Lung Cancer Screening, Towards a Multidimensional Approach: Why and How?

International audienceEarly-stage treatment improves prognosis of lung cancer and two large randomized controlled trials have shown that early detection with low-dose computed tomography (LDCT) reduces mortality. Despite this, lung cancer screening (LCS) remains challenging. In the context of a global shortage of radiologists, the high rate of false-positive LDCT results in overloading of existing lung cancer clinics and multidisciplinary teams. Thus, to provide patients with earlier access to life-saving surgical interventions, there is an urgent need to improve LDCT-based LCS and especially to reduce the false-positive rate that plagues the current detection technology. In this context, LCS can be improved in three ways: (1) by refining selection criteria (risk factor assessment), (2) by using Computer Aided Diagnosis (CAD) to make it easier to interpret chest CTs, and (3) by using biological blood signatures for early cancer detection, to both spot the optimal target population and help classify lung nodules. These three main ways of improving LCS are discussed in this review

Efficacy and Safety of Pacritinib vs Placebo for Patients With Severe COVID-19: A Phase 2 Randomized Clinical Trial

IMPORTANCE: The morbidity and mortality associated with COVID-19 remain high despite advances in standard of care therapy, and the role of anti-inflammatory agents that inhibit the interleukin 6/JAK2 pathway is still being elucidated. OBJECTIVE: To evaluate the efficacy and safety of the oral JAK2/IRAK1 inhibitor pacritinib vs placebo in the treatment of adults with severe COVID-19. DESIGN, SETTING, AND PARTICIPANTS: This phase 2, double-blind, placebo-controlled, randomized clinical trial enrolled hospitalized adult patients with severe COVID-19 at 21 centers across the US between June 2020 and February 2021, with approximately 1.5 months of safety follow-up per patient. Data analysis was performed from September 2021 to July 2022. INTERVENTIONS: Patients were randomized 1:1 to standard of care plus pacritinib (400 mg per os on day 1 followed by 200 mg twice daily on days 2-14) vs placebo, for 14 days. MAIN OUTCOMES AND MEASURES: The primary end point was death or need for invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO) by day 28. All-cause mortality and safety were also assessed. RESULTS: A total of 200 patients were randomized to pacritinib (99 patients; 56 men [56.6%]; median [range] age, 60 [19-87] years) or placebo (101 patients; 64 men [63.4%]; median [range] age 59 [28-94] years). The percentage requiring supplementary oxygen was 99.0% (98 patients) in the pacritinib group vs 98.0% (99 patients) in the placebo group. The percentage who progressed to IMV, ECMO, or death was 17.2% (17 patients) in the pacritinib group vs 22.8% (23 patients) in the placebo group (odds ratio, 0.62; 95% CI, 0.28-1.35; P = .23). Among patients with elevated interleukin 6, the rate was 17.5% (11 of 63 patients) in the pacritinib group vs 30.4% (21 of 96 patients) in the placebo group. The adverse event rate was similar for pacritinib vs placebo (78.1% [75 patients] vs 80.2% [81 patients]), with no excess in infection (14.6% [14 patients] vs 19.8% [20 patients]), bleeding (8.3% [8 patients] vs 10.9% [11 patients]), or thrombosis (8.3% [8 patients] vs 7.9% [8 patients]). Rates of grade 3 or higher adverse events were lower with pacritinib than placebo (29.2% [28 patients] vs 40.6% [41 patients]). CONCLUSIONS AND RELEVANCE: The study did not meet its primary end point in patients with severe COVID-19. Subgroup analyses may indicate specific populations with hyperinflammation that could benefit from pacritinib, although further clinical trials would be needed to confirm these effects. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04404361

Assessing the impact of the expression of splice variants on the biological functions of P2RX7 : role in human bronchopulmonary adenocarcinoma

Le cancer du poumon, découvert classiquement à un stade avancé et non opérable, est la première cause de décès par cancer. Les avancées en immunothérapie anti tumorale ont changé le pronostic de cette pathologie en positionnant cette approche comme un élément principal de la prise en charge à ce jour. Néanmoins la survie à cinq ans du cancer du poumon, tous stades confondus, reste inférieure à 20% et il est donc nécessaire de mieux comprendre sa physiopathologie afin d’identifier de nouvelles approches thérapeutiques. Mon laboratoire d’accueil a récemment montré que le récepteur purinergique P2RX7 restreint le développement de tumeurs dans un modèle murin en orchestrant une réponse immunitaire anti tumorale. L’expression de P2RX7 a été montrée dans l’adénocarcinome bronchique humain (LUAD) mais sa fonction n’a jamais été étudiée. Les objectifs de mon projet de recherche étaient de comprendre pourquoi les cellules tumorales du LUAD expriment P2RX7 dont l’une des fonctions est de déclencher leur propre mort. Nous avons émis l’hypothèse que l’expression de variants d’épissage pourrait impacter les fonctions biologiques de P2RX7. J’ai montré que l’isoforme P2RX7A pleine taille et trois variants d'épissage alternatif P2RX7B, H, J sont exprimés dans les tissus LUAD et qu’il y a globalement moins de messagers dans les tissus tumoraux que dans les tissus sains adjacents. Après avoir développé un essai pour mesurer l’activité biologique de P2RX7, nous avons démontré que seul P2RX7 exprimé dans les cellules immunitaires pulmonaires est fonctionnel, et qu’il existe une altération de ses fonctions biologiques uniquement dans le compartiment tumoral. J’ai ensuite caractérisé le mécanisme moléculaire qui conduit à l’expression d’un récepteur dont la fonction biologique est altérée. Ce mécanisme repose sur l’expression différentielle du variant d'épissage P2RX7B et à la capacité de l’isoforme P2RX7B d’hétéro-oligomériser avec P2RX7A pour former un récepteur moins fonctionnel. Enfin, j’ai observé que les tumeurs des patients LUAD qui présentent un niveau d’expression élevé de P2RX7B sont très faiblement infiltrées en cellules immunitaires. L’ensemble de mes résultats positionnent P2RX7B comme un biomarqueur péjoratif pour les patients souffrant de LUAD, et comme un outil théranostique prometteur dans une perspective curative.Lung cancer, classically discovered at an advanced and non-operable stage, is the leading cause of cancer death. Advances in anti-tumor immunotherapy have changed the prognosis of this pathology by positioning this approach as a central element of therapy. Nevertheless, the five-year survival, all stages confused, remains less than 20% and it is therefore necessary to better understand the pathophysiology of this disease in order to identify new therapeutic approaches. My PhD host laboratory has recently shown that the purinergic receptor P2RX7 restricts tumor development in a murine model by orchestrating an anti-tumor immune response. The expression of P2RX7 has been shown in lung adenocarcinoma (LUAD) but its function has never been studied. The aims of my research project were to understand why LUAD tumor cells express P2RX7, one of the functions of which is to trigger their own death. We hypothesized that the expression of splice variants could impact the biological functions of P2RX7. I showed that the full size P2RX7A isoform and three alternative splice variants P2RX7B, H, J are expressed in LUAD tissues and that there are globally less messenger’s RNA in tumor tissues than in adjacent healthy tissues. After developing an assay to measure the biological activity of P2RX7, we demonstrated that only P2RX7 expressed in lung immune cells is functional, and that there is an alteration of its biological activities only into tumor compartment. I then characterized the molecular mechanism that leads to the expression of a receptor whose biological function is altered. This mechanism is relying on the differential expression of the P2RX7B splice variant and the ability of the P2RX7B isoform to hetero-oligomerize with P2RX7A to form a less functional receptor. Finally, I observed that tumors of LUAD patients having a high level of P2RX7B expression are very poorly infiltrated with immune cells.All these results position P2RX7B as a pejorative biomarker for LUAD patients and as a promising theranostic tool in a curative perspective

Étude de l’impact de l’expression de variants d’épissage sur les fonctions biologiques de P2RX7 : rôle dans l’adénocarcinome broncho-pulmonaire humain

Lung cancer, classically discovered at an advanced and non-operable stage, is the leading cause of cancer death. Advances in anti-tumor immunotherapy have changed the prognosis of this pathology by positioning this approach as a central element of therapy. Nevertheless, the five-year survival, all stages confused, remains less than 20% and it is therefore necessary to better understand the pathophysiology of this disease in order to identify new therapeutic approaches. My PhD host laboratory has recently shown that the purinergic receptor P2RX7 restricts tumor development in a murine model by orchestrating an anti-tumor immune response. The expression of P2RX7 has been shown in lung adenocarcinoma (LUAD) but its function has never been studied. The aims of my research project were to understand why LUAD tumor cells express P2RX7, one of the functions of which is to trigger their own death. We hypothesized that the expression of splice variants could impact the biological functions of P2RX7. I showed that the full size P2RX7A isoform and three alternative splice variants P2RX7B, H, J are expressed in LUAD tissues and that there are globally less messenger’s RNA in tumor tissues than in adjacent healthy tissues. After developing an assay to measure the biological activity of P2RX7, we demonstrated that only P2RX7 expressed in lung immune cells is functional, and that there is an alteration of its biological activities only into tumor compartment. I then characterized the molecular mechanism that leads to the expression of a receptor whose biological function is altered. This mechanism is relying on the differential expression of the P2RX7B splice variant and the ability of the P2RX7B isoform to hetero-oligomerize with P2RX7A to form a less functional receptor. Finally, I observed that tumors of LUAD patients having a high level of P2RX7B expression are very poorly infiltrated with immune cells.All these results position P2RX7B as a pejorative biomarker for LUAD patients and as a promising theranostic tool in a curative perspective.Le cancer du poumon, découvert classiquement à un stade avancé et non opérable, est la première cause de décès par cancer. Les avancées en immunothérapie anti tumorale ont changé le pronostic de cette pathologie en positionnant cette approche comme un élément principal de la prise en charge à ce jour. Néanmoins la survie à cinq ans du cancer du poumon, tous stades confondus, reste inférieure à 20% et il est donc nécessaire de mieux comprendre sa physiopathologie afin d’identifier de nouvelles approches thérapeutiques. Mon laboratoire d’accueil a récemment montré que le récepteur purinergique P2RX7 restreint le développement de tumeurs dans un modèle murin en orchestrant une réponse immunitaire anti tumorale. L’expression de P2RX7 a été montrée dans l’adénocarcinome bronchique humain (LUAD) mais sa fonction n’a jamais été étudiée. Les objectifs de mon projet de recherche étaient de comprendre pourquoi les cellules tumorales du LUAD expriment P2RX7 dont l’une des fonctions est de déclencher leur propre mort. Nous avons émis l’hypothèse que l’expression de variants d’épissage pourrait impacter les fonctions biologiques de P2RX7. J’ai montré que l’isoforme P2RX7A pleine taille et trois variants d'épissage alternatif P2RX7B, H, J sont exprimés dans les tissus LUAD et qu’il y a globalement moins de messagers dans les tissus tumoraux que dans les tissus sains adjacents. Après avoir développé un essai pour mesurer l’activité biologique de P2RX7, nous avons démontré que seul P2RX7 exprimé dans les cellules immunitaires pulmonaires est fonctionnel, et qu’il existe une altération de ses fonctions biologiques uniquement dans le compartiment tumoral. J’ai ensuite caractérisé le mécanisme moléculaire qui conduit à l’expression d’un récepteur dont la fonction biologique est altérée. Ce mécanisme repose sur l’expression différentielle du variant d'épissage P2RX7B et à la capacité de l’isoforme P2RX7B d’hétéro-oligomériser avec P2RX7A pour former un récepteur moins fonctionnel. Enfin, j’ai observé que les tumeurs des patients LUAD qui présentent un niveau d’expression élevé de P2RX7B sont très faiblement infiltrées en cellules immunitaires. L’ensemble de mes résultats positionnent P2RX7B comme un biomarqueur péjoratif pour les patients souffrant de LUAD, et comme un outil théranostique prometteur dans une perspective curative

Lung Cancer Screening, towards a Multidimensional Approach: Why and How?

Early-stage treatment improves prognosis of lung cancer and two large randomized controlled trials have shown that early detection with low-dose computed tomography (LDCT) reduces mortality. Despite this, lung cancer screening (LCS) remains challenging. In the context of a global shortage of radiologists, the high rate of false-positive LDCT results in overloading of existing lung cancer clinics and multidisciplinary teams. Thus, to provide patients with earlier access to life-saving surgical interventions, there is an urgent need to improve LDCT-based LCS and especially to reduce the false-positive rate that plagues the current detection technology. In this context, LCS can be improved in three ways: (1) by refining selection criteria (risk factor assessment), (2) by using Computer Aided Diagnosis (CAD) to make it easier to interpret chest CTs, and (3) by using biological blood signatures for early cancer detection, to both spot the optimal target population and help classify lung nodules. These three main ways of improving LCS are discussed in this review

To inhibit or to boost the ATP/P2RX7 pathway to fight cancer, that is the question

International audienceDespite new biological insights and recent therapeutic advances, many tumors remain at baseline during treatments. Therefore, there is an urgent need to find new therapeutic strategies to improve the care of patients with solid tumors. P2RX7 receptor (P2XR7), an ATPgated ion channel characterized by its ability to form large pore within the cell membrane, is described by most of the investigators as a "chef d'orchestre" of the antitumor immune response. The purpose of this review is to detail the recent information concerning different cellular mechanisms linking P2RX7 to hallmarks of cancer and to discuss different progresses in elucidating how activation of the ATP/P2RX7/NLRP3/IL-18 pathway is a very promising approach to fight cancer progression by increasing antitumor immune responses

The Purinergic Landscape of Non-Small Cell Lung Cancer

International audienceLung cancer is the most common cancer worldwide. Despite recent therapeutic advances, including targeted therapies and immune checkpoint inhibitors, the disease progresses in almost all advanced lung cancers and in up to 50% of early-stage cancers. The purpose of this review is to discuss whether purinergic checkpoints (CD39, CD73, P2RX7, and ADORs), which shape the immune response in the tumor microenvironment, may represent novel therapeutic targets to combat progression of non-small cell lung cancer by enhancing the antitumor immune response