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New Targeted Drugs May Offer Treatment for KRAS-Mutant Lung Cancer

New Targeted Drugs May Offer Treatment for KRAS-Mutant Lung Cancer | Lung Cancer Dispatch | Scoop.it

Abnormalities in the KRAS gene are the most common mutations in lung cancer, especially in lung adenocarcinoma, a type of non-small cell lung cancer (NSCLC). However, no effective targeted therapy directed at KRAS has been found. Instead, researchers have begun to focus on blocking molecules 'downstream' in the chain of chemical reactions through which KRAS affects the cell. Two such molecules are TBK1 and MEK. A recent study found that the drug CYT387 blocks TBK1. CYT387 reduced tumor growth in mice with KRAS-mutant lung adenocarcinoma. Also in mice, CYT387 and the MEK inhibitor AZD6244, given together, shrank aggressive lung tumors with mutations in both the KRAS and the TP53 gene. Researchers now hope to investigate the two drugs in people.

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ASCO Post  |  Jan 29, 2014

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New Compound Targets Previously 'Undruggable' Cancer-Driving Mutation in KRAS Gene

New Compound Targets Previously 'Undruggable' Cancer-Driving Mutation in KRAS Gene | Lung Cancer Dispatch | Scoop.it

Mutations in the KRAS gene are the most common cancer-driving mutations in all cancers; they occur in 20% of lung cancers and 40% of colon cancers. KRAS-mutant cancers are aggressive and do not respond well to current treatments. Although the importance of KRAS mutations in cancer has been known for over 30 years, scientists have so far not succeeded in developing a drug targeting them. Now researchers have located a previously undetected 'pocket' on a certain mutated form of the KRAS protein. The mutation, called KRAS(G12C), occurs in 7% of lung cancer and 9% of colorectal cancer patients. The researchers then created molecules that bind to the 'pocket' and inhibit the mutant KRAS, but not normal KRAS protein. They hope to develop these compounds into drugs against KRAS-mutant cancers.

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Medical Xpress  |  Nov 20, 2013

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Medical Xpress  |  Nov 20, 2013

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Indirect Approach May Finally Make Inhibition of Cancer Gene KRAS Possible

Indirect Approach May Finally Make Inhibition of Cancer Gene KRAS Possible | Lung Cancer Dispatch | Scoop.it

The KRAS gene is mutated in one-third of tumors and its importance in promoting the growth of cancer cells has been known for decades. However, efforts to develop a KRAS inhibitor have so far been unsuccessful. Now, researchers may have found a way to suppress KRAS indirectly using a drug called deltarasin. To function properly, KRAS needs to be attached to the cell's membrane, a process aided by the transport protein PDE-δ. Deltarasin blocks PDE-δ, preventing KRAS from anchoring to the cell membrane. A recent study showed that deltarasin reduced the growth of KRAS-mutant tumor cells both in cell culture and in a mouse model of pancreatic cancer.

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Medical Xpress | Aug 9, 2013

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National Cancer Institute's 'RAS Project' Takes Aim at Common Cancer-Driving Protein

National Cancer Institute's 'RAS Project' Takes Aim at Common Cancer-Driving Protein | Lung Cancer Dispatch | Scoop.it

The National Cancer Institute (NCI) is organizing a massive collaborative initiative between its laboratory and hundreds of outside researchers to discover cancer treatments targeting a class of genes called RAS genes and their products, RAS proteins. RAS genes, including their most common form, KRAS, are mutated in one-third of all cancers. Although the important role of RAS in cancer has been known for over 30 years, no treatments targeting RAS have been developed so far, because RAS proteins lack a 'binding site' where drugs could attack. However, recent research has uncovered potential weaknesses in RAS that future treatment might exploit. The NCI's RAS Project aims to 'crowdsource' the expertise of many researchers to better understand and tackle RAS.

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Science | June 24, 2013

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Science | June 24, 2013

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Science | June 24, 2013

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Clinical Trial Reveals Patients' Willingness to Undergo Genetic Testing for Personalized Cancer Treatment

Clinical Trial Reveals Patients' Willingness to Undergo Genetic Testing for Personalized Cancer Treatment | Lung Cancer Dispatch | Scoop.it

A recently completed clinical trial examining the use of genetic testing to direct cancer treatment was able to exceed its enrollment goal of 600 participants in less than 2 years instead of the expected 5 years. Patients were willing to participate even though they had to undergo an additional biopsy, revealing considerable interest in personalized treatment based on genetic tests. The trial confirmed that erlotinib (Tarceva) is highly effective in non-small cell lung cancer (NSCLC) patients with a mutation in the EGFR gene. It also found that NSCLC patients with mutations in the KRAS gene did not benefit from the novel cancer drug selumetinib. In contrast, not enough small cell lung cancer (SCLC) patients had any of the investigated mutations to properly test how they responded to treatments. Such mutations will require trials involving thousands of patients to draw reliable conclusions.

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ScienceDaily | May 15, 2013

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ScienceDaily | May 15, 2013

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ScienceDaily | May 15, 2013

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Tarceva May Be More Effective in Advanced NSCLC When Combined with Other Targeted Therapies

Tarceva May Be More Effective in Advanced NSCLC When Combined with Other Targeted Therapies | Lung Cancer Dispatch | Scoop.it

An analysis of multiple clinical trials compared erlotinib (Tarceva) alone to combining Tarceva with other targeted therapies as second-line treatment for advanced non-small cell lung cancer (NSCLC). In the various trials, Tarceva was combined with bevacizumab (Avastin), bortezomib (Velcade), everolimus (Afinitor), sorafenib (Nexavar), sunitinib (Sutent), entinostat, tivantinib, and R1507. While combined therapy produced more side effects, it was more effective than Tarceva alone. Notably, the trials included many patients who had not been tested for mutations in the EGFR and KRAS genes. In patients who had EGFR mutations and/or lacked KRAS mutations, Tarceva alone tended to control cancer progression better than combined therapy, highlighting the importance of biomarker testing to identify which patients are most likely to benefit from different therapies.

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PLoS ONE | Feb 8, 2013

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CollabRx Updates Online Tool for Finding Targeted Therapies for Lung Cancer

CollabRx Updates Online Tool for Finding Targeted Therapies for Lung Cancer | Lung Cancer Dispatch | Scoop.it

CollabRx has released a new version of its Therapy Finder™ application for lung cancer, an online tool that recommends targeted therapies and clinical trials to physicians based on genetic information about a patient’s tumor. Available at http://therapy.collabrx.com/lung/, the updated application incorporates information about mutations in the ROS1 gene, which can make patients eligible for treatment with a class of drugs called ALK inhibitors, including crizotinib (Xalkori). The new tool also includes updated information about selumetinib, an investigational drug that may benefit patients whose tumors carry a mutation in the KRAS gene.

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GlobeNewswire | Feb 7, 2013

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Novel Drugs Show Promise in Non-Small Cell Lung Cancer

Novel Drugs Show Promise in Non-Small Cell Lung Cancer | Lung Cancer Dispatch | Scoop.it

Medical experts at the 2012 Chemotherapy Foundation Symposium presented data on the growing number of targeted treatments for non-small cell lung cancer (NSCLC) with so-called driver mutations—specific genetic mutations that drive tumor growth. Among the drugs showing promise in adenocarcinoma are ridaforolimus for KRAS-mutant tumors, ganetespib for ALK- or KRAS-mutant tumors, and afatinib for EGFR-mutant tumors. For squamous cell carcinoma (SCC), new potential treatments include AZD4547 and BGJ398 (FGFR1-mutant), dasatinib and nilotinib (DDR2 mutant), Tarceva and Iressa (EGFRvIII-mutant), and Yervoy and Cadi-05 (all SCC), while anti–PD-1 antibodies such as BMS-936558 may be effective for both adenocarcinoma and SCC.

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OncLive | Jan 14, 2013

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First Success for KRAS Targeted Treatment

A phase II clinical trial found that the addition of selumetinib to docetaxel improves treatment of KRAS-mutant non-small cell lung cancer (NSCLC). Mutated KRAS occurs in 20% of all NSCLC tumors and is more commonly reported in current and former smokers and white patients. This study marks the first time that a targeted KRAS treatment has proven successful in a clinical trial.

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The Lancet Oncology | Jan 2013

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E-Cigarette Vapor Promotes Cancer-Like Transformations of Airway Cells with Predisposing Mutations

E-Cigarette Vapor Promotes Cancer-Like Transformations of Airway Cells with Predisposing Mutations | Lung Cancer Dispatch | Scoop.it

E-cigarettes (electronic cigarettes that use a battery-powered system to deliver nicotine without producing smoke) are advertised as a safer alternative to tobacco cigarettes. However, very few studies have investigated how e-cigarettes affect lung function and lung cancer risk. Researchers examined human airway cells with mutations in the TP53 and KRAS genes, which are often mutated in the airways of current or former smokers at high risk of lung cancer. When the cells were exposed to e-cigarette vapor, they developed cancer-cell-like behaviors and gene expression changes very similar to what was seen when these cells were exposed to tobacco smoke. E-cigarettes may increase the risk of developing lung cancer in high-risk people, including current and former tobacco smokers.

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ASCO Post  |  Jan 8, 2014

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Stronger Case for Targeted Therapies Against Lung Cancer

New research provides compelling evidence that targeted treatments benefit people with lung cancer. Researchers at 14 U.S. centers found that of nearly 1,000 people with lung cancers who were tested for 10 genetic abnormalities, 63% had an abnormality and 23% of these were treated with the appropriate targeted therapy. Those who received targeted treatments lived 1.5 times longer than those who did not (a median of 3.5 vs 2.4 years, respectively). People with ALK abnormalities lived longest at 4.3 years; followed by those with sensitizing EGFR mutations at 4.0 years; other EGFR mutations at 3.3 years; and KRAS mutations at 2.4 years. These findings were presented at the 2013 World Conference on Lung Cancer.

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Medscape│Oct 30, 2013

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Genetic Characteristics of Women With Lung Cancer Differ Depending on Smoking History

Few studies so far have focused specifically on lung cancer in women, despite increasing evidence of differences in lung cancer features between women and men. A striking example is the higher rate among women of nonsmokers who develop lung cancer. A recent study of women with lung adenocarcinoma, a type of non-squamous non-small cell lung cancer (NSCLC), found that those who had never smoked were much more likely to have mutations in the EGFR gene and/or abnormally high levels of estrogen receptors, while smokers were more likely to have mutations in the KRAS gene. Based on these findings, a new phase II clinical trial will explore the effectiveness of treating postmenopausal, nonsmoking women who have advanced non-squamous lung cancer with EGFR inhibitors and anti-estrogen drugs.

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International Association for the Study of Lung Cancer | June 24, 2013

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Biomarker-Guided Targeted Therapy Is Becoming a Reality

A massive database study performed recently in France demonstrates that genetic testing of non-small cell lung cancer (NSCLC) tumors for disease-relevant biomarkers is feasible, and indeed already helps guide treatment strategies for patients. France’s National Cancer Institute funds routine assessment of genetic alterations in six genes for NSCLC patients: EGFR, KRAS, ALK, BRAF, HER2, and PI3K. Since April 2012, these genetic analyses have been collected into a database. By now, biomarker assessments have been performed for 10,000 NSCLC patients. Of the patients for whom treatment data was available, over half received therapies guided directly by their biomarker testing profile. For example, over half of patients who were found to have a mutation in the EGFR gene were treated with EGFR inhibitors. As the database continues to grow, researchers recommend that newer biomarkers, like the ROS1 gene, should be added to the analysis. Furthermore, they urge that the availability of clinical trials of biomarker-targeted treatments needs to be increased.

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CancerNetwork | Jun 4, 2013

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New Lung Cancer Drug Ganetespib Shows Mixed Results in Clinical Trial

New Lung Cancer Drug Ganetespib Shows Mixed Results in Clinical Trial | Lung Cancer Dispatch | Scoop.it

Results from an ongoing phase II clinical trial suggest that the new drug ganetespib may be effective in a subset of patients with advanced non-small cell lung cancer (NSCLC). People with mutations in the genes EGFR or KRAS, who had been the original focus of the study, did not benefit significantly from the drug. However, among patients with mutations in the ALK gene who had not been treated previously with crizotinib (Xalkori), half seemed to benefit from ganetespib. This finding is based on a small number of patients, but Synta Pharmaceuticals, the company developing ganetespib, will investigate it further in a clinical trial focusing specifically on ALK-mutant NSCLC.

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Clinical Cancer Research | Apr 3, 2013

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Mutations in EGFR and KRAS Genes Do Not Predict Lung Cancer Outcome by Themselves

Non-small cell lung cancer (NSCLC) patients with mutations in the EGFR gene are likely to benefit from treatment with tyrosine kinase inhibitors (TKIs) like erlotinib (Tarceva) and gefitinib (Iressa), while KRAS mutations predict poor TKI response. A study of patients who were not taking TKIs and had stages I/II/III NSCLC that had been surgically removed found no difference in recurrence or survival between patients with or without EGFR or KRAS mutations. This finding suggests that, while EGFR and KRAS mutations are useful for identifying patients who may benefit from targeted treatments like TKIs, they do not predict overall clinical outcomes by themselves.


Research paper: http://graphics.tx.ovid.com/ovftpdfs/FPDDNCOBHDNMDO00/fs047/ovft/live/gv024/00000421/00000421-900000000-99450.pdf

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American Journal of Clinical Oncology | Jan 24, 2013

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Various Approaches to EGFR Inhibition Can Be Useful in Lung Cancer

Various Approaches to EGFR Inhibition Can Be Useful in Lung Cancer | Lung Cancer Dispatch | Scoop.it

A review of recent research discusses EGFR inhibition in the treatment of lung cancer. Scientists have now demonstrated that EGFR-tyrosine kinase inhibitors (TKIs), either by themselves or combined with chemotherapy, are effective first-line treatments for advanced non-small cell lung cancer (NSCLC) with EGFR mutations, and as second-line or maintenance treatments for all advanced NSCLC. TKIs like erlotinib (Tarceva) or gefitinib (Iressa), or anti-EGFR antibodies like cetuximab (Erbitux), may also enhance the effectiveness of radiation therapy for locally advanced NSCLC. Other biomarkers, such as KRAS mutations, may also help predict response to EGFR inhibition therapy.

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Biomarker Research | Jan 16, 2013

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Combined Gene Inhibition May Offer Treatment Strategy for Certain Lung Cancers

KRAS is a gene that is mutated in many cancers, including around 30% of lung cancers, but no targeted therapies for KRAS-mutant cancers exist yet. Researchers found that blocking two genes that are part of the KRAS signaling pathway, MEK and BCL-XL, using the targeted inhibitors selumetinib (for MEK) and navitoclax (for BCL-XL) shrank tumors in mouse lung cancer models and human tumor samples. While MEK inhibition alone is not effective in KRAS-mutant lung cancer, combining MEK and BCL-XL inhibitors may offer a promising therapeutic approach.

 

Primary source: http://www.sciencedirect.com/science/article/pii/S1535610812004874

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Cancer Cell | Dec 13, 2012

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