Melanoma BRAF Inhibitors Review
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The Future of ePRO Platforms

It is tempting to imagine the use of the patient’s own mobile computing platform for collection of patient reported outcomes.
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Melanoma BRAF Inhibitors Review
Zelboraf (vemurafenib, Roche) and Tafinlar (dabrafenib, GSK) get FDA and EMA approval for advanced metastatic melanoma. Several follow up BRAF inhibitors are in clinical development by rival pharma companies (Novartis, BMS, J&J, Teva) to get a share of expanding melanoma market and improve complete response rates and overcome resistance. Nexavar (sorafenib, Bayer) for for liver (HCC) and renal (RCC) cancer was the first approved and marketed BRAF inhibitor.
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Vemurafenib (PLX 4032, Roche) Melanoma: FDA Review & Approval - un knol de Krishan Maggon

Vemurafenib (PLX 4032, Roche) Melanoma: FDA Review & Approval - un knol de Krishan Maggon | Melanoma BRAF Inhibitors Review | Scoop.it
Only a single new investigation drug has produced a 81% response rate and extended overall survival by 7 months (range 2-18...
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Designing A Faster, Better, Stronger Immune Response

Designing A Faster, Better, Stronger Immune Response | Melanoma BRAF Inhibitors Review | Scoop.it
It is the antibodies that detect pathogens in order to fight infections and prevent disease, but there is an entire team of immune cells that work together
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Immunovaccine : DepoVax may improve efficacy of checkpoint inhibitors

Immunovaccine : DepoVax may improve efficacy of checkpoint inhibitors | Melanoma BRAF Inhibitors Review | Scoop.it
Preclinical Study Shows Immunovaccine's DepoVax-Based Cancer Vaccine May Improve Efficacy of Checkpoint Inhibitors https://t.co/uvqa3iJies

Halifax, Nova Scotia; April 20, 2016 – Immunovaccine Inc. (“Immunovaccine” or the “company”) (TSX: IMV; OTCQX: IMMVF), a clinical stage vaccine and immunotherapy company, presented new preclinical data at the American Association for Cancer Research (AACR) Annual Meeting 2016. 

The investigators’ findings showed that a combination immunotherapy using a DepoVax™-based vaccine could enhance the anti-tumor effects of a PD-1 blockade, controlling growth in advanced HPV-expressing tumors in animal models. Investigators concluded that combining a DepoVax™-based vaccine with the chemotherapy metronomic cyclophosphamide (mCPA) increased PD-1 and PD-L1 in tumors, which in turn made them increasingly vulnerable to the monoclonal antibody treatment targeting these checkpoint inhibitors.
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Data Presented at AACR Annual Meeting 2016 Show Control of Cancer Growth in Advanced Tumors Previously Non-Responsive to Treatment with PD-1 Blockades Alone

The DepoVax™ platform possesses impressive flexibility, allowing it to work with a broad range of target antigens in various therapeutic applications. The technology is also commercially scalable, with potential for years of stability and ease of use in the clinic. 

 To date, DepoVax™ has served as the basis for Immunovaccine’s two clinical-stage cancer immunotherapies, as well as a number of partnered vaccine programs spanning infectious diseases, bio-terrorism, addiction medicine and animal health. These collaborators include many leaders in their respective areas of focus including the National Institutes of Health and Zoetis (formerly Pfizer Animal Health). 
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Advances in Melanoma Treatment More than Skin Deep

Advances in Melanoma Treatment More than Skin Deep | Melanoma BRAF Inhibitors Review | Scoop.it
La Jolla, CA - May is National Skin Cancer Awareness Month and with summer approaching, this is the best time to learn about skin cancer.
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A Small Molecule RAS-Mimetic Disrupts RAS Association with Effector Proteins to Block Signaling: Cell

A Small Molecule RAS-Mimetic Disrupts RAS Association with Effector Proteins to Block Signaling: Cell | Melanoma BRAF Inhibitors Review | Scoop.it
Highlights 

•Rigosertib binds to the RAS-binding domains (RBDs) of multiple RAS effectors 
•Binding of rigosertib to RAF-RBD inhibits RAS-RAF interaction and impairs the kinase 

•Rigosertib inhibits MEK-ERK pathway activated by growth factors and oncogenic RAS
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Cell Volume 165, Issue 3, p643–655, 21 April 2016


Sai Krishna Athuluri-Divakar, Rodrigo Vasquez-Del Carpio, Kaushik Dutta, Stacey J. Baker, Stephen C. Cosenza, Indranil Basu, Yogesh K. Gupta, M.V. Ramana Reddy, Lynn Ueno, Jonathan R. Hart, Peter K. Vogt, David Mulholland, Chandan Guha, Aneel K. Aggarwal, E. Premkumar Reddy correspondence/email
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Two-Way Traffic | The Scientist Magazine®

Two-Way Traffic | The Scientist Magazine® | Melanoma BRAF Inhibitors Review | Scoop.it
In mice, malignant cells genetically modified to express an anticancer cytokine home in on tumors and reduce their growth.
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Toxicity and management in CAR T-cell therapy

Toxicity and management in CAR T-cell therapy | Melanoma BRAF Inhibitors Review | Scoop.it
MTO

T cells can be genetically modified to target tumors through the expression of a chimeric antigen receptor (CAR). Most notably, CAR T cells have demonstrated clinical efficacy in hematologic malignancies with more modest responses when targeting solid tumors. However, CAR T cells also have the capacity to elicit expected and unexpected toxicities including: cytokine release syndrome, neurologic toxicity, “on target/off tumor” recognition, and anaphylaxis. Theoretical toxicities including clonal expansion secondary to insertional oncogenesis, graft versus host disease, and off-target antigen recognition have not been clinically evident. Abrogating toxicity has become a critical step in the successful application of this emerging technology. To this end, we review the reported and theoretical toxicities of CAR T cells and their management.
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Clinical Utility of an Enzyme-Linked Immunosorbent Assay for Detecting Anti-Melanoma Differentiation-Associated Gene 5 Autoantibodies

Clinical Utility of an Enzyme-Linked Immunosorbent Assay for Detecting Anti-Melanoma Differentiation-Associated Gene 5 Autoantibodies | Melanoma BRAF Inhibitors Review | Scoop.it
Objective Autoantibodies to melanoma differentiation-associated gene 5 (MDA5) are specifically expressed in patients with dermatomyositis (DM) and are associated with a subset of DM patients with rapidly progressive interstitial lung disease (RP-ILD). Here, we examined the clinical utility of a newly developed enzyme-linked immunosorbent assay (ELISA) system for detecting these antibodies. Methods Here we developed an improved ELISA for detecting anti-MDA5 antibodies. We then performed a multicenter clinical study involving 8 medical centers and enrolled 242 adult patients with polymyositis (PM)/DM, 190 with non-PM/DM connective tissue disease (CTD), 154 with idiopathic interstitial pneumonia (IIP), and 123 healthy controls. Anti-MDA5 antibodies in the patients’ serum samples were quantified using our newly developed ELISA, and the results were compared to those obtained using the gold-standard immunoprecipitation (IP) assay. In addition, correlations between the ELISA-quantified anti-MDA5 antibodies and clinical characteristics were evaluated. Results In patients with PM/DM, the anti-MDA5 antibody measurements obtained from the ELISA and IP assay were highly concordant; the ELISA exhibited an analytical sensitivity of 98.2%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 99.5% (compared to the IP assay). Anti-MDA5 antibodies were detected in 22.7% of the DM patients, but not in any of the patients with PM, non-PM/DM CTD, or IIP. Clinically amyopathic DM, RP-ILD, arthritis, and fever were more prevalent in DM patients who were anti-MDA5 antibody-positive than in those who were antibody-negative ( P ≤ 0.0002 for all comparisons). In addition, anti-MDA5 antibody-positive patients with RP-ILD exhibited higher antibody levels than those without RP-ILD ( P = 0.006). Conclusion Our newly developed ELISA can detect anti-MDA5 antibodies as efficiently as the gold standard IP assay and has the potential to facilitate the routine clinical measurement of anti-MDA5 antibodies in patients who suspected to have DM.
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Citation: Sato S, Murakami A, Kuwajima A, Takehara K, Mimori T, Kawakami A, et al. (2016) Clinical Utility of an Enzyme-Linked Immunosorbent Assay for Detecting Anti-Melanoma Differentiation-Associated Gene 5 Autoantibodies. PLoS ONE 11(4): e0154285. doi:10.1371/journal.pone.0154285
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FDA Breakthrough Therapy Designation for KEYTRUDA® (pembrolizumab, Merck) in Classical Hodgkin Lymphoma (cHL) 

FDA Breakthrough Therapy Designation for KEYTRUDA® (pembrolizumab, Merck) in Classical Hodgkin Lymphoma (cHL)  | Melanoma BRAF Inhibitors Review | Scoop.it

KENILWORTH, N.J.--(BUSINESS WIRE)--Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation to KEYTRUDA® (pembrolizumab), the company’s anti-PD-1 therapy, for the treatment of patients with relapsed or refractory classical Hodgkin lymphoma (cHL). This is the fourth Breakthrough Therapy Designation granted for KEYTRUDA.


The Breakthrough Therapy Designation in cHL is based on data from the ongoing Phase 1b KEYNOTE-013 and Phase 2 KEYNOTE-087 studies evaluating single agent KEYTRUDA in patients with cHL. Findings from the KEYNOTE-013 study were presented at the 2015 American Society of Hematology (ASH) Annual Meeting and data from KEYNOTE-087 will be presented at an upcoming medical meeting.

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Dynamic Optical Coherence Tomography in Dermatology - FullText - Dermatology - Karger Publishers

Dynamic Optical Coherence Tomography in Dermatology - FullText - Dermatology - Karger Publishers | Melanoma BRAF Inhibitors Review | Scoop.it
Optical coherence tomography (OCT) represents a non-invasive imaging technology, which may be applied to the diagnosis of non-melanoma skin cancer and which has recently been shown to improve the diagnostic accuracy of basal cell carcinoma. Technical developments of OCT continue to expand the applicability of OCT for different neoplastic and inflammatory skin diseases. Of these, dynamic OCT (D-OCT) based on speckle variance OCT is of special interest as it allows the in vivo evaluation of blood vessels and their distribution within specific lesions, providing additional functional information and consequently greater density of data. In an effort to assess the potential of D-OCT for future scientific and clinical studies, we have therefore reviewed the literature and preliminary unpublished data on the visualization of the microvasculature using D-OCT. Information on D-OCT in skin cancers including melanoma, as well as in a variety of other skin diseases, is presented in an atlas. Possible diagnostic features are suggested, although these require additional validation.
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Dermatology (DOI:10.1159/000444706)

Dynamic Optical Coherence Tomography in Dermatology 

Ulrich M.a · Themstrup L.c · de Carvalho N.d · Manfredi M.d · Grana C.d · Ciardo S.d · Kästle R.b · Holmes J.e · Whitehead R.e · Jemec G.B.E.c · Pellacani G.d · Welzel J.b 

 aCMB Collegium Medicum Berlin, Berlin, and bDepartment of Dermatology, General Hospital Augsburg, Augsburg, Germany; cDepartment of Dermatology, University of Copenhagen, Roskilde Hospital, Roskilde, Denmark; dDepartment of Dermatology, University of Modena and Reggio Emilia, Modena, Italy; eMichelson Diagnostics, Maidstone, UK 

email Corresponding Author Dr. Martina Ulrich, MD CMB Collegium Medicum Berlin Luisenstrasse 54/55 DE-10117 Berlin (Germany) E-Mail m.ulrich@collegiummedicum.de
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Wondering What Caused the Cancer

Wondering What Caused the Cancer | Melanoma BRAF Inhibitors Review | Scoop.it
Many of my patients ask what caused their cancer. I often wonder the same thing.
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Pembrolizumab for the treatment of advanced melanoma | 2 Minute Medicine

Pembrolizumab for the treatment of advanced melanoma | 2 Minute Medicine | Melanoma BRAF Inhibitors Review | Scoop.it
1. For patients with unresectable melanoma or metastatic melanoma that progressed despite treatment, pembrolizumab treatment resulted in objective response rate
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Phase II Study of Autologous Monocyte-Derived mRNA Electroporated Dendritic Cells (TriMixDC-MEL) Plus Ipilimumab in Patients With Pretreated Advanced Melanoma

Phase II Study of Autologous Monocyte-Derived mRNA Electroporated Dendritic Cells (TriMixDC-MEL) Plus Ipilimumab in Patients With Pretreated Advanced Melanoma | Melanoma BRAF Inhibitors Review | Scoop.it
Purpose
Autologous monocyte-derived dendritic cells (DCs) electroporated with synthetic mRNA (TriMixDC-MEL) are immunogenic and have antitumor activity as a monotherapy in patients with pretreated advanced melanoma.

Results The 6-month disease control rate was 51% (95% CI, 36% to 67%), and the overall tumor response rate was 38% (including eight complete and seven partial responses). Seven complete responses and one partial tumor response are ongoing after a median follow-up time of 36 months (range, 22 to 43 months). The most common treatment-related adverse events (all grades) consisted of local DC injection site skin reactions (100%), transient post–DC infusion chills (38%) and flu-like symptoms (84%), dermatitis (64%), hepatitis (13%), hypophysitis (15%), and diarrhea/colitis (15%). Grade 3 or 4 immune-related adverse events occurred in 36% of patients. There was no grade 5 adverse event. 

 Conclusion The combination of TriMixDC-MEL and ipilimumab is tolerable and results in an encouraging rate of highly durable tumor responses in patients with pretreated advanced melanoma.
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Published online before print February 29, 2016, 
doi: 10.1200/JCO.2015.63.4121 

JCO April 20, 2016 vol. 34 no. 12 1330-1338
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Nivolumab (Opdivo) Seen in Clinical Trial to Improve Long-Term Survival in Advanced Melanoma Patients - Melanoma News Today

Nivolumab (Opdivo) Seen in Clinical Trial to Improve Long-Term Survival in Advanced Melanoma Patients - Melanoma News Today | Melanoma BRAF Inhibitors Review | Scoop.it
Read more about Phase 1 study finding that nivolumab (Opdivo) improved long-term survival in patients with advanced and pretreated melanoma.  
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Addition of L19-IL2 can increase radiation therapy-induced immune response against tumours

Addition of L19-IL2 can increase radiation therapy-induced immune response against tumours | Melanoma BRAF Inhibitors Review | Scoop.it
Radiation therapy not only kills cancer cells, but also helps to activate the immune system against their future proliferation.
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Shape of tumour may affect whether cells can metastasize. ecancer - News

Shape of tumour may affect whether cells can metastasize. ecancer - News | Melanoma BRAF Inhibitors Review | Scoop.it
Shape of tumour may affect whether cells can metastasize. ecancer - News https://t.co/DeF8TDLPYP
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The science of cancer spread

The science of cancer spread | Melanoma BRAF Inhibitors Review | Scoop.it
Metastasis, or cancer spread, is complex and still largely mysterious. What do researchers know -- and what do they still need to know to stop metastasis?
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The m6A Methyltransferase METTL3 Promotes Translation in Human Cancer Cells: Molecular Cell

The m6A Methyltransferase METTL3 Promotes Translation in Human Cancer Cells: Molecular Cell | Melanoma BRAF Inhibitors Review | Scoop.it
Highlights 

•METTL3 promotes the translation of important oncogenes such as EGFR and TAZ
•METTL3 promotes translation independent of its catalytic activity and m6A readers 
•METTL3 interacts with translation initiation machinery to enhance translation 
•METTL3 is required for the growth, survival, and invasion of cancer cells
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The m6A Methyltransferase METTL3 Promotes Translation in Human Cancer Cells 

Shuibin Lin5, Junho Choe5, Peng Du, Robinson Triboulet, Richard I. Gregorycorrespondenceemail 5Co-first author 
Molecular Cell Publication stage: In Press Corrected Proof 

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A New and Targetable Epigenetic Biomarker for the Most Common Cancer

A New and Targetable Epigenetic Biomarker for the Most Common Cancer | Melanoma BRAF Inhibitors Review | Scoop.it
THE PULSE OF EPIGENETIC RESEARCH
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The epigenetics of tumour initiation: cancer stem cells and their chromatin

The epigenetics of tumour initiation: cancer stem cells and their chromatin | Melanoma BRAF Inhibitors Review | Scoop.it
Publication date: February 2016
Source:Current Opinion in Genetics & Development, Volume 36
Author(s): Alexandra Avgustinova, Salvador Aznar Benitah
Cancer stem cells (CSCs) have been identified in various tumours and are defined by their potential to initiate tumours upon transplantation, self-renew and reconstitute tumour heterogeneity. Modifications of the epigenome can favour tumour initiation by affecting genome integrity, DNA repair and tumour cell plasticity. Importantly, an in-depth understanding of the epigenomic alterations underlying neoplastic transformation may open new avenues for chromatin-targeted cancer treatment, as these epigenetic changes could be inherently more amenable to inhibition and reversal than hard-wired genomic alterations. Here we discuss how CSC function is affected by chromatin state and epigenomic instability.
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New technology for detecting malignant melanoma skin cancer

New technology for detecting malignant melanoma skin cancer | Melanoma BRAF Inhibitors Review | Scoop.it
Erin Seeley of Protea Biosciences discusses Proteomic Mass Spectrometry Imaging and Protea's exclusive license agreement wit
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Prospective identification of neoantigen-specific lymphocytes in the peripheral blood of melanoma patients

Prospective identification of neoantigen-specific lymphocytes in the peripheral blood of melanoma patients | Melanoma BRAF Inhibitors Review | Scoop.it
Detection of lymphocytes that target tumor-specific mutant neoantigens—derived from products encoded by mutated genes in the tumor—is mostly limited to tumor-resident lymphocytes1, 2, but whether these lymphocytes often occur in the circulation is unclear. We recently reported that intratumoral expression of the programmed cell death 1 (PD-1) receptor can guide the identification of the patient-specific repertoire of tumor-reactive CD8+ lymphocytes that reside in the tumor3. In view of these findings, we investigated whether PD-1 expression on peripheral blood lymphocytes could be used as a biomarker to detect T cells that target neoantigens. By using a high-throughput personalized screening approach, we identified neoantigen-specific lymphocytes in the peripheral blood of three of four melanoma patients. Despite their low frequency in the circulation, we found that CD8+PD-1+, but not CD8+PD-1−, cell populations had lymphocytes that targeted 3, 3 and 1 unique, patient-specific neoantigens, respectively. We show that neoantigen-specific T cells and gene-engineered lymphocytes expressing neoantigen-specific T cell receptors (TCRs) isolated from peripheral blood recognized autologous tumors. Notably, the tumor-antigen specificities and TCR repertoires of the circulating and tumor-infiltrating CD8+PD-1+ cells appeared similar, implying that the circulating CD8+PD-1+ lymphocytes could provide a window into the tumor-resident antitumor lymphocytes. Thus, expression of PD-1 identifies a diverse and patient-specific antitumor T cell response in peripheral blood, providing a novel noninvasive strategy to develop personalized therapies using neoantigen-reactive lymphocytes or TCRs to treat cancer.
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Nature Medicine 22, 433–438 (2016) doi:10.1038/nm.4051
Published online 22 February 2016
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KRAS in Non–Small-Cell Lung Cancer

KRAS in Non–Small-Cell Lung Cancer | Melanoma BRAF Inhibitors Review | Scoop.it

Review from JAMA Oncology — Prognostic and Predictive Value in KRAS in Non–Small-Cell Lung Cancer — A Review


Conclusions and Relevance KRAS is one of the most common oncogenic driver mutations in NSCLC, with prior attempts at direct inhibition being unsuccessful. In recent years, there has been significant advancement in the understanding of the biology of KRAS and its downstream effectors. This has translated into a multitude of important preclinical studies and clinical trials that are currently underway to find effective therapeutic drugs for KRAS mutant lung cancer. Ultimately, better therapeutics need to be engineered to arrive at RAS-driven precision medicine.

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Can the Cancer 'Moonshot' Succeed?

Can the Cancer 'Moonshot' Succeed? | Melanoma BRAF Inhibitors Review | Scoop.it
Landmark breakthroughs in cancer treatment and a policy structure where those advances can flourish have given fuel to the ambitious “Moonshot” to cure the disease. But is it really possible?
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A liquid biopsy for cancer immunotherapy

A liquid biopsy for cancer immunotherapy | Melanoma BRAF Inhibitors Review | Scoop.it
Human T cells that target tumor-specific mutations are attractive for cancer immunotherapy, but obtaining these T cells is challenging. A new study shows that tumor mutation–specific T cells can be isolated from the peripheral blood of patients with melanoma.
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A liquid biopsy for cancer immunotherapy 
 Ton N Schumacher & Wouter Scheper
 Nature Medicine 22, 340–341 (2016) doi:10.1038/nm.4074 Published online 06 April 2016
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Critical Role of Autophagy in the Processing of Adenovirus Capsid-Incorporated Cancer-Specific Antigens

Critical Role of Autophagy in the Processing of Adenovirus Capsid-Incorporated Cancer-Specific Antigens | Melanoma BRAF Inhibitors Review | Scoop.it
Adenoviruses are highly immunogenic and are being examined as potential vectors for immunotherapy. Infection by oncolytic adenovirus is followed by massive autophagy in cancer cells.
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Citation: Klein SR, Jiang H, Hossain MB, Fan X, Gumin J, Dong A, et al. (2016) Critical Role of Autophagy in the Processing of Adenovirus Capsid-Incorporated Cancer-Specific Antigens. PLoS ONE 11(4): e0153814. doi:10.1371/journal.pone.0153814
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