Small cell lung cancer: will recent progress lead to improved outcomes?
ABSTRACT: Small cell lung cancer (SCLC) is an aggressive neuroendocrine malignancy with a unique natural history characterized by a short doubling time, high growth fraction, and early development of widespread metastases. Although a chemotherapy- and radiation-sensitive disease, SCLC typically recurs rapidly after primary treatment, with only 6% of patients surviving 5 years from diagnosis. This disease has been notable for the absence of major improvements in its treatment: Nearly four decades after the introduction of a platinum-etoposide doublet, therapeutic options have remained virtually unchanged, with correspondingly little improvement in survival rates. Here, we summarize specific barriers and challenges inherent to SCLC research and care that have limited progress in novel therapeutic development to date. We discuss recent progress in basic and translational research, especially in the development of mouse models, which will provide insights into the patterns of metastasis and resistance in SCLC. Opportunities in clinical research aimed at exploiting SCLC biology are reviewed, with an emphasis on ongoing trials. SCLC has been described as a recalcitrant cancer, for which there is an urgent need for accelerated progress. The NCI convened a panel of laboratory and clinical investigators interested in SCLC with a goal of defining consensus recommendations to accelerate progress in the treatment of SCLC, which we summarize here.
Project description:Although chemotherapeutic advances have recently been heralded in lung adenocarcinomas, such success with small-cell lung cancer (SCLC) has been ominously absent. Indeed, the dismal outlook of this disease is exemplified by the failure of any significant advances in first line therapy since the introduction of the current standard platinum-etoposide doublet over 30 years ago. Moreover, such sluggish progress is compounded by the dearth of FDA-approved agents for patients with relapsed disease. However, over the past decade, novel formulations of drug classes commonly used in SCLC (e.g. topoisomerase inhibitors, anthracyclines, alkylating and platinum agents) are emerging as potential alternatives that could effectively add to the armamentarium of agents currently at our disposal. This review is introduced with an overview on the historical development of chemotherapeutic regimens used in this disease and followed by the recent encouraging advances witnessed in clinical trials with drugs such as amrubicin and belotecan which are forging new horizons for future treatment algorithms.
Project description:Small-cell lung cancer (SCLC) easily recurs with a multidrug resistant phenotype. However, standard therapeutic strategies for relapsed SCLC remain unestablished. We found that human epidermal growth factor receptor 2 (HER2) is not only expressed in pretreated human SCLC specimens, but is also upregulated when HER2-positive SCLC cells acquire chemoresistance. Trastuzumab induced differential levels of antibody-dependent cell-mediated cytotoxicity (ADCC) to HER2-positive SCLC cells. Furthermore, as a mechanism of the differential levels of ADCC, we have revealed that coexpression of intracellular adhesion molecule (ICAM)-1 on SCLC cells is essential to facilitate and accelerate the trastuzumab-mediated ADCC. Although SN-38-resistant SCLC cells lacking ICAM-1 expression were still refractory to trastuzumab, their in vivo growth was significantly suppressed by bevacizumab treatment due to dependence on their distinctive and abundant production of vascular endothelial growth factor. Collectively, stepwise treatment with trastuzumab and bevacizumab is promising for the treatment of chemoresistant SCLC.
Project description:Small cell lung cancer (SCLC) is an aggressive malignancy with a distinct natural history and dismal prognosis. Given its predisposition for early dissemination, patients are commonly diagnosed with metastatic disease and chemotherapy is regarded as the cornerstone of approved treatment strategies. However, over the last 30 years there has been a distinct paucity of significant breakthroughs in SCLC therapy. Thus, SCLC is characterized as a recalcitrant neoplasm with limited therapeutic options. By employing well-established research approaches, proven to be efficacious in non-small cell lung cancer (NSCLC), a growing amount of data has shed light on the molecular biology of SCLC and enhanced our knowledge of the "drivers" of tumor cell survival and proliferation. New therapeutic targets have emerged, but no significant improvement in patients' survival has been demonstrated thus far. In a sense, the more we know, the more we fail. Nowadays this is starting to change and methodical research efforts are underway. It is anticipated that the next decade will see a revolution in the treatment of SCLC patients with the application of effective precision medicine and immunotherapy strategies.
Project description:Small-cell lung cancer (SCLC) is a special type of lung cancer that belongs to highly aggressive neuroendocrine tumors. At present, radiotherapy and chemotherapy remain the mainstay of treatment for SCLC. Progress in targeted therapies for SCLC with driver mutations has been slow, and these therapies are still under investigation in preclinical or early-phase clinical trials, and research on antiangiogenic tyrosine kinase inhibitors (e.g., anlotinib) has achieved some success. Immunotherapy is becoming an important treatment strategy for SCLC after radiotherapy and chemotherapy. In this article we review the recent advances in immunotherapy for SCLC.
Project description:Small-cell lung cancer (SCLC) accounts for approximately 15% of lung cancer cases; however, it is characterized by easy relapse and low survival rate, leading to one of the most intractable diseases in clinical practice. Despite decades of basic and clinical research, little progress has been made in the management of SCLC. The current standard first-line regimens of SCLC still remain to be cisplatin or carboplatin combined with etoposide, and the adverse events of chemotherapy are by no means negligible. Besides, the immunotherapy on SCLC is still in an early stage and novel studies are urgently needed. In this review, we describe SCLC development and current therapy, aiming at providing useful advices on basic research and clinical strategy.
Project description:CellMiner-SCLC (https://discover.nci.nih.gov/SclcCellMinerCDB/) integrates drug sensitivity and genomic data, including high-resolution methylome and transcriptome from 118 patient-derived small cell lung cancer (SCLC) cell lines, providing a resource for research into this "recalcitrant cancer." We demonstrate the reproducibility and stability of data from multiple sources and validate the SCLC consensus nomenclature on the basis of expression of master transcription factors NEUROD1, ASCL1, POU2F3, and YAP1. Our analyses reveal transcription networks linking SCLC subtypes with MYC and its paralogs and the NOTCH and HIPPO pathways. SCLC subsets express specific surface markers, providing potential opportunities for antibody-based targeted therapies. YAP1-driven SCLCs are notable for differential expression of the NOTCH pathway, epithelial-mesenchymal transition (EMT), and antigen-presenting machinery (APM) genes and sensitivity to mTOR and AKT inhibitors. These analyses provide insights into SCLC biology and a framework for future investigations into subtype-specific SCLC vulnerabilities.
Project description:Small cell lung cancer (SCLC) is an aggressive disease that accounts for approximately 14% of all lung cancers. In the United States, approximately 31,000 patients are diagnosed annually with SCLC. Despite numerous clinical trials, including at least 40 phase 3 trials since the 1970s, systemic treatment for patients with SCLC has not changed significantly in the past several decades. Consequently, the 5-year survival rate remains low at <7% overall, and most patients survive for only 1 year or less after diagnosis. Unlike nonsmall cell lung cancer (NSCLC), in which major advances have been made using targeted therapies, there are still no approved targeted drugs for SCLC. Significant barriers to progress in SCLC include 1) a lack of early detection modalities, 2) limited tumor tissue for translational research (eg, molecular profiling of DNA, RNA, and/or protein alterations) because of small diagnostic biopsies and the rare use of surgical resection in standard treatment, and 3) rapid disease progression with poor understanding of the mechanisms contributing to therapeutic resistance. In this report, the authors review the current state of SCLC treatment, recent advances in current understanding of the underlying disease biology, and opportunities to advance translational research and therapeutic approaches for patients with SCLC.
Project description:Although small cell lung cancer (SCLC) is initially sensitive to chemotherapy, it recurs in most cases. Standard regimens for salvage chemotherapy have not been established, and the prognosis of relapsed SCLC remains poor. In the present study, we investigated the clinical efficacy and safety of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) regimens for the treatment of relapsed SCLC.In this retrospective multicenter analysis, 14 patients (3 women and 11 men; median age 71 years) with relapsed SCLC received nab-paclitaxel alone or in combination with carboplatin between February 2013 and July 2014. The safety and efficacy of the regimens were evaluated.The response rates, disease control rates, and median overall survival for the total patient population were 36%, 64%, and 7.8 months, respectively. Response rates, disease control rates, and the median overall survival were 11%, 44%, and 4 months, respectively, in the monotherapy group; and 80%, 100%, and 10.6 months, respectively, in the combination therapy group. The most common adverse events were hematological toxicities such as neutropenia and anemia. Severe neutropenia appeared in some patients, although it was resolved by treatment in all. The most common nonhematological toxicity was anorexia (64%), followed by neurotoxicity and constipation. All nonhematological toxicities were mild and manageable.Our results suggest that chemotherapy with nab-paclitaxel regimens for relapsed SCLC exhibits moderate clinical efficacy and is well-tolerated. Further clinical trials in relapsed SCLC patients are warranted.
Project description:Small cell lung cancer (SCLC) is a recalcitrant malignancy with distinct biologic properties. Antibody targeting therapy has been actively investigated as a new drug modality.We tested the expression of IGF-1R and calculated the survival in 61 SCLC patients. We also evaluated the anti-tumor effects of anti-IGF-1R monoclonal antibody Figitumumab (CP) on SCLC, and tried two drug combinations to improve CP therapy.Our clinical data suggested that high IGF-1R expression was correlated with low SCLC patient survival. We then demonstrated the effect of CP was likely through IGF-1R blockage and down-regulation without IGF-1R auto-phosphorylation and PI3K/AKT activation. However, we observed elevated MEK/ERK activation upon CP treatment in SCLC cells, and this MEK/ERK activation was enhanced by ß-arrestin1 knockdown while attenuated by ß-arrestin2 knockdown. We found both MEK/ERK inhibitor and metformin could enhance CP treatment in SCLC cells. We further illustrated the additive effect of metformin was likely through promoting further IGF-1R down-regulation.Our results highlighted the potential of anti-IGF-1R therapy and the adjuvant therapy strategy with either MEK/ERK inhibitor or metformin to target SCLC, warranting further studies.
Project description:Small-cell lung cancer (SCLC) is a recalcitrant cancer for its dismal prognosis although extensive research had been done. Four to 6 cycles platinum-based chemotherapy is the mainstay treatment for the extensive-stage disease; but the role of maintenance treatment is not fully understood. This is a phase 2, open-label study. Patients with extensive-stage SCLC reaching an objective response or stable disease (SD) after induction chemotherapy were randomly assigned (1:1) with a minimization procedure. One group received oral S-1 and the other group received placebo as maintenance treatment until disease progression or unacceptable toxicities. The primary end point of this study was progression-free survival (PFS), and the secondary end points were overall survival (OS), response rates, and toxicities. This study was based on earlier work, the preliminary results was reported on 2019 ASCO annual meeting. A total of 89 patients were enrolled, of whom 45 received S-1 maintenance therapy and 44 received placebo. The median PFS and OS were 6.35 months and 10.82 months in the S-1 group, as compared to 5.98 months and 10.09 months in the placebo group. The PFS was 7.2 months and 5.3 months, and OS was 12.9 months and 10.9 months in patients with an objective response compared to in patients with SD after induction chemotherapy, respectively. S-1 maintenance therapy did not prolong PFS or OS in patients with extensive-stage SCLC; tumor regression rate was the prognostic factor of PFS or OS. Further research with novel agents in the maintenance setting is warranted.