Melanoma Research...
Follow
Find
4.1K views | +0 today
 
Scooped by Cancer Commons
onto Melanoma Research Digest
Scoop.it!

Cancer: Killing from the Inside

"Lysosomes are the main degradative compartment in cells, but they are also involved in cell-death pathways. Studies using existing drugs show that lysosomes are excellent pharmacological targets for selectively destroying cancer cells."

Cancer Commons's insight:

Saftig P, Sandhoff K. Nature. Oct 2, 2013.

more...
Cancer Commons's curator insight, October 2, 2013 3:08 PM

Saftig P, Sandhoff K. Nature. Oct 2, 2013.

Cancer Commons's curator insight, October 2, 2013 3:09 PM

Saftig P, Sandhoff K. Nature. Oct 2, 2013.

Adrian Vallejo Blanco's curator insight, November 11, 2013 5:46 AM

Los lisosomas. Excelentes dianas farmacológicas para destruir selectivamente las células cancerosas.


La práctica general desde hace décadas ha sido utilizar la quimioteramia para tratar el cancer. El punto de mira de los tratamientos contra el cancer ha sido hasta ahora extracelular, pero ahora, atacando los lisosomas de sólo células tumorales abre una nueva puerta a fármacos de acción intracelular.


En el lisosoma se degradan las moléculas y la maquinaria celular pero también en porcesos como la reparación de la membrana, la defensa de patógenos, la autofagia y señalización.


Los lisosomas en células cancerosos son mas grandes, mas numerosos y tienen muchísima actividad de la catepsina (mucho mayor que en células normales) y es la liberación d estas moléculas al espacio extracelular lo que permite la progresión del tumor.

 

Es aquí donde va dirigido este nuevo fármaco que podría acabar con gran parte de las progresiones tumorales.

 

Melanoma Research Digest
The latest news on melanoma research, trials and therapies
Curated by Cancer Commons
Your new post is loading...
Your new post is loading...
Rescooped by Cancer Commons from Prostate Cancer Dispatch
Scoop.it!

Minority of Oncologists and Primary Care Physicians Fully Discuss Survivorship Care Plans With Cancer Survivors

Minority of Oncologists and Primary Care Physicians Fully Discuss Survivorship Care Plans With Cancer Survivors | Melanoma Research Digest | Scoop.it

"Of 53 National Cancer Institute cancer centers, only 43% report implementing survivorship care plans for at least some of their cancer survivors. In a study reported in the Journal of Clinical Oncology, Blanch-Hartigan et al found that a minority of a nationally representative sample of oncologists and primary care physicians routinely discuss all aspects of survivorship care or furnish survivorship care plans for cancer survivors."

Cancer Commons's insight:

The ASCO Post  |  May 6, 2014

more...
Tambre Leighn's curator insight, May 24, 2014 3:42 PM

This is an ongoing issue...nearly a decade after 2005 studies showing the value of providing a care plan.  Time for implementation of a low cost strategy with a high quality of life impact potential....and how about a plan that isn't only focused on the medical experience?  Survivors also need a plan for living their life - we need a call for care plans that support the whole individual....now.

Cancer Commons's curator insight, May 6, 2014 2:33 PM

The ASCO Post  |  May 6, 2014

Cancer Commons's curator insight, May 6, 2014 2:32 PM

The ASCO Post  |  May 6, 2014

Scooped by Cancer Commons
Scoop.it!

Molecular Pathways: Response and resistance to BRAF and MEK inhibitors in BRAFV600E tumors

"The RAS-RAF-MEK-ERK pathway plays a central role in driving proliferation, survival and metastasis signals in tumor cells and the prevalence of oncogenic mutations in RAS and BRAF and upstream nodes makes this pathway the focus of significant oncology drug development efforts. This focus has been justified by the recent success of BRAF and MEK inhibitors in prolonging the lives of patients with BRAFV600E/K mutant melanoma. While it is disappointing that cures are relatively rare, this should not detract from the value of these agents to cancer patients and the opportunity they provide in allowing us to gain a deeper understanding of drug response and resistance. These insights have already provided the basis for the evaluation of alternative dosing regimens and combination therapies in melanoma patients."

Cancer Commons's insight:

Das Thakur M, Stuart DS

Clinical Cancer Res. Dec 18 2013

more...
No comment yet.
Scooped by Cancer Commons
Scoop.it!

Genome-Scale CRISPR-Cas9 Knockout Screening in Human Cells

The simplicity of programming the CRISPR-associated nuclease Cas9 to modify specific genomic loci suggests a new way to interrogate gene function on a genome-wide scale. We show that lentiviral delivery of a genome-scale CRISPR-Cas9 knockout (GeCKO) library targeting 18,080 genes with 64,751 unique guide sequences enables both negative and positive selection screening in human cells. First, we used the GeCKO library to identify genes essential for cell viability in cancer and pluripotent stem cells. Next, in a melanoma model, we screened for genes whose loss is involved in resistance to vemurafenib, a therapeutic that inhibits mutant protein kinase BRAF. Our highest-ranking candidates include previously validated genes NF1 and MED12 as well as novel hitsNF2CUL3TADA2B, and TADA1. We observe a high level of consistency between independent guide RNAs targeting the same gene and a high rate of hit confirmation, demonstrating the promise of genome-scale screening with Cas9.

Cancer Commons's insight:

Shalem O, Sanjana NE, HartenianE, Shi X et al.

Science, Dec 12, 2013

more...
No comment yet.
Scooped by Cancer Commons
Scoop.it!

JCI - IL-2 therapy promotes suppressive ICOS+ Treg expansion in melanoma patients

"High-dose (HD) IL-2 therapy in patients with cancer increases the general population of Tregs, which are positive for CD4, CD25, and the Treg-specific marker Foxp3. It is unknown whether specific subsets of Tregs are activated and expanded during HD IL-2 therapy or whether activation of any particular Treg subset correlates with clinical outcome. Here, we evaluated Treg population subsets that were induced in patients with melanoma following HD IL-2 therapy. We identified a Treg population that was positive for CD4, CD25, Foxp3, and the inducible T cell costimulator (ICOS). This Treg population increased more than any other lymphocyte subset during HD IL-2 therapy and had an activated Treg phenotype, as indicated by high levels of CD39, CD73, and TGF-β. ICOS+ Tregs were the most proliferative lymphocyte population in the blood after IL-2 therapy. Patients with melanoma with enhanced expansion of ICOS+Tregs in blood following the first cycle of HD IL-2 therapy had worse clinical outcomes than patients with fewer ICOS+ Tregs. However, there was no difference in total Treg expansion between HD IL-2 responders and nonresponders. These data suggest that increased expansion of the ICOS+ Treg population following the first cycle of HD IL-2 therapy may be predictive of clinical outcome".

Cancer Commons's insight:

Sim GC, Martin-Orozco N, Jin L  Yan Yang Y et al

J. CLinical Investigations, Dec 2, 2013

more...
No comment yet.
Scooped by Cancer Commons
Scoop.it!

The Genetic Landscape of Clinical Resistance to RAF Inhibition in Metastatic Melanoma

The use of RAF inhibitors for BRAFV600-mutant metastatic melanoma improves patient outcomes, but most patients demonstrate early or acquired resistance to this targeted therapy. We reveal the genetic landscape of clinical resistance mechanisms to RAF inhibitors from patients using whole-exome sequencing, and experimentally assess new observed mechanisms to define potential subsequent treatment strategies.

Cancer Commons's insight:

Van Allen EM, Wagle N, Sucker A, Treacy DJ et al

Cancer Discovery, Nov 21, 2013

more...
No comment yet.
Scooped by Cancer Commons
Scoop.it!

Acquired Resistance and Clonal Evolution in Melanoma during BRAF Inhibitor Therapy

"BRAF inhibitors elicit rapid antitumor responses in the majority of patients with BRAFV600-mutant melanoma, but acquired drug resistance is almost universal. We sought to identify the core resistance pathways and the extent of tumor heterogeneity during disease progression. We show that mitogen-activated protein kinase reactivation mechanisms were detected among 70% of disease-progressive tissues, with RAS mutations, mutant BRAF amplification, and alternative splicing being most common. We also detected PI3K–PTEN–AKT–upregulating genetic alterations among 22% of progressive melanomas. Distinct molecular lesions in both core drug escape pathways were commonly detected concurrently in the same tumor or among multiple tumors from the same patient. Beyond harboring extensively heterogeneous resistance mechanisms, melanoma regrowth emerging from BRAF inhibitor selection displayed branched evolution marked by altered mutational spectra/signatures and increased fitness. Thus, melanoma genomic heterogeneity contributes significantly to BRAF inhibitor treatment failure, implying upfront, cotargeting of two core pathways as an essential strategy for durable responses".

Cancer Commons's insight:

Shi H, Hugo W, Kong X, Hong A et al

Cancer Discovery Nov 21, 2013

more...
No comment yet.
Rescooped by Cancer Commons from Lung Cancer Research Digest
Scoop.it!

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.

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

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

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

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

Rescooped by Cancer Commons from Lung Cancer Research Digest
Scoop.it!

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.

more...
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 1:28 PM

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

Scooped by Cancer Commons
Scoop.it!

Phosphoproteomic Characterization of DNA Damage Response in Melanoma Cells Following MEK/PI3K Dual Inhibition

"Growing evidence suggests that successful intervention in many human cancers will require combinations of therapeutic agents. Critical to this effort will be a detailed understanding of the crosstalk between signaling networks that modulate proliferation, cell death, drug sensitivity, and acquired resistance. Here we investigated DNA-damage signaling elicited by small-molecule inhibitors against MAP/ERK kinase (MEK) and PI3K in melanoma cells. This work, performed using cutting-edge mass spectrometry proteomics, uncovered a burst of signaling among proteins in the DNA-damage pathway upon initiation of the cell-death program by agents targeting the RAS–RAF–MEK and PI3K–AKT–mTOR pathways. These signals may prove important to the short- and long-term sensitivity of tumor cells to MEK- and PI3K-targeted therapies."

Cancer Commons's insight:

Kirkpatricka DS, Bustosa DJ, Doganb T, Chanb J, et al. PNAS. Nov 11, 2013.

more...
No comment yet.
Rescooped by Cancer Commons from Prostate Cancer Research Digest
Scoop.it!

Microenvironmental Regulation of Tumor Progression and Metastasis

Microenvironmental Regulation of Tumor Progression and Metastasis | Melanoma 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."

Cancer Commons's insight:

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

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

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

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

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

Rescooped by Cancer Commons from Lung Cancer Research Digest
Scoop.it!

Oncologists Lead on Reform, Ex CMS Head Says

Oncologists Lead on Reform, Ex CMS Head Says | Melanoma Research Digest | Scoop.it

"Oncologists are at the forefront of payment and delivery reforms sweeping medicine today, a former head of Medicare said here Monday. Innovations in cancer care delivery -- such as oncology patient-centered medical homes -- are blazing the trail for all specialists, said Mark McClellan, MD, PhD, director of the Health Care Innovation and Value Initiative at the Brookings Institution in Washington."

Cancer Commons's insight:

Medpage Today | Nov 5, 2013

more...
Cancer Commons's curator insight, November 7, 2013 7:37 PM

Medpage Today | Nov 5, 2013

Cancer Commons's curator insight, November 7, 2013 7:36 PM

Medpage Today | Nov 5, 2013

Rescooped by Cancer Commons from Lung Cancer Research Digest
Scoop.it!

Selective Cancer Targeting with Prodrugs Activated by Histone Deacetylases and a Tumour-Associated Protease

"Eradication of cancer cells while minimizing damage to healthy cells is a primary goal of cancer therapy. Highly selective drugs are urgently needed. Here we demonstrate a new prodrug strategy for selective cancer therapy that utilizes increased histone deacetylase (HDAC) and tumour-associated protease activities produced in malignant cancer cells. By coupling an acetylated lysinegroup to puromycin, a masked cytotoxic agent is created, which is serially activated by HDAC and an endogenous protease cathepsin L (CTSL) that remove the acetyl group first and then the unacetylated lysine group liberating puromycin. The agent selectively kills human cancer cell lines with high HDAC and CTSL activities. In vivo studies confirm tumour growth inhibition in prodrug-treated mice bearing human cancer xenografts. This cancer-selective cleavage of the masking group is a promising strategy for the next generation of anticancer drug development that could be applied to many other cytotoxic agents."

Cancer Commons's insight:

Ueki N, Lee S, Sampson NS, Hayman MJ, et al. Nature Communications. Nov 5, 2013.

more...
Cancer Commons's curator insight, November 6, 2013 1:43 PM

Ueki N, Lee S, Sampson NS, Hayman MJ, et al. Nature Communications. Nov 5, 2013.

Cancer Commons's curator insight, November 6, 2013 1:41 PM

Ueki N, Lee S, Sampson NS, Hayman MJ, et al. Nature Communications. Nov 5, 2013.

Rescooped by Cancer Commons from Prostate Cancer Research Digest
Scoop.it!

Personal History of Prostate Cancer and Increased Risk of Incident Melanoma in the United States

"Purpose: Steroid hormones, particularly androgens, play a major role in prostatic carcinogenesis. Personal history of severe acne, a surrogate for higher androgen activity, has been associated with an increased risk of prostate cancer (PCa), and one recent study indicated that severe teenage acne was a novel risk factor for melanoma. These findings suggest a possible relationship between PCa and risk of melanoma. We prospectively evaluated this association among US men. Methods: A total of 42,372 participants in the Health Professionals’ Follow-Up Study (HPFS; 1986 to 2010) were included. Biennially self-reported PCa diagnosis was confirmed using pathology reports. Diagnosis of melanoma and nonmelanoma skin cancer (NMSC) was self-reported biennially, and diagnosis of melanoma was pathologically confirmed. We sought to confirm the association in 18,603 participants from the Physicians’ Health Study (PHS; 1982 to 1998). Results: We identified 539 melanomas in the HPFS. Personal history of PCa was associated with an increased risk of melanoma (multivariate-adjusted hazard ratio [HR], 1.83; 95% CI, 1.32 to 2.54). Although we also detected a marginally increased risk of NMSC associated with PCa (HR, 1.08; 95% CI, 0.995 to 1.16), the difference in the magnitude of the association between melanoma and NMSC was significant (P for heterogeneity = .002). We did not find an altered risk of melanoma associated with personal history of other cancers. The association between PCa and risk of incident melanoma was confirmed in the PHS (HR, 2.17; 95% CI, 1.12 to 4.21). Conclusion: Personal history of PCa is associated with an increased risk of melanoma, which may not be entirely a result of greater medical scrutiny."

Cancer Commons's insight:

Li WQ, Qureshi AA, Ma J, Goldstein AM, et al. Journal of Clinical Oncology. Nov 4, 2013.

more...
Cancer Commons's curator insight, November 5, 2013 1:23 PM

Li WQ, Qureshi AA, Ma J, Goldstein AM, et al. Journal of Clinical Oncology. Nov 4, 2013.

Scooped by Cancer Commons
Scoop.it!

Targeting the Tumor Microenvironment with Interferon-β Bridges Innate and Adaptive Immune Responses

"Antibodies (Abs) that preferentially target oncogenic receptors have been increasingly used for cancer therapy, but tumors often acquire intrinsic Ab resistance after prolonged and costly treatment. Herein we armed the Ab with IFNβ and observed that it is more potent than the first generation of Ab for controlling Ab-resistant tumors. This strategy controls Ab resistance by rebridging suppressed innate and adaptive immunity in the tumor microenvironment. Mechanistically, Ab-IFNβ therapy primarily and directly targets intratumoral dendritic cells, which reactivate CTL by increasing antigen cross-presentation within the tumor microenvironment. Additionally, blocking PD-L1, which is induced by Ab-IFNβ treatment, overcomes treatment-acquired resistance and completely eradicates established tumors. This study establishes a next-generation Ab-based immunotherapy that targets and eradicates established Ab-resistant tumors."

Cancer Commons's insight:

Yang X,  Zhang X,  Fu ML, Weschlelbaum RR et al.

Cancer Cell, Jan 13, 2013

more...
No comment yet.
Scooped by Cancer Commons
Scoop.it!

BRAF Fusions Define a Distinct Molecular Subset of Melanomas with Potential Sensitivity to MEK Inhibition

Recurrent “driver” mutations at specific loci inBRAFNRASKITGNAQ, and GNA11 define clinically relevant molecular subsets of melanoma, but more than 30% are “pan-negative” for these recurrent mutations. We sought to identify additional potential drivers in “pan-negative” melanoma. We identified a novel PAPSS1-BRAF fusion in a “pan-negative” melanoma.  Activation of the mitogen-activated protein kinase (MAPK) pathway in cells by ectopic expression of PAPSS1-BRAF was abrogated by mitogen-activated protein kinase kinase (MEK) inhibition but not by BRAF inhibition. NGS data analysis of 51 additional melanomas revealed a second BRAF fusion (TRIM24-BRAF) in a “pan-negative” sample; MAPK signaling induced by TRIM24-BRAF was also MEK inhibitor sensitive. Through mining TCGA skin cutaneous melanoma dataset, we further identified two potential BRAF fusions in another 49 “pan-negative” cases.

Conclusions: BRAF fusions define a new molecular subset of melanoma, potentially comprising 4% to 8% of “pan-negative” cases. Their presence may explain an unexpected clinical response to MEK inhibitor therapy or assist in selecting patients for MEK-directed therapy."

Cancer Commons's insight:

Hutchinson KE, Lipson D, Stephens PJ, Otto G et al.

Clinical Cancer res., Dec 17, 2013

more...
No comment yet.
Scooped by Cancer Commons
Scoop.it!

Myeloid-derived suppressor cells predict survival of advanced melanoma patients: comparison with regulatory T cells and NY-ESO-1- or Melan-A-specific T cells

"The percentage of CD14+CD11b+HLA-DR-/low MDSCs, CD4+CD25+FoxP3+ Tregs and the presence of NY-ESO-1- or Melan-A-specific T cells was analyzed in 94 patients and validated in an additional cohort of 39 patients by flow cytometry. NY-ESO-1-specific T cells, the M-category and the frequency of MDSCs were associated with survival. The absence of NY-ESO-1-specific T cells and the M-category M1c independently increased the risk of death. Median survival of patients with a lower frequency of MDSCs was 13 months vs. 8 months for others (p<0.001, combined cohorts). We observed a strong correlation between high levels of MDSCs and the absence of melanoma-antigen-specific T cells implying a causal and clinically relevant interaction. No prognostic impact was observed for Tregs. Circulating CD14+CD11b+HLA-DR-/low MDSCs have a negative impact on survival and inversely correlate with the presence of functional antigen-specific T cells in advanced melanoma patients. Our findings provide a rationale to investigate MDSCs-depleting strategies in the therapeutic setting especially in combination with vaccination or T-cell-transfer approaches."

Cancer Commons's insight:

Weide B,  Martens A, Zelba H, Stutz, C et al

Clinical Cancer Res., Dec 10, 2013

more...
No comment yet.
Scooped by Cancer Commons
Scoop.it!

MAP Kinase Pathway Alterations in BRAF-Mutant Melanoma Patients with Acquired Resistance to Combined RAF/MEK Inhibition

"We performed whole-exome sequencing (WES) and whole-transcriptome sequencing (RNA-seq) on pretreatment and drug-resistant tumors from five patients with acquired resistance to dabrafenib/trametinib. In three of these patients, we identified additional mitogen-activated protein kinase (MAPK) pathway alterations in the resistant tumor that were not detected in the pretreatment tumor, including a novel activating mutation in MEK2 (MEK2Q60P). MEK2Q60P conferred resistance to combined RAF/MEK inhibition in vitro, but remained sensitive to inhibition of the downstream kinase extracellular signal–regulated kinase (ERK). The continued MAPK signaling-based resistance identified in these patients suggests that alternative dosing of current agents, more potent RAF/MEK inhibitors, and/or inhibition of the downstream kinase ERK may be needed for durable control of BRAF-mutant melanoma.

SIGNIFICANCE: This study represents an initial clinical genomic study of acquired resistance to combined RAF/MEK inhibition in BRAF-mutant melanoma, using WES and RNA-seq. The presence of diverse resistance mechanisms suggests that serial biopsies and genomic/molecular profiling at the time of resistance may ultimately improve the care of patients with resistant BRAF-mutant melanoma by specifying tailored targeted combinations to overcome specific resistance mechanisms". 

Cancer Commons's insight:

Wagle N, Van Allen EM, Treacy DJ, Frederick DT et al

Cancer Discovery, Nov 21 2013

more...
No comment yet.
Scooped by Cancer Commons
Scoop.it!

A Novel AKT1 Mutant Amplifies an Adaptive Melanoma Response to BRAF Inhibition

"AKT1Q79K conferred BRAFi resistance via amplification of BRAFi-elicited PI3K–AKT signaling. In addition, mitogen-activated protein kinase pathway inhibition enhanced clonogenic growth dependency on PI3K or AKT. Thus, adaptive or genetic upregulation of AKT critically participates in melanoma survival during BRAFi therapy. This study provides a mechanistic link between early, adaptive and late, acquired BRAF inhibitor resistance in melanoma, with early BRAFi-induced signaling alterations shaping the subsequent evolutionary selective pressure. These findings argue for upfront, combined targeting of the mutant BRAF genotype."

Cancer Commons's insight:

Shi H, Hong A, Kong X, Koya RC et al

Cancer Discovery Nov 21, 2013

more...
No comment yet.
Scooped by Cancer Commons
Scoop.it!

Genome Biology | Abstract | The genetic heterogeneity and mutational burden of engineered melanomas in zebrafish models

To decipher the genetics of melanomas, we sequence the protein coding exons of 53 primary melanomas generated from several BRAFV600E or NRASQ61K driven transgenic zebrafish lines. We find that engineered zebrafish melanomas show an overall low mutation burden, which has a strong, inverse association with the number of initiating germline drivers. Although tumors reveal distinct mutation spectrums, they show mostly C > T transitions without UV light exposure, and enrichment of mutations in melanogenesis, p53 and MAPK signaling. Importantly, a recurrent amplification occurring with pre-configured drivers BRAFV600E and p53-/- suggests a novel path ofBRAF cooperativity through the protein kinase A pathway..

Cancer Commons's insight:

Yen J, White RM, Wedge DC, Van Loo, P et al.

Genome Biology, Nov 19, 2013

more...
No comment yet.
Rescooped by Cancer Commons from Lung Cancer Research Digest
Scoop.it!

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.

more...
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.

Scooped by Cancer Commons
Scoop.it!

Boston Research Institutes, Hospitals Launch Clinical Genomics Center

Boston Research Institutes, Hospitals Launch Clinical Genomics Center | Melanoma 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."

Cancer Commons's insight:

GenomeWeb Daily News | Nov 12, 2013

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

GenomeWeb Daily News | Nov 12, 2013

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

GenomeWeb Daily News | Nov 12, 2013

Scooped by Cancer Commons
Scoop.it!

Differential AKT Dependency Displayed by Mouse Models of BRAFV600E-Initiated Melanoma

"Malignant melanoma is frequently driven by mutational activation of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) accompanied by silencing of the phosphatase and tensin homology (PTEN) tumor suppressor. Despite the implied importance of PI3K signaling in PTENNull melanomas, mutational activation of the gene encoding the catalytic subunit of PI3Kα (PIK3CA), is rarely detected. Since PTEN has both PI3-lipid phosphatase–dependent and –independent tumor suppressor activities, we investigated the contribution of PI3K signaling to BRAFV600E-induced melanomagenesis using mouse models, cultured melanoma cells, and PI3K pathway–targeted inhibitors. These experiments revealed that mutationally activated PIK3CAH1047R cooperates with BRAFV600E for melanomagenesis in mice. Moreover, pharmacological inhibition of PI3Ks prevented growth of BRAFV600E/PTENNull melanomas in vivo and in tissue culture. Combined inhibition of BRAFV600E and PI3K had more potent effects on the regression of established BRAFV600E/PTENNull melanomas and cultured melanoma cells than individual blockade of either pathway. Surprisingly, growth of BRAFV600E/PIK3CAH1047R melanomas was dependent on the protein kinase AKT; however, AKT inhibition had no effect on growth of BRAFV600E/PTENNull melanomas. These data indicate that PTEN silencing contributes a PI3K-dependent, but AKT-independent, function in melanomagenesis. Our findings enhance our knowledge of how BRAFV600E and PI3K signaling cooperate in melanomagenesis and provide preclinical validation for combined pathway–targeted inhibition of PI3K and BRAFV600E in the therapeutic management of BRAFV600E/PTENNull melanomas."

Cancer Commons's insight:

Durban VMDeuker MM, Bosenberg MWPhillips W, McMahon M. The Journal of Clinical Investigation. Nov 1, 2013.

more...
No comment yet.
Scooped by Cancer Commons
Scoop.it!

Tumor Adaptation and Resistance to RAF Inhibitors

Tumor Adaptation and Resistance to RAF Inhibitors | Melanoma Research Digest | Scoop.it

"RAF kinase inhibitors have substantial therapeutic effects in patients with BRAF-mutant melanoma. However, only rarely do tumors regress completely, and the therapeutic effects are often temporary. Several mechanisms of resistance to RAF inhibitors have been proposed. The majority of these cause ERK signaling to become insensitive to treatment with RAF inhibitors by increasing the amount of RAF dimers in cells, whereas others bypass the dependence of the tumor on mutant RAF. One motivation for studying mechanisms of drug resistance is that such efforts may suggest new therapeutic targets or rational combination strategies that delay or prevent the emergence of drug-resistant clones. Here, we review the current model of RAF inhibitor resistance with a focus on the implications of this model on ongoing laboratory and clinical efforts to develop more effective therapeutic strategies for patients with BRAF-mutant tumors."

Cancer Commons's insight:

Lito P, Rosen N, Solit DB. Nature Medicine. Nov 7, 2013.

more...
No comment yet.
Scooped by Cancer Commons
Scoop.it!

A Melanocyte Lineage Program Confers Resistance to MAP Kinase Pathway Inhibition

"Malignant melanomas harbouring point mutations (Val600Glu) in the serine/threonine-protein kinase BRAF (BRAF(V600E)) depend on RAF–MEK–ERK signalling for tumour cell growth1. RAF and MEK inhibitors show remarkable clinical efficacy in BRAF(V600E) melanoma23; however, resistance to these agents remains a formidable challenge24. Global characterization of resistance mechanisms may inform the development of more effective therapeutic combinations. Here we carried out systematic gain-of-function resistance studies by expressing more than 15,500 genes individually in a BRAF(V600E) melanoma cell line treated with RAF, MEK, ERK or combined RAF–MEK inhibitors. These studies revealed a cyclic-AMP-dependent melanocytic signalling network not previously associated with drug resistance, including G-protein-coupled receptors, adenyl cyclase, protein kinase A and cAMP response element binding protein (CREB). Preliminary analysis of biopsies from BRAF(V600E) melanoma patients revealed that phosphorylated (active) CREB was suppressed by RAF–MEK inhibition but restored in relapsing tumours. Expression of transcription factors activated downstream of MAP kinase and cAMP pathways also conferred resistance, including c-FOSNR4A1NR4A2 and MITF. Combined treatment with MAPK-pathway and histone-deacetylase inhibitors suppressed MITF expression and cAMP-mediated resistance. Collectively, these data suggest that oncogenic dysregulation of a melanocyte lineage dependency can cause resistance to RAF–MEK–ERK inhibition, which may be overcome by combining signalling- and chromatin-directed therapeutics."

Cancer Commons's insight:

Johannessen CM, Johnson LA, Piccioni F, Townes A, et al. Nature. Nov 3, 2013.

more...
No comment yet.
Scooped by Cancer Commons
Scoop.it!

Clinicopathologic Predictors of Sentinel Lymph Node Metastasis in Thin Melanoma

"Purpose: Indications for sentinel lymph node biopsy (SLNB) for thin melanoma are continually evolving. We present a large multi-institutional study to determine factors predictive of sentinel lymph node (SLN) metastasis in thin melanoma. Patients and Methods: Retrospective review of the Sentinel Lymph Node Working Group database from 1994 to 2012 identified 1,250 patients who had an SLNB and thin melanomas (≤ 1 mm). Clinicopathologic characteristics were correlated with SLN status and outcome. Results: SLN metastases were detected in 65 (5.2%) of 1,250 patients. On univariable analysis, rates of Breslow thickness ≥ 0.75 mm, Clark level ≥ IV, ulceration, and absence of regression differed significantly between positive and negative SLN groups (all P < .05). These four variables and mitotic rate were used in multivariable analysis, which demonstrated that Breslow thickness ≥ 0.75 mm (P= .03), Clark level ≥ IV (P = .05), and ulceration (P = .01) significantly predicted SLN metastasis with 6.3%, 7.0%, and 11.6% of the patients with these respective characteristics having SLN disease. Melanomas < 0.75 mm had positive SLN rates of < 5% regardless of Clark level and ulceration status. Median follow-up was 2.6 years. Melanoma-specific survival was significantly worse for patients with positive versus negative SLNs (P = .001). Conclusion: Breslow thickness ≥ 0.75 mm, Clark level ≥ IV, and ulceration significantly predict SLN disease in thin melanoma. Most SLN metastases (86.2%) occur in melanomas ≥ 0.75 mm, with 6.3% of these patients having SLN disease, whereas in melanomas < 0.75 mm, SLN metastasis rates are < 5%. By using a 5% metastasis risk threshold, SLNB is indicated for melanomas ≥ 0.75 mm, but further study is needed to define indications for SLNB in melanomas < 0.75 mm."

Cancer Commons's insight:

Han D, Zager JS, Shyr Y, Chen H, et al. Journal of Clinical Oncology. Nov 4, 2013.

more...
No comment yet.