Updates in Oncology
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Rescooped by Geert Maertens from Melanoma BRAF Inhibitors Review
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Paradox-Breaking RAF Inhibitors that Also Target SRC Are Effective in Drug-Resistant BRAF Mutant Melanoma: Cancer Cell

Paradox-Breaking RAF Inhibitors that Also Target SRC Are Effective in Drug-Resistant BRAF Mutant Melanoma: Cancer Cell | Updates in Oncology | Scoop.it

Highlights

 

•pan-RAF inhibitors also inhibit SRC family kinases•The compounds do not induce paradoxical activation of ERK in RAS mutant cells•The compounds are active in BRAF and NRAS mutant melanomas•The compounds are active in PDXs resistant to BRAF or BRAF plus MEK inhibitors

 

Summary

BRAF and MEK inhibitors are effective in BRAF mutant melanoma, but most patients eventually relapse with acquired resistance, and others present intrinsic resistance to these drugs. Resistance is often mediated by pathway reactivation through receptor tyrosine kinase (RTK)/SRC-family kinase (SFK) signaling or mutant NRAS, which drive paradoxical reactivation of the pathway. We describe pan-RAF inhibitors (CCT196969, CCT241161) that also inhibit SFKs. These compounds do not drive paradoxical pathway activation and inhibit MEK/ERK in BRAF and NRAS mutant melanoma. They inhibit melanoma cells and patient-derived xenografts that are resistant to BRAF and BRAF/MEK inhibitors. Thus, paradox-breaking pan-RAF inhibitors that also inhibit SFKs could provide first-line treatment for BRAF and NRAS mutant melanomas and second-line treatment for patients who develop resistance.


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Krishan Maggon 's curator insight, December 12, 2014 2:02 AM

OA

 

Cancer Cell

 

Paradox-Breaking RAF Inhibitors that Also Target SRC Are Effective in Drug-Resistant BRAF Mutant MelanomaMaria Romina Girotti, Filipa Lopes, Natasha Preece, Dan Niculescu-Duvaz, Alfonso Zambon, Lawrence Davies, Steven Whittaker, Grazia Saturno,Amaya Viros, Malin Pedersen, Bart M.J.M. Suijkerbuijk, Delphine Menard, Robert McLeary, Louise Johnson, Laura Fish, Sarah Ejiama,Berta Sanchez-Laorden, Juliane Hohloch, Neil Carragher, Kenneth Macleod, Garry Ashton, Anna A. Marusiak, Alberto Fusi, John Brognard, Margaret Frame,Paul Lorigan, Richard Marais, Caroline Springer DOI: http://dx.doi.org/10.1016/j.ccell.2014.11.006
Rescooped by Geert Maertens from Melanoma BRAF Inhibitors Review
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The immune-related role of BRAF in melanoma

The immune-related role of BRAF in melanoma | Updates in Oncology | Scoop.it

Highlights

 

BRAF and NRAS status was assessed in 113 melanoma metastases by Sanger sequencing and high sensitive allele-specific PCR.

The expression of BRAF-specific genes categorized the metastases in two divergent groups.

The mutant group associated with a poor phenotype.

The association between BRAF mutation and the poor phenotype was stronger in samples displaying low BRAF mRNA expression.

Functional interpretation of BRAF expression-discriminative genes revealed pathways related to an unfavorable phenotype.

 

 

Abstract

Background: The existence of a dichotomy between immunologically active and quiescent tumor phenotypes has been recently recognized in several types of cancer. The activation of a Th1 type of immune signature has been shown to confer better prognosis and likelihood to respond to immunotherapy. However, whether such dichotomy depends on the genetic make-up of individual cancers is not known yet. BRAF and NRAS mutations are commonly acquired during melanoma progression. Here we explored the role of BRAF and NRAS mutations in influencing the immune phenotype based on a classification previously identified by our group.

Methods

One-hundred-thirteen melanoma metastases underwent microarray analysis and BRAF and NRAS genotyping. Allele-specific PCR was also performed in order to exclude low-frequency mutations.

Results

Comparison between BRAF and NRAS mutant versus wild type samples identified mostly constituents or regulators of MAPK and related pathways. When testing gene lists discriminative of BRAF, NRAS and MAPK alterations, we found that 112 BRAF-specific transcripts were able to distinguish the two immune-related phenotypes already described in melanoma, with the poor phenotype associated mostly with BRAF mutation. Noteworthy, such association was stronger in samples displaying low BRAF mRNA expression. However, when testing NRAS mutations, we were not able to find the same association.

Conclusion

This study suggests that BRAF mutation-related specific transcripts associate with a poor phenotype in melanoma and provide a nest for further investigation.


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Geert Maertens's insight:

BRAF mutants expressed at low levels correlated with poor immune phenotype

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Krishan Maggon 's curator insight, October 3, 2014 11:38 AM
Molecular Oncology

Available online 6 August 2014

In Press, Corrected Proof — Note to users

 

The immune-related role of BRAF in melanomaSara Tomeia, b, c, , , Davide Bedognettia, c, Valeria De Giorgia, Michele Sommarivaa, d, Sara Civinie,Jennifer Reinbotha, f, g, Muna Al Hashmic, Maria Libera Asciertoa, h, Qiuzhen Liua, Ben D. Ayottei, Andrea Worschechb, Lorenzo Uccellinia, l, Paolo A. Asciertom, David Stronceke, Giuseppe Palmierin, Lotfi Chouchaneb, Ena Wanga, c, Francesco M. Marincolaa, c  Show moreDOI: 10.1016/j.molonc.2014.07.014
Rescooped by Geert Maertens from Melanoma BRAF Inhibitors Review
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MD Anderson Correlation Between Oncogene BRAF Mutation and therapeutic response

MD Anderson Correlation Between Oncogene BRAF Mutation and therapeutic response | Updates in Oncology | Scoop.it
BioNews Texas
MD Anderson Researcher Reveals Correlation Between Oncogene Mutation ...
BioNews Texas
... Ph.D.

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Rescooped by Geert Maertens from Melanoma Dispatch
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FDA Grants Merck’s Anti-PD1 Antibody Priority Review

FDA Grants Merck’s Anti-PD1 Antibody Priority Review | Updates in Oncology | Scoop.it

"The FDA has granted Merck’s anti-PD1 antibody MK-3475 a priority review designation for the treatment of unresectable or metastatic melanoma in patients who have previously been treated with ipilimumab. Priority review status is reserved for drugs considered to offer a significant improvement in the safety or efficacy of the treatment of a serious condition. It will shorten the drug’s FDA review period from 10 months to 6 months."

 

Editor's note: MK-3475 is an immunotherapy drug that works by boosting a patient's own immune system to fight cancer. Once it is approved by the FDA for unresectable or metastatic melanoma, doctors in the U.S. will be able to prescribe it to their patients outside of the clinical trial system.


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Cancer Commons's curator insight, May 22, 2014 2:15 PM

Cancer Network  |  May 21, 2014

Cancer Commons's curator insight, May 22, 2014 2:18 PM

Cancer Network  |  May 21, 2014

Cancer Commons's curator insight, May 22, 2014 2:19 PM

Cancer Network  |  May 21, 2014

Rescooped by Geert Maertens from Melanoma BRAF Inhibitors Review
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Differential influence of vemurafenib and dabrafenib on patients’ lymphocytes despite similar clinical efficacy in melanoma

Differential influence of vemurafenib and dabrafenib on patients’ lymphocytes despite similar clinical efficacy in melanoma | Updates in Oncology | Scoop.it

While both compounds have comparable clinical efficacy, vemurafenib but not dabrafenib decreases patients peripheral lymphocyte counts and alters CD4+ T cell phenotype and function. Thus, selective BRAFi can significantly affect patients' peripheral lymphocyte populations. Fully understanding these effects could be critical for successfully implementing combinatorial therapies of BRAFi with immunomodulatory agents.


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Krishan Maggon 's curator insight, March 13, 2014 5:24 AM

Full article

 

Oxford JournalsMedicineAnnals of OncologyVolume 25, Issue 3Pp. 747-753.

  Differential influence of vemurafenib and dabrafenib on patients’ lymphocytes despite similar clinical efficacy in melanomaB. Schilling1,2,*, W. Sondermann1,2, F. Zhao1,2, K. G. Griewank1,2,E. Livingstone1,2, A. Sucker1,2, H. Zelba3, B. Weide2,3, U. Trefzer2,4,T. Wilhelm2,4, C. Loquai2,5, C. Berking2,6, J. Hassel2,7, K. C. Kähler8,J. Utikal2,9,10, P. Al Ghazal11, R. Gutzmer11, S. M. Goldinger12, L. Zimmer1,2,A. Paschen1,2, U. Hillen1,2,† and D. Schadendorf1,2,† on behalf of DeCOG

+Author Affiliations

1Department of Dermatology, University Hospital, West German Cancer Center, University Duisburg-Essen, Essen2German Cancer Consortium (DKTK)3University Medical Center, University of Tübingen, Tübingen4Department of Dermatology, Venerology and Allergy, Charité Universitätsmedizin Berlin, Humboldt University, Berlin5Department of Dermatology, University of Mainz, Mainz6Department of Dermatology and Allergology, Ludwig-Maximilian University, Munich7Department of Dermatology, Heidelberg University Hospital, Heidelberg8Department of Dermatology, Venerology and Allergology, University of Schleswig-Holstein Hospital, Campus Kiel9Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg10Department of Dermatology, Venereology and Allergology, University Medical Centre Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim11Department of Dermatology and Allergy, Hannover Medical School, Hannover, Germany12Department of Dermatology, University Hospital Zurich, Zurich, Switzerland↵*Correspondence to: Dr Bastian Schilling, Department of Dermatology, University Hospital, West German Cancer Center, University Duisburg-Essen, Hufelandstr. 55, Essen 45147, Germany. Tel: +49-20172383590; Fax: +49-2017235935; E-mail: bastian.schilling@uk-essen.deReceived September 17, 2013.Revision received October 21, 2013.Accepted December 2, 2013.melanoma vemurafenib dabrafenib lymphocytes T cells treatment
Rescooped by Geert Maertens from Cancer Immunotherapy Review
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Dendreon files for chapter 11 bankruptcy

Dendreon announced Monday that it filed for Chapter 11 bankruptcy protection in the US and has reached agreements on the terms of a financial restructuring with certain bond holders. The drugmaker noted that the restructuring "may take the form of a stand-alone recapitalisation or a sale of the company or its assets." Dendreon added that the move will allow the continued delivery of its prostate cancer immunotherapy Provenge (sipuleucel-T).


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Krishan Maggon 's curator insight, November 10, 2014 6:37 AM

Dendreon revived the cancer vaccine by getting FDA approval of its prostate cancer dendreon cell vaccine Provenge (sipuleucel-T). Provenge remains a commercial failure and sales have failed to match expectations or rosy forecasts/projections.


Warning to speculators about vulture capital flooding the immunotherpy field?

Rescooped by Geert Maertens from Cancer Immunotherapy Review
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Nivolumab Phase 3 First-Line Melanoma Study Stopped Early. BMS PD-1 Checkpoint Inhibitor, Demonstrates Superior Overall Survival

Nivolumab Phase 3 First-Line Melanoma Study Stopped Early. BMS PD-1 Checkpoint Inhibitor, Demonstrates Superior Overall Survival | Updates in Oncology | Scoop.it

Tuesday, June 24, 2014 4:45 pm EDT  

PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE:BMY) today announced that a randomized blinded comparative Phase 3 study evaluating nivolumab versus dacarbazine (DTIC) in patients with previously untreated BRAF wild-type advanced melanoma was stopped early because an analysis conducted by the independent Data Monitoring Committee (DMC) showed evidence of superior overall survival in patients receiving nivolumab compared to the control arm. Patients in the trial will be unblinded and allowed to cross over to nivolumab. The Company will share these data with health authorities.

“The outcome of CheckMate -066 is an important milestone in the field of immuno-oncology as it represents the first well-controlled, randomized Phase 3 trial of an investigational PD-1 checkpoint inhibitor to demonstrate an overall survival benefit,” said Michael Giordano, MD, Head of Oncology Development. “Bristol-Myers Squibb is committed to continuing to lead advances in immuno-oncology and to executing our strategy to provide patients with the best opportunity to achieve the potential for long term survival.”

CheckMate -066 investigators have been informed of the decision to stop the blinded comparative portion of the trial. Bristol-Myers Squibb will ensure that patients are informed of the opportunity to continue or start treatment with nivolumab in an open-label extension as part of the Company’s commitment to characterize long-term survival. The study, which was designed in consultation with the Committee for Medicinal Products for Human Use (CHMP), was primarily conducted in countries where DTIC is a commonly-used treatment in the first-line setting, including Canada, but not at U.S. trial sites. The Company will complete a full evaluation of the final CheckMate -066 data and work with investigators on the future presentation and publication of the results.

About the Study

CheckMate -066 is a Phase 3 randomized, double-blind study of patients with previously untreated BRAF wild-type unresectable Stage III and IV melanoma. The trial enrolled 418 patients who were randomized to receive either nivolumab 3 mg/kg every two weeks or DTIC 1000 mg/m2 every three weeks. The primary endpoint was overall survival. Secondary endpoints included progression free survival and objective response rate.

About Nivolumab

Cancer cells may exploit “regulatory” pathways, such as checkpoint pathways, to hide from the immune system and shield the tumor from immune attack. Nivolumab is an investigational, fully-human PD-1 immune checkpoint inhibitor that binds to the checkpoint receptor PD-1 (programmed death-1) expressed on activated T-cells. We are investigating whether by blocking this pathway, nivolumab would enable the immune system to resume its ability to recognize, attack and destroy cancer cells.

Bristol-Myers Squibb has a broad, global development program to study nivolumab in multiple tumor types consisting of more than 35 trials – as monotherapy or in combination with other therapies – in which more than 7,000 patients have been enrolled worldwide. Among these are several potentially registrational trials in non-small cell lung cancer melanoma, renal cell carcinoma (RCC), head and neck cancer, glioblastoma and non-Hodgkin lymphoma. In 2013, the FDA granted Fast Track designation for nivolumab in NSCLC, melanoma and RCC. In May 2014, the FDA granted nivolumab Breakthrough Therapy Designation for the treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplant and brentuximab.

- See more at: http://news.bms.com/press-release/phase-3-first-line-melanoma-study-nivolumab-investigational-pd-1-checkpoint-inhibitor-&t=635392373910100446#sthash.BBVexiXe.dpuf


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Krishan Maggon 's curator insight, June 24, 2014 8:27 PM

Nivolumab increases Overall survival and the efficacy end point was reached earlier. Likely to get fast track FDA/EMA approval in 2014.

Rescooped by Geert Maertens from Melanoma BRAF Inhibitors Review
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Mixed lineage kinases activate MEK independently of RAF to mediate resistance to RAF inhibitors : Nature Communications : Nature Publishing Group

Mixed lineage kinases activate MEK independently of RAF to mediate resistance to RAF inhibitors : Nature Communications : Nature Publishing Group | Updates in Oncology | Scoop.it

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Krishan Maggon 's curator insight, May 22, 2014 11:15 AM

MLK (or MEK) kinases 1-4 switch the BRAF back even in the presence of vemurafenib leading to resistance to BRAF inhibitors within a few months of therapy.

 

Blocking MLK enzymes can thus overcome BRAF resistance in melanoma.

Rescooped by Geert Maertens from A Tale of Two Medicines
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Grape seed proanthocyanidins reactivate silenced tumor suppressor genes in human skin cancer cells by targeting epigenetic regulators.

Grape seed proanthocyanidins (GSPs) have been shown to have anti-skin carcinogenic effects in in vitro and in vivo models. However, the precise epigenetic molecular mechanisms remain unexplored. This study was designed to investigate whether GSPs reactivate silenced tumor suppressor genes following epigenetic modifications in skin cancer cells. For this purpose, A431 and SCC13 human squamous cell carcinoma cell lines were used as in vitro models. The effects of GSPs on DNA methylation, histone modifications and tumor suppressor gene expressions were studied in these cell lines using enzyme activity assays, western blotting, dot-blot analysis and real-time polymerase chain reaction (RT-PCR). We found that treatment of A431 and SCC13 cells with GSPs decreased the levels of: (i) global DNA methylation, (ii) 5-methylcytosine, (iii) DNA methyltransferase (DNMT) activity and (iv) messenger RNA (mRNA) and protein levels of DNMT1, DNMT3a and DNMT3b in these cells. Similar effects were noted when these cancer cells were treated identically with 5-aza-2'-deoxycytidine, an inhibitor of DNA methylation. GSPs decreased histone deacetylase activity, increased levels of acetylated lysines 9 and 14 on histone H3 (H3-Lys 9 and 14) and acetylated lysines 5, 12 and 16 on histone H4, and reduced the levels of methylated H3-Lys 9. Further, GSP treatment resulted in re-expression of the mRNA and proteins of silenced tumor suppressor genes, RASSF1A, p16(INK4a) and Cip1/p21. Together, this study provides a new insight into the epigenetic mechanisms of GSPs and may have significant implications for epigenetic therapy in the treatment/prevention of skin cancers in humans.


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