bims-meluca 2019-10-20 papers

Mol Cancer Res. 2019 Oct 18. pii: molcanres.0239.2019. [Epub ahead of print]

Targeting the kynurenine pathway for the treatment of cisplatin resistant lung cancer.

Dan Jm Nguyen, George Theodoropoulos, Ying-Ying Li, Chunjing Wu, Wei Sha, Lynn G Feun, Theodore J Lampidis, Niramol Savaraj, Medhi Wangpaichitr.

Cisplatin resistance is a major barrier in the effective treatment of lung cancer. Cisplatin resistant (CR) lung cancer cells do not primarily use glucose, but rather consume amino acids such as glutamine and tryptophan (TRP) for survival. CR cells activate the kynurenine (KYN) pathway (KP) to cope with excessive reactive oxygen species (ROS) and maintain homeostasis for growth and proliferation. Consequently, indoleamine 2,3-dioxygenase-1 (IDO1) becomes an essential enzyme for CR cells' survival since it initiates and regulates the first step in the KP. Increased IDO1 activities and ROS levels are found in CR cells vs. cisplatin sensitive lung cancer. Importantly, significantly greater KYN/TRP ratio (p=0.005) is detected in serum of patients who fail cisplatin when compared to naive treatment. Knocking down IDO1 using shRNA or IDO1 inhibitors heightens ROS levels and results in a significant growth inhibitory effect only on CR cells and not cisplatin sensitive cells. Exposing CR cells to antioxidant (TIRON) results in suppression of IDO1 activity and confers resistance to IDO1 inhibition, indicating an interrelationship between ROS and IDO1. Since KYN plays a critical role in reprogramming naïve T-cells to the immune suppressive regulatory T-cell (T-reg) phenotype, we observed higher expression of T-reg (TGFβ, FoxP3 and CD4+CD25+) in mice bearing CR tumors compared to tumors from cisplatin sensitive counterparts. Implications: Findings suggest that the enzyme inhibitory activity and anti-tumor efficacy of IDO1 inhibitors rely in part on ROS levels, arguing that IDO1 expression alone may be insufficient to determine the clinical benefits for this class of experimental cancer drugs. Importantly, IDO1 inhibitors maybe more suitable to treat lung cancer patients who failed cisplatin therapy than naïve treatment patients.

DOI: https://doi.org/10.1158/1541-7786.MCR-19-0239

Cancer Manag Res. 2019 ;11 7707-7719

Prospect of immunotherapy combined with anti-angiogenic agents in patients with advanced non-small cell lung cancer.

Hongge Liang, Mengzhao Wang.

In the latest years, some drugs have been approved by European Medicines Agency (EMA) and/or the US Food and Drug Administration (FDA) for the treatment of patients with advanced non-small cell lung cancer (NSCLC), particularly for the treatment of those who have no targeted gene mutations or who have progressed on previously targeted therapy or platinum-containing dual-agent chemotherapy. In general, these drugs fall into two categories: anti-angiogenic agents and immune checkpoint inhibitors (ICIs). Anti-angiogenic agents currently approved by the FDA and/or EMA for advanced NSCLC treatment include bevacizumab, nintedanib, and ramucirumab. Anlotinib has been approved in advanced NSCLC by Chinese Food and Drug Administration (CFDA). These anti-angiogenic agents can induce anti-angiogenesis by targeting vascular endothelial growth factor (VEGF)/VEGF2 or inhibiting multiple small molecules involved in angiogenic and proliferative pathways such as platelet-derived growth factor receptors (PDGFRs) and fibroblast growth factor receptors (FGFRs). Although these drugs show significant therapeutic efficacy, most patients inevitably experience disease progression resulting in death. ICIs approved by the FDA and/or EMA for advanced NSCLC treatment include nivolumab, pembrolizumab, and atezolizumab. These ICIs can significantly improve efficacy compared with standard chemotherapy by targeting programmed cell death protein 1 (PD-1) receptor or PD-2 receptor with longer response duration and acceptable toxicity. However, the response rate of ICIs is suboptimal, and only a few patients ultimately benefit from immunotherapy. So current efforts have focused on exploring new potential combinatorial strategies with synergistic antitumor activity. Here, we summarized the theoretical basis, current clinical data, and potential future perspective of immunotherapy combined with anti-angiogenic agents for advanced NSCLC.

Keywords: anti-angiogenic agents; immunotherapy; non-small cell lung cancer

DOI: https://doi.org/10.2147/CMAR.S212238

Oncol Lett. 2019 Nov;18(5): 4744-4752

Prognostic value of insulin-like growth factor 2 mRNA-binding protein 3 and vascular endothelial growth factor-A in patients with primary non-small-cell lung cancer.

Jiannan Liu, Ying Liu, Wenjing Gong, Xiangshuo Kong, Congcong Wang, Shuhua Wang, Aina Liu.

Insulin-like growth factor 2 mRNA-binding protein 3 (IMP3) and vascular endothelial growth factor-A (VEGF-A) may play important roles in the process of tumor progression and tumor angiogenesis. The aim of the present study was to examine the co-expression of IMP3 and VEGF-A in primary human non-small cell lung cancer (NSCLC), to investigate the association between these two expression levels and determine the clinicopathological implications, including changes to microvessel density (MVD), and to assess the prognostic value of co-expression. Using immunohistochemical staining, the expression of IMP3, VEGF-A and CD34 expression was detected in 128 primary NSCLC tissue samples. According to the expression of IMP3 and VEGF-A, the cases were divided into four groups. Next, the clinicopathological features, MVD and survival time were investigated across the different groups. The immunohistochemical analyses demonstrated that there was a significant correlation between IMP3 and VEGF-A expression in NSCLC (r=0.181; P=0.041). Co-expression of IMP3 and VEGF-A was significantly associated with larger primary tumor size (P=0.016), poorer differentiation (P=0.014), more advanced Tumor-Node-Metastasis stage (P=0.012), increased MVD (P=0.004) and positive lymph node metastasis (P=0.002). Survival analysis demonstrated that cases with IMP3 and VEGF-A double-positive staining were significantly associated with lower survival rates compared with cases with double-negative staining (P=0.039). In the early NSCLC (I-IIa) subgroup, the mean survival time of the double-positive staining group was significantly shorter compared with that of the double-negative staining group (P=0.015). Co-expression of IMP3 and VEGF-A was associated with angiogenesis and a poorer prognosis in NSCLC, and may therefore play a critical role in NSCLC progression.

Keywords: insulin-like growth factor 2 mRNA-binding protein 3; non-small cell lung cancer; prognosis; vascular endothelial growth factor-A

DOI: https://doi.org/10.3892/ol.2019.10835