Incorporation of Antiangiogenic Therapy Into the Non-Small-Cell Lung Cancer Paradigm.

Although molecular targeted agents have improved the treatment of lung cancer, their use has largely been restricted to limited subsets of the overall population that carry specific mutations. Angiogenesis, the formation of new blood vessels from existing networks, is an attractive, more general process for the development of targeted anticancer therapies, because it is critical for the growth of solid tumors, including non-small-cell lung cancer. Growing tissues require a vascular supply within a few millimeters. Therefore, solid tumors create a proangiogenic microenvironment to facilitate the development of new tumor-associated blood vessels, thus providing an adequate vascular supply for continued tumor growth. Antiangiogenic agents can specifically target the vascular endothelial growth factor (VEGF) signaling pathways, broadly inhibit multiple tyrosine kinases, or interfere with other angiogenic processes, such as disruption of existing tumor vasculature. The present report provides an overview of antiangiogenic therapy for non-small-cell lung cancer, including both currently approved antiangiogenic therapies (bevacizumab [anti-VEGF] and ramucirumab [anti-VEGF receptor 2] monoclonal antibodies), and a variety of promising novel agents in development. Although recent data have demonstrated promising efficacy for some novel agents, the overall development of antiangiogenic therapy has been hampered by redundancy in signaling pathways and the highly heterogeneous nature of tumors. An improved understanding of the molecular basis of angiogenesis will guide the development of new antiangiogenic therapies and the identification of biomarkers to predict which patients with lung cancer are most likely to benefit from antiangiogenic therapy.

CT Gray-Level Texture Analysis as a Quantitative Imaging Biomarker of Epidermal Growth Factor Receptor Mutation Status in Adenocarcinoma of the Lung.

OBJECTIVE: The purpose of this study was to investigate the radiogenomic correlation between CT gray-level texture features and epidermal growth factor receptor (EGFR) mutation status in adenocarcinoma of the lung. MATERIALS AND METHODS: This retrospective study included 25 patients with exon 19 short inframe deletion (exon 19) and 21 patients with exon 21 L858R point (exon 21) EGFR mutations among 125 patients with EGFR mutant adenocarcinoma of the lung. The randomly formed control group consisted of 20 patients selected from 126 patients with EGFR mutation-negative (wild-type) adenocarcinomas. Five gray-level texture features (contrast, correlation, inverse difference moment, angular second moment, and entropy) were analyzed. RESULTS: Contrast differentiated both exon 19 (p = 0.00027) and exon 21 (p = 0.00001) mutants from the wild type. Wild-type adenocarcinomas had high scores for contrast (mean, 1598.547) compared with EGFR mutants (mean, 679.463). Correlation differentiated both exon 19 (p = 0.017) and exon 21 (p = 0.0015) mutants from wild-type adenocarcinomas. Inverse difference moment differentiated exon 19 mutants from exon 21 mutants (p = 0.019) and both exon 19 (p = 0.044) and exon 21 (p = 0.00001) mutants from wild-type adenocarcinomas. Angular second moment and entropy were not associated with statistically significant differences between mutation statuses. CONCLUSION: Contrast, correlation, and inverse difference moment texture features correlate with EGFR mutation status in adenocarcinoma of the lung. Further investigation with larger prospective studies is needed to validate the role of CT gray-level texture analysis as a quantitative imaging biomarker.

Long-Term Therapy with Lenalidomide in a Patient with POEMS Syndrome.

Lenalidomide is an effective therapy against malignant plasma cells and a potent agent against proinflammatory and proangiogenic cytokines. The use of lenalidomide in POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein with plasma cells, skin changes) has been reported, but its benefit in long-term use is not well established. A 55-year-old man with POEMS and debilitating polyneuropathy was treated with lenalidomide and dexamethasone followed by maintenance lenalidomide. He remains in haematologic remission and in complete recovery of functional status 3.5 years after diagnosis. This case supports the long-term use of lenalidomide in patients with POEMS syndrome.

A 3-bp deletion in the HBS1L-MYB intergenic region on chromosome 6q23 is associated with HbF expression.

Fetal hemoglobin (HbF) is regulated as a multigenic trait. By genome-wide association study, we confirmed that HBS1L-MYB intergenic polymorphisms (HMIP) and BCL11A polymorphisms are highly associated with HbF in Chinese ß-thalassemia heterozygotes. In this population, the variance in HbF resulting from the HMIP is 13.5%; that resulting from the BCL11A polymorphism is 6.4%. To identify the functional variant in HMIP, we used 1000 Genomes Project data, single nucleotide polymorphism imputation, comparisons of association results across populations, potential transcription factor binding sites, and analysis of phylogenetic conservation. Based on these studies, a hitherto unreported association between HbF expression and a 3-bp deletion, between 135 460 326 and 135 460 328 bp on chromosome 6q23 was found. This 3-bp deletion is in complete linkage disequilibrium with rs9399137, which is the single nucleotide polymorphism in HMIP most significantly associated with HbF among Chinese, Europeans, and Africans. Chromatin immunoprecipitation assays confirmed erythropoiesis-related transcription factors binding to this region in K562 cells. Based on transient expression of a luciferase reporter plasmid, the DNA fragment encompassing the 3-bp deletion polymorphism has enhancer-like activity that is further augmented by the introduction of the 3-bp deletion. This 3-bp deletion polymorphism is probably the most significant functional motif accounting for HMIP modulation of HbF in all 3 populations.

Identification of compounds selectively killing multidrug-resistant cancer cells.

There is a great need for the development of novel chemotherapeutic agents that overcome the emergence of multidrug resistance (MDR) in cancer. We catalogued the National Cancer Institute's DTP drug repository in search of compounds showing increased toxicity in MDR cells. By comparing the sensitivity of parental cell lines with MDR derivatives, we identified 22 compounds possessing MDR-selective activity. Analysis of structural congeners led to the identification of 15 additional drugs showing increased toxicity in Pgp-expressing cells. Analysis of MDR-selective compounds led to the formulation of structure activity relationships and pharmacophore models. This data mining coupled with experimental data points to a possible mechanism of action linked to metal chelation. Taken together, the discovery of the MDR-selective compound set shows the robustness of the developing field of MDR-targeting therapy as a new strategy for resolving Pgp-mediated MDR.

Selective toxicity of NSC73306 in MDR1-positive cells as a new strategy to circumvent multidrug resistance in cancer.

ATP-binding cassette (ABC) proteins include the best known mediators of resistance to anticancer drugs. In particular, ABCB1 [MDR1/P-glycoprotein (P-gp)] extrudes many types of drugs from cancer cells, thereby conferring resistance to those agents. Attempts to overcome P-gp-mediated drug resistance using specific inhibitors of P-gp has had limited success and has faced many therapeutic challenges. As an alternative approach to using P-gp inhibitors, we characterize a thiosemicarbazone derivative (NSC73306) identified in a generic screen as a compound that exploits, rather than suppresses, P-gp function to induce cytotoxicity. Cytotoxic activity of NSC73306 was evaluated in vitro using human epidermoid, ovarian, and colon cancer cell lines expressing various levels of P-gp. Our findings suggest that cells become hypersensitive to NSC73306 in proportion to the increased P-gp function and multidrug resistance (MDR). Abrogation of both sensitivity to NSC73306 and resistance to P-gp substrate anticancer agents occurred with specific inhibition of P-gp function using either a P-gp inhibitor (PSC833, XR9576) or RNA interference, suggesting that cytotoxicity was linked to MDR1 function, not to other, nonspecific factors arising during the generation of resistant or transfected cells. Molecular characterization of cells selected for resistance to NSC73306 revealed loss of P-gp expression and consequent loss of the MDR phenotype. Although hypersensitivity to NSC73306 required functional expression of P-gp, biochemical assays revealed no direct interaction between NSC73306 and P-gp. This article shows that NSC73306 kills cells with intrinsic or acquired P-gp-induced MDR and indirectly acts to eliminate resistance to MDR1 substrates.