bims-meluca 2023-01-08 papers

Drug Dev Res. 2023 Jan 04.

Thrombospondin-1 mimic peptide PKHB1 induced endoplasmic reticulum stress-mediated but CD47-independent apoptosis in non-small cell lung cancer.

Jiani Ye, Yinan Yao, Jianfeng Zhao, Luyun Cui, Guohua Lu, Qing Wang, Pei Zhang, Jianying Zhou.

Non-small cell lung cancer (NSCLC) is one of the most common malignancies with high morbidity and mortality. PKHB1, a serum-stable Thrombospondin-1 (TSP-1) mimic peptide, has shown some effective ability in triggering cell death against several cancers. Here, we aimed to study the potential biological function of PKHB1 and its molecular mechanism in NSCLC. Our results revealed that PKHB1 significantly suppressed NSCLC cell proliferation, cell migration, and induced apoptosis in a dose-dependent manner. Additionally, we found that PKHB1 treatment resulted in mitochondrial transmembrane potential depolarization, Ca2+ overloading as well as the upregulation of proapoptotic proteins. Mechanistically, PKHB1 induced NSCLC cells apoptosis in a CD47-independent manner. Further study revealed that PKHB1 provoked endoplasmic reticulum (ER) stress principally through the activation of CHOP and JNK signaling, which could be alleviated in the presence of 4-PBA, an ER stress inhibitor. Furthermore, xenograft tumor models showed that PKHB1 treatment could notably inhibit NSCLC tumor growth in vivo. In conclusion, these findings suggested that PKHB1 exerted antitumor efficacy in NSCLC via triggering ER stress-mediated but CD47-independent apoptosis, potentially functioned as a promising peptide-based therapeutic agent for NSCLC.

Keywords: CD47; ER stress; NSCLC; PKHB1; TSP-1; apoptosis

DOI: https://doi.org/10.1002/ddr.22028

Clin Nutr. 2022 Dec 22. pii: S0261-5614(22)00439-3. [Epub ahead of print]42(2): 190-198

GLIM diagnosed malnutrition predicts clinical outcomes and quality of life in patients with non-small cell lung cancer.

Maria Landgrebe, Randi Tobberup, Andreas Carus, Henrik Højgaard Rasmussen.

BACKGROUND & AIMS: The high prevalence of malnutrition in non-small cell lung cancer (NSCLC) patients has numerous negative consequences on patients' outcome when undergoing anti-neoplastic treatment. The Global Leadership Initiative on Malnutrition (GLIM) criteria for diagnosis of malnutrition are currently being verified; however, studies validating GLIM criteria in NSCLC patients are lacking. This study aimed to evaluate clinical outcomes and Quality of Life (QoL) in malnourished compared to well-nourished NSCLC patients to determine the predictive validity of GLIM criteria.
METHODS: We collected data on adverse events, survival, and QoL from NSCLC patients undergoing first line anti-neoplastic treatment collected from two prospective trials. Patients were categorized by GLIM criteria as malnourished or well-nourished, based on non-volitional weight loss, low Body Mass Index, reduced muscle mass (Computed Tomography-scans), reduced food intake (24-h recall), and inflammatory condition (modified Glasgow Prognostic Score). Differences in descriptive data, adverse events, survival, and QoL between the malnourished and well-nourished patients were analyzed.
RESULTS: Overall, 120 patients were included in the study. Malnourished patients compared to well-nourished patients had significantly worse outcome in terms of treatment cessation (n = 21 vs 13, p = 0.049), disease progression (n = 20 vs 12, p = 0.034) and shorter overall survival (HR 2.0, 95% CI: 1.2, 3.4, p = 0.009). Stratifying by severity, moderately malnourished patients had a shorter overall survival compared to well-nourished patients (HR 2.1, 95% CI: 1.2, 3.6, p = 0.007). Malnutrition at baseline was associated with poor QoL by lower physical (p < 0.001) and role functioning (p = 0.011), more symptoms of fatigue (p = 0.001), nausea and vomiting (p = 0.009), pain (p < 0.001), dyspnea (p = 0.032), appetite loss (p < 0.001), and constipation (p = 0.029). No significant differences were found in hospitalization, dose reductions, or treatment postponement.
CONCLUSIONS: Malnutrition defined by GLIM criteria in NSCLC patients was associated with more frequent early cessation of anti-neoplastic treatment, shorter overall survival, and poorer QoL compared to well-nourished patients.

Keywords: Cachexia; Malignancy; Muscle; NSCLC; Nutrition; Sarcopenia

DOI: https://doi.org/10.1016/j.clnu.2022.12.011

Cancer Treat Res Commun. 2022 Dec 23. pii: S2468-2942(22)00167-8. [Epub ahead of print]34 100676

The association of body mass index with safety and effectiveness of first-line carboplatin-based chemotherapy in patients with metastatic non-small cell lung cancer.

Santeon NSCLC study group

INTRODUCTION: Carboplatin is an anticancer drug used for treatment of various types of cancer including non-small cell lung cancer (NSCLC). Dosing is based on estimated glomerular filtration rate (GFR) using the Cockcroft-Gault formula. In overweight patients, the GFR is more likely overestimated, resulting in a potentially overdose of carboplatin affecting treatment response. This study investigated the association of body mass index (BMI) on overall survival (OS) and progression-free survival (PFS) in stage-IV NSCLC patients treated with first-line carboplatin-based chemotherapy. Secondary safety endpoints were thrombocytopenia and toxicity-related hospitalizations.
MATERIALS AND METHODS: This was a retrospective multicenter cohort study. Patients were categorized according to BMI<25.0 kg/m2 (normal weight and reference), 25.0-29.9 kg/m2 (overweight) or ≥30.0 kg/m2 (obese). For survival analyses adjusted hazard ratios [aHR] were calculated using multivariate Cox regression analysis. Secondary outcomes were analyzed using multivariate logistic regression providing adjusted odd ratios [aOR].
RESULTS: Overweight patients (n=174) had a significantly better OS (aHR=0.72, 95%-CI:0.59-0.89) and PFS (aHR=0.74, 95%-CI:0.61-0.90) compared to normal weight patients (n=268). OS nor PFS were different in obese (n=51) compared to normal weight patients. However, obesity was associated with significantly higher incidences of thrombocytopenia grade ≥3 (aOR=3.47, 95%-CI:1.75-6.90).
CONCLUSION: This study shows a significantly longer survival for overweight compared to normal weight patients. Obese patients have an increased risk for grade ≥3 thrombocytopenia without a difference in survival following carboplatin-based chemotherapy. The implications for clinical practice are to use the Cockcroft-Gault formula with caution in patients with BMI≥30.0 kg/m2, and to verify calculated dosing of carboplatin for appropriateness.

Keywords: BMI; NSCLC; Overdosing; Overweight; Survival; Toxicity

DOI: https://doi.org/10.1016/j.ctarc.2022.100676

Biomed Res Int. 2022 ;2022 7406636

Identification of Cuproptosis-Related Subtypes in Lung Cancer, Characterization of Tumor Microenvironment Infiltration, and Establishment of a Prognostic Model.

Jin Cui, Ying Xiong, Yuting Liu, Min Sun, Xinyue Gu, Luhui Zhong, Xiaohua Hong, Li Liu.

Cuproptosis, a recently found kind of programmed cell death, has been linked to tumor development, prognosis, and therapeutic response. The roles of cuproptosis-related genes (CRG) in the tumor microenvironment (TME) are, nevertheless, unknown. We evaluated alterations in CRG and assessed the related expression patterns in 1445 lung cancer (LC) samples from three separate datasets, analyzing genetic, and transcriptional domains. We discovered two separate molecular subtypes of CRG and discovered that various subtypes of CRG were connected with patient clinical features and prognosis. Furthermore, we discovered connections between distinct CRG subtypes and TME cell infiltration features. The CRG_score was then developed and validated for predicting overall survival (OS). Following that, we investigated the relationship between CRG_score and the cancer stem cell (CSC) index and chemotherapeutic treatment sensitivity. In addition, we created a very accurate nomogram to increase the clinical usefulness of CRG_score. The potential roles of CRG in the tumor-immune-microenvironment, clinical characteristics, and prognosis in LC are demonstrated by our multiplex study. These findings expand our understanding of CRG in LC and may open up new options for assessing LC patients' prognosis and generating more effective immunotherapeutic treatments.

DOI: https://doi.org/10.1155/2022/7406636

Cell Death Discov. 2023 Jan 02. 9(1): 1

Co-targeting BCL-XL and MCL-1 with DT2216 and AZD8055 synergistically inhibit small-cell lung cancer growth without causing on-target toxicities in mice.

Sajid Khan, Patrick Kellish, Nick Connis, Dinesh Thummuri, Janet Wiegand, Peiyi Zhang, Xuan Zhang, Vivekananda Budamagunta, Nan Hua, Yang Yang, Umasankar De, Lingtao Jin, Weizhou Zhang, Guangrong Zheng, Robert Hromas, Christine Hann, Maria Zajac-Kaye, Frederic J Kaye, Daohong Zhou.

Small-cell lung cancer (SCLC) is an aggressive malignancy with limited therapeutic options. The dismal prognosis in SCLC is in part associated with an upregulation of BCL-2 family anti-apoptotic proteins, including BCL-XL and MCL-1. Unfortunately, the currently available inhibitors of BCL-2 family anti-apoptotic proteins, except BCL-2 inhibitors, are not clinically relevant because of various on-target toxicities. We, therefore, aimed to develop an effective and safe strategy targeting these anti-apoptotic proteins with DT2216 (our platelet-sparing BCL-XL degrader) and AZD8055 (an mTOR inhibitor) to avoid associated on-target toxicities while synergistically optimizing tumor response. Through BH3 mimetic screening, we identified a subset of SCLC cell lines that is co-dependent on BCL-XL and MCL-1. After screening inhibitors of selected tumorigenic pathways, we found that AZD8055 selectively downregulates MCL-1 in SCLC cells and its combination with DT2216 synergistically killed BCL-XL/MCL-1 co-dependent SCLC cells, but not normal cells. Mechanistically, the combination caused BCL-XL degradation and suppression of MCL-1 expression, and thus disrupted MCL-1 interaction with BIM leading to an enhanced apoptotic induction. In vivo, the DT2216 + AZD8055 combination significantly inhibited the growth of cell line-derived and patient-derived xenografts and reduced tumor burden accompanied by increased survival in a genetically engineered mouse model of SCLC without causing appreciable thrombocytopenia or other normal tissue injuries. Thus, these preclinical findings lay a strong foundation for future clinical studies to test DT2216 + mTOR inhibitor combinations in a subset of SCLC patients whose tumors are co-driven by BCL-XL and MCL-1.

DOI: https://doi.org/10.1038/s41420-022-01296-8