bims-meluca 2023-10-15 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2023–10–15
seven papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

Combined inhibition of pyruvate dehydrogenase kinase 1 and lactate dehydrogenase a induces metabolic and signaling reprogramming and enhances lung adenocarcinoma cell killing.
Male sex and pretreatment weight loss are associated with poor outcome in patients with advanced non-small cell lung cancer treated with immunotherapy: a retrospective study.
The influence of plasma sPD-L1 concentration on the effectiveness of immunotherapy in advanced NSCLC patients.
Blood Immune Cells as Biomarkers in Long-Term Surviving Patients with Advanced Non-Small-Cell Lung Cancer Undergoing a Combined Immune/Chemotherapy.
EFFECT OF LACTATE DEHYDROGENASE INHIBITION BY OXAMATE ON LEWIS LUNG CARCINOMA CELLS WITH DIFFERENT METASTATIC POTENTIAL.
Factors associated with early discontinuation of anamorelin in patients with cancer-associated cachexia.
SLC17A9 as a prognostic biomarker correlated with immune infiltrates in human non-small cell lung cancer.

Cancer Lett. 2023 Oct 05. pii: S0304-3835(23)00376-2. [Epub ahead of print] 216425

Combined inhibition of pyruvate dehydrogenase kinase 1 and lactate dehydrogenase a induces metabolic and signaling reprogramming and enhances lung adenocarcinoma cell killing.

Yan Zhou, Yizhen Guo, Maoxin Ran, Wenying Shan, Carlotta Granchi, Elisa Giovannetti, Filippo Minutolo, Godefridus J Peters, Kin Yip Tam.

  Lung adenocarcinoma (LUAD) is one of the most prevalent and aggressive types of lung cancer. Metabolic reprogramming plays a critical role in the development and progression of LUAD. Pyruvate dehydrogenase kinase 1 (PDK1) and lactate dehydrogenase A (LDHA) are two key enzymes involved in glucose metabolism, whilst their aberrant expressions are often associated with tumorigenesis. Herein, we investigated the anticancer effects of combined inhibition of PDK1 and LDHA in LUAD in vitro and in vivo and its underlying mechanisms of action. The combination of a PDK1 inhibitor, 64, and a LDHA inhibitor, NHI-Glc-2, led to a synergistic growth inhibition in 3 different LUAD cell lines and more than additively suppressed tumor growth in the LUAD xenograft H1975 model. This combination also inhibited cellular migration and colony formation, while it induced a metabolic shift from glycolysis to oxidative phosphorylation (OXPHOS) resulting in mitochondrial depolarization and apoptosis in LUAD cells. These effects were related to modulation of multiple cell signaling pathways, including AMPK, RAS/ERK, and AKT/mTOR. Our findings demonstrate that simultaneous inhibition of multiple glycolytic enzymes (PDK1 and LDHA) is a promising novel therapeutic approach for LUAD.

Keywords:  Anticancer; Combination treatment; Non-small cell lung cancer; Warburg effect

DOI:  https://doi.org/10.1016/j.canlet.2023.216425
Sci Rep. 2023 10 09. 13(1): 17047

Male sex and pretreatment weight loss are associated with poor outcome in patients with advanced non-small cell lung cancer treated with immunotherapy: a retrospective study.

Jingxiao Jin, Jacqueline Visina, Timothy F Burns, Brenda Diergaarde, Laura P Stabile.

The influence of sex and body mass index (BMI) on the efficacy of immune checkpoint inhibitors (ICIs) in advanced non-small cell lung cancer (NSCLC) patients remains unclear. We conducted a retrospective study to evaluate the relationship between sex, BMI, pretreatment weight loss (PWL), and clinical outcomes in 399 stage IV NSCLC patients treated with ICIs using data abstracted from medical records. Multivariable Cox proportional hazards models were used to assess the impact on overall survival and progression-free survival. Females were significantly more likely to experience immune-related adverse events and had a significantly lower risk of death compared to males in our patient cohort. In stratified analyses, the latter was limited to those receiving first-line monotherapy. BMI was overall not significantly associated with outcome. However, underweight patients had a significantly higher risk of both progression and death compared to normal weight patients in the first-line monotherapy group. When stratified by sex, underweight males had a significantly higher risk of progression and death compared to normal weight males. This was not observed among females. Those with PWL had overall significantly worse outcomes compared to those without. In stratified analyses, PWL was associated with significantly worse OS in both females and males. Stratified by treatment, the worse outcome was limited to those receiving ICI monotherapy. In summary, utilizing real-world data, this study suggests that male sex, being underweight, and PWL negatively impact ICI efficacy in NSCLC patients. Therapeutic approaches to improve ICI outcomes in underweight patients and those with PWL should be investigated.

DOI: https://doi.org/10.1038/s41598-023-43866-5
Cancer Immunol Immunother. 2023 Oct 10.

The influence of plasma sPD-L1 concentration on the effectiveness of immunotherapy in advanced NSCLC patients.

Izabela Chmielewska, Anna Grenda, Paweł Krawczyk, Małgorzata Frąk, Barbara Kuźnar Kamińska, Weronika Mitura, Janusz Milanowski.

   INTRODUCTION: PD-L1 (Programmed Cell Death Ligand 1) is currently the only recognised marker of response to immunotherapy with anti-PD-1 or anti-PD-L1 antibodies in patients with advanced non-small cell lung cancer (NSCLC). However, this marker is not perfect. Soluble PD-L1 (sPD-L1) may be a novel predictor of immunotherapy efficacy in NSCLC patients.
MATERIAL AND METHODS: We enrolled 120 patients (median age 68 ± 6.81 years, 70 males and 50 females) with locally advanced (stage IIIB; 10 patients) or advanced (stage IV; 110 patients) NSCLC. PD-L1 expression in tumour cells was assessed by immunohistochemistry (IHC) in 117 (97.5%) patients. The soluble PD-L1 concentration in plasma samples was measured using enzyme-linked immunosorbent assay (ELISA). The response to immunotherapy, progression-free survival (PFS), and overall survival (OS), calculated from the start of immunotherapy, were assessed in 119 patients.
RESULTS: Patients with disease control had significantly lower (p = 0.0006) concentrations of sPD-L1 in blood plasma than patients with progression during the first months of immunotherapy or chemoimmunotherapy Patients with ≥ 6 month progression-free survival had a significantly higher (p = 0.013) percentage of tumor cells with PD-L1 expression than patients with shorter PFS. Patients with ≥ 6 months OS had significantly lower (p = 0.0142) plasma sPD-L1 concentrations than those with shorter overall survival. The median PFS was significantly higher in patients with low sPD-L1 concentrations than in those with high concentrations of this protein (5.8 vs. 2.5 months, HR = 0.6021, p = 0.0156). Similarly, patients with low sPD-L1 levels had a significantly higher median overall survival than those with sPD-L1 levels above the median (16.5 vs. 7 months, HR = 0.5354, p = 0.0071). There was no significant correlation between the percentage of tumour cells expressing PD-L1 and the concentration of sPD-L1 in the blood plasma.
CONCLUSION: High sPD-L1 concentration is a negative predictor of immunotherapy efficacy in patients with NSCLC. It is worthwhile to determine sPD-L1 concentration to predict the risk of resistance to anti-PD-1 or anti-PD-L1 antibodies with greater certainty.

Keywords:  Immunotherapy; Non-small cell lung cancer; PD-L1; Soluble PD-L1

DOI:  https://doi.org/10.1007/s00262-023-03552-x
Cancers (Basel). 2023 Oct 06. pii: 4873. [Epub ahead of print]15(19):

Blood Immune Cells as Biomarkers in Long-Term Surviving Patients with Advanced Non-Small-Cell Lung Cancer Undergoing a Combined Immune/Chemotherapy.

Miriam Möller, Wolfgang Schütte, Steffi Turzer, Barbara Seliger, Dagmar Riemann.

  An important challenge remains in identifying the baseline characteristics of cancer patients who will mostly benefit from immune checkpoint inhibitor (ICI) therapies. Furthermore, biomarkers could help in the choice of an optimal therapy duration after a primary therapy response. In this pilot study, the time courses of four different immune cell parameters were followed in 12 patients with advanced non-small-cell lung cancer (NSCLC) undergoing ICI therapy combined with chemotherapy and surviving at least 12 months. Blood was collected at the time point of the first and third antibody administration, as well as after 12 months of patients' survival. Using multi-color flow cytometry, two suppressive markers (neutrophil/lymphocyte ratio (NLR) and the frequency of circulating HLA-DRlow monocytes), as well as two markers of an ongoing immune response (6-Sulfo LacNAc (slan)+ non-classical monocytes and dendritic cell (DC) subtypes), were determined. In most of those who survived > 12 months, a low NLR and a low number of HLA-DRlow monocytes combined with clearly detectable numbers of slan+ non-classical monocytes and of DC subtypes were seen. Two of the patients had an increase in the suppressive markers paired with a decrease in slan+ non-classical monocytes and in DC subtypes, which, in at least one patient, was the correlate of an ongoing clinical progression. Our results implicate that the NLR, specific subtypes of monocytes, and the number of blood DCs might be useful predictive biomarkers for cancer patients during long-term treatment with ICI/chemotherapy.

Keywords:  HLA-DRlow monocytes; biomarkers; dendritic cells; immune checkpoint blockade; long-term survival; neutrophil/lymphocyte ratio; non-small-cell lung cancer; slan+ non-classical monocytes

DOI:  https://doi.org/10.3390/cancers15194873
Exp Oncol. 2023 Oct 11. 45(2): 242-251

EFFECT OF LACTATE DEHYDROGENASE INHIBITION BY OXAMATE ON LEWIS LUNG CARCINOMA CELLS WITH DIFFERENT METASTATIC POTENTIAL.

D L Kolesnik, I V Prokhorova, O N Pyaskovskaya, G I Solyanik.

BACKGROUND: Today, the ability for metabolic reprogramming is considered one of the distinguishing features of metastatically active tumor cells, a classic example of which is aerobic glycolysis. Despite a large number of studies in this direction, the question of the relationship between the intensity of aerobic glycolysis and the metastatic potential of tumor cells remains almost completely open. The work aimed to investigate the effect of the lactate dehydrogenase (LDH) inhibitor on the viability and several characteristics of Lewis lung carcinoma cells with different metastatic potential.
MATERIALS AND METHODS: High-metastatic (LLC) and low-metastatic (LLC/R9) variants of Lewis lung carcinoma cells were used. After 24 h of tumor cells incubation with or without 40 mM sodium oxamate, cell viability, the concentration of glucose and lactate in the incubation medium, distribution of cells by the cell cycle phases, and intracellular ROS production were estimated.
RESULTS: It was revealed that regardless of the metastatic potential, LLC cells are heterogeneous in terms of both the involvement of aerobic glycolysis in their growth and survival processes and the sensitivity to the cytotoxic/cytostatic action of an LDH inhibitor. 35% of cells of either LLC variant form an oxamate-resistant subpopulation while 65% are oxamate-sensitive. The rate of glucose consumption of LLC/R9 cells in the absence of oxamate is almost twice higher compared to LLC and, as a result, the sensitivity of these cells to the cytotoxic/cytostatic effect of oxamate also is significantly higher (the IC50 for LLC/R9 cells is by 35.8% lower than that for LLC cells, p < 0.05). Approximately one-third of the cells of both LLC and LLC/R9 variants can survive and proliferate when aerobic glycolysis is completely inhibited by oxamate. This indicates metabolic reprogramming (either pre-existing or dynamically arising in response to inhibition of glycolysis) of this subpopulation of cells, within which not only the survival of cells but also their proliferative activity is most likely based on glutamine metabolism.
CONCLUSIONS: Such metabolic heterogeneity of metastatically active cells indicates that inhibition of glycolysis as monotherapy is insufficient for effective antimetastatic therapy. Presumably, more effective would be to involve various inhibitors of metabolic processes that ensure the metabolic plasticity of metastatic cells.

DOI: https://doi.org/10.15407/exp-oncology.2023.02.242
Support Care Cancer. 2023 Oct 10. 31(12): 621

Factors associated with early discontinuation of anamorelin in patients with cancer-associated cachexia.

Ikuto Tsukiyama, Takashi Iwata, Tomoko Takeuchi, Ryoko Inuzuka Kato, Masaki Sakuma, Sumiyo Tsukiyama, Mana Kato, Yoshiaki Ikeda, Wataru Ohashi, Akihito Kubo, Naoharu Mori.

   PURPOSE: Cancer-associated cachexia, a multifactorial syndrome involving loss of muscle mass and anorexia, is an unremitting problem for cancer patients. Anamorelin has become available for cancer-associated cachexia, but early discontinuation is common in clinical practice. This study aimed to explore factors related to the early discontinuation of anamorelin and its relationship to survival.
PATIENTS AND METHODS: This prospective, observational study of multimodal clinical practice involved patients who took anamorelin (100 mg) for cancer-associated cachexia at Aichi Medical University Hospital between 14 May 2021 and 31 March 2022. In July 2022, clinical data were extracted from electronic clinical records. Patients who discontinued anamorelin less than 4 weeks after initiation were defined as the early discontinuation group, and their clinical data and survival time were compared with those of the continuation group. This study was approved by the Ethics Committee of the university (approval no. 2021-124).
RESULTS: Of the 42 patients treated with anamorelin, 40 (median age 72.5 years, median BMI 18.7 kg/m2) were analyzed, including 13 with non-small cell lung cancer, and 12 with pancreatic, 8 with colorectal, and 7 with gastric cancers. On univariate analysis, the early discontinuation group included more patients with worse performance status (PS) (p=0.028), low prognostic nutritional index (PNI) (p=0.001), and no concomitant anticancer drugs (p=0.003). On multivariate analysis, PS and PNI were related to anamorelin continuation. Survival time was significantly shorter in the early discontinuation group (p=0.039).
CONCLUSION: Worse PS and low PNI were associated with early discontinuation of anamorelin. Longer survival time was observed in the continuation group.

Keywords:  Anamorelin; Cancer-associated cachexia; Early discontinuation; Performance status; Prognostic nutrition index; Risk factor

DOI:  https://doi.org/10.1007/s00520-023-08097-4
Am J Cancer Res. 2023 ;13(9): 3963-3982

SLC17A9 as a prognostic biomarker correlated with immune infiltrates in human non-small cell lung cancer.

Yan Gao, Yijia Chen, Min Liu, Daobing Zeng, Fan Tan, Huabing Wan, Xusheng Liu, Shanchun Su, Yaohua Zhang, Yu Zhang, Changbin Ke, Zhijun Pei.

The vesicular nucleotide transporter (SLC17A9) has been overexpressed in various cancers. Nonetheless, little is known about its influence on non-small cell lung cancer (NSCLC), including human lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). Integrative bioinformatics analysis was performed to investigate the prognostic significance and underlying mechanisms of SLC17A9 in patients with NSCLC. Here, we found that SLC17A9 up-regulation was significantly correlated with overall survival in LUAD and LUSC (P < 0.05). Gene set enrichment analysis and protein-protein interaction results revealed that SLC17A9 up-regulation was linked to metabolic process, the hallmark of MYC targets, DNA repair, coagulation and complement. SLC17A9 expression was negatively associated with overall survival and positively related to most LUSC immune cells and immunoinhibitor (20/23), particularly immuno A2aR, PD-1, and CTLA-4 (P < 0.001). High SLC17A9 was associated with infiltrating levels of B cells, CD4+ T cells, M1 macrophages, and T cell exhaustion checkpoints such as PD-1, CTLA4, and LAG3 in LUAD. Moreover, Real-time PCR, MTS assay, EdU assay, ATP production assays and cell cycle analysis were performed to validate SLC17A9 knockdown in LUAD cells. SLC17A9 knockdown significantly inhibited cell proliferation and ATP levels by affecting P2X1, Cytochrome C, and STAT3 expression in lung cancer cells. In conclusion, the present study suggested that SLC17A9 could potentially serve as a prognostic biomarker and correlated with immune infiltrates in LUAD and LUSC.

Keywords: SLC17A9; immune infiltrates; lung adenocarcinoma; lung squamous cell carcinoma; prognosis