1,721,230 research outputs found
Molecular mechanisms of PARP inhibitors In BRCA-related ovarian cancer
Full text linkOvarian cancer continues to be the main cause of death among all gynecological tumors. After standard treatments, most of patients are destined to recur within a short period, thus new therapies are urgently needed. The increasing knowledge of molecular mechanisms in ovarian cancer pathogenesis allowed identifying several targeted agents that are now entering in clinical practice. The family of poly(ADP-ribose) polymerase inhibitors represents a widely investigated and promising alternative for the targeted therapy of ovarian malignancies. PARP inhibitors exploit the synthetic lethality concept to prevent the repair of DNA damage, causing cancer cell death. This review describes the molecular mechanisms at the basis of PARP inhibition, particularly in BRCA-related ovarian malignancies and analyzes the main agents under investigations in preclinical and clinical studies. © 2013 Toss A, et al
Response to: COVID-related upsurge in diagnoses of advanced breast cancer-is a disruption in mammography screening the one to be blamed?
No full textBlood-Based Diagnostics in Solid Tumors: An Overview
No full textThe application of patient-specific genetic information and molecular tumor characteristics enables the selection of treatment strategies for individual patients, improving the therapeutic efficacy and expanding the scope of personalized medicine. Emerging evidence from clinical research provides demonstration that the genetic landscape of any given tumor will dictate its sensitivity or resistance profile to anticancer agents. Nevertheless, the inter-and intra-tumor genetic heterogeneity can be a substantial impediment to the successful clinical application of this approach. Since acquired drug resistance is common during the course of the disease, there is an urgent need to monitor tumor evolution. On these bases, the importance of molecular re-characterization of metastatic disease has been prospectively confirmed and has been recently acknowledged in the clinical guidelines for the management of advanced malignancies. Nevertheless, obtaining serial samples of metastatic tissue is impractical and complicated by spatial heterogeneity, sampling bias, and invasive procedures. An attractive alternative to overcome these limitations is represented by the analysis of peripheral blood sample as a “liquid biopsy.” Blood draws can easily be performed serially; thus blood would be an ideal compartment for detection of prognostic and predictive biomarkers. Nowadays, the principal sources for liquid biopsies are represented by cells and intracellular materials that are released by the tumor mass and are swept away by the bloodstream, such as CTCs, ctDNA, and exosomes. This book provides an overview of the technological approaches to perform and enhance the strategy and the principal applications in clinical practice of “liquid biopsy.
Molecular characterization and targeted therapeutic approaches in breast cancer
Full text linkDespite the wide improvements in breast cancer (BC) detection and adjuvant treatment, BC is still responsible for approximately 40,000 deaths annually in the United States. Novel biomarkers are fundamental to assist clinicians in BC detection, risk stratification, disease subtyping, prediction of treatment response, and surveillance, allowing a more tailored approach to therapy in both primary and metastatic settings. In primary BC, the development of molecular profiling techniques has added prognostic and predictive information to conventional biomarkers - estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. Moreover, the application of next-generation sequencing and reverse-phase protein microarray methods in the metastatic setting holds the promise to further advance toward a personalized management of cancer. The improvement in our understanding on BC biology associated with the study of the genomic aberrations characterizing the most common molecular subtypes allows us to explore new targets for drug development. Finally, the integration of cancer stem cell-targeted therapies and immune therapies in future combination regimens increases our chances to successfully treat a larger proportion of women with more aggressive and resistant metastatic disease. This article reviews the current state of novel biological markers for BC, the evidence to demonstrate their clinical validity and utility, and the implication for therapeutic targeting
Academic authorship: who, why and in what order?
Full text linkWe are frequently asked by our colleagues and students for advice on authorship for scientific articles. This short paper outlines some of the issues that we have experienced and the advice we usually provide. This editorial follows on from our work on submitting a paper1 and also on writing an academic paper for publication.2 We should like to start by noting that, in our view, there exist two separate, but related issues: (a) authorship and (b) order of authors. The issue of authorship centres on the notion of who can be an author, who should be an author and who definitely should not be an author, and this is partly discipline specific. The second issue, the order of authors, is usually dictated by the academic tradition from which the work comes. One can immediately envisage disagreements within a multi-disciplinary team of researchers where members of the team may have different approaches to authorship order
Germline mutations in other homologous recombination repair-related genes than brca1/2: Predictive or prognostic factors?
Full text linkThe homologous recombination repair (HRR) pathway repairs double-strand DNA breaks, mostly by BRCA1 and BRCA2, although other proteins such as ATM, CHEK2, and PALB2 are also involved. BRCA1/2 germline mutations are targeted by PARP inhibitors. The aim of this commentary is to explore whether germline mutations in HRR-related genes other than BRCA1/2 have to be considered as prognostic factors or predictive to therapies by discussing the results of two articles published in December 2020. The TBCRC 048 trial published by Tung et al. showed an impressive objective response rate to olaparib in metastatic breast cancer patients with germline PALB2 mutation compared to germline ATM and CHEK2 mutation carriers. Additionally, Yadav et al. observed a significantly longer overall survival in pancreatic adenocarcinoma patients with germline HRR mutations compared to non-carriers. In our opinion, assuming that PALB2 is a high-penetrant gene with a key role in the HRR system, PALB2 mutations are predictive factors for response to treatment. Moreover, germline mutations in the ATM gene provide a better outcome in pancreatic adenocarcinoma, being more often associated to wild-type KRAS. In conclusion, sequencing of HRR-related genes other than BRCA1/2 should be routinely offered as part of a biological characterization of pancreatic and breast cancers
PARP inhibitors for the treatment of ovarian cancer
No full textThe standard of treatment for advanced ovarian cancer is represented by optimal surgical debulking preceded or followed by chemotherapeutic regimens including taxanes and platinum agents, possibly associated with bevacizumab and/or intraperitoneal therapy. Despite this comprehensive treatment strategy, almost 75% of patients relapse or progress and are therefore candidates for a second-line treatment, showing, at this point, less chemo-sensitivity and worse prognosis. An interesting approach to improve outcomes of these patients has been developed in the last decade, in BRCA-related ovarian cancer. Mutations in one of the BRCA genes result in impaired homologous-recombination DNA repair, which causes genetic abnormalities that promote carcinogenesis. Interestingly, this defect has been exploited by the introduction of poly (ADP-ribose) polymerase (PARP) inhibitors to provide specific cancer cell cytotoxicity. Particularly, the inhibition of PARP in BRCA-mutation carriers leads to the persistence of DNA damage usually repaired by the homologous-recombination system, resulting in cell cycle arrest and thus apoptosis. Despite the mechanism of action, an activity of PARP inhibitors was also observed in “BRCAness” ovarian tumors, and in BRCA-related tumors other than ovarian, suggesting that these agents may be active regardless of BRCA mutation status or site of origin. This review aims to describe the principal evidence that led to the development and the study of PARP inhibitors and to discuss their main implications in our daily clinical practice
CTC enumeration and characterization: Moving toward personalized medicine
Full text linkThe primary cause of tumor-related death in breast cancer (BC) is still represented by distant metastasization. The dissemination of tumor cells from the primary tumor to distant sites through bloodstream cannot be early detected by standard imaging methods. The enumeration of circulating tumor cells (CTCs) represents an effective prognostic and predictive biomarker, which is able to monitor efficacy of adjuvant therapies, detect early development of (micro)metastases and at last, assess therapeutic responses of advanced disease earlier than traditional imaging methods. Moreover, since repeated tissue biopsies are invasive, costly and not always feasible, the assessment of tumor characteristics on CTCs, by a peripheral blood sample as a 'liquid biopsy', represents an attractive opportunity. The implementation of molecular and genomic characterization of CTCs could contribute to improve the treatment selection and thus, to move toward more personalized treatments. This review describes the current state of the art on CTC detection strategies, the evidence to demonstrate their clinical validity, and their potential impact for both future clinical trial design and, decision-making process in our daily practice
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