Robotic Approach in the Treatment of Locally Advanced (Stage IIIA-pN2) non Small Cell Lung Cancer after Induction Therapy

Introduction: Despite there are already many studies on robotic surgery as minimally invasive approach for non-small cell lung cancer (NSCLC) patients, the use of this technique for stage III disease is still poorly described. These are the preliminary results of our prospective study on safety and effectiveness of robotic approach in patients with locally advanced NSCLC, in terms of postoperative complications and oncological outcome. Methods: Since 2016, we prospectively investigated, using standardized questionnaire and protocol, 21 consecutive patients with NSCLC stage IIIA-pN2 (diagnosed by EBUS-TBNA) who underwent lobectomy and radical lymph node dissection with robotic approach after induction treatment. Then, we performed a matched case-control study with 54 patients treated with open surgery during the same period of time, with similar age, clinical and pathological tumor stage. Results: The individual matched population was composed of 14 robot-assisted thoracic surgery and 14 patients who underwent open surgery. The median time range of resection was inferior in the open group compared to robotic lobectomy (148 vs 229 minutes; P=0.002). Lymph nodes resection and positivity were not statistically significantly different (p=0.66 and p=0.73 respectively). No difference was observed also for PFS (P=0.99) or OS (P=0.94). Conclusions: Our preliminary results demonstrated that the early outcomes and oncological results of N2-patients after robotic lobectomy were similar to open surgery. Considering the advantages of minimally invasive surgery, robotic assisted lobectomy should be a safe approach also to patients with local advanced disease.

A phase II, single arm study of CarbopLatin plus Etoposide with Bevacizumab and Atezolizumab in patients with exTEnded-disease small-cell lung cancer (SCLC) – CeLEBrATE trial

Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor diagnosed at extended disease SCLC (ES-SCLC) stage in about 70% of cases. The new standard of treatment for patients with ES-SCLC is a combination of platinum-etoposide chemotherapy and atezolizumab or durvalumab, two programmed cell death ligand 1 (PD-L1) inhibitory monoclonal antibodies (mAb). However, the benefit derived from the addition of PD-L1 inhibitors to chemotherapy in ES-SCLC was limited and restricted to a subset of patients. The vascular endothelial growth factor (VEGF) is the most important pro-angiogenic factor implicated in cancer angiogenesis, which is abundant in SCLC and associated with poor prognosis. Antiangiogenic agents, such as bevacizumab, a humanized mAb against VEGF, added to platinum-etoposide chemotherapy improved progression-free survival in SCLC in two trials, but it did not translate into a benefit in overall survival. Nevertheless, VEGF has also acts as a mediator of an immunosuppressive microenvironment and its inhibition can revert the immune-suppressive tumor microenvironment and potentially enhance the efficacy of immunotherapies. Based on available preclinical data, we hypothesized that VEGF inhibition by bevacizumab could improve atezolizumab efficacy in a synergistic way and designed a phase II single-arm trial of bevacizumab in combination with carboplatin, etoposide, and atezolizumab as first-line treatment in ES-SCLC. The trial, which is still ongoing, enrolled 53 patients, including those with treated or untreated asymptomatic brain metastases (provided criteria are met), who received atezolizumab, bevacizumab, carboplatin and etoposide for 4-6 cycles (induction phase), followed by maintenance with atezolizumab and bevacizumab for a maximum of 18 total cycles or until disease progression, patient refusal, unacceptable toxicity. The evaluation of efficacy of the experimental combination in terms of 1-year overall survival rate is not yet mature (primary objective of the trial). The combination was feasible and the toxicity profile manageable (secondary objective of the trial).

Preclinical evaluation of a MYCN-specific inhibitor for the treatment of small cell lung cancer

Small cell lung cancer (SCLC) is the most aggressive form of lung cancer, characterized by rapid growth, early metastasis and acquired drug resistance. SCLC is usually sensitive to initial treatment, however, most patients relapse within few months; thus more effective therapies are urgently needed. Key genetic alterations very frequently observed in SCLC include loss of TP53 and RB1 and mutations in the MYC family genes (MYC, MYCL or MYCN). One of them is amplified and overexpressed in a mutually exclusive manner and represents the most prominent activating oncogene alteration in this malignancy. In particular, MYCN amplification is associated with tumor progression, treatment failure and poor prognosis. Given the role of MYCN in SCLC and its restricted expression profile, MYCN represents a promising therapeutic target; although it is considered undruggable by traditional approaches. An innovative approach to target the oncogene concerns specific MYCN expression inhibition, acting directly at the level of DNA, through an antigene peptide nucleic acid (agPNA) oligonucleotide, called BGA002. This thesis focused on the study of BGA002, as a possible targeted therapeutic strategy for the treatment of MYCN-related SCLC. In this context, BGA002 proved to be a specific and highly effective inhibitor. Furthermore, MYCN silencing induced alterations in many downstream pathways and led to apoptosis, in concomitance with autophagy reactivation. Moreover, systemic administration of BGA002 was effective in vivo as well, significantly increasing survival in MNA mouse models, even in the scenario of multidrug-resistance. In addition, BGA002 treatment successfully reduced N-Myc protein expression and, more importantly, caused a massive diminishment in tumor vascularization in the multidrug-resistant model. Overall, these results proved that MYCN inhibition by BGA002 may represent a new promising precision medicine approach, to treat MYCN-related SCLC.

Understanding molecular mechanisms of resistance to immune checkpoint inhibitors in advanced non-small cell lung cancer (NSCLC)

Immune checkpoint inhibitors (ICI) that target PD-1/PD-L1 have recently emerged as an integral component of front-line treatment in metastatic NSCLC patients. The PD-1 inhibitor pembrolizumab is approved as monotherapy for advanced NSCLC with a PD-L1 tumor proportion score (TPS) of ≥1% and in combination with platinum doublet chemotherapy regardless of PD-L1 expression level. However, responses to either regimen occur in only a minority of cases, and PD-L1 TPS is limited as a biomarker in predicting whether a cancer will respond to PD-1 inhibition alone or would be more likely to benefit from PD-1 inhibition plus chemotherapy. Additional biomarkers of immunotherapy efficacy, such as tumor mutational burden (TMB), have not been incorporated into routine clinical practice for treatment selection. The identification of patients who have the greatest likelihood of responding to immunotherapies is critical for guiding treatment decisions. IN addition, early indicators of response could theoretically prevent patients from staying on an ineffective therapy where they might experience complications due to disease progression or develop toxicities from unnecessary exposure to an inactive agent. The aim of this research project is to investigate the clinicopathologic and molecular determinant of response/resistance to the currently available immune checkpoint inhibitors, in order to identify therapeutic vulnerabilities that can be exploited to improve the clinical outcomes of patients with advanced NSCLC.

The RAS-Lung project: implementing blood and tissue genotyping in KRAS-Positive non-small cell lung cancer treatment

Background: The frontline management of non-oncogene addicted non-small cell lung cancer (NSCLC) involves immunotherapy (ICI) alone or combined with chemotherapy (CT-ICI). As therapeutic options expand, refining NSCLC genotyping gains paramount importance. The dynamic landscape of KRAS-positive NSCLC presents a spectrum of treatment options, including ICI, targeted therapy, and combination strategies currently under investigation. Methods: The two-year RASLUNG project, featuring both retrospective and prospective cohorts, aimed to analyze the predictive and prognostic impact of KRAS mutations on tumor tissue and circulating DNA (ctDNA). Secondary objectives included assessing the roles of co-mutations and longitudinal changes in KRAS mutant copies concerning treatment response and survival outcomes. An external validation study confirmed the prognostic or predictive significance of co-mutations. Results: In the prospective cohort (n=24), patients with liver metastases exhibited significantly elevated ctDNA levels(p=0.01), while those with >3 metastatic sites showed increased Allele Frequency (AF) (P=0.002). Median overall survival (OS) was 7.5 months, progression-free survival (PFS) was 4.0 months, and the objective response rate (ORR) was 33.3%. Higher AF correlated with an increased risk of death (HR 1.04, p = 0.03), though not progression. Notably, a reduction in plasma DNA levels was significantly associated with objective response(p=0.01). In the retrospective cohort, KRAS and STK11 mutations co-occurred in 14/21 patients (p=0.053). STK11 mutations were independently detrimental to OS (HR 1.97, p=0.025) after adjusting for various factors. KRAS tissue AF did not correlate with OS or PFS. Within the validation dataset, STK11 mutations were significantly associated with an increased risk of death in univariate (HR 2.01, p<0.001) and multivariate models (HR 1.66, p=0.001) after adjustments. Conclusion: The RAS-Lung Project, employing innovative genotyping techniques, underscores the significance of comprehensive NSCLC genotyping. Tailored next-generation sequencing (NGS) and ctDNA monitoring may offer potential benefits in navigating the evolving landscape of KRAS-positive NSCLC treatment.

Developing a radiomic based machine learning model to identify patients with resected non-small-cell lung cancer at high risk of relapse

Background There is a wide variation of recurrence risk of Non-small-cell lung cancer (NSCLC) within the same Tumor Node Metastasis (TNM) stage, suggesting that other parameters are involved in determining this probability. Radiomics allows extraction of quantitative information from images that can be used for clinical purposes. The primary objective of this study is to develop a radiomic prognostic model that predicts a 3 year disease free-survival (DFS) of resected Early Stage (ES) NSCLC patients. Material and Methods 56 pre-surgery non contrast Computed Tomography (CT) scans were retrieved from the PACS of our institution and anonymized. Then they were automatically segmented with an open access deep learning pipeline and reviewed by an experienced radiologist to obtain 3D masks of the NSCLC. Images and masks underwent to resampling normalization and discretization. From the masks hundreds Radiomic Features (RF) were extracted using Py-Radiomics. Hence, RF were reduced to select the most representative features. The remaining RF were used in combination with Clinical parameters to build a DFS prediction model using Leave-one-out cross-validation (LOOCV) with Random Forest. Results and Conclusion A poor agreement between the radiologist and the automatic segmentation algorithm (DICE score of 0.37) was found. Therefore, another experienced radiologist manually segmented the lesions and only stable and reproducible RF were kept. 50 RF demonstrated a high correlation with the DFS but only one was confirmed when clinicopathological covariates were added: Busyness a Neighbouring Gray Tone Difference Matrix (HR 9.610). 16 clinical variables (which comprised TNM) were used to build the LOOCV model demonstrating a higher Area Under the Curve (AUC) when RF were included in the analysis (0.67 vs 0.60) but the difference was not statistically significant (p=0,5147).

Inhibition of human lung cancer cell proliferation and survival by wine

Compounds of plant origin and food components have attracted scientific attention for use as agents for cancer prevention and treatment. Wine contains polyphenols that were shown to have anti-cancer and other health benefits. The survival pathways of Akt and extracellular signal-regulated kinase (Erk), and the tumor suppressor p53 are key modulators of cancer cell growth and survival. In this study, we examined the effects of wine on proliferation and survival of human Non-small cell lung cancer (NSCLC) cells and its effects on signaling events.

Inhibition of human lung cancer cell proliferation and survival by wine

Compounds of plant origin and food components have attracted scientific attention for use as agents for cancer prevention and treatment. Wine contains polyphenols that were shown to have anti-cancer and other health benefits. The survival pathways of Akt and extracellular signal-regulated kinase (Erk), and the tumor suppressor p53 are key modulators of cancer cell growth and survival. In this study, we examined the effects of wine on proliferation and survival of human Non-small cell lung cancer (NSCLC) cells and its effects on signaling events.

Toward an early diagnosis of lung cancer: an autoantibody signature for squamous cell lung carcinoma

Serum-based diagnosis offers the prospect of early lung carcinoma detection and of differentiation between benign and malignant nodules identified by CT. One major challenge toward a future blood-based diagnostic consists in showing that seroreactivity patterns allow for discriminating lung cancer patients not only from normal controls but also from patients with non-tumor lung pathologies. We addressed this question for squamous cell lung cancer, one of the most common lung tumor types. Using a panel of 82 phage-peptide clones, which express potential autoantigens, we performed serological spot assay. We screened 108 sera, including 39 sera from squamous cell lung cancer patients, 29 sera from patients with other non-tumor lung pathologies, and 40 sera from volunteers without known disease. To classify the serum groups, we employed the standard Naïve Bayesian method combined with a subset selection approach. We were able to separate squamous cell lung carcinoma and normal sera with an accuracy of 93%. Low-grade squamous cell lung carcinoma were separated from normal sera with an accuracy of 92.9%. We were able to distinguish squamous cell lung carcinoma from non-tumor lung pathologies with an accuracy of 83%. Three phage-peptide clones with sequence homology to ROCK1, PRKCB1 and KIAA0376 reacted with more than 15% of the cancer sera, but neither with normal nor with non-tumor lung pathology sera. Our study demonstrates that seroreactivity profiles combined with statistical classification methods have great potential for discriminating patients with squamous cell lung carcinoma not only from normal controls but also from patients with non-tumor lung pathologies.

Refining the diagnosis and EGFR status of non-small cell lung carcinoma in biopsy and cytologic material, using a panel of mucin staining, TTF-1, cytokeratin 5/6, and P63, and EGFR mutation analysis.

INTRODUCTION: The dichotomization of non-small cell carcinoma (NSCLC) subtype into squamous (SQCC) and adenocarcinoma (ADC) has become important in recent years and is increasingly required with regard to management. The aim of this study was to determine the utility of a panel of commercially available antibodies in refining the diagnosis on small biopsies and also to determine whether cytologic material is suitable for somatic EGFR genotyping in a prospectively analyzed series of patients undergoing investigation for suspected lung cancer. METHODS: Thirty-two consecutive cases of NSCLC were first tested using a panel comprising cytokeratin 5/6, P63, thyroid transcription factor-1, 34betaE12, and a D-PAS stain for mucin, to determine their value in refining diagnosis of NSCLC. After this test phase, two further pathologists independently reviewed the cases using a refined panel that excluded 34betaE12 because of its low specificity for SQCC, and refinement of diagnosis and concordance were assessed. Ten cases of ADC, including eight derived from cytologic samples, were sent for EGFR mutation analysis. RESULTS: There was refinement of diagnosis in 65% of cases of NSCLC to either SQCC or ADC in the test phase. This included 10 of 13 cases where cell pellets had been prepared from transbronchial needle aspirates. Validation by two further pathologists with varying expertise in lung pathology confirmed increased refinement and concordance of diagnosis. All samples were adequate for analysis, and they all showed a wild-type EGFR genotype. CONCLUSION: A panel comprising cytokeratin 5/6, P63, thyroid transcription factor-1, and a D-PAS stain for mucin increases diagnostic accuracy and agreement between pathologists when faced with refining a diagnosis of NSCLC to SQCC or ADC. These small samples, even cell pellets derived from transbronchial needle aspirates, seem to be adequate for EGFR mutation analysis.

Imaging and lung cancer

Lung cancer remains the most common cause of cancer-related mortality in Scotland, accounting for 28.9% of all cancer deaths in 2007. Current guidelines recommend assessment of patient fitness and operability by a multidisciplinary team when selecting management options. Two of the most important prognostic markers are the stage of disease and ECOG performance status. In 1996, the International Association for the Study of Lung Cancer (IASLC) launched a worldwide TNM staging project to create international databases that would be used to continue the excellent efforts of Dr. Cliff Mountain, who pioneered this approach to lung cancer staging in 1973. Successive iterations of tumor, nodule, metastasis (TNM) staging for lung cancer have addressed shortcomings identified by the oncology community. Similarly, the IASLC recognized that it is important that further revisions continue to be made to ensure that the international staging system for lung cancer remains fit for its purpose. The last work of the International Staging Committee (ISC) was the conduct of the study that informed the seventh edition of the international staging system for lung cancer, in 2010. This review of image and staging in non small cell lung cancer (NSCLC), includes a summary of the different noninvasive tests currently available for staging non small cell lung cancer.

Study of glycosidic changes in lung cancer: potential effectors in hematogenous metastasis

RESUMO: O cancro do pulmão (LC), uma das principais causas de mortalidade relacionada com cancro em Portugal, pode levar à formação de metástases hematogénicas. A adesão das células tumorais ao endotélio é considerada um dos passos fundamentais envolvidos na metástase. Em células sanguíneas, esta adesão é mediada por ligandos de E-selectina (E-SL), glicoproteínas ou glicolípidos decorados principalmente com sialyl-Lewis x (sLex) e sialyl-Lewis a (sLea). Tem sido descrito a expressão destes antigénios em LC, contudo o seu papel funcional em permitir a adesão das células de LC ao endotélio é ainda pouco compreendido. Foram analisadas amostras emparelhadas normais e tumorais de pacientes com cancro de pulmão de não-pequenas células (NSCLC) e três linhas celulares de LC. Immunoblotting assays com anti-sLex/sLea e molécula quimérica de E-selectina demonstraram que tecidos tumorais de LC sobreexpressam significativamente E-SL e resultados de citometria de fluxo demonstraram uma expressão elevada de E-SL nas linhas celulares. Para compreender o mecanismo da sobreexpressão de E-SL em tecidos tumorais e linhas celulares de LC, foi analisada a expressão de genes envolvidos na biossíntese de E-SL, nomeadamente FUT3, FUT4, FUT6, FUT7, ST3GAL3, ST3GAL4, ST3GAL6, β4GALT1, GCNT1 e GALNT3. Observou-se a sobreexpressão das fucosiltransferases FUT3, FUT6 e FUT7 em tecidos tumorais de LC e FUT3 em linhas celulares de LC, sendo que neste último, esta expressão é correlacionada com um aumento da adesão das células de LC às selectinas endoteliais. Foi observado que uma baixa expressão de FUT4 em tecidos tumorais está associada com estadios menos avançados de NSCLC. Foram analisadas ainda proteínas decoradas com sLex/sLea, tendo-se identificado como E-SL o antigénio carcinoembrionário em NSCLC. Em resumo, esta tese contribuiu para uma melhor compreensão das alterações glicosídicas e moléculas que podem influenciar a progressão tumoral do LC, podendo permitir identificar futuramente novos biomarcadores de diagnóstico/prognóstico e potenciais alvos terapêuticos para o NSCLC.--------------------------ABSTRACT: Lung cancer (LC), one of the major causes of mortality related to cancer in Portugal, may lead to hematogenous metastasis. Adhesion of cancer cells to endothelium is considered one of the crucial steps involved in metastasis. In blood cells, this adhesion is initiated by endothelial selectin ligands (E-SL) that are glycoproteins or glycolipids decorated mostly with sialyl-Lewis x (sLex) and sialyl-Lewis a (sLea). While LC has been described as expressing these sialyl Lewis antigens, its functional role in allowing LC adhesion to endothelium is still poorly understood. We analyzed paired tumor and normal tissues samples from non-small cell lung cancer (NSCLC) patients and three LC cell lines. Immunoblotting assays with anti-sLex/sLea and E-selectin chimera demonstrated that LC tumor tissues significantly overexpress E-SL and flow cytometry results indicated that E-SL are also abundantly expressed in LC cell lines. To understand the mechanism behind the overexpression of E-SL in LC tissues and cell lines, we analyzed the expression of genes involved in its biosynthesis, namely FUT3, FUT4, FUT6, FUT7, ST3GAL3, ST3GAL4, ST3GAL6, β4GALT1, GCNT1 and GALNT3. It was observed the overexpression of fucosyltransferases FUT3, FUT6 and FUT7 in LC tumor tissues and FUT3 in LC cell lines, being this last one correlated with an increased reactivity of the LC cells to endothelial selectins. It was described that low expression of FUT4 in tumor tissues is correlated with early stages of NSCLC. We also analyzed scaffolds proteins of sLex/sLea and it was identified the carcinoembryonic antigen as an E-SL in NSCLC. In summary, this thesis contributed to a better understanding of the glycosidic changes and molecules that can influence tumor progression of LC, allowing identifying in the future new diagnosis/prognosis biomarkers and potential therapeutic targets for NSCLC.

The tumour suppressor LATS2 interacts with both Signalosome and E3 ubiquitin ligases : implications in control of cell cycle progression

SUMMARY LATS2 is a member of the Lats tumour suppressor gene family. The human LATS2 gene is located at chromosome 13q11-12, which has been shown to be a hot spot (67%) for LOH in nonsmall cell lung cancer. Both lats mosaic flies and LATS1 deficient mice spontaneously develop tumours, an observation that is explained by the function of LATS1 in suppressing tumourigenesis by negatively regulating cell proliferation by modulating Cdc2/Cyclin A activity. LATS1 also plays a critical role in maintenance of ploidy through its action on the spindle assembly checkpoint. Initial insights into the function of LATS2 reveals that the protein is involved in the G2/M transition of the cell cycle, whereby it controls the phosphorylation status of Cdc25C. The aim of the present study was to identify LATS2 interacting partners that would provide a more thorough understanding of the molecular pathways in which the protein is involved. The yeast two-hybrid system identified a number of candidate genes that interact with LATS2. Most of the interactions were confirmed biochemically by GST-pull down assays that enabled us to demonstrate that LATS2 is an integral component of the Signalosome complex. The Signalosome is thought to be required for the establishment of functional Cullin-based E3 ubiquitin ligases, the substrate-recognition elements of the ubiquitin-mediated protein proteolytic pathway. The findings that LATS2 also interacts with all of the components of the E3 enzymes allows us to postulate that LATS2 is probably involved in the regulation of this Signalosome-E3 super-complex. In addition, the discovery that LATS2 associates with multiple protein kinases localised at the cellular membrane and in various signalling cascades supports the idea that LATS2 functions as an integrator of signals which allows it to monitor the activity of these pathways and translate these signals through its action on the Signalosome. Furthermore, the observation that a kinase-dead LATS2 mutant arrests at the G2/M phase of the cell cycle, demonstrates that the protein, through the action of its kinase domain, is crucial for progression through the cell cycle, an action in accordance to its proposed role as a regulator of E3 ubiquitin ligases. The findings presented herein provide evidence that LATS2 associates with the Signalosome-E3 ubiquitin ligases super-complex which governs protein stability. Any alteration of the protein would have a strong impact on pathways that modulate cell proliferation, as shown by its implication in tumourigenesis. RESUME LATS2 est un membre de la famille de gènes suppresseurs de tumeurs LATS. Le gène humain LATS2 est situé sur le chromosome 13q11-12, une région qui s'est avérée être un point sensible (67%) dans la perte d'hétérozigosité (LOH) notamment pour le cancer du poumon. Le fait que des tumeurs se développent spontanément chez les souris qui sont déficientes pour le gène LATS1 ainsi que dans des cellules mutantes pour LATS chez la Drosophile, est expliqué Par la fonction de LATS1, qui est de supprimer l'apparition de tumeurs en réprimant la prolifération cellulaire à travers sa capacité à réguler l'activité de Cdc2/Cyciine A. LATS1 joue également un rôle important au niveau du maintient de la ploïdie de la cellule, au travers de son action sur les points de contrôle de l'assemblage du fuseau mitotique. Les premières études du gène LATS2 indiquent que la protéine est, par son contrôle des réactions de phosphorylation de la Cdc25C, impliquée dans la transition 021M. Le but de cette étude était d'identifier les protéines qui interagissent avec LATS2, en vue d'obtenir une compréhension plus approfondie des mécanismes moléculaires dans lesquels LATS2 se trouve engagée. Le système de double-hybride chez la levure a permis l'identification d'un grand nombre de gènes qui interagissent avec LATS2. La plupart des interactions ont été confirmées par GST «pull clown», une technique in vitro qui a permis de démontrer que LATS2 est un composant intégral du Signalosome. Ce complexe est supposé réguler l'activité des E3 ubiquitine-rigases, les éléments responsables du recrutement des substrats qui doivent être recyclés par la voie de dégradation ubiquitine-dépendante. Les résultats obtenus indiquent également que LATS2 interagit avec tous les composants des enzymes E3, ce qui nous permet de soumettre l'idée selon laquelle la protéine LATS2 est en fait impliquée dans la régulation du complexe Signalosorne-E3. De plus, la découverte que LATS2 se trouve associée à plusieurs protéines kinases localisées au niveau de la membrane cellulaire, ainsi que dans diverses voies de transduction, confirment l'idée que LATS2 fonctionne en tant que molécule qui intègre les signaux en provenance de ces différentes voies cellulaires. De ce fait, il lui serait possible de coordonner la destruction des protéines au moyen du complexe Signalosome, permettant ainsi de réprimer l'activité des voies de signalisation. En outre, l'introduction d'une mutation dans le domaine kinase de LATS2 résulte en l'arrêt du cycle cellulaire en G2/M, ce qui montre que la protéine, au travers de son domaine kinase, est cruciale pour le bon fonctionnement du cycle cellulaire, ceci en accord avec son rôle proposé comme régulateur des E3 ubiquitine-ligases. Les résultats présentés dans ce manuscrit démontrent que la protéine LATS2 se trouve associée au complexe Signalosome-E3 qui régule la dégradation des protéines. La moindre modification de la protéine engendrerait des répercussions importantes au niveau des voies de transduction qui contrôlent fa prolifération ceilulaire, ce qui atteste du rôle déterminant que joue LAT32 dans la tumorigénèse.

Stereotactic body radiation therapy in stage I inoperable lung cancer: from palliative to curative options.

Surgery has historically been the standard of care for operable stage I non-small cell lung cancer (NSCLC). However, nearly one-quarter of patients with stage I NSCLC will not undergo surgery because of medical comorbidity or other factors. Stereotactic ablative radiotherapy (SABR) is the new standard of care for these patients. SABR offers high local tumour control rates rivalling the historical results of surgery and is generally well tolerated by patients with both peripheral and centrally located tumours. This article reviews the history of SABR for stage I NSCLC, summarises the currently available data on efficacy and toxicity, and describes some of the currently controversial aspects of this treatment.

Modulation of MDR1 and MRP3 Gene Expression in Lung Cancer Cells after Paclitaxel and Carboplatin Exposure

Carboplatin-paclitaxel is a reference regimen in the treatment of locally advanced or disseminated non-small cell lung cancer (NSCLC). This paper discusses the multidrug resistance developed with this drug combination, which is one of the major obstacles to successful treatment. In order to understand and overcome the drug resistance pattern of NSCLC after carboplatin plus paclitaxel exposure, levels of mRNA expression of multidrug resistance 1 (MDR1) and multidrug resistance-associated protein 3 (MRP3) were investigated in primary NSCLC cell lines (A-549 and A-427) and a metastasis-derived NSCLC cell line (NODO). Our results showed that exposure of the three NSCLC lines to plasma concentrations of paclitaxel (5 μM) produced an increase in MDR1 expression, while MRP3 showed no alteration in expression. By contrast, the same cells exposed to carboplatin plasma concentrations (30 μM) showed overexpression of MRP3. In these cells, MDR1 showed no expression changes. Interestingly, the combination of both paclitaxel and carboplatin caused increased expression of the MDR1 drug resistance gene rather than the individual treatments. These results suggest that carboplatin and paclitaxel may induce drug resistance mediated by MDR1 and MRP3, which may be enhanced by the simultaneous use of both drugs.