1,721,089 research outputs found
RESEARCH OF PREDICTIVE AND PROGNOSTIC TISSUE AND MOLECULAR MARKERS AND OF NEW THERAPEUTIC TARGETS IN MALIGNANT PLEURAL MESOTHELIOMA
Full text linkBACKGROUND: Malignant pleural mesothelioma (MPM) is an aggressive tumor with increasing incidence in industrialized countries, because of previous widespread asbestos exposure and long latency time before symptoms appearance. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) belongs to the tumor necrosis factor (TNF) family of death ligands; it was identified as a promising anticancer agent thanks to its property of killing cancer cells while sparing normal cells. Conflicting evidences about MPM resistance rather than sensitivity to TRAIL-induced apoptosis were previously reported. While TRAIL-dependent apoptosis is thought to be p53-independent, p53 wild type cancer cells can be sensitized to TRAIL through p53 activation. In contrast to most solid tumors, MPM cells frequently express wild type p53, thus p53 reactivation might be considered as an effective strategy to sensitize MPM cells to TRAIL-dependent apoptosis. DNA-damaging agents such as chemotherapy or radiotherapy and other agents targeting negative regulators of p53, may be considered as useful strategies to reactivate p53. Murine Double Minute 2 (MDM2) is a transcriptional target of p53: once activated, MDM2 binds p53 to the amino-terminus, targeting it for ubiquitylation and subsequent proteasomal degradation. Recently, many researchers have investigated a possible role of MDM2 in promoting tumor neoangiogenesis (Vascular Endothelial Growth Factor, VEGF; hypoxia inducible factor, HIF1alpha). Thus MDM2 might be a promising target for anticancer treatment because of its antiapoptotic and proangiogenetic role. The poor prognosis of affected patients, the lack of effective treatment options, with particular reference to biologic drugs, the absence of predictive markers for targeted treatment and the lack of knowledge about the basis of different biological and clinical behaviour of the two main histologic subtypes, epithelioid versus non-epithelioid (sarcomatoid/biphasic), constitute the rationale for the present study.
AIMS: The first purpose of the study was to investigate new treatment options through preclinical evaluation of extrinsic apoptosis triggers (recombinant human Apo2L/TRAIL) in combination with intrinsic apoptosis inducers acting through the reactivation of p53, such as DNA-damaging agents (carboplatin/pemetrexed) or p53-MDM2 inhibitors (nutlin3-RG7112), both in vitro and in vivo. Moreover, the study aims to investigate new targets (MDM2, HIF1alpha, VEGF) for treatment in MPM tumor samples, testing possible different expression levels of such targets in the different histologic subtypes. Some morphological features, such as inflammation, necrosis and proliferation were quantified in the different histotypes and correlated with MDM2 and HIF1alpha. Finally, correlations between molecular data and clinical features were performed.
METHODS: Anticancer effects of rhApo2L/TRAIL (Amgen, Genentech) plus chemotherapy (Carboplatin/Pemetrexed) or nutlin3-RG7112 (Roche) was evaluated in different cell lines through annexin V and caspases assay, and in a Severe Combined ImmunoDeficiency (SCID) mouse model. p53 expression levels were evaluated through western blot. TRAIL receptors were evaluated through flow cytometry. Formalin-Fixed Paraffin Embedded (FFPE) chemonaive tumor samples from MPM patients were analyzed: MDM2, VEGF and HIF1alpha mRNA and protein expression levels were investigated through RT-qPCR and immunohistochemistry (IHC) with specific antibodies, respectively. Proliferation was quantified through staining with Ki67 antibodies. Necrosis and inflammation were also quantified on histological sections using a grading score. Normal pleura samples from patients undergoing diagnostic surgery for non cancer disease were used as negative controls. Clinical data of the patients under study were collected in a password-protected database: age, gender, ECOG PS (Performance Status), EORTC score, stage, systemic treatments, surgery, radiotherapy, first progression and last follow-up date, status (alive/dead).
RESULTS: In vitro and in vivo results showed a significant increase of apoptosis in cell lines and reduction of tumor volume in animal models treated with rhApo2L/TRAIL plus chemotherapy or nutlin3-RG7112 compared with those receiving single treatments. This synergistic effect was dependent on the ability of chemotherapy or nutlin3-RG7112 to increase the expression of the TRAIL receptors DR4 and DR5 in a p53 manner. Higher MDM2 and HIF1alpha IHC expression was significantly associated with sarcomatoid/biphasic histologic subtype (p=0.010 and p=0.007, respectively) with positive correlation between MDM2 and HIF1alpha expression levels (correlation coefficient=0.533; p value= 0.00626). Proliferation index was significantly higher in sarcomatoid/biphasic compared with epithelioid samples (p=0.005) and also significantly higher in tumor samples with higher MDM2 expression (p=0.008). Clinical and pathological features or biomarker did not show any correlation with prognosis, except for proliferation index and Progression Free Survival (PFS), even though the results of this exploratory analysis should be considered with caution because of the limited number of patients, the heterogeneous treatment received and the insufficient follow-up time in some patients.
CONCLUSION: Our preclinical in vitro and in vivo results confirm that reactivation of p53 by chemotherapy or p53-MDM2 inhibitors effectively sensitizes to TRAIL-dependent apoptosis in malignant pleural mesothelioma.
Our translational study in tumor samples from MPM patients confirmed different biological and pathological features and molecular targets expression in the two main histologic subtypes. It is tempting to speculate that MDM2 and Ki67 might be considered as further useful diagnostic tools to identify poor prognosis patients. Moreover, MDM2 and HIF1alpha might be considered as promising targets for anticancer treatment of MPM
Editorial: Understanding the Interplay Between the Tumor Immune Microenvironment and Genetic Alterations in Thoracic Malignancies
Full text linkPET/CT And The Response To Immunotherapy In Lung Cancer
No full textIn the recent years, the introduction of immune checkpoint inhibitors has significantly changed the outcome of patients affected by lung cancer and cutaneous melanoma. Although the clinical advantages, the selection of patients and the evaluation of response to immunotherapy remain unclear. The immune-related Response Evaluation Criteria in Solid Tumor (irRECIST) was proposed as an update of the RECIST criteria for the assessment of response to immunotherapy. However, morphological images cannot predict the early response to therapy that represents a challenge in clinical practice. 18F-FDG PET/CT before and after immunotherapy has an indeterminate role, demonstrating ambiguous results due to inflammatory effects secondary to the activation of immune system. The aim of the present review was to analyze the role of PET/CT as a guide for immunotherapy, by analyzing the current status and future perspectives
Second and third line treatment in advanced non-small cell lung cancer
No full textNon-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide. About 50% of the patients present locally advanced or metastatic disease at the time of diagnosis. First line therapy usually consists of a combination of cisplatin or carboplatin with a third-generation agent (paclitaxel, docetaxel, gemcitabine, or vinorelbine) that results in less than 5% 5-year survival (Goldstraw et al., 2007). Recently a different approach based on histological subtype has been introduced in the first line treatment of NSCLC: in the non-squamous histotypes, cisplatin plus pemetrexed, compared to the cisplatin plus gemcitabine combination, showed a better outcome, leading to its introduction in the first line treatment setting. In recent years advances in the second and third line treatments have led to a prognostic improvement. Two cytotoxic agents, docetaxel and pemetrexed, are approved as NSCLC second line treatment, and a new class of drugs against specific molecular targets -- tyrosine Kinase inhibitors (TKI) -- has emerged as an alternative to conventional treatment. Many trials are ongoing to assess the activity of new drugs, alone or in combination with other agents, or new combinations of third-generation chemotherapeutic agents
A triple rare E709K and L833V/H835L EGFR mutation responsive to an irreversible pan-HER inhibitor: A case report of lung adenocarcinoma treated with afatinib
No full text
Atypical skin reaction in a patient treated with gefitinib for advanced lung cancer: A case report and review of the literature
No full textCritical review about MDM2 in cancer: Possible role in malignant mesothelioma and implications for treatment
No full textTherapeutic perspectives for brain metastases in non-oncogene addicted non-small cell lung cancer (NSCLC): Towards a less dismal future?
No full textRisk of brain metastases (BM) affects a remarkable number of non-small cell lung cancer (NSCLC) patients, impacting on their quality of life (QoL) and prognosis. While tyrosine-kinase inhibitors (TKIs) showed interesting intracranial control rates in oncogene-addicted NSCLC, BM still represent an unmet need for the counterpart without driver gene mutations. For these patients, new treatment options include anti-angiogenic drugs and immune-checkpoint inhibitors, possibly combined with standard chemotherapy, even though the benefit on BM has not been clearly defined. A multidisciplinary team including neurosurgeons, medical and radiation oncologists is needed in order to integrate systemic and loco-regional strategies at the right time point. Ad-hoc designed clinical trials are slowly emerging for previously treated patients with uncontrolled BM. The aim of this review is to offer a detailed and updated picture of possible approaches for non oncogene-addicted NSCLC patients having BM, in order to support clinicians in their daily practice
- …
