Angiogenesis Inhibitors in Small Cell Lung Cancer.
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ABSTRACT:
SUBMITTER: Montanino A
PROVIDER: S-EPMC8195287 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Small cell lung cancer (SCLC) is a highly aggressive and lethal malignancy. Despite high initial response rates to systemic chemotherapy, the disease eventually relapses; further treatment only modestly improves outcomes and overall survival (OS) for patients with extensive stage disease is less than one year. Little progress has been made during the past decades, with no new drugs approved. Consequently, the development of novel strategies is an unmet need. The inhibition of angiogenesis, a defining characteristic of cancer, has demonstrated modest efficacy in several human malignancies, including non-small cell lung cancer (NSCLC). However, results from clinical trials in SCLC have been disappointing, and no anti-angiogenic agent has received regulatory approval due to lack of clinical efficacy. The elucidation of underlying mechanisms responsible for tumor resistance to angiogenic therapy and the simultaneous blockade of multiple elements that play a role in angiogenesis need to be further explored.
| S-EPMC5009078 | biostudies-literature
Project description:BackgroundSmall cell lung cancer (SCLC) is a highly invasive and lethal neuroendocrine tumor. Antiangiogenic drugs have been reported in the treatment of SCLC. We aimed to provide a comprehensive evaluation of the impact of angiogenic inhibitors on SCLC survival using network meta-analysis.MethodsThe impact of five angiogenesis inhibitors, that is, vandetanib (Van), bevacizumab (Bev), Rh-endostatin (End), sunitinib (Sun), and thalidomide (Tha), on progression-free survival (PFS) and overall survival (OS) was evaluated by conducting a network meta-analysis. RNA sequencing data were downloaded from publicly available databases.ResultsNine phase II and III randomized controlled trials (RCTs), that involved 1599 participants, that investigated angiogenesis inhibitors in the treatment of SCLC were included in this meta-analysis. Sun and Bev achieved better PFS than Tha (Bev VS. Tha, HR = 0.88, 95% CI: 0.79-0.98, Sun VS. Tha, HR = 0.80, 95% CI: 0.65-1.00). Moreover, Sun and Bev were superior to placebo in terms of PFS (Bev VS. Placebo, HR = 0.89, 95%CI: 0.81-0.97, Sun VS. Placebo, HR = 0.81, 95% CI: 0.66-1.00). Based on this study, we found no significant difference of OS of SCLC. The angiogenesis pathway and expression of target genes were globally deactivated in SCLC tissue.ConclusionResults of this network meta-analysis indicate that the PFS outcome of SCLC with Sun or Bev drugs is superior to that of Tha. The improved therapeutic impact of angiogenesis inhibitors on SCLC needs more evidence, such as long-term observation in clinical trials, to be validated.
| S-EPMC6792507 | biostudies-literature
Project description:Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, and can be further classified as nonsquamous carcinoma (including adenocarcinoma, which accounts for 40 % of NSCLCs) and squamous NSCLC, which makes up 30 % of NSCLC cases. The emergence of inhibitors of epidermal growth factor receptors, anaplastic lymphoma kinase, and vascular endothelial growth factors (VEGF) in the last decade has resulted in steady improvement in clinical outcomes for patients with advanced lung adenocarcinoma. However, improvements in the survival of patients with squamous NSCLC have remained elusive, presenting an urgent need for understanding and investigating therapeutically relevant molecular targets, specifically in squamous NSCLC. Although anti-VEGF therapy has been studied in squamous NSCLC, progress has been slow, in part due to issues related to pulmonary hemorrhage. In addition to these safety concerns, several phase III trials that initially included patients with squamous NSCLC failed to demonstrate improved overall survival (primary endpoint) with the addition of antiangiogenic therapy to chemotherapy compared with chemotherapy alone. Angiogenesis is an established hallmark of tumor progression and metastasis, and the role of VEGF signaling in angiogenesis is well established. However, some studies suggest that, while inhibiting VEGF signaling may be beneficial, prolonged exposure to VEGF/VEGF receptor (VEGFR) inhibitors may allow tumor cells to utilize alternative angiogenic mechanisms and become resistant. As a result, agents that target multiple angiogenic pathways simultaneously are also under evaluation. This review focuses on current and investigational antiangiogenic targets in squamous NSCLC, including VEGF/VEGFRs, fibroblast growth factor receptors, platelet-derived growth factor receptors, and angiopoietin. Additionally, clinical trials investigating VEGF- and multi-targeted antiangiogenic therapies are discussed.
| S-EPMC4014113 | biostudies-literature
Project description:Lung cancer is the leading cause of cancer-related mortality in the United States. Over the past 40 years, treatments with standard chemotherapy agents have not resulted in substantial improvements in long-term survival for patients with advanced lung cancer. Therefore, new targets have been sought, and angiogenesis is a promising target for non-small cell lung cancer (NSCLC). Bevacizumab, a monoclonal antibody targeted against the vascular endothelial growth factor, is the only antiangiogenic agent currently recommended by NCCN for the treatment of advanced NSCLC. However, several antibody-based therapies and multitargeted tyrosine kinase inhibitors are currently under investigation for the treatment of patients with NSCLC. This article summarizes the available clinical trial data on the efficacy and safety of these agents in patients with advanced lung cancer.
| S-EPMC6628716 | biostudies-literature
Project description:Tumor angiogenesis is a frequent event in the development and progression of non-small cell lung cancer (NSCLC) and has been identified as a promising therapeutic target. The vascular endothelial growth factor (VEGF) family and other angiogenic factors, including fibroblast growth factor and platelet-derived growth factor, promote the growth of newly formed vessels from preexisting vessels and change the tumor microenvironment. To date, two antiangiogenic monoclonal antibodies, bevacizumab and ramucirumab, which target VEGF-A and its receptor VEGF receptor-2, respectively, have been approved for the treatment of locally advanced or metastatic NSCLC when added to first-line standard chemotherapy. Numerous oral multitargeting angiogenic small molecule tyrosine kinase inhibitors (TKIs) have been widely evaluated in advanced NSCLC, but only nintedanib in combination with platinum-based doublet chemotherapy has demonstrated a survival benefit in the second-line setting. Additionally, small-molecule TKIs remain the standard of care for patients with mutated EGFR, ALK or ROS1. Moreover, immune checkpoint inhibitors that target the programmed cell death protein 1 (PD-1) and programmed cell death protein ligand 1 (PD-L1) are changing the current strategy in the treatment of advanced NSCLC without driver gene mutations. The potential synergistic activity of antiangiogenic agents and TKIs or immunotherapy is an interesting topic of research. This review will summarize the novel antiangiogenic agents, antiangiogenic monotherapy, as well as potential combination therapeutic strategies for the clinical management of advanced NSCLC.
| S-EPMC5581155 | biostudies-literature
Project description:RAF family proteins are serine-threonine kinases that play a central role in the MAPK pathway which is involved in embryogenesis, cell differentiation, cell proliferation and death. Deregulation of this pathway is found in up to 30% of all human cancers and BRAF mutations can be identified in 1.5-3.5% of NSCLC patients. Following the positive results obtained through the combination of BRAF and MEK inhibitors in BRAF-mutant melanoma, the same combination was prospectively assessed in BRAF-mutant NSCLC. In cohort B of the BRF113928 trial, 57 pretreated NSCLC patients were treated with dabrafenib plus trametinib: an ORR of 68.4%, a disease control rate of 80.7%, a median PFS of 10.2 months and a median OS of 18.2 months were observed. Similar results were reported in the first-line setting (cohort C), with an ORR of 63.9%, a DCR of 75% and a median PFS and OS of 10.2 and 17.3 months, respectively. The combination was well tolerated: the main adverse events were pyrexia (64%), nausea (56%), diarrhoea (56%), fatigue (36%), oedema (36%) and vomiting (33%). These positive results led to the approval of the combination of dabrafenib and trametinib for the treatment of BRAF V600E metastatic NSCLC patients regardless of previous therapy. Ongoing research should better define the role of new generation RAF inhibitors for patients with acquired resistance, the activity of chemo-immunotherapy or the combination of TKIs with chemotherapy or with immunotherapy in patients with BRAF-mutated cancers.
| S-EPMC9562258 | biostudies-literature
Project description:RET rearrangements are observed in 1-2% of non-small-cell lung cancer (NSCLC) patients and result in the constitutive activation of downstream pathways normally implied in cell proliferation, growth, differentiation and survival. In NSCLC patients, RET rearrangements have been associated with a history of non-smoking, a higher rate of brain metastasis at initial diagnosis and a low immune infiltrate. Traditionally, RET fusions are considered mutually exclusive with other oncogenic drivers, even though a co-occurrence with EGFR mutations and MET amplifications has been observed. Cabozantinib, vandetanib and lenvatinib are the first multi-kinase inhibitors tested in RET-rearranged NSCLC patients with contrasting results. More recently, two selective RET inhibitors, selpercatinib and pralsetinib, demonstrated higher efficacy rates and good tolerability and they were approved for the treatment of patients with metastatic RET fusion-positive NSCLC on the bases of the results of phase II studies. Two ongoing phase III clinical trials are currently comparing selpercatinib or pralsetinib to standard first line treatments and will definitively establish their efficacy in RET-positive NSCLC patients.
| S-EPMC8431193 | biostudies-literature
Project description:BackgroundThis study aimed to assess the effectiveness and safety of angiogenesis inhibitors for the treatment of patients with small cell lung cancer (SCLC) via meta-analysis.MethodsElectronic databases including PubMed, Embase, and Cochrane Library were searched to look for eligible studies through February 1, 2016. RCTs comprising angiogenesis inhibitors and nonangiogenesis inhibitors for SCLC patients were investigated. The extracted data including overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) were summarized. In addition, the common adverse events (AEs) were also explored.ResultsThere were 7 phase II/III RCTs, encompassing 1322 SCLC patients eligible for meta-analysis. In comparison to nonangiogenesis inhibitors, angiogenesis inhibitors treatment was not associated with improvement of PFS [HR = 0.87, 95% CI (0.74-1.02), P = 0.09), OS [HR = 0.99, 95% CI (0.88-1.12), P = 0.91], or ORR [OR = 1.12, 95% CI (0.85-1.47), P = 0.41). Also, there was no improvement in 1-year survival rate [OR = 0.96, 95% CI (0.74-1.19), P = 0.63)], 2-year survival rate [OR = 1.00, 95% CI (0.66-1.51), P = 1.00)] or 1-year progression-free survival rates [OR = 0.95, 95% CI (0.69-1.31), P = 0.76)]. However, from subgroup analyses, it was observed that angiogenesis inhibitors improved ORR [HR = 1.66 (95% CI 1.02-2.71), P = 0.04] in phase II studies and bevacizumab improved PFS [HR = 0.73 (95% CI 0.42-0.97), P = 0.04]. It is important to note that angiogenesis inhibitors reduced emesis [OR = 0.38, 95% CI (0.17-0.85), P = 0.02], but increased incidence of constipation [OR = 4.02, 95% CI (2.14-7.55), P < 0.0001) and embolism [OR = 2.24, 95% CI (1.45-3.47), P = 0.0003).ConclusionAdding angiogenesis inhibitors to chemotherapy did not improve PFS, OS, ORR, 1-year survival rate, 2-year survival rate or 1-year progression-free survival rate for SCLC. However, subgroup analysis revealed that bevacizumab enhanced PFS. Angiogenesis inhibitors also had a high incidence of constipation and embolism.
| S-EPMC5380252 | biostudies-literature
Project description:Immune checkpoint blockade (ICB) has become a standard treatment for non-small cell lung cancer (NSCLC). However, most patients with NSCLC do not benefit from these treatments. Abnormal vasculature is a hallmark of solid tumors and is involved in tumor immune escape. These abnormalities stem from the increase in the expression of pro-angiogenic factors, which is involved in the regulation of the function and migration of immune cells. Anti-angiogenic agents can normalize blood vessels, and thus transforming the tumor microenvironment from immunosuppressive to immune-supportive by increasing the infiltration and activation of immune cells. Therefore, the combination of immunotherapy with anti-angiogenesis is a promising strategy for cancer treatment. Here, we outline the current understanding of the mechanisms of vascular endothelial growth factor/vascular endothelial growth factor receptor (VEGF/VEGFR) signaling in tumor immune escape and progression, and summarize the preclinical studies and current clinical data of the combination of ICB and anti-angiogenic drugs in the treatment of advanced NSCLC.
| S-EPMC8206805 | biostudies-literature
Project description:Small cell lung cancer (SCLC), characterized by early metastasis, relapse, relapse and resistance and poor prognosis, still faces difficulties in treatment. Recently, Immunotherapy is a novel treatment for SCLC, researchers are also eager to achieve a breakthrough in targeted treatment of SCLC. Genomic instability of SCLC and sensitivity to cytotoxic chemotherapy, therefore, poly ADP-ribose polymerase (PARP) inhibitors targeting DNA repair related pathways have become a hotspot in the research of SCLC targeted therapy. Studies on PARP inhibitors in SCLC have been conducted in combination with other therapeutic strategies, including the treatment of recurrent SCLC and first-line treatment,as well as maintenance treatment after induction. These studies also explored the predictive markers of PARP inhibitors in SCLC. Although the current results of PARP inhibitors in SCLC are limited, and the predictive markers are also inconsistent, we also see that PARP inhibitors could be a breakthroughfor precision medicine of SCLC.?.
| S-EPMC7519958 | biostudies-literature