bims-meluca 2024-12-15 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2024–12–15
eight papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

Association of baseline plasma D-dimer and platelets with progression-free survival in patients with stage IV non-small cell lung cancer treated with anti-PD-1 antibody.
Image-Based Measures of Obesity are Associated with Alterations in Metabolic Pathways in Non-small Cell Lung Cancer.
GDF15-GFRAL signaling drives weight loss and lipid metabolism in mouse model of amyotrophic lateral sclerosis.
Neutralizing GDF-15 can overcome anti-PD-1 and anti-PD-L1 resistance in solid tumours.
Lactate dehydrogenase B noncanonically promotes ferroptosis defense in KRAS-driven lung cancer.
The Prognostic Value of Preoperative C-Reactive Protein Levels in Resected Early-Stage Lung Cancer.
Are Hyperlipidaemia and Insulin Resistance Risks For Sarcopenia?
The prevalence and prognostic significance of Sarcopenia and Adipopenia in Pleural Mesothelioma.

Transl Lung Cancer Res. 2024 Nov 30. 13(11): 3106-3121

Association of baseline plasma D-dimer and platelets with progression-free survival in patients with stage IV non-small cell lung cancer treated with anti-PD-1 antibody.

Boyue Pang, Jing Wang, Jing Wang, Jiali Zhang, Xiubao Ren, Ying Han.

   Background: In past studies, peripheral blood D-dimer and platelets have shown predictive value in the treatment of non-small cell lung cancer (NSCLC). However, it remains unclear whether pretreatment D-dimer and platelets can serve as biomarkers for predicting efficacy and prognosis in stage IV NSCLC patients without driver gene mutations receiving programmed cell death protein 1 (PD-1) antibody. Therefore, this study aims to investigate the correlation between baseline D-dimer and platelet levels and the efficacy and prognosis in the study population, aiding in determining the significance of baseline D-dimer and platelet levels as biomarkers.
Methods: This study included 150 patients who were newly diagnosed with stage IV NSCLC without driver gene mutations and conducted a retrospective analysis. Among them, 100 patients received first-line treatment with anti-PD-1 plus chemotherapy, while 50 patients received chemotherapy alone (2:1). Basic and clinical information for all patients was collected before treatment. Firstly, the differences in progression-free survival (PFS) and objective response rate (ORR) between the two treatment regimens were compared. Subsequently, the anti-PD-1 plus chemotherapy group and chemotherapy-alone group were analyzed separately, dividing patients into pretreatment high and low D-dimer group, as well as pretreatment high and low platelet group. Kaplan-Meier analysis and Cox proportional hazards models were used to analyze PFS data. Chi-squared tests and logistic regression analysis were employed to evaluate treatment efficacy, specifically ORR differences. All patients were followed up through electronic medical records and telephone, and disease assessment was conducted via imaging examinations, with the follow-up deadline being May 19, 2024.
Results: Kaplan-Meier analysis demonstrated that patients receiving anti-PD-1 plus chemotherapy had longer PFS compared to those receiving chemotherapy alone (median, 8.5 versus 5.5 months; P<0.001). Multivariate Cox regression analysis revealed that first-line chemotherapy (P<0.001), high baseline D-dimer level (P=0.002) and platelet count (P=0.04) were independent risk factors for shorter PFS. Pearson's Chi-squared test showed that the ORR was 46.00% for the anti-PD-1 plus chemotherapy group and 14.00% for the chemotherapy group (P<0.001). In the anti-PD-1 plus chemotherapy group, patients with low baseline D-dimer levels had longer PFS compared to those with high D-dimer level (median, 13.0 versus 8.0 months; P=0.005). Similar results were observed for baseline platelet count (median, 9.5 versus 6.5 months; P=0.005). In this group, no statistically significant differences were found in ORR between high and low D-dimer subgroups or high and low platelet subgroups (P=0.51 for D-dimer subgroups, P=0.87 for platelet subgroups). In the chemotherapy group, no correlation was observed between baseline D-dimer or platelet levels and PFS or ORR.
Conclusions: Pretreatment plasma D-dimer and platelet levels could serve as convenient prognostic biomarkers for stage IV NSCLC patients without driver gene mutations receiving anti-PD-1 antibody. Patients with higher baseline D-dimer and platelet levels might have poor PFS.

Keywords:  D-dimer; biomarkers; non-small cell lung cancer (NSCLC); platelets; progression-free survival (PFS)

DOI:  https://doi.org/10.21037/tlcr-24-763
Ann Surg Oncol. 2024 Dec 13.

Image-Based Measures of Obesity are Associated with Alterations in Metabolic Pathways in Non-small Cell Lung Cancer.

Akhil Goud Pachimatla, Kaylan Gee, Hua-Hsin Hsiao, Sai Yendamuri, Spencer Rosario.

   BACKGROUND: Studies suggest that the obesity paradox in non-small cell lung cancer (NSCLC) results from the use of body mass index (BMI) as a measure of obesity. However, the mechanistic basis linking body fat and lung cancer behavior remains unclear. We examined the association of image-based measures of obesity with tumor gene expression to identify transcriptional signatures concordant with adiposity and their underlying biology.
PATIENTS AND METHODS: RNA-sequencing data for 143 NSCLC tumor samples generated by the ORIEN consortium was compiled with image-based measurements of total fat. Total fat area (TFA) was quantified at the third lumbar vertebra level using computed tomography images and the SliceOmatic software. Differential gene expression analysis was conducted between patients in the highest and lowest TFA tertiles. Utilizing a validated metabolic analysis pipeline, these differences in gene expression were used to enrich dysregulated metabolic pathways crucial in carcinogenesis.
RESULTS: We identified 1154 gene transcripts as differentially expressed (p ≤ 0.05 and log fold change ≥ 0.58) in metabolic pathways of normal physiology as well as cancer growth. Utilizing the metabolic pipeline, we found 58/114 metabolic pathways were significantly enriched (p ≤ 0.05) in the high TFA individuals, some of which are expected in obese individuals (lipids metabolism), and some were novel. Gene set enrichment analysis (GSEA) identified transcriptional alterations to inflammatory mediation, cell-signaling, and cellular respiration pathways based on TFA.
CONCLUSIONS: Image-based measures of adiposity correlate with significant gene expression changes in NSCLC tumors. We have identified altered biological processes associated with obesity, including metabolic vulnerabilities, that can be leveraged in developing new treatment strategies.

Keywords:  Image-based measures; Lung cancer; Metabolic pathways obesity

DOI:  https://doi.org/10.1245/s10434-024-16402-6
Brain Behav Immun. 2024 Dec 11. pii: S0889-1591(24)00739-6. [Epub ahead of print]

GDF15-GFRAL signaling drives weight loss and lipid metabolism in mouse model of amyotrophic lateral sclerosis.

Germana Cocozza, Ludovica Maria Busdraghi, Giuseppina Chece, Antonio Menini, Marco Ceccanti, Laura Libonati, Chiara Cambieri, Francesco Fiorentino, Dante Rotili, Ferdinando Scavizzi, Marcello Raspa, Eleonora Aronica, Maurizio Inghilleri, Stefano Garofalo, Cristina Limatola.

  Weight loss is a common early sign in amyotrophic lateral sclerosis (ALS) patients and negatively correlates with survival. In different cancers and metabolic disorders, high levels of serum growth differentiation factor 15 (GDF15) contribute to a decrease of food intake and body weight, acting through GDNF family receptor alpha-like (GFRAL). Here we report that GDF15 is highly expressed in the peripheral blood of ALS patients and in the hSOD1G93A mouse model and that GFRAL is upregulated in the brainstem of hSOD1G93A mice. We demonstrate that the localized GFRAL silencing by shRNA in the area postrema/nucleus tractus solitarius of hSOD1G93A mice induces weight gain, reduces adipose tissue wasting, ameliorates the motor function and muscle atrophy and prolongs the survival time. We report that microglial cells could be involved in mediating these effects because their depletion with PLX5622 reduces brainstem GDF15 expression, weight loss and the expression of lipolytic genes in adipose tissue. Altogether these results reveal a key role of GDF15-GFRAL signaling in regulating weight loss and the alteration of and lipid metabolism in the early phases of ALS.

Keywords:  Adipose tissue; Feeding behaviour; GDF15; GFRAL; Microglia; Neurodegenerative disease

DOI:  https://doi.org/10.1016/j.bbi.2024.12.010
Nature. 2024 Dec 11.

Neutralizing GDF-15 can overcome anti-PD-1 and anti-PD-L1 resistance in solid tumours.

Ignacio Melero, Maria de Miguel Luken, Guillermo de Velasco, Elena Garralda, Juan Martín-Liberal, Markus Joerger, Guzman Alonso, Maria-Elisabeth Goebeler, Martin Schuler, David König, Reinhard Dummer, Maria Reig, Maria-Esperanza Rodriguez Ruiz, Emiliano Calvo, Jorge Esteban-Villarrubia, Arjun Oberoi, Paula Sabat, Juan José Soto-Castillo, Kira-Lee Koster, Omar Saavedra, Cyrus Sayehli, Tanja Gromke, Heinz Läubli, Egle Ramelyte, Marta Fortuny, Ana Landa-Magdalena, Irene Moreno, Javier Torres-Jiménez, Alberto Hernando-Calvo, Dagmar Hess, Fabricio Racca, Heike Richly, Andreas M Schmitt, Corinne Eggenschwiler, Marco Sanduzzi-Zamparelli, Anna Vilalta-Lacarra, Jörg Trojan, Christine Koch, Peter R Galle, Friedrich Foerster, Zlatko Trajanoski, Hubert Hackl, Falk Gogolla, Florestan J Koll, Peter Wild, Felix Kyoung Hwan Chun, Henning Reis, Peter Lloyd, Matthias Machacek, Thomas F Gajewski, Wolf H Fridman, Alexander M M Eggermont, Ralf Bargou, Sandra Schöniger, Josef Rüschoff, Anastasiia Tereshchenko, Carina Zink, Antonio da Silva, Felix S Lichtenegger, Julia Akdemir, Manfred Rüdiger, Phil L'Huillier, Aradhana Dutta, Markus Haake, Alexandra Auckenthaler, Ana Gjorgjioska, Bernhard Rössler, Frank Hermann, Mara Liebig, Daniela Reichhardt, Christine Schuberth-Wagner, Jörg Wischhusen, Petra Fettes, Marlene Auer, Kathrin Klar, Eugen Leo.

Cancer immunotherapies with antibodies blocking immune checkpoint molecules are clinically active across multiple cancer entities and have markedly improved cancer treatment1. Yet, response rates are still limited, and tumour progression commonly occurs2. Soluble and cell-bound factors in the tumour microenvironment negatively affect cancer immunity. Recently, growth differentiation factor 15 (GDF-15), a cytokine that is abundantly produced by many cancer types, was shown to interfere with antitumour immune response. In preclinical cancer models, GDF-15 blockade synergistically enhanced the efficacy of anti-PD-1-mediated checkpoint inhibition3. In a first-in-human phase 1-2a study (GDFATHER-1/2a trial, NCT04725474 ), patients with advanced cancers refractory to anti-PD-1 or anti-PD-L1 therapy (termed generally as anti-PD-1/PD-L1 refractoriness) were treated with the neutralizing anti-GDF-15 antibody visugromab (CTL-002) in combination with the anti-PD-1 antibody nivolumab. Here we show that durable and deep responses were achieved in some patients with non-squamous non-small cell lung cancer and urothelial cancer, two cancer entities identified as frequently immunosuppressed by GDF-15 in an in silico screening of approximately 10,000 tumour samples in The Cancer Genome Atlas database. Increased levels of tumour infiltration, proliferation, interferon-γ-related signalling and granzyme B expression by cytotoxic T cells were observed in response to treatment. Neutralizing GDF-15 holds promise in overcoming resistance to immune checkpoint inhibition in cancer.

DOI: https://doi.org/10.1038/s41586-024-08305-z
Cell Death Differ. 2024 Dec 07.

Lactate dehydrogenase B noncanonically promotes ferroptosis defense in KRAS-driven lung cancer.

Liang Zhao, Haibin Deng, Jingyi Zhang, Nicola Zamboni, Haitang Yang, Yanyun Gao, Zhang Yang, Duo Xu, Haiqing Zhong, Geert van Geest, Rémy Bruggmann, Qinghua Zhou, Ralph A Schmid, Thomas M Marti, Patrick Dorn, Ren-Wang Peng.

Ferroptosis is an oxidative, non-apoptotic cell death frequently inactivated in cancer, but the underlying mechanisms in oncogene-specific tumors remain poorly understood. Here, we discover that lactate dehydrogenase (LDH) B, but not the closely related LDHA, subunits of active LDH with a known function in glycolysis, noncanonically promotes ferroptosis defense in KRAS-driven lung cancer. Using murine models and human-derived tumor cell lines, we show that LDHB silencing impairs glutathione (GSH) levels and sensitizes cancer cells to blockade of either GSH biosynthesis or utilization by unleashing KRAS-specific, ferroptosis-catalyzed metabolic synthetic lethality, culminating in increased glutamine metabolism, oxidative phosphorylation (OXPHOS) and mitochondrial reactive oxygen species (mitoROS). We further show that LDHB suppression upregulates STAT1, a negative regulator of SLC7A11, thereby reducing SLC7A11-dependent GSH metabolism. Our study uncovers a previously undefined mechanism of ferroptosis resistance involving LDH isoenzymes and provides a novel rationale for exploiting oncogene-specific ferroptosis susceptibility to treat KRAS-driven lung cancer.

DOI: https://doi.org/10.1038/s41418-024-01427-x
J Surg Res. 2024 Dec 10. pii: S0022-4804(24)00722-4. [Epub ahead of print]305 85-92

The Prognostic Value of Preoperative C-Reactive Protein Levels in Resected Early-Stage Lung Cancer.

Alberto Lopez-Pastorini, Zehra Tatli, Antonia von Bargen, Dennis Faltenberg, Hendrik Beling, Thomas Galetin, Aris Koryllos, Erich Stoelben.

   INTRODUCTION: C-reactive protein (CRP) is the most widely used marker of the systemic inflammatory response. An association between preoperative elevated levels and prognosis has been demonstrated for numerous tumors. The aim of this study was to investigate the association between preoperative CRP levels and survival in early-stage nonsmall cell lung cancer.
METHODS: Data from 915 consecutive patients who underwent complete resection for stage I and II nonsmall cell lung cancer were retrospectively analyzed. Recurrence-free survival (RFS) and overall survival (OS) according to preoperative CRP levels were evaluated by the Kaplan-Meier method. The Cox proportional hazards model and logistic regression analysis were used for multivariate analysis.
RESULTS: Five-year RFS and OS were 61.0% and 70.3% in the low CRP group (<4 mg/L) and 41.8% and 49.4% in the high CRP group (≥4 mg/L), respectively (P < 0.001). In univariate analysis, CRP levels were correlated with indicators of tumor burden and pulmonary comorbidity. In multivariate analysis, CRP levels were identified as an independent predictor of RFS and OS.
CONCLUSIONS: Elevated preoperative CRP is associated with poor prognosis in patients with early-stage lung cancer. CRP may guide risk-adapted follow-up and adjuvant therapy decisions. As CRP elevation is also associated with nontumor related conditions patients need to be screened for coexisting comorbidities.

Keywords:  Biomarkers; C-reactive protein; Lung cancer; Prognosis

DOI:  https://doi.org/10.1016/j.jss.2024.11.003
J Coll Physicians Surg Pak. 2024 Dec;34(12): 1473-1477

Are Hyperlipidaemia and Insulin Resistance Risks For Sarcopenia?

Mustafa Tuna, Bilgehan Kolutek Ay, Hatice Incebiyik.

OBJECTIVE: To investigate whether insulin resistance and lipid metabolism disorders could be associated with sarcopenia.
STUDY DESIGN: Cross-sectional descriptive study. Place and Duration of the Study: Department of Physical Medicine and Rehabilitation, Sanliurfa Training and Research Hospital, Sanliurfa, Turkiye, from December 2023 and May 2024.
METHODOLOGY: The study included 135 patients who met the inclusion and exclusion criteria. Data such as age, gender, body mass index (BMI), lipid profile, fasting blood glucose, C-peptide, and insulin levels were collected. Following sarcopenia screening, participants were divided into two groups for further examination, and the correlation between sarcopenia and other parameters was assessed.
RESULTS: BMI levels were significantly higher in the sarcopenia group (p = 0.003). Triglyceride levels were also significantly elevated in the sarcopenia group (p = 0.001). The number of patients with dyslipidaemia in the sarcopenia group was higher compared to the non-sarcopenia group (p = 0.003). Correlation analysis revealed a positive association between sarcopenia and BMI, insulin resistance, high triglyceride levels, and the presence of dyslipidaemia (p = 0.002, p = 0.032, p = 0.002, p = 0.004, respectively).
CONCLUSION: This study suggests that high triglyceride levels may represent a risk factor associated with sarcopenia and that sarcopenia may be associated with conditions such as high BMI, insulin resistance, and dyslipidaemia. Controlling lipid levels could be beneficial in reducing the risk of sarcopenia.
KEY WORDS: Chronic disease, Hyperlipidaemia, Hypertriglyceridaemia, Insulin Resistance, Sarcopenia.

DOI: https://doi.org/10.29271/jcpsp.2024.12.1473
Cancer Treat Res Commun. 2024 Dec 02. pii: S2468-2942(24)00068-6. [Epub ahead of print]42 100856

The prevalence and prognostic significance of Sarcopenia and Adipopenia in Pleural Mesothelioma.

Andrew C Kidd, Gordon W Cowell, Geoffrey A Martin, Jenny Ferguson, Dean A Fennell, Matt Evison, Kevin G Blyth.

   INTRODUCTION: Altered body composition is associated with adverse survival in multiple cancers. We determined the prevalence, prognostic significance and clinicopathological correlates of sarcopenia and adipopenia in Pleural Mesothelioma (PM) patients receiving chemotherapy.
METHODS: We performed a multi-centre retrospective cohort study. Clinical data and CT images were retrieved for 111 patients from 4 UK centres. Skeletal muscle (at L3 and T4) and fat tissue areas (at L3 only) were measured on pre- and post-chemotherapy CT scans (ImageJ software) and normalised for height. Pre-chemotherapy sarcopenia and adipopenia were defined using validated thresholds, where available or indices <25th percentile. Muscle/fat loss were defined by < 0 % change (%∆) between CT scans. Extreme muscle/fat loss were defined by <25th percentile of %∆. Overall survival associations were evaluated using Kaplan-Meier methodology ± Cox proportional hazards models.
RESULTS: T4 and L3 measurements were possible in 111/111 and 91/111 (82 %). L3 sarcopenia was observed at baseline in 35 % (32/91); all other features were observed in 25 % at baseline, as defined a priori. Body composition changes during chemotherapy were heterogeneous. Overall, 61.5 % and 53.1 % patients lost muscle at L3 and T4. 60.4 % lost fat (at L3 only). Extreme T4 muscle loss and total fat loss were independently prognostic (HR 2.99, p < 0.001; HR 1.92, p = 0.014). Pre-chemotherapy T4 muscle indices were inversely associated with age. No associations were observed with tumour volume, histology, weight, inflammatory markers.
CONCLUSION: T4 muscle indices were feasible in all cases and outperformed L3 values in prognostication. Extreme T4 muscle and total fat loss were independently prognostic.

Keywords:  Adipopenia; Cachexia; Mesothelioma; Sarcopenia; Survival

DOI:  https://doi.org/10.1016/j.ctarc.2024.100856