterogeneous disease, not only on the molecular level, but also on the pathologic and clinical levels. TNBC is associated with a significantly higher probability of relapse and poorer overall survival in the first few years after diagnosis when compared with other breast cancer subtypes. This is observed despite its usual high sensitivity to chemotherapy. In the advanced setting, responses observed with chemotherapy lack durability. Early-stage clinical studies suggested impressive potential when a poly (ADP-ribose) polymerase (PARP) inhibitor is given for the treatment of advanced TNBC with BRCA gene dysfunction. The molecular complexity of TNBC has led to proposed subclassifications, which will be of great value for the development of targeted therapies. In this review, we discuss the biology of TNBC at the pathologic and the molecular levels. We also elaborate on the role of systemic therapies and the results of the first phase III clinical trial evaluating the addition of iniparib, a novel investigational anticancer agent that does not possess characteristics typical of the PARP inhibitor class, in combination with chemotherapy in advanced TNBC.
390 citations
TL;DR: It is found that the nitroso metabolite of iniparib forms adducts with many cysteine-containing proteins in tumor cells, and the primary mechanism of action for inipirib is likely not via inhibition of PARP activity.
Abstract: Purpose: PARP inhibitors are being developed as therapeutic agents for cancer. More than six compounds have entered clinical trials. The majority of these compounds are β-nicotinamide adenine dinucleotide (NAD + )-competitive inhibitors. One exception is iniparib, which has been proposed to be a noncompetitive PARP inhibitor. In this study, we compare the biologic activities of two different structural classes of NAD + -competitive compounds with iniparib and its C -nitroso metabolite. Experimental Design: Two chemical series of NAD + -competitive PARP inhibitors, iniparib and its C -nitroso metabolite, were analyzed in enzymatic and cellular assays. Viability assays were carried out in MDA-MB-436 ( BRCA 1-deficient) and DLD1 −/− ( BRCA 2-deficient) cells together with BRCA -proficient MDA-MB-231 and DLD1 +/+ cells. Capan-1 and B16F10 xenograft models were used to compare iniparib and veliparib in vivo . Mass spectrometry and the 3 H-labeling method were used to monitor the covalent modification of proteins. Results: All NAD + -competitive inhibitors show robust activity in a PARP cellular assay, strongly potentiate the activity of temozolomide, and elicit robust cell killing in BRCA -deficient tumor cells in vitro and in vivo . Cell killing was associated with an induction of DNA damage. In contrast, neither iniparib nor its C -nitroso metabolite inhibited PARP enzymatic or cellular activity, potentiated temozolomide, or showed activity in a BRCA- deficient setting. We find that the nitroso metabolite of iniparib forms adducts with many cysteine-containing proteins. Furthermore, both iniparib and its nitroso metabolite form protein adducts nonspecifically in tumor cells. Conclusions: Iniparib nonselectively modifies cysteine-containing proteins in tumor cells, and the primary mechanism of action for iniparib is likely not via inhibition of PARP activity. Clin Cancer Res; 18(2); 510–23. ©2011 AACR .
177 citations
TL;DR: The addition of docetaxel to a non-taxane-containing regimen improves DFS and OS in high risk EBC patients and was seen across all subgroups regardless of nodal status, age, hormone receptor or HER2 status (including triple negative status), or administration schedule.
Abstract: The benefit of taxanes in the adjuvant setting for node-negative (N0) early breast cancer (EBC) has not yet been established. We conducted a meta-analysis of randomized adjuvant trials comparing docetaxel-containing versus non-taxane-containing regimens. The purpose of this study was to determine whether the incorporation of docetaxel improves disease-free survival (DFS) and overall survival (OS) in early stage breast cancer. Studies were retrieved by searching major databases and the proceedings of leading breast cancer conferences. We extracted hazard ratios (HRs) and 95% confidence intervals (CIs) for DFS and OS and obtained pooled estimates using an inverse-variance model. Fourteen randomized phase III studies were included (25,067 patients). The pooled HR estimate was 0.84 (95% CI 0.78–0.89; P < 0.001) favoring docetaxel for DFS and 0.86 (0.78–0.94; P < 0.001) for OS. In N0 patients (4,274 patients), the pooled HR estimate for DFS was 0.86 (0.73–1.00; P = 0.05). The HR for OS was equal to 1 (0.75–1.34). The improvement in DFS with docetaxel-containing regimens was observed across all subgroups (age, under or over 50; number of involved nodes; hormone receptor or HER2 status (including triple negative status), or administration schedule (sequential or concomitant). The addition of docetaxel to a non-taxane-containing regimen improves DFS and OS in high risk EBC patients. The benefit in DFS was seen across all subgroups regardless of nodal status, age, hormone receptor or HER2 status (including triple negative status), or administration schedule.
43 citations
TL;DR: Better trial design with a focus on biomarkers should lower barriers to regulatory approval as well as increase cost effectiveness and it appears worthwhile to adopt less conventional approaches to breast cancer care.
Abstract: The prevalence of breast cancer is increasing as more women are living with the disease. Outcomes have improved as a result of progress in all major aspects of multidisciplinary care. These include surgery, radiotherapy, hormonal therapy, chemotherapy and newer targeted drugs. Two aspects merit particular attention here. First, there is an understanding now that cancer is a heterogenous disease and a ‘one-size-fits-all’ approach is becoming redundant, albeit slowly. Second, basic science and an appreciation of cellular molecular targets in those different types of breast cancer is being translated into the clinic and has led to the development of exciting new drugs for both triple negative and HER2-positive relapsed disease. An improved understanding of endocrine resistance remains an unmet need in drug development and here, it appears worthwhile to adopt less conventional approaches. Better trial design with a focus on biomarkers should lower barriers to regulatory approval as well as increase cost effec...
22 citations
TL;DR: Compounds 8c and 20u are orally available, and have demonstrated significant efficacy in a B16 murine xenograft model, potentiating the efficacy of temozolomide (TMZ), and a new tetrahydropyridopyridazinone series of PARP-1 inhibitors.
19 citations
TL;DR: The experience with bevacizumab may illustrate how better to achieve rapid innovation and true progress in advanced breast cancer.
Abstract: Few drugs in oncology have generated as much discussion in both the medical literature and the popular and financial press as has bevacizumab for advanced breast cancer. The recent decision on the part of the US Food and Drug Administration (FDA) not to grant full approval for bevacizumab for first-line metastatic breast cancer (MBC) after granting accelerated approval 3 years earlier has sparked renewed debate about the oncology drug approval process and how best to measure clinical benefit in the setting of advanced cancer. Some have argued that the drug approval criteria are inconsistent and that regulatory standards are endangering progress in the treatment of MBC. Fortunately, that is not the case. Indeed, the experience with bevacizumab may illustrate how better to achieve rapid innovation and true progress in advanced breast cancer.
15 citations