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Microenvironmental Regulation of Tumor Progression and Metastasis

Microenvironmental Regulation of Tumor Progression and Metastasis | Lung Cancer Research Digest | Scoop.it

"Cancers develop in complex tissue environments, which they depend on for sustained growth, invasion and metastasis. Unlike tumor cells, stromal cell types within the tumor microenvironment (TME) are genetically stable and thus represent an attractive therapeutic target with reduced risk of resistance and tumor recurrence. However, specifically disrupting the pro-tumorigenic TME is a challenging undertaking, as the TME has diverse capacities to induce both beneficial and adverse consequences for tumorigenesis. Furthermore, many studies have shown that the microenvironment is capable of normalizing tumor cells, suggesting that re-education of stromal cells, rather than targeted ablation per se, may be an effective strategy for treating cancer. Here we discuss the paradoxical roles of the TME during specific stages of cancer progression and metastasis, as well as recent therapeutic attempts to re-educate stromal cells within the TME to have anti-tumorigenic effects."

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Quail DF, Joyce JA. Nature Medicine. Nov 7, 2013.

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Cancer Commons's curator insight, November 8, 2013 1:50 PM

Quail DF, Joyce JA. Nature Medicine. Nov 7, 2013.

Cancer Commons's curator insight, November 8, 2013 1:51 PM

Quail DF, Joyce JA. Nature Medicine. Nov 7, 2013.

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Lung Cancer Research Digest
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Identification of cancer initiating cells in K-Ras driven lung adenocarcinoma

K-RAS oncogene-driven lung adenocarcinomas is one of the most malignant human tumors for which there are no efficacious therapeutic strategies. Here, we have used a mouse tumor model that closely recapitulates this human disease to illustrate that adult lung cells are uniquely sensitive to transformation by this oncogene. Monitoring lung cells at the single-cell level revealed that they respond differently to K-Ras oncogenic signals. Whereas K-Ras–expressing Clara cells required an inflammatory response to yield hyperplasias and adenomas, alveolar type II cells or their committed precursors led to the generation of malignant adenocarcinoma regardless of their surrounding microenvironment.

Cancer Commons's insight:

Mainardi S, Mijimolle N, Francoz S, Vicente-Dueña C et al

PNAS, Dec 23 2013

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Reproducible copy number variation patterns among single circulating tumor cells of lung cancer patients

In a few milliliters of blood from a cancer patient, one can isolate a few circulating tumor cells (CTCs). Originating from the primary tumor, CTCs seed metastases, which account for the majority of cancer-related deaths. We demonstrate the analyses of the whole genome of single CTCs, which are highly needed for personalized treatment. We discovered that copy number variations (CNVs), one of the major genomic variations, are specific to cancer types, reproducible from cell to cell, and even from patient to patient. We hypothesize that CNVs at certain genomic loci are selected for and lead to metastasis. Our work shows the prospect of noninvasive CTC-based cancer diagnostics.

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Ni X, Zhuo M, Su Z, Duan J et al.

PNAS, Dec 9 2013

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Co-clinical trials demonstrate superiority of crizotinib to chemotherapy in ALK-rearranged non-small cell lung cancer and predict strategies to overcome resistance

"We performed a co-clinical trial in a mouse model comparing the ALK inhibitor crizotinib to the standard-of-care cytotoxic agents docetaxel or pemetrexed. Results:Concordant with the clinical outcome in humans, crizotinib produced a substantially higher response rate compared to chemotherapy, associated with significantly longer progression-free survival. Overall survival was also prolonged in crizotinib- compared to chemotherapy-treated mice. Pemetrexed produced superior overall survival compared to docetaxel, suggesting that this agent may be the preferred chemotherapy in the ALK population. Additionally, in the EML4-ALK-driven mouse lung adenocarcinoma model, HSP90 inhibition can overcome both primary and acquired crizotinib resistance. Furthermore, HSP90 inhibition, as well as the second-generation ALK inhibitor TAE684, demonstrated activity in newly developed lung adenocarcinoma models driven by crizotinib-insensitive EML4-ALK L1196M or F1174L. Conclusions:Our findings suggest that crizotinib is superior to standard chemotherapy in ALK inhibitor-naïve disease and support further clinical investigation of HSP90 inhibitors and second-generation ALK inhibitors in tumors with primary or acquired crizotinib resistance."

Cancer Commons's insight:

Chen Z, Akbay EA, Mikse OR, Tupper T et al

Clinical Cancer Res., Dec 11 2013

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Cell-autonomous and non-cell-autonomous mechanisms of transformation by amplified FGFR1 in lung cancer

"The 8p12 locus (containing the FGFR1 tyrosine kinase gene) is frequently amplified in squamous-cell lung cancer (SQLC). However, it is currently unknown, which of the 8p12-amplified tumors are also sensitive to FGFR inhibition. We found that, in contrast to other recurrent amplifications, the 8p12 region included multiple centers of amplification, suggesting marked genomic heterogeneity. FGFR1-amplified tumor cells were dependent on FGFR ligands in vitro and in vivo. Furthermore, ectopic expression of FGFR1 was oncogenic, which was enhanced by expression of MYC. We found that MYC was co-expressed in 40% of FGFR1-amplified tumors. Tumor cells co-expressing MYC were more sensitive to FGFR inhibition, suggesting that patients with FGFR1-amplified and MYC-overexpressing tumors may benefit from FGFR inhibitor therapy. Thus, both cell-autonomous and non-cell-autonomous mechanisms of transformation modulate FGFR dependency in FGFR1-amplified lung cancer, which may have implications for patient selection for treatment with FGFR inhibitors."


Cancer Commons's insight:

Malchers F, Dietlein F, Schöttle J, Lu X et al

Cancer Discovery, Dec 3, 2013 

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Targeting epithelial to mesenchymal transition with Met inhibitors reverts chemoresistance in small cell lung cancer

"Met receptor phosphorylation is associated with poor prognosis in human SCLC. The aim of our work was to investigate the effects of hepatocyte growth factor (HGF)/Met mediated epithelial mesenchymal transition in SCLC and to evaluate the role of Met inhibition in mesenchymal/chemorefractory SCLC models. We identified that the activation of the Met receptor through HGF induced expression of mesenchymal markers, an aggressive phenotype and chemoresistance. Blockade of this process with the Met inhibitor resensitized cells to chemotherapy in vitro and in vivo. Moreover, mesenchymal markers in human SCLC specimens were associated with Met activation, predicted worse survival and were upregulated in chemorefractory disease. These results provide novel evidence on an important role of Met-dependent EMT in the adverse clinical behavior of SCLC and supports clinical trials of Met inhibitors and chemotherapy in this fatal disease."

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Israel Canadas, Federico Rojo, Alvaro Taus, Oriol Arpi et al.

CLinical Cancer Research, Nov. 27, 2013

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K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions

"Somatic mutations in the small GTPase K-Ras are the most common activating lesions found in human cancer, and are generally associated with poor response to standard therapies123. Efforts to target this oncogene directly have faced difficulties owing to its picomolar affinity for GTP/GDP4and the absence of known allosteric regulatory sites. Oncogenic mutations result in functional activation of Ras family proteins by impairing GTP hydrolysis56. With diminished regulation by GTPase activity, the nucleotide state of Ras becomes more dependent on relative nucleotide affinity and concentration. This gives GTP an advantage over GDP7 and increases the proportion of active GTP-bound Ras. Here we report the development of small molecules that irreversibly bind to a common oncogenic mutant, K-Ras(G12C). These compounds rely on the mutant cysteine for binding and therefore do not affect the wild-type protein. Crystallographic studies reveal the formation of a new pocket that is not apparent in previous structures of Ras, beneath the effector binding switch-II region. Binding of these inhibitors to K-Ras(G12C) disrupts both switch-I and switch-II, subverting the native nucleotide preference to favour GDP over GTP and impairing binding to Raf. Our data provide structure-based validation of a new allosteric regulatory site on Ras that is targetable in a mutant-specific manner."

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Ostrem JM, Peters U, Sos MJ,  Wells JA, Shokat KM.

NAture, Nov 20, 2013

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Next-Generation Genome Screening is Step toward Precision Cancer Medicine for Lung Cancer

Next-Generation Genome Screening is Step toward Precision Cancer Medicine for Lung Cancer | Lung Cancer Research Digest | Scoop.it

"Precision cancer medicine has taken a strong step forward at the Ohio State University Comprehensive Cancer Center. The technology, known as next generation "multiplex" gene sequencing, analyzes 50-plus genes in DNA extracted from a tumor biopsy for particular genetic mutations. Previous technology required pathologists to analyze one mutation per tissue sample. This second-generation genome sequencing assesses more than 2,500 mutations in a single reaction."

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Medical Xpress. NOv 14, 2013.

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Foretinib is a Potent Inhibitor of Oncogenic ROS1 Fusion Proteins

"We demonstrate that foretinib is a more potent ROS1 inhibitor than crizotinib in vitro and in vivo and remains effective against crizotinib-resistant ROS1 kinase domain mutations, including ROS1 G2032R. Taken together, our findings establish foretinib as a highly promising therapeutic candidate for treating patients with ROS1-driven malignancies and provide rationale for rapid clinical translation."

Cancer Commons's insight:

Davare MA, Saborowski A, Eide CA, Tognon C, et al. PNAS USA. Nov 11, 2013.

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Genome-wide Consequences of Deleting Any Single Gene

"Loss or duplication of chromosome segments can lead to further genomic changes associated with cancer. However, it is not known whether only a select subset of genes is responsible for driving further changes. To determine whether perturbation of any given gene in a genome suffices to drive subsequent genetic changes, we analyzed the yeast knockout collection for secondary mutations of functional consequence. Unlike wild-type, most gene knockout strains were found to have one additional mutant gene affecting nutrient responses and/or heat-stress-induced cell death. Moreover, independent knockouts of the same gene often evolved mutations in the same secondary gene. Genome sequencing identified acquired mutations in several human tumor suppressor homologs. Thus, mutation of any single gene may cause a genomic imbalance, with consequences sufficient to drive adaptive genetic changes. This complicates genetic analyses but is a logical consequence of losing a functional unit originally acquired under pressure during evolution."

Cancer Commons's insight:

Teng X, Dayhoff-Brannigan M, Cheng WC, Gilbert CE, et al. Molecular Cell. Nov 7, 2013.

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Cancer Commons's curator insight, November 14, 2013 1:32 PM

Teng X, Dayhoff-Brannigan M, Cheng WC, Gilbert CE, et al. Molecular Cell. Nov 7, 2013.

Cancer Commons's curator insight, November 14, 2013 1:32 PM

Teng X, Dayhoff-Brannigan M, Cheng WC, Gilbert CE, et al. Molecular Cell. Nov 7, 2013.

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Boston Research Institutes, Hospitals Launch Clinical Genomics Center

Boston Research Institutes, Hospitals Launch Clinical Genomics Center | Lung Cancer Research Digest | Scoop.it

"A quartet of Boston-area research centers including Dana-Farber Cancer Institute, Brigham and Women's Hospital, Boston Children's Hospital, and the Broad Institute have teamed to create a new clinical cancer genomics center that will be headquartered at Dana-Farber. Dana-Farber said today that the new Joint Center for Cancer Precision Medicine will harness a wide range of scientific resources and clinical capabilities from the partners to treat cancer patients and feed treatment data into research programs. The multiple capabilities these partners will share and use in the new center include DNA sequencing and other tumor molecular profiling tools, pathology, radiology, surgery, computational interpretation, and tumor modeling systems, they said."

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GenomeWeb Daily News | Nov 12, 2013

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Cancer Commons's curator insight, November 13, 2013 8:09 PM

GenomeWeb Daily News | Nov 12, 2013

Cancer Commons's curator insight, November 13, 2013 8:10 PM

GenomeWeb Daily News | Nov 12, 2013

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Requirement for Interaction of PI3-Kinase p110α with RAS in Lung Tumor Maintenance

"RAS proteins directly activate PI3-kinases. Mice bearing a germline mutation in the RAS binding domain of the p110α subunit of PI3-kinse are resistant to the development of RAS-driven tumors. However, it is unknown whether interaction of RAS with PI3-kinase is required in established tumors. The need for RAS interaction with p110α in the maintenance of mutant Kras-driven lung tumors was explored using an inducible mouse model."

Cancer Commons's insight:

Castellano E, Sheridan C, Thin MZ, Nye E, et al. Cancer Cell. Nov 11, 2013.

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Foundation Medicine Partners with Broad-based Coalition to Advance Revolutionary New Clinical Trial Design in Lung Cancer

"Foundation Medicine announced that it has partnered with Friends of Cancer Research, as well as federal health and regulatory agencies, pharmaceutical companies, multiple cooperative groups and patient advocacy organizations to develop the clinical trial design for the "Master Protocol" study in patients with squamous cell carcinoma of the lung."

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The Wall Street Journal. Nov 7, 2013.

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Targeting Resistance in Lung Cancer

Two investigational drugs, AstraZeneca's AZD9291 and Clovis Oncology's CO-1686, both showed encouraging results in early trials of patients with EGFR-mutated non–small cell lung cancer (NSCLC) who have developed resistance to targeted therapies. Pfizer's investigational agent PF-06463922, developed for patients with ALK-mutated NSCLC who have developed resistance to crizotinib, demonstrated strong activity and selectivity in preclinical research and will be studied in a phase I clinical trial launching by year-end.

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Cancer Discovery. Nov 7, 2013.

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Structural, Biochemical, and Clinical Characterization of Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertion Mutations in Lung Cancer

"Epidermal growth factor receptor (EGFR) gene mutations (G719X, exon 19 deletions/insertions, L858R, and L861Q) predict favorable responses to EGFR tyrosine kinase inhibitors (TKIs) in advanced non–small cell lung cancer (NSCLC). However, EGFR exon 20 insertion mutations (~10% of all EGFR mutations) are generally associated with insensitivity to available TKIs (gefitinib, erlotinib, and afatinib). The basis of this primary resistance is poorly understood. We studied a broad subset of exon 20 insertion mutations, comparing in vitro TKI sensitivity with responses to gefitinib and erlotinib in NSCLC patients, and found that most are resistant to EGFR TKIs. The crystal structure of a representative TKI-insensitive mutant (D770_N771insNPG) reveals an unaltered adenosine triphosphate–binding pocket, and the inserted residues form a wedge at the end of the C helix that promotes the active kinase conformation. Unlike EGFR-L858R, D770_N771insNPG activates EGFR without increasing its affinity for EGFR TKIs. Unexpectedly, we find that EGFR-A763_Y764insFQEA is highly sensitive to EGFR TKIs in vitro, and patients whose NSCLCs harbor this mutation respond to erlotinib. Analysis of the A763_Y764insFQEA mutant indicates that the inserted residues shift the register of the C helix in the N-terminal direction, altering the structure in the region that is also affected by the TKI-sensitive EGFR-L858R. Our studies reveal intricate differences between EGFR mutations, their biology, and their response to EGFR TKIs."

Cancer Commons's insight:

Yasuda H, Park E, Yun C-H, Sng NG et al.

Science Translational Medicine, Dec 19, 2013

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Impeding Macrophage Entry into Hypoxic Tumor Areas by Sema3A/Nrp1 Signaling Blockade Inhibits Angiogenesis and Restores Antitumor Immunity

"We report that hypoxia-induced Semaphorin 3A (Sema3A) acts as an attractant for TAMs by triggering vascular endothelial growth factor receptor 1 phosphorylation through the associated holoreceptor, composed of Neuropilin-1 (Nrp1) and PlexinA1/PlexinA4. Importantly, whereas Nrp1 levels are downregulated in the hypoxic environment, Sema3A continues to regulate TAMs in an Nrp1-independent manner by eliciting PlexinA1/PlexinA4-mediated stop signals, which retain them inside the hypoxic niche. Consistently, gene deletion of Nrp1 in macrophages favors TAMs’ entrapment in normoxic tumor regions, which abates their pro-angiogenic and immunosuppressive functions, hence inhibiting tumor growth and metastasis. This study shows that TAMs’ heterogeneity depends on their localization, which is tightly controlled by Sema3A/Nrp1 signaling. "

Cancer Commons's insight:

Casazza A, Laoui D,  Wenes M, Rizzolio S et al

Cancer Cell, Dec 11 2013

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Epithelial to mesenchymal transition rewires the molecular path to PI3-Kinase-dependent proliferation

"Tumors showing evidence of epithelial to mesenchymal transition (EMT) have been associated with metastasis, drug resistance, and poor prognosis. Heterogeneity along the EMT spectrum is observed between and within tumors. To develop effective therapeutics, a mechanistic understanding of how EMT affects the molecular requirements for proliferation is needed. We found that while cells utilize PI3K for proliferation in both the epithelial and mesenchymal states, EMT rewires the mechanism of PI3K pathway activation. In epithelial cells autocrine ErbB3 activation maintains PI3K signaling, while after EMT, downregulation of ErbB3 disrupts autocrine signaling to PI3K. Loss of ErbB3 leads to reduced serum-independent proliferation after EMT which can be rescued through reactivation of PI3K by enhanced signaling from p110α, ErbB3 re-expression, or growth factor stimulation. In vivo, we demonstrate that PIK3CA expression is upregulated in mesenchymal tumors with low levels of ERBB3. This study defines how ErbB3 downregulation after EMT affects PI3K-dependent proliferation."

Cancer Commons's insight:

Salt MB, Bandyopadhyay S, and McCormick F.

Cancer Discovery, Dec 3 2013

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JCI - Targeting SOD1 reduces experimental non–small-cell lung cancer

"Approximately 85% of lung cancers are non–small-cell lung cancers (NSCLCs), which are often diagnosed at an advanced stage and associated with poor prognosis. Currently, there are very few therapies available for NSCLCs due to the recalcitrant nature of this cancer. Mutations that activate the small GTPase KRAS are found in 20% to 30% of NSCLCs. Here, we report that inhibition of superoxide dismutase 1 (SOD1) by the small molecule ATN-224 induced cell death in various NSCLC cells, including those harboring KRAS mutations. ATN-224–dependent SOD1 inhibition increased superoxide, which diminished enzyme activity of the antioxidant glutathione peroxidase, leading to an increase in intracellular hydrogen peroxide (H2O2) levels. We found that ATN-224–induced cell death was mediated through H2O2-dependent activation of P38 MAPK and that P38 activation led to a decrease in the antiapoptotic factor MCL1, which is often upregulated in NSCLC. Treatment with both ATN-224 and ABT-263, an inhibitor of the apoptosis regulators BCL2/BCLXL, augmented cell death. Furthermore, we demonstrate that ATN-224 reduced tumor burden in a mouse model of NSCLC. Our results indicate that antioxidant inhibition by ATN-224 has potential clinical applications as a single agent, or in combination with other drugs, for the treatment of patients with various forms of NSCLC, including KRAS-driven cancers."

Cancer Commons's insight:

Glasauer A, Sena LA, Diebold LP, Mazar AP and Chandel NS

J. Clinicla Investigations, Dec 2, 2013

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Activity of the Monocarboxylate Transporter 1 inhibitor AZD3965 in Small Cell Lung Cancer

"The monocarboxylate transporter 1 (MCT1) inhibitor AZD3965 is undergoing Phase I evaluation in the UK. We investigated the therapeutic potential of AZD3965 in small cell lung cancer (SCLC) seeking rationale for clinical testing in this disease and putative predictive biomarkers for trial use. AZD3965 sensitivity varied in vitro and was highest in hypoxia. Resistance in hypoxia was associated with increased MCT4 expression. In vivo, AZD3965 reduced tumor growth and increased intra-tumor lactate. In the tissue microarray, high MCT1 expression was associated with worse prognosis (p=0.014). MCT1 and hypoxia marker CA IX expression in the absence of MCT4 was observed in 21% of SCLC tumors. Conclusions: This study provides a rationale to test AZD3965 in SCLC patients. Our results suggest that patients with tumors expressing MCT1 and lacking in MCT4 are most likely to respond."

Cancer Commons's insight:

Polanski R, Hodgkinson C, Fusi A, Nonaka D et al.

Clinical Cancer Resrarch, Nov 26, 2013

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PLOS ONE: Combination of EGFR-TKIs and Chemotherapy as First-Line Therapy for Advanced NSCLC: A Meta-Analysis

The impact of combining epidermal growth factor receptor tyrosine kinase inhibitors (EGFR–TKIs) and chemotherapy as first-line therapy for patients with advanced non-small-cell lung cancer (NSCLC) remains controversial. Therefore, randomized trials that compared this combined regimen with chemotherapy or EGFR–TKIs monotherapy were included for this meta-analysis. We used published hazard ratios (HRs), if available, or derived treatment estimates from other survival data.  Eight trials eventually entered into this meta-analysis, including 4585 patients. Overall, the combined regimen significantly delayed disease progression (HR = 0.81, 95% CI 0.69–0.95, P = 0.01); subgroup analysis showed significantly higher progression free survival advantages in Asian patients (P<0.001), with sequential combination of TKIs and chemotherapy (P = 0.02). In selected patients by EGFR-mutation, both mutation positive (HR = 0.48, 95% CI 0.28–0.83, P = 0.009) and negative (HR = 0.84, 95% CI 0.72–0.98, P = 0.02) patients gained progression free survival benefit from the combined regimen, albeit the magnitude of benefit was marginally larger in mutation positive patients (P = 0.05). In selected patients by smoking history, never/light smokers achieved a great progression free survival benefit from the combined regimen (HR = 0.51, 95% CI 0.35–0.74, P = 0.0004). Unfortunately, the combined regimen had no significant impact on overall survival, irrespective of ethnicity, dose schedules or EGFR-mutation status.
Cancer Commons's insight:

Ouyang PY, Su Z, Mao YP, Deng W, Xie FY.

PLoS Nov 13, 2013

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Experimental Regimen Tested for Small Cell Lung Cancer

"A new Cedars-Sinai Phase I-II clinical trial may improve treatment approaches and combat disease recurrence. But first, Mita, co-director of the Experimental Therapeutics Program at the Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, needs to find patients to participate in the clinical trial. The approach being tested in the clinical trial works by combining the standard-of-care chemotherapy (etoposide and cisplatin) with a NOTCH inhibitor (OMP-59R5), a targeted therapy aimed to directly attack cancerous stem cells."



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Science News. Nov 13, 2013.

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Regulation of Heterochromatin Transcription by Snail1/LOXL2 During Epithelial-to-Mesenchymal Transition

"Although heterochromatin is enriched with repressive traits, it is also actively transcribed, giving rise to large amounts of noncoding RNAs. Although these RNAs are responsible for the formation and maintenance of heterochromatin, little is known about how their transcription is regulated. Here, we show that the Snail1 transcription factor represses mouse pericentromeric transcription, acting through the H3K4 deaminase LOXL2. Since Snail1 plays a key role in the epithelial-to-mesenchymal transition (EMT), we analyzed the regulation of heterochromatin transcription in this process. At the onset of EMT, one of the major structural heterochromatin proteins, HP1α, is transiently released from heterochromatin foci in a Snail1/LOXL2-dependent manner, concomitantly with a downregulation of major satellite transcription. Moreover, preventing the downregulation of major satellite transcripts compromised the migratory and invasive behavior of mesenchymal cells. We propose that Snail1 regulates heterochromatin transcription through LOXL2, thus creating the favorable transcriptional state necessary for completing EMT."

Cancer Commons's insight:

Millanes-Romero AHerranz NPerrera VIturbide A, et al. Molecular Cell. Nov 14, 2013.

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Cancer Commons's curator insight, November 14, 2013 1:35 PM

Millanes-Romero AHerranz NPerrera VIturbide A, et al. Molecular Cell. Nov 14, 2013.

Cancer Commons's curator insight, November 14, 2013 1:36 PM

Millanes-Romero AHerranz NPerrera VIturbide A, et al. Molecular Cell. Nov 14, 2013.

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Molecular Cell - HDAC5, a Key Component in Temporal Regulation of p53-Mediated Transactivation in Response to Genotoxic Stress

"Despite being one of the most well-studied transcription factors, the temporal regulation of p53-mediated transcription is not very well understood. Recent data suggest that target specificity of p53-mediated transactivation is achieved by posttranslational modifications of p53. K120 acetylation is a modification critical for recruitment of p53 to proapoptotic targets. Our data reveal that histone deacetylase 5 (HDAC5) binds to p53 and abrogates K120 acetylation, resulting in preferential recruitment of p53 to proarrest and antioxidant targets at early phases of stress. However, upon prolonged genotoxic stress, HDAC5 undergoes nuclear export. Concomitantly, p53 is acetylated at the K120 residue and selectively transactivates proapoptotic target genes, leading to onset of apoptosis. Furthermore, upon genotoxic stress in mice where HDAC5 expression is downregulated, the onset of apoptosis is accelerated in the highly vulnerable tissues. These findings suggest that HDAC5 is a key determinant of p53-mediated cell fate decisions in response to genotoxic stress."

Cancer Commons's insight:

Sen NKumari R, Singh MIDas S. Molecular Cell. Oct 10, 2013.

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Cancer Commons's curator insight, November 14, 2013 1:29 PM

Sen NKumari R, Singh MIDas S. Molecular Cell. Oct 10, 2013.

Cancer Commons's curator insight, November 14, 2013 1:29 PM

Sen NKumari R, Singh MIDas S. Molecular Cell. Oct 10, 2013.

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Runx3 Inactivation Is a Crucial Early Event in the Development of Lung Adenocarcinoma

Runx3 Inactivation Is a Crucial Early Event in the Development of Lung Adenocarcinoma | Lung Cancer Research Digest | Scoop.it

"A functional genetic screen of a fly mutant library and molecular analysis in cultured cell lines revealed that Runx3 forms a complex with BRD2 in a K-Ras-dependent manner in the early phase of the cell cycle; this complex induces expression of p14ARF/p19Arf and p21WAF/CIP. When K-Ras was constitutively activated, the Runx3-BRD2 complex was stably maintained and expression of both p14ARF and p21WAF/CIP was prolonged. These results provide a missing link between oncogenic K-Ras and the p14ARF-p53 pathway, and may explain how cells defend against oncogenic K-Ras."

Cancer Commons's insight:

Lee YS, Lee JW, Jang JW, Chi XZ, et al. Cancer Cell. Nov 11, 2013.

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Long-Lasting Disease Stabilization in the Absence of Toxicity in Metastatic Lung Cancer Patients Vaccinated with an Epitope Derived from Indoleamine 2,3 Dioxygenase

"Purpose: To investigate targeting of indoleamine 2.3 dioxygenase (IDO) enzyme using a synthetic peptide vaccine administered to patients with metastatic NSCLC. Conclusions: The vaccine was well-tolerated with no severe toxicity occurring. A median overall survival of 25.9 months was demonstrated and long-lasting partial response and disease stabilization were seen in 47% of the patients."

Cancer Commons's insight:

Iversen TZ,  Engell-Noerregaard LEllebaek EAndersen R, et al. Clinical Cancer Research. Nov 11, 2013.

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KDM2A Promotes Lung Tumorigenesis by Epigenetically Enhancing ERK1/2 Signaling

We found that the histone H3 lysine 36 (H3K36) demethylase KDM2A (also called FBXL11 and JHDM1A) is frequently overexpressed in NSCLC tumors and cell lines. KDM2A and its catalytic activity were required for in vitro proliferation and invasion of KDM2A-overexpressing NSCLC cells. We identified dual-specificity phosphatase 3 (DUSP3) as a key KDM2A target gene and found that DUSP3 dephosphorylates ERK1/2 in NSCLC cells. KDM2A activated ERK1/2 through epigenetic repression of DUSP3 expression via demethylation of dimethylated H3K36 at the DUSP3 locus. High KDM2A levels correlated with poor prognosis in NSCLC patients.

Cancer Commons's insight:

Wagner KW,  Alam H,  Dhar SS, Giri U et al. The Journal of Clinical Investigation. Nov 8, 2013.

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