bims-meluca Biomed News
on Metabolism of non-small cell lung carcinoma
Issue of 2024–09–15
nine papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge
  1. The prognosis and metabolite changes of NSCLC patients receiving first-line immunotherapy combined chemotherapy in different M1c categories according to 9th edition of TNM classification.
  2. Dietary Counseling Outcomes in Patients with Lung Cancer in an Upper-Middle-Income Country: An Open-Label Randomized Controlled Trial.
  3. Relationship between energetic gap and sensitivity to anti- programmed cell death 1 immune checkpoint inhibitors in non-small cell lung cancer patients: The ELY-2 Study.
  4. Inflammatory factors and risk of lung adenocarcinoma: a Mendelian randomization study mediated by blood metabolites.
  5. Glycemic Control in Diabetic Patients Improved Overall Lung Cancer Survival across Diverse Populations.
  6. Increasing membrane polyunsaturated fatty acids sensitizes non-small cell lung cancer to anti-PD-1/PD-L1 immunotherapy.
  7. Unraveling the obesity paradox in small cell lung cancer immunotherapy: unveiling prognostic insights through body composition analysis.
  8. The antitumor effect of diisopropylamine dichloroacetate on non-small cell lung cancer and its influence on the tumor immune microenvironment.
  9. Mitochondrial VDAC1 Silencing in Urethane-Induced Lung Cancer Inhibits Tumor Growth and Alters Cancer Oncogenic Properties.
  1. Cancer Med. 2024 Sep;13(17): e70223
    The prognosis and metabolite changes of NSCLC patients receiving first-line immunotherapy combined chemotherapy in different M1c categories according to 9th edition of TNM classification.
    Liang Zheng, Fang Hu, Wei Nie, Jun Lu, Bo Zhang, Jianlin Xu, Shuyuan Wang, Ying Li, Xiaoxuan Zheng, Wei Zhang, Yinchen Shen, Runbo Zhong, Tianqing Chu, Baohui Han, Hua Zhong, Xueyan Zhang.
       BACKGROUND: The 9th edition of the TNM Classification for lung cancer delineates M1c into two subcategories: M1c1 (Multiple extrathoracic lesions within a single organ system) and M1c2 (Multiple extrathoracic lesions involving multiple organ systems). Existing research indicates that patients with lung cancer in stage M1c1 exhibit superior overall survival compared to those in stage M1c2. The primary frontline therapy for patients with advanced non-small cell lung cancer (NSCLC), lacking driver gene mutations, involves the use of immune checkpoint inhibitors (ICIs) combined with chemotherapy. Nevertheless, a dearth of evidence exists regarding potential survival disparities between NSCLC patients with M1c1 and M1c2 undergoing first-line immune-chemotherapy, and reliable biomarkers for predicting treatment outcomes are elusive. Serum metabolic profiles may elucidate distinct prognostic mechanisms, necessitating the identification of divergent metabolites in M1c1 and M1c2 undergoing combination therapy. This study seeks to scrutinize survival discrepancies between various metastatic patterns (M1c1 and M1c2) and pinpoint metabolites associated with treatment outcomes in NSCLC patients undergoing first-line ICIs combined with chemotherapy.
    METHOD: In this study, 33 NSCLC patients lacking driver gene mutations diagnosed with M1c1, and 22 similarly diagnosed with M1c2 according to the 9th edition of TNM Classification, were enrolled. These patients received first-line PD-1 inhibitor plus chemotherapy. The relationship between metastatic patterns and progression-free survival (PFS) in patients undergoing combination therapy was analyzed using univariate and multivariate Cox regression models. Serum samples were obtained from all patients before treatment initiation for untargeted metabolomics analysis, aiming to identify differential metabolites.
    RESULTS: In the univariate analysis of PFS, NSCLC patients in M1c1 receiving first-line PD-1 inhibitor plus chemotherapy exhibited an extended PFS (HR = 0.49, 95% CI, 0.27-0.88, p = 0.017). In multivariate PFS analyses, these M1c1 patients receiving first-line PD-1 inhibitor plus chemotherapy also demonstrated prolonged PFS (HR = 0.45, 95% CI, 0.22-0.92, p = 0.028). The serum metabolic profiles of M1c1 and M1c2 undergoing first-line PD-1 inhibitors plus chemotherapy displayed notable distinctions. In comparison to M1c1 patients, M1c2 patients exhibited alterations in various pathways pretreatment, including platelet activation, linoleic acid metabolism, and the VEGF signaling pathway. Diminished levels of lipid-associated metabolites (diacylglycerol, sphingomyelin) were correlated with adverse outcomes.
    CONCLUSION: NSCLC patients in M1c1, devoid of driver gene mutations, receiving first-line PD-1 inhibitors combined with chemotherapy, experienced superior outcomes compared to M1c2 patients. Moreover, metabolomic profiles strongly correlated with the prognosis of these patients, and M1c2 patients with unfavorable outcomes manifested distinct changes in metabolic pathways before treatment. These changes predominantly involved alterations in lipid metabolism, such as decreased diacylglycerol and sphingomyelin, which may impact tumor migration and invasion.
    Keywords:  9th edition TNM classification; immune‐checkpoint inhibitors; non‐small cell lung cancer; prognosis; untargeted metabolomics
    DOI:  https://doi.org/10.1002/cam4.70223
  2. J Clin Med. 2024 Sep 04. pii: 5236. [Epub ahead of print]13(17):
    Dietary Counseling Outcomes in Patients with Lung Cancer in an Upper-Middle-Income Country: An Open-Label Randomized Controlled Trial.
    Busyamas Chewaskulyong, Haritchanan Malairungsakul, Supawan Buranapin, Panas Jesadaporn, Thanika Ketpueak, Thatthan Suksombooncharoen, Chaiyut Charoentum.
      Background: Malnutrition harms treatment outcomes, QoL, and survival in lung cancer patients. Effective dietary counseling can improve nutrition, but few randomized controlled trials have focused on lung cancer patients. The objective of this study was to determine if dietary counseling improves nutritional and treatment outcomes when compared to routine care. Methods: This open-label parallel RCT was conducted at Maharaj Nakorn Chiang Mai Hospital in Thailand. The investigators used computer-generated blocked randomization to assign patients to dietary counseling by a nutritionist or routine care. The nutritionist sessions occurred before treatment, with follow-ups at 3-4 weeks and 12 weeks. The primary outcome was the mean percentage change in the body weight of patients at 12 weeks. Secondary outcomes included changes in the BMI, nutrition score, QoL, serum albumin level, lymphocyte count, energy and protein intake, treatment response, PFS, and OS. Results: Between April 2020 and May 2022, after completing recruitment, 80 lung cancer patients were randomized: 43 to dietary counseling and 37 to routine care. The dietary counseling group showed significant benefits, with smaller decreases in body weight at 3-4 weeks (-0.8% vs. -2.6%, p = 0.05) and 12 weeks (-1.1% vs. -4.3%, p = 0.05). They also had higher energy and protein intake levels and better treatment response rates. The secondary outcomes and significant adverse events did not differ significantly between the groups. Conclusions: Dietary counseling helps to maintain body weight, maintain dietary intake, and enhance treatment responses in lung cancer patients. Although not all nutritional markers or survival outcomes were affected, these findings highlight the importance of early nutritional interventions.
    Keywords:  dietary counseling; lung cancer; malnutrition; nutritional status
    DOI:  https://doi.org/10.3390/jcm13175236
  3. Clin Nutr ESPEN. 2024 Sep 05. pii: S2405-4577(24)01301-9. [Epub ahead of print]
    Relationship between energetic gap and sensitivity to anti- programmed cell death 1 immune checkpoint inhibitors in non-small cell lung cancer patients: The ELY-2 Study.
    Manuela Tiako Meyo, Pascaline Boudou-Rouquette, Jennifer Arrondeau, Jeanne Qiong Yu Chen, Laure Hirsch, Nathalie Neveux, Elizabeth Fabre, Caroline Guidet, Diane Damotte, Marie Wislez, Jérôme Alexandre, Jean-Philippe Durand, Guillaume Ulmann, François Goldwasser.
       BACKGROUND & AIMS: We previously reported in the ELY prospective study that increased resting energy expenditure (REE) - so-called hypermetabolism - worsened tumor response, 6-month progression-free (PFS) and overall survival (OS) in metastatic non-small cell lung cancer (mNSCLC) patients treated with immune checkpoint inhibitors (ICI). Here, we investigated the effect of caloric coverage on the sensitivity to ICI.
    METHODS: We retrospectively analysed a multicentric database of mNSCLC patients treated with ICI. All patients had a baseline nutritional assessment including REE measured with indirect calorimetry and a dietitian estimation of food intakes. Measured/theoretical REE ≥ 110% defined hypermetabolism. Intakes ≥ 90% of estimated needs defined caloric coverage. The primary endpoint was PFS. Secondary endpoints included response rate and OS.
    RESULTS: Among 162 patients, 84 (51.9%) were normometabolic, and 78 (48.1%) hypermetabolic. In hypermetabolic patients, 40 (51.3%) met their caloric needs (group A) while 38 (48.7%) did not (group B). Median PFS was 4.3 vs. 1.9 months in groups A and B, respectively (HR: 0.49, 95%CI [0.31-0.80], p = 0.004). The PFS achieved in the group A and in normometabolic patients were similar (HR: 0.99, 95%CI [0.65-1.51], p = 0.95). In multivariate analysis, caloric coverage was independently associated with improved PFS in hypermetabolic patients (HR: 0.56, 95%CI [0.31 - 0.99], p = 0.048). Among hypermetabolic patients, the median OS was higher in the group A (HR: 0.58, 95%CI [0.35-0.95], p = 0.03).
    CONCLUSION: Energy supply is a critical determinant of the sensitivity to ICI in NSCLC patients. A randomized study to evaluate the benefit of early nutritional intervention is warranted.
    Keywords:  Basal metabolism; Immunotherapy; Indirect calorimetry; Lung cancer; Survival
    DOI:  https://doi.org/10.1016/j.clnesp.2024.09.002
  4. Front Endocrinol (Lausanne). 2024 ;15 1446863
    Inflammatory factors and risk of lung adenocarcinoma: a Mendelian randomization study mediated by blood metabolites.
    Zheng Ding, Juan Chen, Bohan Li, Xinyu Ji.
       Background: Lung adenocarcinoma (LUAD) is the most common type of lung cancer, and its pathogenesis remains not fully elucidated. Inflammation and metabolic dysregulation are considered to play crucial roles in LUAD development, but their causal relationships and specific mechanisms remain unclear.
    Methods: This study employed a two-sample Mendelian randomization (MR) approach to systematically evaluate the causal associations between 91 circulating inflammatory factors, 1,400 serum metabolites, and LUAD. We utilized LUAD genome-wide association studies (GWAS) data from the FinnGen biobank and GWAS data of metabolites and inflammatory factors from the GWAS catalog to conduct two-sample MR analyses. For the identified key metabolites, we further used mediator MR to investigate their mediating effects in the influence of IL-17A on LUAD and explored potential mechanisms through protein-protein interaction and functional enrichment analyses.
    Results: The MR analyses revealed that IL-17A (OR 0.78, 95%CI 0.62-0.99) was negatively associated with LUAD, while 71 metabolites were significantly associated with LUAD. Among them, ferulic acid 4-sulfate may play a crucial mediating role in the suppression of LUAD by IL-17A (OR 0.87, 95%CI 0.78-0.97). IL-17A may exert its anti-LUAD effects through extensive interactions with genes related to ferulic acid 4-sulfate metabolism (such as SULT1A1, CYP1A1, etc.), inhibiting oxidative stress and inflammatory responses, as well as downstream tumor-related pathways of ferulic acid 4-sulfate (such as MAPK, NF-κB, etc.).
    Conclusion: This study discovered causal associations between IL-17A, multiple serum metabolites, and LUAD occurrence, revealing the key role of inflammatory and metabolic dysregulation in LUAD pathogenesis. Our findings provide new evidence-based medical support for specific inflammatory factors and metabolites as early predictive and risk assessment biomarkers for LUAD, offering important clues for subsequent mechanistic studies and precision medicine applications.
    Keywords:  blood metabolites; causal inference; inflammatory factors; lung adenocarcinoma; mediation analysis; mendelian randomization
    DOI:  https://doi.org/10.3389/fendo.2024.1446863
  5. JNCI Cancer Spectr. 2024 Sep 12. pii: pkae081. [Epub ahead of print]
    Glycemic Control in Diabetic Patients Improved Overall Lung Cancer Survival across Diverse Populations.
    Yi-Hung Wu, Brian Luke, Xiao-Cheng Wu, J Jack Lee, Yong Yi, Samuel C Okpechi, Barry Gause, Paras Mehta, Steven I Sherman, Augusto Ochoa, Ethan Dmitrovsky, Xi Liu.
       BACKGROUND: The consequence of diabetes on lung cancer overall survival (OS) is debated. This retrospective study used two large lung cancer databases to assess comprehensively diabetes effects on lung cancer OS in diverse demographic populations, including health disparity.
    METHODS: The University of Texas MD Anderson Cancer Center database (32,643 lung cancer cases with 11,973 diabetics) was extracted from electronic health records (EHRs) using natural language processing (NLP). Associations were between diabetes and lung cancer prognostic features [age, sex, race, body mass index (BMI), insurance status, smoking, stage, and histopathology]. Hemoglobin A1C (HgbA1c) and glucose levels assessed glycemic control. Validation was with a Louisiana cohort (17,768 lung cancer cases with 4,746 diabetics) enriched for health disparity cases. Kaplan-Meier analysis, log-rank test, multivariable Cox proportional hazard models, and survival tree analyses were employed.
    RESULTS: Lung cancer patients with diabetes exhibited marginally elevated OS or no statistically-significant difference versus non-diabetic patients. When examining OS for two glycemic levels (HgbA1c > 7.0 or glucose > 154 mg/dL versus HgbA1c > 9.0 or glucose > 215 mg/dL), a statistically significant improvement in OS occurred in lung cancers with controlled versus uncontrolled glycemia (P < 0.0001). This improvement spanned gender, age, smoking status, insurance status, stage, race, BMI, histopathology and therapy. Survival tree analysis revealed that obese and morbidly obese patients with controlled glycemia or no known diabetes had higher lung cancer OS than comparison groups.
    CONCLUSION: These findings indicate a need for optimal glycemic control to improve lung cancer OS in diverse populations with diabetes.
    Keywords:  and health disparity; body mass index; diabetes; diversity; lung cancer; overall survival
    DOI:  https://doi.org/10.1093/jncics/pkae081
  6. Cancer Lett. 2024 Sep 06. pii: S0304-3835(24)00616-5. [Epub ahead of print]604 217221
    Increasing membrane polyunsaturated fatty acids sensitizes non-small cell lung cancer to anti-PD-1/PD-L1 immunotherapy.
    Sofia La Vecchia, Simona Fontana, Iris Chiara Salaroglio, Dario Pasquale Anobile, Sabrina Digiovanni, Muhlis Akman, Niloufar Jafari, Martina Godel, Costanzo Costamagna, Cyril Corbet, Joanna Kopecka, Chiara Riganti.
      Immune checkpoints inhibitors (ICIs) as anti-PD-1/anti-PD-L1 have been approved as first-line treatment in patients with non-small cell lung cancer (NSCLC), but only 25 % of patients achieve durable response. We previously unveiled that estrogen receptor α transcriptionally up-regulates PD-L1 and aromatase inhibitors such as letrozole increase the efficacy of pembrolizumab. Here we investigated if letrozole may have additional immune-sensitizing mechanisms. We found that higher the level of PD-L1 in NSCLC, higher the activation of SREBP1c that transcriptionally increases fatty acid synthase and stearoyl-CoA desaturase enzymes, increasing the amount of polyunsaturated fatty acids (PUFAs). Letrozole further up-regulated SREBP1c-mediated transcription of lipogenic genes, and increased the amount of PUFAs, thereby leading to greater membrane fluidity and reduced binding between PD-L1 and PD-1. The same effects were observed upon supplementation with ω3-PUFA docosahexaenoic acid (DHA) that enhanced the efficacy of pembrolizumab in humanized NSCLC immune-xenografts. We suggest that PUFA enrichment in membrane phospholipids improves the efficacy of ICIs. We propose to repurpose letrozole or DHA as new immune-sensitizing agents in NSCLC.
    Keywords:  Docosahexaenoic acid; Immune checkpoints inhibitors; Letrozole; Non-small cell lung cancer; Phospholipidome
    DOI:  https://doi.org/10.1016/j.canlet.2024.217221
  7. Front Immunol. 2024 ;15 1439877
    Unraveling the obesity paradox in small cell lung cancer immunotherapy: unveiling prognostic insights through body composition analysis.
    Ruoxin Fang, Ling Yan, Sha Xu, Yuchen Xu, Tian Gan, Jun Gong, Junhong Zhang, Conghua Xie, Zhengkai Liao.
       Background: The advent of immunotherapy has changed the landscape of SCLC treatment, although the identification of reliable prognostic biomarkers remains a formidable challenge. Our objective was to investigate the prognostic implications of obesity and body composition in SCLC immunotherapy while seeking a straightforward anthropometric measure.
    Methods: This retrospective study analyzed data from patients with SCLC who underwent immunotherapy between 2019 and 2023. Body composition and waist circumference (WC) were analyzed using 3D slicer software on baseline CT images. Quantitative measures, including skeletal muscle index (SMI), total adipose tissue index (TATI), and other indicators at the L3 level, along with body shape index (BSI) and additional indicators based on WC, were obtained. The relationships between these indicators, response, PFS, OS, and their interconnections were examined.
    Results: A total of 145 SCLC patients who received immunotherapy were identified, of whom 133 met the inclusion criteria. In univariate analysis, a BMI≥28 kg/m2 was associated with a PFS advantage (HR 0.42, p=0.04), but this trend vanished in multivariate analysis. Body measurements exhibited stronger correlations with adipose tissue content, with BSI showing the highest correlation with muscle. In multivariate analysis, lower BSI was associated with poorer OS (HR 1.79, p=0.02). The association between muscle composition and prognosis was robust in univariate analysis but dissipated in multivariate analysis. However, accounting for a high TATI background significantly heightened the adverse effect of SMI on prognosis in the multivariate model.
    Conclusion: No clear association between BMI and SCLC immunotherapy prognosis was observed. However, high adiposity exacerbated the adverse effects of sarcopenia in SCLC immunotherapy, and BSI demonstrated potential as a straightforward prognostic measure.
    Keywords:  body mass index; immunotherapy; obesity; sarcopenia; small cell lung cancer
    DOI:  https://doi.org/10.3389/fimmu.2024.1439877
  8. Front Oncol. 2024 ;14 1447828
    The antitumor effect of diisopropylamine dichloroacetate on non-small cell lung cancer and its influence on the tumor immune microenvironment.
    Min Wei, Xiaoyan Shen, Ye Liu, Xiaotong Chen, Shu Su, Xin Lv, Xiaoping Qian, Lixia Yu, Lifeng Wang.
       Objective: To evaluate the antitumor effects of diisopropylamine dichloroacetate (DADA) alone or in combination with chemotherapy/radiotherapy/immunotherapy in NSCLC and explore the underlying mechanisms involved.
    Methods: MTT, UV spectrophotometry, flow cytometry, fluorescence microscopy, and clonogenic survival assays were used. In LLC mouse models, the antitumor effects of radiotherapy, DADA, and the anti-PD-1 antibody alone or in combination were evaluated, and the T cell numbers were evaluated in different groups.
    Results: DADA significantly inhibited lactate production and promoted apoptosis in NSCLC in vitro. Compared with pemetrexed or DADA alone, the combination of DADA with pemetrexed significantly inhibited proliferation and promoted apoptosis (p<0.05). This may be related to the decrease in the mitochondrial membrane potential in the combined group. Moreover, compared with radiotherapy alone, the combination of DADA with radiotherapy induced remarkable DNA damage. In vivo, the combination of radiotherapy, an anti-PD-1 antibody and DADA resulted in superior tumor inhibition than the combination of radiotherapy and anti-PD-1 antibody did (p < 0.05). The underlying mechanism may be partially related to the increased number of CD3+ T cells in the triplet combination group (p < 0.05).
    Discussion: Our results showed that DADA has strong antitumor effects on NSCLC, either alone or in combination with chemotherapy or radiotherapy. Interestingly, the combination of radiotherapy, anti-PD-1 antibody and DADA had a more pronounced tumor-suppressing effect, which may be related to DADA-induced T-cell generation by reducing local lactic acid production in the tumor microenvironment. This study lays the foundation for further exploration of DADA in lung cancer, especially in the era of immunotherapy, on the basis of its possible immunomodulatory effects.
    Keywords:  DADA; non-small cell lung cancer; pemetrexed; radiotherapy sensitization; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2024.1447828
  9. Cancers (Basel). 2024 Aug 26. pii: 2970. [Epub ahead of print]16(17):
    Mitochondrial VDAC1 Silencing in Urethane-Induced Lung Cancer Inhibits Tumor Growth and Alters Cancer Oncogenic Properties.
    Nataly Melnikov, Srinivas Pittala, Anna Shteinfer-Kuzmine, Varda Shoshan-Barmatz.
      Alterations in cellular metabolism are vital for cancer cell growth and motility. Here, we focused on metabolic reprogramming and changes in tumor hallmarks in lung cancer by silencing the expression of the mitochondrial gatekeeper VDAC1. To better mimic the clinical situation of lung cancer, we induced lung cancer in A/J mice using the carcinogen urethane and examined the effectiveness of si-m/hVDAC1-B encapsulated in PLGA-PEI nanoparticles. si-m/hVDAC1-B, given intravenously, induced metabolism reprogramming and inhibited tumor growth as monitored using MRI. Mice treated with non-targeted (NT) PLGA-PEI-si-NT showed many large size tumors in the lungs, while in PLGA-PEI-si-m/hVDAC-B-treated mice, lung tumor number and area were markedly decreased. Immunofluorescence staining showed decreased expression of VDAC1 and metabolism-related proteins and altered expression of cancer stem cell markers. Morphological analysis showed two types of tumors differing in their morphology; cell size and organization within the tumor. Based on specific markers, the two tumor types were identified as small cell (SCLC) and non-small cell (NSCLC) lung cancer. These two types of tumors were found only in control tumors, suggesting that PLGA-PEI-si-m/hVDAC1-B also targeted SCLC. Indeed, using a xenograft mouse model of human-derived SCLC H69 cells, si-m/hVDAC1-B inhibited tumor growth and reduced the expression of VDAC1 and energy- and metabolism-related enzymes, and of cancer stem cells in the established xenograft. Additionally, intravenous treatment of urethane-induced lung cancer mice with the VDAC1-based peptide, Retro-Tf-D-LP4, showed inhibition of tumor growth, and decreased expression levels of metabolism- and cancer stem cells-related proteins. Thus, silencing VDAC1 targeting both NSCLC and SCLC points to si-VDAC1 as a possible therapeutic tool to treat these lung cancer types. This is important as target NSCLC tumors undergo transformation to SCLC.
    Keywords:  Metabolism; Mitochondria; VDAC1; apoptosis; cancer; cancer stem cells; lung cancer
    DOI:  https://doi.org/10.3390/cancers16172970
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