ABSTRACT
Targeted therapy and immunotherapy have revolutionized cancer treatment. However, the ability of cancer to evade the immune system remains a major barrier for effective treatment. Related to this, several targeted DNA-damage response inhibitors (DDRis) are being tested in the clinic and have been shown to potentiate anti-tumor immune responses. Seminal studies have shown that these agents are highly effective in a pan-cancer class of tumors with genetic defects in key DNA repair genes such as BRCA1/2, BRCA-related genes, ataxia telangiectasia mutated (ATM), and others. Here, we review the molecular consequences of targeted DDR inhibition, from tumor cell death to increased engagement of the anti-tumor immune response. Additionally, we discuss mechanistic and clinical rationale for pairing targeted DDRis with immunotherapy for enhanced tumor control. We also review biomarkers for patient selection and promising new immunotherapy approaches poised to form the foundation of next-generation DDRi and immunotherapy combinations.
Subject(s)
DNA Damage , Neoplasms , Humans , Neoplasms/genetics , DNA Repair , Ataxia Telangiectasia Mutated Proteins/geneticsABSTRACT
Small cell lung cancer (SCLC) is characterized by rapid growth and high metastatic capacity. It has strong epidemiologic and biologic links to tobacco carcinogens. Although the majority of SCLCs exhibit neuroendocrine features, an important subset of tumors lacks these properties. Genomic profiling of SCLC reveals genetic instability, almost universal inactivation of the tumor suppressor genes TP53 and RB1, and a high mutation burden. Because of early metastasis, only a small fraction of patients are amenable to curative-intent lung resection, and these individuals require adjuvant platinum-etoposide chemotherapy. Therefore, the vast majority of patients are currently being treated with chemoradiation with or without immunotherapy. In patients with disease confined to the chest, standard therapy includes thoracic radiotherapy and concurrent platinum-etoposide chemotherapy. Patients with metastatic (extensive-stage) disease are treated with a combination of platinum-etoposide chemotherapy plus immunotherapy with an anti-programmed death-ligand 1 monoclonal antibody. Although SCLC is initially very responsive to platinum-based chemotherapy, these responses are transient because of the development of drug resistance. In recent years, the authors have witnessed an accelerating pace of biologic insights into the disease, leading to the redefinition of the SCLC classification scheme. This emerging knowledge of SCLC molecular subtypes has the potential to define unique therapeutic vulnerabilities. Synthesizing these new discoveries with the current knowledge of SCLC biology and clinical management may lead to unprecedented advances in SCLC patient care. Here, the authors present an overview of multimodal clinical approaches in SCLC, with a special focus on illuminating how recent advancements in SCLC research could accelerate clinical development.
Subject(s)
Biological Products , Lung Neoplasms , Small Cell Lung Carcinoma , Humans , Small Cell Lung Carcinoma/diagnosis , Small Cell Lung Carcinoma/therapy , Lung Neoplasms/diagnosis , Lung Neoplasms/therapy , Etoposide/therapeutic use , Combined Modality Therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biological Products/therapeutic useABSTRACT
Recent genomic analyses of pathologically defined tumor types identify "within-a-tissue" disease subtypes. However, the extent to which genomic signatures are shared across tissues is still unclear. We performed an integrative analysis using five genome-wide platforms and one proteomic platform on 3,527 specimens from 12 cancer types, revealing a unified classification into 11 major subtypes. Five subtypes were nearly identical to their tissue-of-origin counterparts, but several distinct cancer types were found to converge into common subtypes. Lung squamous, head and neck, and a subset of bladder cancers coalesced into one subtype typified by TP53 alterations, TP63 amplifications, and high expression of immune and proliferation pathway genes. Of note, bladder cancers split into three pan-cancer subtypes. The multiplatform classification, while correlated with tissue-of-origin, provides independent information for predicting clinical outcomes. All data sets are available for data-mining from a unified resource to support further biological discoveries and insights into novel therapeutic strategies.
Subject(s)
Neoplasms/classification , Neoplasms/genetics , Cluster Analysis , Humans , Neoplasms/pathology , TranscriptomeABSTRACT
Intermediary metabolism in cancer cells is regulated by diverse cell-autonomous processes, including signal transduction and gene expression patterns, arising from specific oncogenotypes and cell lineages. Although it is well established that metabolic reprogramming is a hallmark of cancer, we lack a full view of the diversity of metabolic programs in cancer cells and an unbiased assessment of the associations between metabolic pathway preferences and other cell-autonomous processes. Here, we quantified metabolic features, mostly from the 13C enrichment of molecules from central carbon metabolism, in over 80 non-small cell lung cancer (NSCLC) cell lines cultured under identical conditions. Because these cell lines were extensively annotated for oncogenotype, gene expression, protein expression, and therapeutic sensitivity, the resulting database enables the user to uncover new relationships between metabolism and these orthogonal processes.
Subject(s)
Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line, Tumor/metabolism , Metabolome/physiology , Biomarkers, Tumor/metabolism , Gas Chromatography-Mass Spectrometry/methods , Gene Expression Regulation, Neoplastic/physiology , Glucose/metabolism , Glutamine/metabolism , Humans , Metabolic Networks and Pathways/genetics , Metabolomics/methods , Neoplasms/metabolismABSTRACT
Further analysis has revealed that the signal reported in Extended Data Fig. 1c of this Letter is attributed to phosphorylethanolamine, not carbamoyl phosphate. A newly developed derivatization method revealed that the level of carbamoyl phosphate in these NSCLC extracts is below the detection threshold of approximately 10 nanomoles. These findings do not alter the overall conclusions of the Letter; see associated Amendment for full details. The Letter has not been corrected online.
ABSTRACT
BACKGROUND: We explored potential predictive biomarkers of immunotherapy response in patients with extensive-stage small-cell lung cancer (ES-SCLC) treated with durvalumab (D) + tremelimumab (T) + etoposide-platinum (EP), D + EP, or EP in the randomized phase 3 CASPIAN trial. METHODS: 805 treatment-naïve patients with ES-SCLC were randomized (1:1:1) to receive D + T + EP, D + EP, or EP. The primary endpoint was overall survival (OS). Patients were required to provide an archived tumor tissue block (or ≥ 15 newly cut unstained slides) at screening, if these samples existed. After assessment for programmed cell death ligand-1 expression and tissue tumor mutational burden, residual tissue was used for additional molecular profiling including by RNA sequencing and immunohistochemistry. RESULTS: In 182 patients with transcriptional molecular subtyping, OS with D ± T + EP was numerically highest in the SCLC-inflamed subtype (n = 10, median 24.0 months). Patients derived benefit from immunotherapy across subtypes; thus, additional biomarkers were investigated. OS benefit with D ± T + EP versus EP was greater with high versus low CD8A expression/CD8 cell density by immunohistochemistry, but with no additional benefit with D + T + EP versus D + EP. OS benefit with D + T + EP versus D + EP was associated with high expression of CD4 (median 25.9 vs. 11.4 months) and antigen-presenting and processing machinery (25.9 vs. 14.6 months) and MHC I and II (23.6 vs. 17.3 months) gene signatures, and with higher MHC I expression by immunohistochemistry. CONCLUSIONS: These findings demonstrate the tumor microenvironment is important in mediating better outcomes with D ± T + EP in ES-SCLC, with canonical immune markers associated with hypothesized immunotherapy mechanisms of action defining patient subsets that respond to D ± T. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03043872.
Subject(s)
Biomarkers, Tumor , Immunotherapy , Lung Neoplasms , Small Cell Lung Carcinoma , Humans , Small Cell Lung Carcinoma/drug therapy , Small Cell Lung Carcinoma/genetics , Small Cell Lung Carcinoma/pathology , Small Cell Lung Carcinoma/immunology , Small Cell Lung Carcinoma/therapy , Small Cell Lung Carcinoma/metabolism , Small Cell Lung Carcinoma/mortality , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Lung Neoplasms/mortality , Lung Neoplasms/genetics , Lung Neoplasms/immunology , Lung Neoplasms/therapy , Lung Neoplasms/metabolism , Female , Male , Immunotherapy/methods , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Middle Aged , Aged , Antibodies, Monoclonal/therapeutic use , Treatment Outcome , Neoplasm Staging , Antibodies, Monoclonal, Humanized/therapeutic use , Prognosis , AdultABSTRACT
Metabolic reprogramming by oncogenic signals promotes cancer initiation and progression. The oncogene KRAS and tumour suppressor STK11, which encodes the kinase LKB1, regulate metabolism and are frequently mutated in non-small-cell lung cancer (NSCLC). Concurrent occurrence of oncogenic KRAS and loss of LKB1 (KL) in cells specifies aggressive oncological behaviour. Here we show that human KL cells and tumours share metabolomic signatures of perturbed nitrogen handling. KL cells express the urea cycle enzyme carbamoyl phosphate synthetase-1 (CPS1), which produces carbamoyl phosphate in the mitochondria from ammonia and bicarbonate, initiating nitrogen disposal. Transcription of CPS1 is suppressed by LKB1 through AMPK, and CPS1 expression correlates inversely with LKB1 in human NSCLC. Silencing CPS1 in KL cells induces cell death and reduces tumour growth. Notably, cell death results from pyrimidine depletion rather than ammonia toxicity, as CPS1 enables an unconventional pathway of nitrogen flow from ammonia into pyrimidines. CPS1 loss reduces the pyrimidine to purine ratio, compromises S-phase progression and induces DNA-polymerase stalling and DNA damage. Exogenous pyrimidines reverse DNA damage and rescue growth. The data indicate that the KL oncological genotype imposes a metabolic vulnerability related to a dependence on a cross-compartmental pathway of pyrimidine metabolism in an aggressive subset of NSCLC.
Subject(s)
Carbamoyl-Phosphate Synthase (Ammonia)/metabolism , DNA/biosynthesis , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Protein Serine-Threonine Kinases/genetics , Proto-Oncogene Proteins p21(ras)/genetics , Pyrimidines/metabolism , AMP-Activated Protein Kinase Kinases , AMP-Activated Protein Kinases/metabolism , Ammonia/metabolism , Animals , Bicarbonates/metabolism , Carbamoyl-Phosphate Synthase (Ammonia)/deficiency , Carbamoyl-Phosphate Synthase (Ammonia)/genetics , Carbamyl Phosphate/metabolism , Carcinoma, Non-Small-Cell Lung/enzymology , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Cell Death , Cell Proliferation , DNA Damage/drug effects , DNA Replication , DNA-Directed DNA Polymerase/metabolism , Female , Gene Silencing , Humans , Lung Neoplasms/enzymology , Lung Neoplasms/pathology , Male , Metabolomics , Mice , Mitochondria/metabolism , Nitrogen/metabolism , Protein Serine-Threonine Kinases/metabolism , Purines/metabolism , Pyrimidines/pharmacology , S Phase , Transcription, Genetic , Xenograft Model Antitumor AssaysABSTRACT
INTRODUCTION: Small cell lung cancer (SCLC) is an aggressive malignancy with no established biomarkers. Schlafen 11(SLFN11), a DNA/RNA helicase that sensitises cancer cells to DNA-damaging agents, has emerged as a promising predictive biomarker for several drug classes including platinum and PARP inhibitors. Detection of SLFN11 in circulating tumour cells (CTCs) may provide a valuable alternative to tissue sampling. METHODS: SLFN11 expression was evaluated in tumour samples and characterised in circulating tumour cells (CTC) longitudinally to determine its potential role as a biomarker of response. RESULTS: Among 196 SCLC tumours, 51% expressed SLFN11 by IHC. In addition, 20/29 extra-thoracic high-grade neuroendocrine tumours expressed SLFN11 expression. In 64 blood samples from 42 SCLC patients, 83% (53/64) of samples had detectable CTCs, and SLFN11-positive CTCs were detected in 55% (29/53). Patients actively receiving platinum treatment had the lowest number of CTCs and a lower percentage of SLFN11-positive CTCs (p = 0.014). Analysis from patients with longitudinal samples suggest a decrease in CTC number and in SLFN11 expression that correlates with clinical response. CONCLUSIONS: SLFN11 levels can be monitored in CTCs from SCLC patients using non-invasive liquid biopsies. The ability to detect SLFN11 in CTCs from SCLC patients adds a valuable tool for the detection and longitudinal monitoring of this promising biomarker.
Subject(s)
Lung Neoplasms , Neoplastic Cells, Circulating , Nuclear Proteins , Small Cell Lung Carcinoma , Biomarkers , Biomarkers, Tumor , Cell Line, Tumor , DNA/therapeutic use , Humans , Lung Neoplasms/drug therapy , Neoplastic Cells, Circulating/pathology , Nuclear Proteins/genetics , Platinum/therapeutic use , Small Cell Lung Carcinoma/drug therapyABSTRACT
INTRODUCTION: Neuroendocrine neoplasms (NEN) are heterogeneous malignancies that can arise at almost any anatomical site and are classified as biologically distinct well-differentiated neuroendocrine tumors (NET) and poorly differentiated neuroendocrine carcinomas (NEC). Current systemic therapies for advanced disease, including targeted therapies, chemotherapy, and immunotherapy, are associated with limited duration of response. New therapeutic targets are needed. One promising target is delta-like ligand 3 (DLL3), an inhibitory ligand of the Notch receptor whose overexpression on the surface of NEN is associated with tumorigenesis. METHODS: This article is a narrative review that highlights the role of DLL3 in NEN progression and prognosis, the potential for therapeutic targeting of DLL3, and ongoing studies of DLL3-targeting therapies. Classification, incidence, pathogenesis, and current management of NEN are reviewed to provide biological context and illustrate the unmet clinical needs. DISCUSSION: DLL3 is overexpressed in many NENs, implicated in tumor progression, and is typically associated with poor clinical outcomes, particularly in patients with NEC. Targeted therapies using DLL3 as a homing beacon for cytotoxic activity mediated via several different mechanisms (eg, antibody-drug conjugates, T-cell engager molecules, CAR-Ts) have shown promising clinical activity in small-cell lung cancer (SCLC). DLL3 may be a clinically actionable target across NEN. CONCLUSIONS: Current treatment options for NEN do not provide sustained responses. DLL3 is expressed on the cell surface of many NEN types and is associated with poor clinical outcomes. Initial clinical studies targeting DLL3 therapeutically in SCLC have been promising, and additional studies are expanding this approach to the broader group of NEN.
Subject(s)
Carcinoma, Neuroendocrine , Lung Neoplasms , Neuroendocrine Tumors , Small Cell Lung Carcinoma , Humans , Lung Neoplasms/drug therapy , Ligands , Intracellular Signaling Peptides and Proteins/genetics , Membrane Proteins/genetics , Small Cell Lung Carcinoma/drug therapy , Neuroendocrine Tumors/drug therapy , Neuroendocrine Tumors/genetics , Neuroendocrine Tumors/pathology , Carcinoma, Neuroendocrine/pathologyABSTRACT
The therapeutic landscape of drugs targeting the DNA damage response (DDR) is rapidly expanding; however, an urgent unmet need remains for validated predictive biomarkers of response. SLFN11 has emerged as a promising predictor of sensitivity to DNA-damaging chemotherapies, and recently, been associated with sensitivity to PARP inhibition. We discuss its use as a predictive biomarker of response for targeting the DDR.
Subject(s)
DNA Damage , Drug Resistance, Neoplasm , Biomarkers , Cell Line, Tumor , Humans , Nuclear Proteins/geneticsABSTRACT
Nucleosome assembly proceeds through DNA replication-coupled or replication-independent mechanisms. For skeletal myocytes, whose nuclei have permanently exited the cell cycle, replication-independent assembly is the only mode available for chromatin remodeling. For this reason, any nucleosome composition alterations accompanying transcriptional responses to physiological signals must occur through a DNA replication-independent pathway. HIRA is the histone chaperone primarily responsible for replication-independent incorporation of histone variant H3.3 across gene bodies and regulatory regions. Thus, HIRA would be expected to play an important role in epigenetically regulating myocyte gene expression. The objective of this study was to determine the consequence of eliminating HIRA from mouse skeletal myocytes. At 6â weeks of age, myofibers lacking HIRA showed no pathological abnormalities; however, genes involved in transcriptional regulation were downregulated. By 6â months of age, myofibers lacking HIRA exhibited hypertrophy, sarcolemmal perforation and oxidative damage. Genes involved in muscle growth and development were upregulated, but those associated with responses to cellular stresses were downregulated. These data suggest that elimination of HIRA produces a hypertrophic response in skeletal muscle and leaves myofibers susceptible to stress-induced degeneration.
Subject(s)
Cell Cycle Proteins/deficiency , Histone Chaperones/deficiency , Muscle, Skeletal/metabolism , Muscular Diseases/metabolism , Oxidative Stress , Transcription Factors/deficiency , Animals , Hypertrophy , Mice , Mice, Transgenic , Muscle, Skeletal/pathology , Muscular Diseases/genetics , Muscular Diseases/pathologyABSTRACT
To identify novel therapeutic targets for non-small cell lung cancer (NSCLC), we conducted an integrative study in the following 3 stages: (i) identification of potential target gene(s) through shRNA functional screens in 2 independent NSCLC cell lines; (ii) validation of the clinical relevance of identified gene(s) using public databases; and (iii) investigation of therapeutic potential of targeting the identified gene(s) in vitro. A semi-genome-wide shRNA screen was performed in NCI-H358 cells, and was integrated with data from our previous screen in NCI-H460 cells. Among genes identified in shRNA screens, 24 were present in both NCI-H358 and NCI-H460 cells and were considered potential targets. Among the genes, we focused on eIF2ß, which is a subunit of heterotrimeric G protein EIF2 and functions as a transcription initiation factor. The eIF2ß protein is highly expressed in lung cancer cell lines compared with normal bronchial epithelial cells, and gene copy number analyses revealed that eIF2ß is amplified in a subset of NSCLC cell lines. Gene expression analysis using The Cancer Genome Atlas (TCGA) dataset revealed that eIF2ß expression is significantly upregulated in lung cancer tissues compared with corresponding normal lung tissues. Furthermore, high eIF2ß expression was correlated with poor survival in patients with lung adenocarcinoma, as shown in other cohorts using publicly available online tools. RNAi-mediated depletion of eIF2ß suppresses growth of lung cancer cells independently of p53 mutation status, in part through G1 cell cycle arrest. Our data suggest that eIF2ß is a therapeutic target for lung cancer.
Subject(s)
Adenocarcinoma/genetics , Carcinoma, Non-Small-Cell Lung/genetics , Eukaryotic Initiation Factor-2/genetics , Gene Expression Regulation, Neoplastic , Lung Neoplasms/genetics , A549 Cells , Adenocarcinoma/drug therapy , Adenocarcinoma/metabolism , Aged , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/metabolism , Cell Line , Cell Line, Tumor , Eukaryotic Initiation Factor-2/metabolism , Female , Humans , Kaplan-Meier Estimate , Lung Neoplasms/drug therapy , Lung Neoplasms/metabolism , Male , Middle Aged , Molecular Targeted Therapy , Protein Subunits/genetics , Protein Subunits/metabolism , RNA InterferenceABSTRACT
BACKGROUND: Extrapulmonary neuroendocrine carcinomas (NECs) are poorly studied and are managed similar to lung NECs, which may not account for differences between the 2 groups of tumors as well as the heterogeneity within extrapulmonary NEC. METHODS: Data from the Surveillance, Epidemiology, and End Results program between 1973 and 2012 were used to estimate the relative percentages of lung NECs and subgroups of extrapulmonary NECs, epidemiological patterns at these sites, and the median and 5-year overall survival rates. RESULTS: Of 162,983 NEC cases, 14,732 were extrapulmonary; of these, 5509 were gastrointestinal (37.44%), 4151 were of unknown primary (28.2%), and 5072 were of other sites (34.4%). Lung NEC had the highest percentage of small cell morphology (95.2%) and gastrointestinal NEC had the least (38.7%), with the rest being other morphologies. Significant differences were noted with regard to median age (range, 48-74 years), percentage of cases of distant stage disease (24%-77%), and incidence according to sex and race. The median survival of patients with lung NEC was 7.6 months, that for patients with gastrointestinal NEC was 7.5 months (range, 25.1 months for NEC at the small intestine to 5.7 months for NEC at the pancreas), and that for patients with unknown NEC was 2.5 months. The 5-year survival rate for patients with local stage disease ranged from 58% to 60% for NECs of the female genital tract and small intestine to 25% for esophageal NECs. The primary tumor site remained statistically significant for survival even after adjusting for known prognostic variables (P<.0001). CONCLUSIONS: To the authors' knowledge, the current study is the largest study of NECs performed to date and also the first with comprehensive epidemiological data. Significant differences in incidence patterns and large variations in survival depending on anatomical site and morphological subtype were noted. A curative approach is possible for patients with nonmetastatic NECs. Cancer 2018;124:807-15. © 2017 American Cancer Society.
Subject(s)
Carcinoma, Neuroendocrine/pathology , Gastrointestinal Neoplasms/pathology , Lung Neoplasms/pathology , Small Cell Lung Carcinoma/pathology , Aged , Carcinoma, Neuroendocrine/epidemiology , Female , Gastrointestinal Neoplasms/epidemiology , Humans , Incidence , Lung Neoplasms/epidemiology , Male , Middle Aged , Prognosis , SEER Program/statistics & numerical data , Small Cell Lung Carcinoma/epidemiology , Survival Analysis , United States/epidemiologyABSTRACT
BACKGROUND: Rovalpituzumab tesirine is a first-in-class antibody-drug conjugate directed against delta-like protein 3 (DLL3), a novel target identified in tumour-initiating cells and expressed in more than 80% of patients with small-cell lung cancer. We aimed to assess the safety and activity of rovalpituzumab tesirine in patients who progressed after one or more previous regimen. METHODS: We conducted a phase 1 open-label study at ten cancer centres in the USA. Eligible patients were aged 18 years or older and had histologically or cytologically confirmed small-cell lung cancer or large-cell neuroendocrine tumours with progressive measurable disease (according to Response Evaluation Criteria in Solid Tumors [RECIST], version 1.1) previously treated with one or two chemotherapeutic regimens, including a platinum-based regimen. We assigned patients to dose-escalation or expansion cohorts, ranging from 0·05 mg/kg to 0·8 mg/kg rovalpituzumab tesirine intravenously every 3 weeks or every 6 weeks, followed by investigation of the dose schedules 0·3 mg/kg and 0·4 mg/kg every 6 weeks and 0·2 mg/kg every 3 weeks. Primary objectives were to assess the safety of rovalpituzumab tesirine, including the maximum tolerated dose and dose-limiting toxic effects. The primary activity endpoint was objective response by intention-to-treat analysis. This study is registered with ClinicalTrials.gov, number NCT01901653. The study is closed to enrolment; this report focuses on the cohort with small-cell lung cancer. FINDINGS: Between July 22, 2013, and Aug 10, 2015, 82 patients were enrolled, including 74 patients with small-cell lung cancer and eight with large-cell neuroendocrine carcinoma, all of whom received at least one dose of rovalpituzumab tesirine. Dose-limiting toxic effects of rovalpituzumab tesirine occurred at a dose of 0·8 mg/kg every 3 weeks, including grade 4 thrombocytopenia (in two of two patients at that dose level) and grade 4 liver function test abnormalities (in one patient). The most frequent grade 3 or worse treatment-related adverse events in 74 patients with small-cell lung cancer were thrombocytopenia (eight [11%]), pleural effusion (six [8%]), and increased lipase (five [7%]). Drug-related serious adverse events occurred in 28 (38%) of 74 patients. The maximum tolerated dose of rovalpituzumab tesirine was 0·4 mg/kg every 3 weeks; the recommended phase 2 dose and schedule is 0·3 mg/kg every 6 weeks. At active doses of rovalpituzumab tesirine (0·2 mg/kg or 0·4 mg/kg every 3 weeks or 0·3 mg/kg or 0·4 mg/kg every 6 weeks), 11 (18%) of 60 assessable patients had a confirmed objective response. 11 (18%) of 60 assessable patients had a confirmed objective response, including ten (38%) of 26 patients confirmed to have high DLL3 expression (expression in 50% or more of tumour cells). INTERPRETATION: Rovalpituzumab tesirine shows encouraging single-agent antitumour activity with a manageable safety profile. Further development of rovalpituzumab tesirine in DLL3-expressing malignant diseases is warranted. FUNDING: Stemcentrx Inc.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents/therapeutic use , Benzodiazepinones/therapeutic use , Carcinoma, Large Cell/drug therapy , Carcinoma, Neuroendocrine/drug therapy , Immunoconjugates/therapeutic use , Intracellular Signaling Peptides and Proteins/immunology , Lung Neoplasms/drug therapy , Membrane Proteins/immunology , Neoplasm Recurrence, Local/drug therapy , Small Cell Lung Carcinoma/drug therapy , Aged , Carcinoma, Large Cell/immunology , Carcinoma, Large Cell/pathology , Carcinoma, Neuroendocrine/immunology , Carcinoma, Neuroendocrine/pathology , Dose-Response Relationship, Drug , Female , Follow-Up Studies , Humans , Immunoconjugates/pharmacology , Lung Neoplasms/immunology , Lung Neoplasms/pathology , Male , Maximum Tolerated Dose , Middle Aged , Neoplasm Recurrence, Local/immunology , Neoplasm Recurrence, Local/pathology , Neoplasm Staging , Prognosis , Small Cell Lung Carcinoma/immunology , Small Cell Lung Carcinoma/pathology , Survival RateABSTRACT
To identify potential therapeutic targets for lung cancer, we performed semi-genome-wide shRNA screening combined with the utilization of genome-wide expression and copy number data. shRNA screening targeting 5043 genes in NCI-H460 identified 51 genes as candidates. Pathway analysis revealed that the 51 genes were enriched for the five pathways, including ribosome, proteasome, RNA polymerase, pyrimidine metabolism and spliceosome pathways. We focused on the proteasome pathway that involved six candidate genes because its activation has been demonstrated in diverse human malignancies, including lung cancer. Microarray expression and array CGH data showed that PSMA6, a proteasomal subunit of a 20S catalytic core complex, was highly expressed in lung cancer cell lines, with recurrent gene amplifications in some cases. Therefore, we further examined the roles of PSMA6 in lung cancer. Silencing of PSMA6 induced apoptosis or G2/M cell cycle arrest in cancer cell lines but not in an immortalized normal lung cell line. These results suggested that PSMA6 serves as an attractive target with a high therapeutic index for lung cancer.
Subject(s)
Carcinoma, Non-Small-Cell Lung/genetics , Catalytic Domain/genetics , Gene Expression Regulation, Neoplastic , Lung Neoplasms/genetics , Proteasome Endopeptidase Complex/genetics , A549 Cells , Aged , Apoptosis/genetics , Blotting, Western , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line , Cell Line, Tumor , Cell Proliferation/genetics , Cell Survival/genetics , Female , G2 Phase Cell Cycle Checkpoints/genetics , Gene Amplification , Gene Expression Profiling/methods , Humans , Immunohistochemistry , Kaplan-Meier Estimate , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Male , Molecular Targeted Therapy , Proteasome Endopeptidase Complex/metabolism , RNA Interference , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction/geneticsABSTRACT
MOTIVATION: Nonlinear dose-response models are primary tools for estimating the potency [e.g. half-maximum inhibitory concentration (IC) known as IC50] of anti-cancer drugs. We present drexplorer software, which enables biologists to evaluate replicate reproducibility, detect outlier data points, fit different models, select the best model, estimate IC values at different percentiles and assess drug-drug interactions. drexplorer serves as a computation engine within the R environment and a graphical interface for users who do not have programming backgrounds.
Subject(s)
Antineoplastic Agents/pharmacology , Drug Screening Assays, Antitumor/methods , Software , Algorithms , Dose-Response Relationship, Drug , Drug Interactions , Inhibitory Concentration 50 , Nonlinear Dynamics , Reproducibility of ResultsABSTRACT
OBJECTIVES: Small cell cervical cancer is a rare malignancy with limited treatment options for recurrent disease. We sought to determine if tumor specimens of small cell cervical cancer harbor common somatic mutations and if any of these are actionable. METHODS: Using a registry of patients with neuroendocrine cervical cancer, we identified 44 patients with pure or mixed small cell cervical cancer who had undergone mutational analysis. Mutations had been detected using next generation sequencing of mutational hotspots in 50 cancer-related genes. RESULTS: Thirty-five mutations were identified in 24 patients (55%). Fifteen of these 24 patients (63%) had 1 mutation, 7 patients (29%) had 2 mutations, and 2 patients (8%) had 3 mutations. In all 44 patients, the most commonly seen mutations were mutations in PIK3CA (8 patients; 18%), KRAS (6 patients; 14%), and TP53 (5 patients; 11%). No other mutation was found in >7% of specimens. Of the 24 patients who had a mutation, 21 (88%) had at least 1 alteration for which there currently exists a class of biological agents targeting that mutation. In the entire cohort of 44 patients, 48% had at least 1 actionable mutation. CONCLUSION: Although no single mutation was found in the majority of patients with small cell cervical cancer, almost half had at least 1 actionable mutation. As treatment options for patients with recurrent small cell cervical cancer are currently very limited, molecular testing for targetable mutations, which may suggest potential therapeutic strategies, may be useful for clinicians and patients.
Subject(s)
Carcinoma, Neuroendocrine/genetics , Carcinoma, Small Cell/genetics , Mutation , Uterine Cervical Neoplasms/genetics , Adult , Class I Phosphatidylinositol 3-Kinases , DNA Mutational Analysis , Female , Genes, p53 , Humans , Middle Aged , Phosphatidylinositol 3-Kinases/genetics , Proto-Oncogene Proteins p21(ras)/genetics , Retrospective Studies , Tumor Suppressor Protein p53/genetics , Young AdultSubject(s)
Biomarkers, Tumor/antagonists & inhibitors , Immunotherapy , Lung Neoplasms/therapy , Molecular Targeted Therapy , Small Cell Lung Carcinoma/therapy , Biomarkers, Tumor/immunology , Biomarkers, Tumor/metabolism , Humans , Lung Neoplasms/immunology , Lung Neoplasms/metabolism , Patient Selection , Small Cell Lung Carcinoma/immunology , Small Cell Lung Carcinoma/metabolismABSTRACT
Approximately 15% of lung cancer cases are of the small cell subtype, but this variant is highly aggressive and is often diagnosed at advanced stages. Outcomes after current treatment regimens have been poor, with 5-year survival rates as low as 25% for patients with limited-stage disease. Advances in therapy for small cell lung cancer have included the development of more effective chemotherapeutic agents and radiation techniques. For example, hyperfractionated radiotherapy given early in the course of the disease can reduce local recurrence and extend survival. Other technologic advances in radiation planning and delivery such as intensity-modulated radiotherapy, image-guided adaptive radiotherapy, and 4-dimensional computed tomography/positron emission tomography have facilitated the design of treatment volumes that closely conform to the shape of the tumor, which allows higher radiation doses to be given while minimizing radiation-induced toxicity to adjacent structures. Future improvements in outcomes will require clarifying the molecular basis for this disease.
Subject(s)
Lung Neoplasms , Neoplasm Recurrence, Local/prevention & control , Small Cell Lung Carcinoma , Dose Fractionation, Radiation , Four-Dimensional Computed Tomography/methods , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/mortality , Lung Neoplasms/radiotherapy , Neoplasm Recurrence, Local/radiotherapy , Neoplasm Staging , Positron-Emission Tomography/methods , Radiotherapy, Image-Guided/methods , Radiotherapy, Intensity-Modulated/methods , Small Cell Lung Carcinoma/drug therapy , Small Cell Lung Carcinoma/mortality , Small Cell Lung Carcinoma/radiotherapy , Survival Rate , Treatment OutcomeABSTRACT
BACKGROUND: The goal of the current study was to assess the rates of recurrence in the neck for patients with lymph node-positive human papillomavirus-associated cancer of the oropharynx who were treated with definitive radiotherapy (with or without chemotherapy). METHODS: This is a single-institution retrospective study. Methodology included database search, and statistical testing including frequency analysis, Kaplan-Meier tests, and comparative tests including chi-square, logistic regression, and log-rank. RESULTS: The cohort consisted of 401 patients with lymph node-positive disease who underwent radiotherapy between January 2006 and June 2012. A total of 388 patients had computed tomography restaging, and 251 had positron emission tomography and/or ultrasound as a component of their postradiation staging. Eighty patients (20%) underwent neck dissection, and 21 patients (26%) had a positive specimen. The rate of neck dissection increased with increasing lymph node stage, and was lower in patients who had positron emission tomography scans or ultrasound in addition to computed tomography restaging. The median follow-up was 30 months. The 2-year actuarial neck recurrence rate was 7% and 5%, respectively, in all patients and those with local control. Lymph node recurrence rates were greater in current smokers (P = .008). There was no difference in lymph node recurrence rates noted between patients who did and those who did not undergo a neck dissection (P = .4) CONCLUSIONS: A treatment strategy of (chemo)radiation with neck dissection performed based on response resulted in high rates of regional disease control in patients with human papillomavirus-associated oropharyngeal cancer.