bims-meluca 2023-02-12 papers

Nucl Med Commun. 2023 Feb 09.

Usefulness of 18F-FDG PET/computed tomography metabolic parameters in predicting sarcopenia and prognosis of treatment-naive patients with non-small cell lung cancer.

Dongjiang Li, Xiaoyue Tan, Hui Yuan, Xinchao Yao, Xiaolin Sun, Li He, Lei Jiang.

PURPOSE: Sarcopenia tremendously impacts the quality of life but remains debatable in prognostication in treatment-naive patients with non-small cell lung cancer (NSCLC). Hence, this study aimed to find a clinically feasible approach using 18F-FDG PET/computed tomography (CT) imaging parameters and clinical characteristics to predict sarcopenia and determine independent prognostic factors.METHODS: Clinical characteristics and 18F-FDG PET/CT metabolic parameters, including maximum standard uptake value, metabolic tumor volume, and total lesion glycolysis of primary tumor (SUVmax_P, MTV_P, and TLG_P) and combination of whole-body lesions (MTV_C and TLG_C) were collected in 344 treatment-naive patients with NSCLC. Skeletal muscle index at the third lumbar vertebra was calculated to determine sarcopenia. SUVmax of the psoas major muscle (SUVmax_M) was measured at the third lumbar vertebra as well. The diagnostic endpoint is the probability of sarcopenia, and the survival endpoints include progression-free survival (PFS) and overall survival (OS).
RESULTS: Among 344 patients with NSCLC there were 271 patients with adenocarcinoma and 73 with squamous cell carcinoma (SCC). One hundred forty-seven patients (42.7%) were diagnosed with sarcopenia. Higher age, male, lower BMI, SCC, and lower SUVmax_M were correlated with a higher incidence of sarcopenia (P < 0.05), while age, sex and SUVmax_M were independently predictive of sarcopenia. Multivariate Cox-regression analysis revealed that BMI, advanced stage and TLG_C were independent predictors of PFS and OS, while sex was independently predictive of OS.
CONCLUSIONS: The incidence of sarcopenia increased with declining SUVmax of muscle. BMI, tumor stage, and TLG_C, but not sarcopenia, were found independently predictive of both PFS and OS.

DOI: https://doi.org/10.1097/MNM.0000000000001669

Cancers (Basel). 2023 Jan 29. pii: 834. [Epub ahead of print]15(3):

Kynureninase Upregulation Is a Prominent Feature of NFR2-Activated Cancers and Is Associated with Tumor Immunosuppression and Poor Prognosis.

Ricardo A León-Letelier, Ali H Abdel Sater, Yihui Chen, Soyoung Park, Ranran Wu, Ehsan Irajizad, Jennifer B Dennison, Hiroyuki Katayama, Jody V Vykoukal, Samir Hanash, Edwin J Ostrin, Johannes F Fahrmann.

The nuclear factor erythroid 2-related factor 2 (NRF2) pathway is frequently activated in various cancer types. Aberrant activation of NRF2 in cancer is attributed to gain-of-function mutations in the NRF2-encoding gene NFE2L2 or a loss of function of its suppressor, Kelch-like ECH-associated protein 1 (KEAP1). NRF2 activation exerts pro-tumoral effects in part by altering cancer cell metabolism. Previously, we reported a novel mechanism of NRF2 tumoral immune suppression through the selective upregulation of the tryptophan-metabolizing enzyme kynureninase (KYNU) in lung adenocarcinoma. In the current study, we explored the relevance of NRF2-mediated KYNU upregulation across multiple cancer types. Specifically, using a gene expression dataset for 9801 tumors representing 32 cancer types from The Cancer Genome Atlas (TCGA), we demonstrated that elevated KYNU parallels increased gene-based signatures of NRF2-activation and that elevated tumoral KYNU mRNA expression is strongly associated with an immunosuppressive tumor microenvironment, marked by high expression of gene-based signatures of Tregs as well as the immune checkpoint blockade-related genes CD274 (PDL-1), PDCD1 (PD-1), and CTLA4, regardless of the cancer type. Cox proportional hazard models further revealed that increased tumoral KYNU gene expression was prognostic for poor overall survival in several cancer types, including thymoma, acute myeloid leukemia, low-grade glioma, kidney renal papillary cell carcinoma, stomach adenocarcinoma, and pancreatic ductal adenocarcinoma (PDAC). Using PDAC as a model system, we confirmed that siRNA-mediated knockdown of NRF2 reduced KYNU mRNA expression, whereas activation of NFE2L2 (the coding gene for NRF2) through either small-molecule agonists or siRNA-mediated knockdown of KEAP1 upregulated KYNU in PDAC cells. Metabolomic analyses of the conditioned medium from PDAC cell lines revealed elevated levels of KYNU-derived anthranilate, confirming that KYNU was enzymatically functional. Collectively, our study highlights the activation of the NRF2-KYNU axis as a multi-cancer phenomenon and supports the relevance of tumoral KYNU as a marker of tumor immunosuppression and as a prognostic marker for poor overall survival.

Keywords: KYNU; NRF2; immunosuppression; multi-cancer; prognosis

DOI: https://doi.org/10.3390/cancers15030834

PLoS One. 2023 ;18(2): e0277708

Effect of body tissue composition on the outcome of patients with metastatic non-small cell lung cancer treated with PD-1/PD-L1 inhibitors.

Dimitrios Makrakis, Konstantinos Rounis, Alexandros-Pantelis Tsigkas, Alexandra Georgiou, Nikolaos Galanakis, George Tsakonas, Simon Ekman, Chara Papadaki, Alexia Monastirioti, Meropi Kontogianni, Ioannis Gioulbasanis, Dimitris Mavroudis, Sofia Agelaki.

Obesity and sarcopenia have been reported to affect outcomes in patients with non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs). We analyzed prospective data from 52 patients with non-oncogene driven metastatic NSCLC treated with ICIs. Body tissue composition was calculated by measuring the fat and muscle densities at the level of 3rd lumbar vertebra in each patient computed tomography scan before ICI initiation using sliceOmatic tomovision. We converted the densities to indices [Intramuscular Fat Index (IMFI), Visceral Fat Index (VFI), Subcutaneous Fat Index (SFI), Lumbar Skeletal Muscle Index (LSMI)] by dividing them by height in meters squared. Patients were dichotomized based on their baseline IMFI, VFI and SFI according to their gender-specific median value. The cut-offs that were set for LMSI values were 55 cm2/m2 for males and 39 cm2/m2 for females. SFI distribution was significantly higher (p = 0.040) in responders compared to non-responders. None of the other variables affected response rates. Low LSMI HR: 2.90 (95% CI: 1.261-6.667, p = 0.012) and low SFI: 2.20 (95% CI: 1.114-4.333, p = 0.023) values predicted for inferior OS. VFI and IMFI values did not affect survival. Subcutaneous adipose and skeletal muscle tissue composition significantly affected immunotherapy outcomes in our cohort.

DOI: https://doi.org/10.1371/journal.pone.0277708

Biochem Pharmacol. 2023 Feb 04. pii: S0006-2952(23)00037-0. [Epub ahead of print] 115446

CEMIP promotes small cell lung cancer proliferation by activation of glutamine metabolism via FBXW7/c-Myc-dependent axis.

Xiaoxiang Mo, Xiaoju Shen, Xiaocheng Mo, Fei Yu, Weidan Tan, Zhihua Deng, Jingchuan He, Zhuo Luo, Zhiquan Chen, Jie Yang.

Small cell lung cancer (SCLC) is the most malignant lung cancer with rapid growth and early metastasis, but still lacks effective targeted therapies to improve the prognosis. Here, we demonstrated that a novel oncogenic protein, cell migration inducing hyaluronic binding protein (CEMIP), was robustly overexpressed in SCLC tissues than that in noncancerous tissues and high expression of CEMIP predicted poor outcomes in clinical specimens and in large sample size cohorts from public databases (GEPIA 2 and CPTAC). Liquid chromatography mass spectrometry (LC-MS) and in vitro/in vivo functional assays indicated that CEMIP contributed to the proliferation by increasing glutamine consumption and their metabolites (glutamate and glutathione) levels in SCLC cells. Moreover, the addition of a GLS1 inhibitor CB-839 dramatically reduced CEMIP-induced SCLC cell proliferation. Mechanistically, beyond as a scaffold protein, CEMIP facilitates glutamine-dependent cell proliferation through inhibiting c-Myc ubiquitination and increasing c-Myc stabilization and nuclear accumulation via hindering the interaction between FBXW7 (a E3 ubiquitin ligase) and its target substrate c-Myc. Taken together, our findings reveal a novel oncogenic role of CEMIP in sustaining SCLC growth via FBXW7/c-Myc-dependent axis, and provide new evidence that inhibition of CEMIP might be a potential therapeutic strategy for the treatment of SCLC.

Keywords: CEMIP; FBXW7/c-Myc aix; Glutamine metabolism; Proliferation; Small cell lung cancer

DOI: https://doi.org/10.1016/j.bcp.2023.115446