Targeting KRASG12C in Non-Small-Cell Lung Cancer: Current Standards and Developments.

Among the most common molecular alterations detected in non-small-cell lung cancer (NSCLC) are mutations in Kristen Rat Sarcoma viral oncogene homolog (KRAS). KRAS mutant NSCLC is a heterogenous group of diseases, different from other oncogene-driven tumors in terms of biology and response to therapies. Despite efforts to develop drugs aimed at inhibiting KRAS or its signaling pathways, KRAS had remained undruggable for decades. The discovery of a small pocket in the binding switch II region of KRASG12C has revolutionized the treatment of KRASG12C-mutated NSCLC patients. Sotorasib and adagrasib, direct KRASG12C inhibitors, have been approved by the US Food and Drug Administration (FDA) and other regulatory agencies for patients with previously treated KRASG12C-mutated NSCLC, and these advances have become practice changing. However, first-line treatment in KRASG12C-mutated NSCLC does not differ from NSCLC without actionable driver genomic alterations. Treatment with KRASG12C inhibitors is not curative and patients develop progressive disease, so understanding associated mechanisms of drug resistance is key. New KRASG12C inhibitors and several combination therapy strategies, including with immune checkpoint inhibitors, are being studied in clinical trials. The aim of this review is to explore the clinical impact of KRAS, and outline different treatment approaches, focusing on the novel treatment of KRASG12C-mutated NSCLC.

Future Perspectives in the Second Line Therapeutic Setting for Non-Oncogene Addicted Non-Small-Cell Lung Cancer.

Immune checkpoint inhibitors (ICIs) have revolutionized the management of non-oncogene addicted non-small-cell lung cancer (NSCLC). Blocking the anti-PD-1 axis represents the current standard of care in the first-line setting, with drugs administered either as monotherapy or in combination with chemotherapy. Despite notable successes achieved with ICIs, most of their long-term benefits are restricted to approximately 20% of patients. Consequently, the post-failure treatment landscape after failure to first-line treatment remains a complex challenge. Currently, docetaxel remains the preferred option, although its benefits remain modest as most patients do not respond or progress promptly. In recent times, novel agents and treatment combinations have emerged, offering fresh opportunities to improve patient outcomes. ICIs combined either with antiangiogenic or other novel immunotherapeutic compounds have shown promising preliminary activity. However, more mature data concerning specific combinations do not support their benefit over standard of care. In addition, antibody-drug conjugates seem to be the most promising alternative among all available compounds according to already-published phase I/II data that will be confirmed in soon-to-be-published phase III trial data. In this report, we provide a comprehensive overview of the current second-line treatment options and discuss future therapeutic perspectives.

A narrative review of methods for the identification of ALK fusions in patients with non-small cell lung carcinoma.

Background and Objective: This narrative review is intended to provide pragmatic knowledge of current methods for the search of anaplastic lymphoma kinase (ALK) fusions in patients with non-small cell lung carcinoma (NSCLC). This information is very timely, because a recent survey has identified that almost 50% of patients with advanced NSCLC were not candidates for targeted therapies because of biomarker testing issues. Methods: PubMed was searched from January 1st, 2012 to February 28th, 2023 using the following keywords: "ALK" and "lung", including reviews and our own work. Key Content and Findings: Testing rates have not reached 85% among patients' candidates to ALK inhibition. The advantages and disadvantages of the different analytical options [immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), real-time polymerase chain reaction and next-generation sequencing (NGS)] are discussed. The key factor for success in ALK testing is a deep understanding of the concept of "molecular redundancy". This notion has been recommended and endorsed by all the major professional organizations in the field and can be summarized as follows: "laboratories should ensure that test results that are unexpected, discordant, equivocal, or otherwise of low confidence are confirmed or resolved using an alternative method or sample". In-depth knowledge of the different ALK testing methodologies can help clinical and molecular tumor boards implement and maintain sensible algorithms for a rapid and effective detection of predictive biomarkers in patients with NSCLC. Conclusions: Multimodality testing has the potential to increase both the testing rate and the accuracy of ALK fusion identification.

Targeted therapy for lung cancer: Beyond EGFR and ALK.

Precision oncology comprises the set of strategies that aim to design the best cancer treatment based on tumor biology. A recognized subset of patients with non-small cell lung cancer (NSCLC) harbor actionable genomic aberrations that can benefit from targeted therapy. In lung cancer, epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements are well characterized oncogenic drivers for which the therapeutic use of tyrosine kinase inhibitors has demonstrated improved outcomes compared with chemotherapy. Other druggable targets are also well characterized, and effective inhibitors have been developed and commercialized, leading to a paradigm shift in NSCLC treatment. Here, the authors provide a review of the oncogenic role of the most relevant molecular alterations in NSCLC and emerging treatments in this setting beyond EGFR-driven and ALK-driven diseases.

A Multicomponent Exercise Intervention that Reverses Frailty and Improves Cognition, Emotion, and Social Networking in the Community-Dwelling Frail Elderly: A Randomized Clinical Trial.

BACKGROUND: Frailty can be an important clinical target to reduce rates of disability. OBJECTIVE: To ascertain if a supervised-facility multicomponent exercise program (MEP) when performed by frail older persons can reverse frailty and improve functionality; cognitive, emotional, and social networking; as well as biological biomarkers of frailty, when compared with a controlled population that received no training. DESIGN: This is an interventional, controlled, simple randomized study. Researchers responsible for data gathering were blinded for this study. SETTING: Participants from 2 primary rural care centers (Sollana and Carcaixent) of the same health department in Spain were enrolled in the study between December 2013 and September 2014. PATIENTS: We randomized a volunteer sample of 100 men and women who were sedentary, with a gait speed lower than 0.8 meters per second and frail (met at least 3 of the frailty phenotype criteria). INTERVENTIONS: Participants were randomized to a supervised-facility MEP (n = 51, age = 79.5, SD 3.9) that included proprioception, aerobic, strength, and stretching exercises for 65 minutes, 5 days per week, 24 weeks, or to a control group (n = 49, age = 80.3, SD 3.7). The intervention was performed by 8 experienced physiotherapists or nurses. Protein-calorie and vitamin D supplementation were controlled in both groups. RESULTS: Our MEP reverses frailty (number needed to treat to recover robustness in subjects with attendance to ≥50% of the training sessions was 3.2) and improves functional measurements: Barthel (trained group 91.6 SD 8.0 vs 82.0 SD 11.0 control group), Lawton and Brody (trained group 6.9 SD 0.9 vs 5.7 SD 2.0 control group), Tinetti (trained group 24.5 SD 4.4 vs 21.7 SD 4.5 control group), Short Physical Performance Battery (trained group 9.5 SD 1.8 vs 7.1 SD 2.8 control group), and physical performance test (trained group 23.5 SD 5.9 vs 16.5 SD 5.1 control group) as well as cognitive, emotional, and social networking determinations: Mini-Mental State Examination (trained group 28.9 SD 3.9 vs 25.9 SD 7.3 control group), geriatric depression scale from Yesavage (trained group 2.3 SD 2.2 vs 3.2 SD 2.0 control group), EuroQol quality-of-life scale (trained group 8.2 SD 1.6 vs 7.6 SD 1.3 control group), and Duke social support (trained group 48.5 SD 9.3 vs 41.2 SD 8.5 control group). This program is unique in that it leads to a decrease in the number of visits to primary care physician (trained group 1.3 SD 1.4 vs 2.4 SD 2.9 control group) and to a significant improvement in frailty biomarkers. CONCLUSIONS: We have designed a multicomponent exercise intervention that reverses frailty and improves cognition, emotional, and social networking in a controlled population of community-dwelling frail older adults. TRIAL REGISTRATION: ClinicalTrials.gov. Identifier: NCT02331459.

Redox modulation of mitochondriogenesis in exercise. Does antioxidant supplementation blunt the benefits of exercise training?

Physical exercise increases the cellular production of reactive oxygen species (ROS) in muscle, liver, and other organs. This is unlikely due to increased mitochondrial production but rather to extramitochondrial sources such as NADPH oxidase or xanthine oxidase. We have reported a xanthine oxidase-mediated increase in ROS production in many experimental models from isolated cells to humans. Originally, ROS were considered as detrimental and thus as a likely cause of cell damage associated with exhaustion. In the past decade, evidence showing that ROS act as signals has been gathered and thus the idea that antioxidant supplementation in exercise is always recommendable has proved incorrect. In fact, we proposed that exercise itself can be considered as an antioxidant because training increases the expression of classical antioxidant enzymes such as superoxide dismutase and glutathione peroxidase and, in general, lowering the endogenous antioxidant enzymes by administration of antioxidant supplements may not be a good strategy when training. Antioxidant enzymes are not the only ones to be activated by training. Mitochondriogenesis is an important process activated in exercise. Many redox-sensitive enzymes are involved in this process. Important signaling molecules like MAP kinases, NF-κB, PGC-1α, p53, heat shock factor, and others modulate muscle adaptation to exercise. Interventions aimed at modifying the production of ROS in exercise must be performed with care as they may be detrimental in that they may lower useful adaptations to exercise.

Methodological considerations to determine the effect of exercise on brain-derived neurotrophic factor levels.

OBJECTIVES: Physical exercise up-regulates brain-derived neurotrophic factor (BDNF) in the brain and blood. However, there is yet no consensus about the adequate blood processing conditions to standardize its assessment. We aimed to find a reliable blood sample processing method to determine changes in BDNF due to exercise. DESIGN AND METHODS: Twelve healthy university students performed an incremental cycling test to exhaustion. At baseline, immediately after exercise, and 30 and 60 min of recovery, venous blood was drawn and processed under different conditions, i.e. whole blood, serum coagulated for 10 min and 24 h, total plasma, and platelet-free plasma. BDNF concentration was measured by ELISA. RESULTS: Exercise increased BDNF in whole blood and in serum coagulated for 24 h when corrected by hemoconcentration. We did not find effects of exercise on BDNF in serum coagulated for 10 min or in plasma samples. Plasma shows heterogeneous BDNF values in response to exercise that are not prevented when platelets are eliminated while homogeneous BDNF levels were found in whole blood or serum coagulated for 24 hour samples. CONCLUSIONS: In exercise studies, BDNF levels should be adjusted by hemoconcentration. Our data highlight the importance of blood sample selection since the differences between each one affect significantly the BDNF factor changes due to exercise.

Roles of sedentary aging and lifelong physical activity in exchange of glutathione across exercising human skeletal muscle.

Reactive oxygen species (ROS) are important signaling molecules with regulatory functions, and in young and adult organisms, the formation of ROS is increased during skeletal muscle contractions. However, ROS can be deleterious to cells when not sufficiently counterbalanced by the antioxidant system. Aging is associated with accumulation of oxidative damage to lipids, DNA, and proteins. Given the pro-oxidant effect of skeletal muscle contractions, this effect of age could be a result of excessive ROS formation. We evaluated the effect of acute exercise on changes in blood redox state across the leg of young (23 ± 1 years) and older (66 ± 2 years) sedentary humans by measuring the whole blood concentration of the reduced (GSH) and oxidized (GSSG) forms of the antioxidant glutathione. To assess the role of physical activity, lifelong physically active older subjects (62 ± 2 years) were included. Exercise increased the venous concentration of GSSG in an intensity-dependent manner in young sedentary subjects, suggesting an exercise-induced increase in ROS formation. In contrast, venous GSSG levels remained unaltered during exercise in the older sedentary and active groups despite a higher skeletal muscle expression of the superoxide-generating enzyme NADPH oxidase. Arterial concentration of GSH and expression of antioxidant enzymes in skeletal muscle of older active subjects were increased. The potential impairment in exercise-induced ROS formation may be an important mechanism underlying skeletal muscle and vascular dysfunction with sedentary aging. Lifelong physical activity upregulates antioxidant systems, which may be one of the mechanisms underlying the lack of exercise-induced increase in GSSG.

Redox regulation of E3 ubiquitin ligases and their role in skeletal muscle atrophy.

Muscle atrophy is linked to reactive oxygen species (ROS) production during hindlimb-unloading due, at least in part, to the activation of xanthine oxidase (XO). The major aim of our study was to determine the mechanism by which ROS cause muscle atrophy and its possible prevention by allopurinol, a well-known inhibitor of XO widely used in clinical practice, and indomethacin, a nonsteroidal anti-inflammatory drug. We studied the activation of p38 MAP Kinase and NF-?B pathways, and the expression of two E3 ubiquitin ligases involved in proteolysis, the Muscle atrophy F-Box (MAFb) and Muscle RING Finger-1 (MuRF-1). Male Wistar rats (3 mold) conditioned by 14 days of hindlimb unloading (n=18), with or without the treatment, were compared with freely ambulating controls (n=18). After the experimental intervention, soleus muscles were removed, weighted and analyzed to determine oxidative stress and inflammatory parameters. We found that hindlimb unloading induced a significant increase in XO activity in plasma (39%, p=0.001) and in the protein expression of CuZnSOD and Catalase in skeletal muscle. Inhibitionof XO partially prevented protein carbonylation, both in plasma and in soleus muscle, in the unloaded animals. The most relevant new fact reported is that allopurinol prevents soleus muscle atrophy by ~20% after hindlimb unloading. Combining allopurinol and indomethacin we found a further prevention in the atrophy process. This is mediated by the inhibition of the p38 MAPK-MAFbx and NF-?B -MuRF-1 pathways. Our data point out the potential benefit of allopurinol and indomethacin administration for bedridden, astronauts, sarcopenic and cachexic patients.