bims-meluca Biomed News
on Metabolism of non-small cell lung carcinoma
Issue of 2024–12–08
two papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge
  1. Mitochondrial Metabolism as a Potential Novel Therapeutic Target for Lung Adenocarcinoma.
  2. Efficacy and safety of combining anti-angiogenic therapy, radiotherapy, and PD-1 inhibitors in patients with driver gene-negative non-small cell lung cancer brain metastases: a retrospective study.
  1. Anticancer Res. 2024 Dec;44(12): 5241-5252
    Mitochondrial Metabolism as a Potential Novel Therapeutic Target for Lung Adenocarcinoma.
    Makoto Fujiwara, Takahiro Mimae, Kei Kushitani, Norifumi Tsubokawa, Yoshihiro Miyata, Yukio Takeshima, Morihito Okada.
       BACKGROUND/AIM: Oxidative phosphorylation (OXPHOS) is implicated in cancer progression and metastasis. However, its role in lung adenocarcinoma (LUAD) is unknown. We assessed OXPHOS in LUAD cases and cell lines and investigated the effect of OXPHOS inhibition on LUAD cells.
    MATERIALS AND METHODS: The cases with high expression of OXPHOS-related genes and peroxisome proliferator-activated receptor gamma (PPAR-γ) were extracted using RNA-seq data from The Cancer Genome Atlas (TCGA) LUAD dataset and the clinicopathological features and survival were assessed. Resected LUAD specimens were stained for PPAR-γ. Real-time qPCR and western blot were used to examine the expression of OXPHOS- and glycolysis-related genes and proteins in four LUAD cell lines. Cell proliferation was evaluated in LUAD cells treated with OXPHOS inhibitors.
    RESULTS: The TCGA database analysis revealed that cases with high OXPHOS or PPAR-γ expression had a worse prognosis (p=0.07 and p=0.01, respectively). High OXPHOS cases were associated with lymph node metastasis (p<0.01). PPAR-γ was expressed only in the peripheral area of the papillary component of LUAD. We identified A549, HTB181 and H322 as OXPHOS-high type cells and H596 as OXPHOS-low type cells. Oligomycin treatment inhibited cell proliferation in the OXHOS-high cells (0.72-, 0.69-, and 0.77- fold change in oligomycin vs. DMSO, for A549, HTB181, and H322 cells, respectively, p<0.01) but not in the OXPHOS-low cells.
    CONCLUSION: High expression of OXPHOS-related genes and PPAR-γ is a poor prognostic factor in LUAD. The levels of OXPHOS vary among cases and within different areas of the tumor. Targeting OXPHOS metabolism may represent a novel therapeutic approach for treating LUAD.
    Keywords:  Lung neoplasms; adenocarcinoma of lung; oxidative phosphorylation; therapeutics
    DOI:  https://doi.org/10.21873/anticanres.17352
  2. BMC Cancer. 2024 Dec 03. 24(1): 1492
    Efficacy and safety of combining anti-angiogenic therapy, radiotherapy, and PD-1 inhibitors in patients with driver gene-negative non-small cell lung cancer brain metastases: a retrospective study.
    Xianwen Zhang, Qian Sun, Rujun Chen, MengDie Zhao, Feng Cai, Zhen Cui, Hao Jiang.
       BACKGROUND: The efficacy and safety of anti-angiogenic combination therapy in patients with driver gene-negative non-small cell lung cancer (NSCLC) with brain metastases (BM) are uncertain.
    METHODS: Eighty-eight records of driver gene-negative patients with NSCLC treated with craniocerebral radiotherapy (RT) and programmed death factor-1 (PD-1) inhibitors between May 2021 and May 2023 were collected. Based on whether anti-angiogenic therapy (AT) is combined or not, patients are categorized into the AT group and the non anti-angiogenic therapy (NAT) group. The NAT group patients received craniocerebral RT and PD-1 inhibitor and those in the AT group received craniocerebral RT and PD-1 inhibitor with ≥ 4 cycles of AT. Comparing the clinical efficacy and safety in these two patient cohorts was the main goal of the study.
    RESULTS: By May 1, 2024, the iORR was 94.0% and 63.2% for AT and NAT group, respectively. The 1- and 2-year iLPFS for AT and NAT group were 93.6%, 80.9% and 69.7%, 36.4%, respectively. The 1- and 2-year iDPFS were 86.7%, 56.3% and 59.1%, 48.3%, respectively. The 1- and 2-year OS were 82.0%, 36.6% and 68.4%, 34.6%, respectively. Compared to the standard treatment (RT and PD-1 inhibitors), the addition of AT prolonged the median iLPFS (NR vs. 22.0 months, hazard ratio [HR] = 11.004, P < 0.001) and the median iDPFS (NR vs. 20.0 months, HR = 8.732, P = 0.003), but was not significant in the extension of the OS (21.0 vs. 19.0 months, HR = 1.601, P = 0.206). Multivariable analysis showed that combination therapy with AT is significantly associated with prolonged iLPFS (HR = 4.233, P = 0.002) and iDPFS (HR = 2.824, P = 0.007), whereas only GPA score is significantly associated with improved OS (HR = 0.589, P = 0.019). The incidence of hypertension in the AT group showed an increasing trend, and no significant increased risk of radiation-induced brain necrosis was found. No drug-related intracranial hemorrhage events occurred.
    CONCLUSION: Combining AT, RT, and PD-1 inhibitors can substantially improve iLPFS and iDPFS for patients with driver gene-negative NSCLC with BM; however, it is not significantly associated with better OS.
    Keywords:  Anti-angiogenic therapy; Brain metastases; Non-small cell lung cancer; Programmed death factor-1 inhibitors; Radiotherapy
    DOI:  https://doi.org/10.1186/s12885-024-13264-9
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