Melanoma BRAF Inhibitors Review
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TIL Melanoma Program (Lion Biotech) 54% ORR in Phase II metastatic melanoma. ASH 2014

TIL Melanoma Program (Lion Biotech)  54% ORR in Phase II metastatic melanoma. ASH 2014 | Melanoma BRAF Inhibitors Review | Scoop.it

 Lion Biotechnologies, Inc. (LBIO), a biotechnology company that is developing novel cancer immunotherapies based on tumor-infiltrating lymphocytes (TILs) under a Cooperative Research and Development Agreement with the National Cancer Institute (NCI), today announced that Steven A. Rosenberg, MD, PhD, chief of surgery at the NCI, presented positive, new data from a Phase 2 clinical trial of TIL therapy in metastatic melanoma. The updated results were presented on December 7, 2014 in a scientific symposium on adoptive T-cell therapy (ACT) at the American Society of Hematology annual meeting in San Francisco, CA.

New data from a Phase 2 clinical trial in patients with Stage 4 metastatic melanoma, which NCI is conducting with Lion under a collaborative research and development agreement, confirmed that TIL treatment was associated with high, durable objective response rates (ORR), including in patients who were refractory to checkpoint inhibitors.

In the randomized, 101-patient study, ORR was 54%, representing a significant improvement over data from recent clinical studies of ipilimumab (ORR 10-15%) and anti-PD-1 therapy (ORR 31-41%).  Fourteen patients had complete responses, 13 of which are ongoing beyond two years.  Of the 41 partial responders, 22 are ongoing beyond one year and 15 are ongoing beyond two years. Additionally, Dr. Rosenberg noted, TILs produced objective response rates in 19/45 (ORR 42%) patients who were ipilimumab refractory, and 5/10 (ORR 50%) patients who had previously progressed on anti-PD1.

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TILs Demonstrate 54% Objective Response Rate in Phase 2 Metastatic Melanoma Trial

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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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Metastatic Melanoma Cells: Image Details - NCI Visuals Online

Metastatic Melanoma Cells: Image Details - NCI Visuals Online | Melanoma BRAF Inhibitors Review | Scoop.it
Image information and view/download options.
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Creating a New Generation of Melanoma Models

Creating a New Generation of Melanoma Models | Melanoma BRAF Inhibitors Review | Scoop.it
We all can remember the eruption that happened when our 1st grade science teacher combined vinegar and baking soda together to represent a volcano. In some ways, this is just like experiments that take place every day in the search for better treatments, and ultimately a cure, for melanoma.
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Melanoma cells resistant towards MAPK inhibitors exhibit reduced TAp73 expression mediating enhanced sensitivity to platinum-based drugs

Melanoma cells resistant towards MAPK inhibitors exhibit reduced TAp73 expression mediating enhanced sensitivity to platinum-based drugs | Melanoma BRAF Inhibitors Review | Scoop.it
The efficacy of targeted MAPK signalling pathway inhibitors (MAPKi) in metastatic melanoma therapy is limited by the development of resistance mechanisms that results in disease relapse. This situation still requires treatment alternatives for melanoma patients with acquired resistance to targeted therapy. We found that melanoma cells, which developed resistance towards MAPKi show an enhanced susceptibility to platinum-based drugs, such as cisplatin and carboplatin. We found that this enhanced susceptibility inversely correlates with the expression level of the p53 family member TAp73. We show that the lower expression of the TAp73 isoform in MAPKi-resistant melanoma cells enhances accumulation of DNA double-strand breaks upon cisplatin and carboplatin treatment by reducing the efficiency of nucleotide excision repair. These data suggest that a subgroup of melanoma patients with acquired resistance to MAPKi treatment and low TAp73 expression can benefit from chemotherapy with platinum-based drugs as a second-line therapy.
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Generation of Tumor-Reactive T s by Co-culture of Peripheral Blood Lymphocytes and Tumor Organoids

Generation of Tumor-Reactive T s by Co-culture of Peripheral Blood Lymphocytes and Tumor Organoids | Melanoma BRAF Inhibitors Review | Scoop.it
A modified patient-derived tumor organoids system allows the expansion of tumor-specific
T cells from blood for personalized analysis of their anti-cancer properties.

Via Gilbert C FAURE
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Melanoma

Melanoma | Melanoma BRAF Inhibitors Review | Scoop.it
Cutaneous melanoma causes 55 500 deaths annually. The incidence and mortality rates
of the disease differ widely across the globe depending on access to early detection
and primary care. Once melanoma has spread, this type of cancer rapidly becomes life-threatening.
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Neighbourhood deaths cause a switch in cancer subtype

Neighbourhood deaths cause a switch in cancer subtype | Melanoma BRAF Inhibitors Review | Scoop.it
How the same type of cell can form different kinds of tumour isn’t always clear. The discovery that cancer subtype in mice is influenced by the type of cell death occurring in the microenvironment provides some insight.
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E-ALPHA® | T-cell therapies | Eureka Therapeutics

E-ALPHA® | T-cell therapies | Eureka Therapeutics | Melanoma BRAF Inhibitors Review | Scoop.it
Our proprietary E-ALPHA® antibody discovery platform is composed of a highly diverse human-derived antibody phage library.
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Cancer – The Investigational Therapy Multikine® (Leukocyte Interleukin, Injection)

Cancer – The Investigational Therapy Multikine® (Leukocyte Interleukin, Injection) | Melanoma BRAF Inhibitors Review | Scoop.it
Cancer - The Investigational Therapy Multikine® (Leukocyte Interleukin, Injection) Multikine (Leukocyte Interleukin, Injection) is the full name of this investigational therapy, which, for simplicity, is referred to in the remainder of this page as Multikine*. CEL-SCI's lead investigational therapy Multikine is currently being developed as a potential therapeutic agent directed at using the immune system to produce an anti-tumor immune response. Data from Phase I and Phase II clinical trials suggest that Multikine may simulate a healthy person's immune system, enabling it to use the body's own anti-tumor immune response. If it were to be approved for use following completion of our clinical development program, Multikine would be a different kind of therapy in the fight against cancer: one that is designed with the intent to employ our body's natural ability to fight tumors. CEL-SCI is currently conducting a large Phase III clinical study with Multikine in head and neck cancer patients with advanced disease who are treatment naïve (i.e., have received no prior treatment). The current standard of care for initial treatment of these patients according to the NCCN guidelines (published by the National Comprehensive Cancer Network) is surgery followed by radiotherapy or surgery followed by combined radiochemotherapy - depending on pathology assessment of the resected tumor following surgery. In CEL-SCI's ongoing study, Multikine is administered to patients before these other treatments are given. At the completion of CEL-SCI's clinical development program, if the results indicate that this investigational therapy met its pre-specified endpoints, a Biologics License Application will be prepared and submitted to the FDA by CEL-SCI. Multikine has the potential to be the first of a new class of cancer immunotherapy drugs. It is thought to be the first known combination immunotherapy, possessing both active and passive properties. Multikine is designed to directly affect both the tumor cells themselves and activate an anti-tumor immune response. Read more about Multikine CEL-SCI's business strategy is to create genuinely new and innovative therapies that meet unmet medical needs, as opposed to minor innovations to existing therapies or 'me-too' products. In order to truly understand the potential for Multikine to be an innovative immunotherapy product, we invite you to read a brief summary of the field of cancer immunotherapy, which briefly summarizes the different therapies in this field.   o Introduction to Cancer Immunotherapy           o Types of Biological Cancer Immunotherapy                 o Passive Immunotherapy                 ° Monoclonal Antibodies (mAbs)             > Limitations of mAbs               o Active Immunotherapy                 ° Cancer Vaccines           ° Cellular Therapies           ° Adjuvants             o Investigational Combination Immunotherapy             o Limitations of Current Immunotherapies             o What is the Investigational Therapy Multikine?                 o Introduction to Investigational Therapy Multikine             o Multikine has the potential to be in a new class of immunotherapy drugs             o Clinical Trial Status of Investigational Therapy Multikine             o Investigational Therapy Multikine Phase III clinical trial design             o Current Knowledge of the Mechanism of Action of the Investigational Therapy Multikine             o Potential Relevance of The Investigational Therapy Multikine to the Medical Community Responsible for Head and Neck Cancer Patients with Advanced Disease if Approved for Marketing by the FDA             o Head and Neck Cancer                 ° Introduction             ° Key Points             ° Questions and Answers           ° Related Resources                   * Multikine is the trademark that CEL-SCI has registered for this investigational therapy, and this proprietary name is subject to FDA review in connection with our future anticipated regulatory submission for approval. Multikine has not been licensed or approved for sale, barter or exchange by the FDA or by any other regulatory agency. Similarly, its safety or efficacy has not been established for any use. Moreover, no definitive conclusions can be drawn from the early-phase, clinical-trials data summarized on this page or elsewhere on this website involving the investigational therapy Multikine (Leukocyte Interleukin, Injection). Further research is required, and early-phase clinical trial results must be confirmed in the well-controlled, Phase III clinical trial of this investigational therapy that is currently in progress.
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A machine learning approach for somatic mutation discovery

A machine learning approach for somatic mutation discovery | Melanoma BRAF Inhibitors Review | Scoop.it
Somatic mutation calling is essential for the proper diagnosis and treatment of most cancer patients. Wood et al . developed a machine learning approach called Cerebro that increased the accuracy of calling validated somatic mutations in tumor samples from cancer patients. Cerebro outperformed six other mutation detection methods by better distinguishing technical sequencing artifacts. An analysis of non–small cell lung cancer and melanoma patient samples revealed that Cerebro more accurately classified patients according to their immunotherapy response, suggesting that the authors’ mutation calling approach could favorably affect patient care.

Variability in the accuracy of somatic mutation detection may affect the discovery of alterations and the therapeutic management of cancer patients. To address this issue, we developed a somatic mutation discovery approach based on machine learning that outperformed existing methods in identifying experimentally validated tumor alterations (sensitivity of 97% versus 90 to 99%; positive predictive value of 98% versus 34 to 92%). Analysis of paired tumor-normal exome data from 1368 TCGA (The Cancer Genome Atlas) samples using this method revealed concordance for 74% of mutation calls but also identified likely false-positive and false-negative changes in TCGA data, including in clinically actionable genes. Determination of high-quality somatic mutation calls improved tumor mutation load–based predictions of clinical outcome for melanoma and lung cancer patients previously treated with immune checkpoint inhibitors. Integration of high-quality machine learning mutation detection in clinical next-generation sequencing (NGS) analyses increased the accuracy of test results compared to other clinical sequencing analyses. These analyses provide an approach for improved identification of tumor-specific mutations and have important implications for research and clinical management of cancer patients.
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Targeting quiescent leukemic stem cells using second generation autophagy inhibitors

Targeting quiescent leukemic stem cells using second generation autophagy inhibitors | Melanoma BRAF Inhibitors Review | Scoop.it
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CD40 Antibody APX005M, Nivolumab & Chemotherapy Phase 1b 2 Study to Explore Combo Chemotherapy and 2 Immunotherapy Agents

CD40 Antibody APX005M, Nivolumab & Chemotherapy Phase 1b 2 Study to Explore Combo Chemotherapy and 2 Immunotherapy Agents | Melanoma BRAF Inhibitors Review | Scoop.it
David Feltquate Head of Early Clinical Development at BRISTOL-MYERS SQUIBB discusses the the phase 1b/2 open-label study which will explore the combination of standard chemotherapy and two immunotherapy agents: an anti-PD-1 checkpoint inhibitor and a novel antibody targeting CD40 in pancreatic...
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Combined Nivolumab and Ipilimumab in Melanoma Metastatic to the Brain | NEJM

Original Article from The New England Journal of Medicine — Combined Nivolumab and Ipilimumab in Melanoma Metastatic to the Brain...
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IMPRES predicts which melanomas will respond to immunotherapy

IMPRES predicts which melanomas will respond to immunotherapy | Melanoma BRAF Inhibitors Review | Scoop.it
In a new study, NCI-led researchers developed a gene expression predictor that can indicate whether melanoma in a specific patient is likely to respond to treatment with immune checkpoint inhibitors, a type of immunotherapy.
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Parker Institute for Cancer Immunotherapy

Parker Institute for Cancer Immunotherapy | Melanoma BRAF Inhibitors Review | Scoop.it
The Parker Institute for Cancer Immunotherapy coordinates cancer research efforts between the best scientists, clinicians and partners in the industry.
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Tumor evolution and chemoresistance in ovarian cancer

Tumor evolution and chemoresistance in ovarian cancer | Melanoma BRAF Inhibitors Review | Scoop.it
Development of novel strategies to overcome chemoresistance is central goal in ovarian cancer research. Natural history of the cancer development and progression is being reconstructed by genomic datasets to understand the evolutionary pattern and direction. Recent studies suggest that intra-tumor heterogeneity (ITH) is the main cause of treatment failure by chemoresistance in many types of cancers including ovarian cancer. ITH increases the fitness of tumor to adapt to incompatible microenvironment. Understanding ITH in relation to the evolutionary pattern may result in the development of the innovative approach based on individual variability in the genetic, environment, and life style. Thus, we can reach the new big stage conquering the cancer. In this review, we will discuss the recent advances in understanding ovarian cancer biology through the use of next generation sequencing (NGS) and highlight areas of recent progress to improve precision medicine in ovarian cancer.
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Immune Checkpoint Inhibitor-Associated Colits and Hepatitis

Immune Checkpoint Inhibitor-Associated Colits and Hepatitis | Melanoma BRAF Inhibitors Review | Scoop.it
Immune checkpoint inhibitors (ICPIs) are monoclonal antibodies that target downregulators of the anti-cancer immune response: cytotoxic T-lymphocyte antigen-4, programmed cell death protein-1, and its ligand PD-L1. ICPIs are now approved for the treatment of a wide array of malignancies, with rates of durable responses in the metastatic setting far exceeding what would be expected from conventional chemotherapy. ICPIs have also been associated with rare but serious immune-related adverse events due to over-activation of the immune system that can affect any organ, including the gastrointestinal tract and liver. As the use of ICPIs in oncology continues to increase, ICPI-associated colitis and hepatitis will be encountered frequently by gastroenterologists and hepatologists. This review will focus on the diagnosis and management of ICPI-associated colitis and hepatitis. We will also compare these ICPI-related toxicities with sporadic inflammatory bowel disease and autoimmune liver disease.
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Emerging biomarkers for cancer immunotherapy in melanoma - ScienceDirect

Emerging biomarkers for cancer immunotherapy in melanoma - ScienceDirect | Melanoma BRAF Inhibitors Review | Scoop.it
The treatment and prognosis of metastatic melanoma has changed substantially since the advent of novel immune checkpoint inhibitors (ICI), agents that enhance the anti-tumor immune response. Despite the success of these agents, clinically actionable biomarkers to aid patient and regimen selection are lacking. Herein, we summarize and review the evidence for candidate biomarkers of response to ICIs in melanoma. Many of these candidates can be examined as parts of a known molecular pathway of immune response, while others are clinical in nature. Due to the ability of ICIs to illicit dramatic and durable responses, well-validated biomarkers that can be effectively implemented in the clinic will require strong negative predictive values that do not limit patients with who may benefit from ICI therapy.
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Experimental Vaccine-Adjuvant Combination Eliminates Melanoma in Mice | Medicine | Sci-News.com

Experimental Vaccine-Adjuvant Combination Eliminates Melanoma in Mice | Medicine | Sci-News.com | Melanoma BRAF Inhibitors Review | Scoop.it
A team of scientists from the Scripps Research Institute and the University of Texas Southwestern Medical Center has demonstrated that adding an ‘adjuvant’ molecule called diprovocim to a new vaccine can draw cancer-fighting cells to tumor sites.
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Treating skin cancer with HPV vaccines. ecancer - News

Treating skin cancer with HPV vaccines. ecancer - News | Melanoma BRAF Inhibitors Review | Scoop.it
Treating skin cancer with HPV vaccines 04 Jul 2018 Squamous cell carcinoma is the second-most-common form of skin cancer. Evidence suggests the human papilloma virus plays a role in the development of some types of this skin cancer. Two years ago, a 97-year-old woman whose right leg was covered with squamous cell tumours went to see dermatologist Anna Nichols, M.D., Ph.D., at Sylvester Comprehensive Cancer Center. Surgery is the standard of care for most patients with skin cancer. "She was not a candidate for surgery because of the sheer number and size of her tumours. She wasn't a candidate for radiotherapy, again for the same reasons," said Dr. Nichols, an assistant professor at the University of Miami Miller School of Medicine, whose report on this case was published online in JAMA Dermatology. In 2017, a case report by Dr. Nichols showed the HPV vaccine Gardasil reduced the number of new basal and squamous cell skin cancers in two patients. Tim Ioannides, M.D., a voluntary faculty member at UM, suggested using the vaccine as an off-label treatment by directly injecting it into the tumours. Since her patient had no other options, Dr. Nichols offered her the treatment. It is considered an "off-label" use because Gardasil is only approved for the prevention of cervical, anal, vulvar and vaginal cancers caused by the human papilloma virus. "I think we had a really reasonable expectation and good data that this was actually going to, at the very least, do no harm to this patient, and possibly provide some benefit," said Dr. Ioannides. "To have this type of result in such an advanced patient I think was beyond all our expectations." The patient was first given two doses of the 9-valent HPV vaccine in her arm, six weeks apart. A few weeks later Dr. Nichols directly injected several but not all of the patient's tumours. The direct intratumoral injections were given four times over 11 months. "All of her tumours completely resolved 11 months after the first direct tumour injection, and she has had no recurrence," Dr. Nichols said. "It has been about 24 months now since we started with the treatment." "They decided to try it and it worked. It killed them all off," said the patient, who is now looking forward to celebrating her 100th birthday this fall. Source: University of Miami Miller School of Medicine
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Targeting nucleotide exchange to inhibit constitutively active G protein α subunits in cancer cells

Targeting nucleotide exchange to inhibit constitutively active G protein α subunits in cancer cells | Melanoma BRAF Inhibitors Review | Scoop.it
Activating mutations in G protein α subunits cause various diseases, including some forms of uveal melanoma (UM), an aggressive eye cancer. Onken et al . found that the plant-derived compound FR900359 blocked the growth of Gα-mutant UM cells in culture. FR900359 allosterically inhibited the guanine nucleotide exchange activity of constitutively active Gαq, thereby trapping it in inactive heterotrimers. The loss of Gαq signaling in UM cells induced redifferentiation and cell death. Targeting this compound, if safe, or synthetic derivatives to the uveal tumor tissue may be an effective treatment for patients.

Constitutively active G protein α subunits cause cancer, cholera, Sturge-Weber syndrome, and other disorders. Therapeutic intervention by targeted inhibition of constitutively active Gα subunits in these disorders has yet to be achieved. We found that constitutively active Gαq in uveal melanoma (UM) cells was inhibited by the cyclic depsipeptide FR900359 (FR). FR allosterically inhibited guanosine diphosphate–for–guanosine triphosphate (GDP/GTP) exchange to trap constitutively active Gαq in inactive, GDP-bound Gαβγ heterotrimers. Allosteric inhibition of other Gα subunits was achieved by the introduction of an FR-binding site. In UM cells driven by constitutively active Gαq, FR inhibited second messenger signaling, arrested cell proliferation, reinstated melanocytic differentiation, and stimulated apoptosis. In contrast, FR had no effect on BRAF -driven UM cells. FR promoted UM cell differentiation by reactivating polycomb repressive complex 2 (PRC2)–mediated gene silencing, a heretofore unrecognized effector system of constitutively active Gαq in UM. Constitutively active Gαq and PRC2 therefore provide therapeutic targets for UM. The development of FR analogs specific for other Gα subunit subtypes may provide novel therapeutic approaches for diseases driven by constitutively active Gα subunits or multiple G protein–coupled receptors (GPCRs) where targeting a single receptor is ineffective.
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Survival in Male vs Female Patients Receiving Immune Checkpoint Inhibitors - The ASCO Post

Survival in Male vs Female Patients Receiving Immune Checkpoint Inhibitors - The ASCO Post | Melanoma BRAF Inhibitors Review | Scoop.it
Survival in Male vs Female Patients Receiving Immune Checkpoint Inhibitors By Matthew Stenger and compiled by Sarah Jackson August 25, 2018 In a systematic review and meta-analysis reported in The Lancet Oncology by Fabio Conforti, MD, of the Division of Medical Oncology for Melanoma & Sarcoma, European Institute of Oncology, Milan, and colleagues, a significant difference in overall survival benefit favoring male vs female patients receiving immune checkpoint inhibitor therapy for advanced cancers was reported. The study involved database searches of the literature through November 2017 for randomized controlled trials of immune checkpoint inhibitors that included hazard ratios (HRs) for death according to patient sex. A total of 20 trials of ipilimumab (Yervoy), tremelimumab, nivolumab (Opdivo), and pembrolizumab (Keytruda) were identified, including a total of 11,351 patients with advanced or metastatic disease. Of them, 7,646 (67%) were men and 3,705 (33%) were women; the most common types of cancer were melanoma (n = 3,632, 32%) and non–small cell lung cancer (n = 3,482, 31%). Among all patients, 2,881 were enrolled in ipilimumab trials; 1,226, in tremelimumab trials; 3,893, in nivolumab trials; 3,209, in pembrolizumab trials; and 142, in a nivolumab plus ipilimumab trial. Survival by Sex Among all patients, the pooled overall survival hazard ratios were 0.72 (95% confidence interval [CI] = 0.65–0.79) for immune checkpoint inhibitor vs control treatment in male patients and 0.86 (95% CI = 0.79–0.93) in female patients. The difference in efficacy between men and women receiving immune checkpoint inhibitors was significant (P = .0019), with the pooled interaction hazard ratio for men vs women being 0.85. Subgroup analyses for cancer type (P = .72 for heterogeneity); line of treatment (P = .77 for heterogeneity); type of immune checkpoint inhibitor (anti–programmed cell death protein 1 [PD-1], anti–cytotoxic T-lymphocyte–associated protein 4 (CTLA-4); P = .40 for heterogeneity); and control group (immunotherapy, no immunotherapy; P = .72) showed better hazard ratios for men vs women for each subgroup, with the heterogeneity test for the sex interaction being nonsignificant in each subgroup. The investigators concluded, “Immune checkpoint inhibitors can improve overall survival for patients with advanced cancers such as melanoma and non–small cell lung cancer, but the magnitude of benefit is sex-dependent. Future research should guarantee greater inclusion of women in trials and focus on improving the effectiveness of immunotherapies in women, perhaps exploring different immunotherapeutic approaches in men and women.” ■ Conforti F, et al: Lancet Oncol 19:737-746, 2018.
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Oncotarget | Vitamin C and Doxycycline: A synthetic lethal combination therapy targeting metabolic flexibility in cancer stem cells (CSCs)

Oncotarget | Vitamin C and Doxycycline: A synthetic lethal combination therapy targeting metabolic flexibility in cancer stem cells (CSCs) | Melanoma BRAF Inhibitors Review | Scoop.it
Vitamin C and Doxycycline: A synthetic lethal combination therapy targeting metabolic flexibility in cancer stem cells (CSCs)...
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Turning Off Protein Could Boost Immunotherapy Effectiveness on Cancer Tumors - 07/31/2018

Turning Off Protein Could Boost Immunotherapy Effectiveness on Cancer Tumors - 07/31/2018 | Melanoma BRAF Inhibitors Review | Scoop.it
Researchers at the Bloomberg~Kimmel Institute for Cancer Immunotherapy in the Johns Hopkins Kimmel Cancer Center discovered inhibiting a previously known protein could reduce tumor burdens and enhance the effectiveness of immunotherapy treatments.
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Loss of GCNT2/I-branched glycans enhances melanoma growth and survival

Loss of GCNT2/I-branched glycans enhances melanoma growth and survival | Melanoma BRAF Inhibitors Review | Scoop.it
Abstract
Cancer cells often display altered cell-surface glycans compared to their nontransformed counterparts. However, functional contributions of glycans to cancer initiation and progression remain poorly understood. Here, from expression-based analyses across cancer lineages, we found that melanomas exhibit significant transcriptional changes in glycosylation-related genes. This gene signature revealed that, compared to normal melanocytes, melanomas downregulate I-branching glycosyltransferase, GCNT2, leading to a loss of cell-surface I-branched glycans. We found that GCNT2 inversely correlated with clinical progression and that loss of GCNT2 increased melanoma xenograft growth, promoted colony formation, and enhanced cell survival. Conversely, overexpression of GCNT2 decreased melanoma xenograft growth, inhibited colony formation, and increased cell death. More focused analyses revealed reduced signaling responses of two representative glycoprotein families modified by GCNT2, insulin-like growth factor receptor and integrins. Overall, these studies reveal how subtle changes in glycan structure can regulate several malignancy-associated pathways and alter melanoma signaling, growth, and survival.
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APOBEC mutation drives early-onset squamous cell carcinomas in recessive dystrophic epidermolysis bullosa

APOBEC mutation drives early-onset squamous cell carcinomas in recessive dystrophic epidermolysis bullosa | Melanoma BRAF Inhibitors Review | Scoop.it
Individuals with the inherited skin disease recessive dystrophic epidermolysis bullosa (RDEB) are predisposed to developing aggressive squamous cell carcinomas (SCCs), although why this patient group is prone to these cancers at such early ages is unknown. Cho et al . sequenced multiple RDEB SCC tumors and found that the mutation profile in these carcinomas was most consistent with APOBEC-associated mutagenesis, unlike other types of SCC that may be driven by ultraviolet light or tobacco smoke exposure. This finding could open up new lines of thinking on how to successfully prevent or target SCCs in RDEB patients.

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare inherited skin and mucous membrane fragility disorder complicated by early-onset, highly malignant cutaneous squamous cell carcinomas (SCCs). The molecular etiology of RDEB SCC, which arises at sites of sustained tissue damage, is unknown. We performed detailed molecular analysis using whole-exome, whole-genome, and RNA sequencing of 27 RDEB SCC tumors, including multiple tumors from the same patient and multiple regions from five individual tumors. We report that driver mutations were shared with spontaneous, ultraviolet (UV) light–induced cutaneous SCC (UV SCC) and head and neck SCC (HNSCC) and did not explain the early presentation or aggressive nature of RDEB SCC. Instead, endogenous mutation processes associated with apolipoprotein B mRNA-editing enzyme catalytic polypeptide–like (APOBEC) deaminases dominated RDEB SCC. APOBEC mutation signatures were enhanced throughout RDEB SCC tumor evolution, relative to spontaneous UV SCC and HNSCC mutation profiles. Sixty-seven percent of RDEB SCC driver mutations was found to emerge as a result of APOBEC and other endogenous mutational processes previously associated with age, potentially explaining a >1000-fold increased incidence and the early onset of these SCCs. Human papillomavirus–negative basal and mesenchymal subtypes of HNSCC harbored enhanced APOBEC mutational signatures and transcriptomes similar to those of RDEB SCC, suggesting that APOBEC deaminases drive other subtypes of SCC. Collectively, these data establish specific mutagenic mechanisms associated with chronic tissue damage. Our findings reveal a cause for cancers arising at sites of persistent inflammation and identify potential therapeutic avenues to treat RDEB SCC.
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