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https://www.readbyqxmd.com/read/29113321/radiation-alters-pd-l1-nkg2d-ligand-levels-in-lung-cancer-cells-and-leads-to-immune-escape-from-nk-cell-cytotoxicity-via-il-6-mek-erk-signaling-pathway
#1
Ming Jing Shen, Li Jun Xu, Li Yang, Ying Tsai, Peter C Keng, Yongbing Chen, Soo Ok Lee, Yuhchyau Chen
We investigated whether radiation influences the susceptibility of non-small cell lung cancer (NSCLC) cells to NK cell mediated cytotoxicity. We found radiation treatment increased expression of programmed cell death ligand 1 (PD-L1), but decreased NK group 2, member D (NKG2D) ligand expressions in A549 and H157 NSCLC cells. Both types of changes would have protected tumor cells from the cytotoxic action of NK cells. Consistently, we detected similar alteration in these molecules in radioresistant A549R26-1 and H157R24-1 subline cells...
October 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/29067643/a-multi-arm-phase-i-study-of-the-pi3k-mtor-inhibitors-pf-04691502-and-gedatolisib-pf-05212384-plus-irinotecan-or-the-mek-inhibitor-pd-0325901-in-advanced-cancer
#2
Zev A Wainberg, Maria Alsina, Heloisa P Soares, Irene Braña, Carolyn D Britten, Gianluca Del Conte, Patrick Ezeh, Brett Houk, Kenneth A Kern, Stephen Leong, Nuzhat Pathan, Kristen J Pierce, Lillian L Siu, Jennifer Vermette, Josep Tabernero
BACKGROUND: This phase I, four-arm, open-label study (NCT01347866) evaluated the PI3K/mTOR inhibitors PF-04691502 (arms A, B) and gedatolisib (PF-05212384; arms C, D) in combination with the MEK inhibitor PD-0325901 (arm A, D) or irinotecan (arm B, C) in patients with advanced solid tumors. OBJECTIVES: Primary endpoint was dose-limiting toxicity with each combination. Secondary endpoints included safety, pharmacokinetics and preliminary antitumor activity. PATIENTS AND METHODS: Dose escalation followed a 3 + 3 design in arm C and a zone-based design in arm D...
October 24, 2017: Targeted Oncology
https://www.readbyqxmd.com/read/29050517/the-safety-and-efficacy-of-dabrafenib-and-trametinib-for-the-treatment-of-melanoma
#3
Sarah Knispel, Lisa Zimmer, Theodora Kanaki, Selma Ugurel, Dirk Schadendorf, Elisabeth Livingstone
The introduction of BRAF and MEK inhibitors into clinical practice improved the prognosis of metastatic melanoma patients. The combination of BRAF inhibitor dabrafenib with MEK inhibitor trametinib has shown its superiority to single agent therapy and is characterized by a tolerable spectrum of adverse events which shows a decrease in incidence over time on treatment. Areas covered: The current scientific literature on safety and adverse events (AEs) related to BRAF and MEK-inhibition has been investigated with special focus on the large phase 3 studies (COMBI-v, COMBI-d and CoBRIM) as well as recent updates presented at oncology and melanoma meetings...
October 20, 2017: Expert Opinion on Drug Safety
https://www.readbyqxmd.com/read/28978077/am1241-alleviates-mptp-induced-parkinson-s-disease-and-promotes-the-regeneration-of-da-neurons-in-pd-mice
#4
Jun Shi, Qiong Cai, Jingxing Zhang, Xiaolie He, Yigang Liu, Rongrong Zhu, Lingjing Jin
The main pathological feature of Parkinson's disease (PD) is the loss of dopaminergic neurons in the substantia nigra. In this study, we investigated the role of cannabinoid receptor 2 (CB2R) agonist AM1241 on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity in a mouse model of PD. Upon treatment with AM1241, the decreased CB2R level in the PD mouse brain was reversed and the behavior score markedly elevated, accompanied with a dose-dependent increase of dopamine and serotonin. In addition, western blot assay and immunostaining results suggested that AM1241 significantly activated PI3K/Akt/MEK phosphorylation and increased the expression of Parkin and PINK1, both in the substantia nigra and hippocampus...
September 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28914644/systemic-therapy-in-advanced-melanoma-integrating-targeted-therapy-and-immunotherapy-into-clinical-practice
#5
Inês P Silva, Georgina V Long
PURPOSE OF REVIEW: Here we review the results from relevant phase III trials and discuss treatment strategies for challenging subgroups of melanoma patients. RECENT FINDINGS: Targeted therapies induce rapid responses in the majority of BRAF-mutant patients, however, 50% of these responders will develop resistance within approximately 13 months. In contrast, inhibitors of checkpoints on T cells, particularly inhibitors of PD-1, induce responses in 40-55% of patients (monotherapy or whenever combined with anti-CTLA-4), and these responses tend to be durable...
November 2017: Current Opinion in Oncology
https://www.readbyqxmd.com/read/28881828/shp2-negatively-regulates-hla-abc-and-pd-l1-expression-via-stat1-phosphorylation-in-prostate-cancer-cells
#6
Zhuqing Liu, Yu Zhao, Juemin Fang, Ran Cui, Yuanyuan Xiao, Qing Xu
Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2) is a ubiquitous protein tyrosine phosphatase that activates the signal transduction pathways of several growth factors and cytokines. In our study, SHP2 expression was very high in prostate cancer (PCa) cell lines, and the expression of phospho-signal transducer and activator of transcription 1 (p-STAT1) and STAT1 was very low. SHP2 knockdown upregulated the expression of p-STAT1 and downregulated phospho-extracellular signal regulated kinase (p-ERK)...
August 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28861871/combinatorial-therapies-in-melanoma-mapk-inhibitors-and-beyond
#7
REVIEW
Alice Y Zhou, Douglas B Johnson
Melanoma is the most aggressive of the skin cancers, with historically high rates of morbidity and mortality due to its resistance to traditional cytotoxic therapies. Recently, however, breakthroughs in new therapies have dramatically changed clinical outcomes of this disease. These advances emerged from an improved understanding of tumor oncogenesis and the interacting tumor microenvironment. Small molecules that target the oncogenic mitogen-activated protein kinase (MAPK) pathway, specifically the tyrosine kinase BRAF and its downstream signaling partner MEK, have demonstrated an improved overall survival and progression-free survival for BRAF-mutant melanoma...
August 31, 2017: American Journal of Clinical Dermatology
https://www.readbyqxmd.com/read/28827234/multiple-treatment-comparison-of-seven-new-drugs-for-patients-with-advanced-malignant-melanoma-a-systematic-review-and-health-economic-decision-model-in-a-norwegian-setting
#8
Eva Pike, Vida Hamidi, Ingvil Saeterdal, Jan Odgaard-Jensen, Marianne Klemp
OBJECTIVE: To assess the relative effectiveness and cost-effectiveness of seven new drugs (cobimetinib, dabrafenib, ipilimumab, nivolumab, pembrolizumab, trametinib and vemurafenib) used for treatment of patients with advanced malignant melanoma in the Norwegian setting. DESIGN: A multiple technology assessment. PATIENTS: Patients with advanced malignant melanoma aged 18 or older. DATA SOURCES: A systematic search for randomised controlled trials in relevant bibliographic databases...
August 21, 2017: BMJ Open
https://www.readbyqxmd.com/read/28801607/enhancing-nk-cell-mediated-cytotoxicity-to-cisplatin-resistant-lung-cancer-cells-via-mek-erk-signaling-inhibition
#9
Li Yang, MingJing Shen, Li Jun Xu, Xiaodong Yang, Ying Tsai, Peter C Keng, Yuhchyau Chen, Soo Ok Lee
Major progress has been made clinically in inhibiting the programmed death receptor 1 (PD-1)/PD-L1 interaction to enhance T cell-mediated immune function, yet the effectiveness of anti-PD-L1/PD-1 agents in enhancing natural killer (NK) cell's function remains largely unknown. Susceptibilities of cisplatin-resistant A549CisR and H157CisR cells vs. parental cells to the cytotoxic action of NK cells were examined. We found cisplatin-resistant cells more resistant to NK cell cytotoxicity than parental cells. There were constitutively higher expressions of PD-L1 in A549CisR and H157CisR cells than in parental cells in vitro, as well as in H157CisR cell-derived tumors than H157P cell-derived tumors...
August 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28756137/survival-of-patients-with-advanced-metastatic-melanoma-the-impact-of-novel-therapies-update-2017
#10
REVIEW
Selma Ugurel, Joachim Röhmel, Paolo A Ascierto, Keith T Flaherty, Jean Jacques Grob, Axel Hauschild, James Larkin, Georgina V Long, Paul Lorigan, Grant A McArthur, Antoni Ribas, Caroline Robert, Dirk Schadendorf, Claus Garbe
The treatment of metastatic melanoma is still undergoing a process of major change. The two most important novel therapeutic strategies, selective kinase inhibitors and immune checkpoint blockers, both significantly prolong survival times of patients with advanced metastatic disease. Different agents, dose regimens and combinations have been tested against each other vigorously within these two groups. However, results from prospective head-to-head comparative studies of both strategies are still lacking. We performed an exploratory analysis of survival data from selected clinical trials representative for the new treatment strategies in advanced metastatic melanoma...
September 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28733540/am1241-alleviates-mptp-induced-parkinson-s-disease-and-promotes-the-regeneration-of-da-neurons-in-pd-mice
#11
Jun Shi, Qiong Cai, Jingxing Zhang, Xiaolie He, Yigang Liu, Rongrong Zhu, Lingjing Jin
The main pathological feature of Parkinson's disease (PD) is the loss of dopaminergic neurons in the substantia nigra. In this study, we investigated the role of cannabinoid receptor 2 (CB2R) agonist AM1241 on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity in a mouse model of PD. Upon treatment with AM1241, the decreased CB2R level in the PD mouse brain was reversed and the behavior score markedly elevated, accompanied with a dose-dependent increase of dopamine and serotonin. In addition, western blot assay and immunostaining results suggested that AM1241 significantly activated PI3K/Akt/MEK phosphorylation and increased the expression of Parkin and PINK1, both in the substantia nigra and hippocampus...
June 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28732383/radiation-alters-pd-l1-nkg2d-ligand-levels-in-lung-cancer-cells-and-leads-to-immune-escape-from-nk-cell-cytotoxicity-via-il-6-mek-erk-signaling-pathway
#12
Ming Jing Shen, Li Jun Xu, Li Yang, Ying Tsai, Peter C Keng, Yongbing Chen, Soo Ok Lee, Yuhchyau Chen
We investigated whether radiation influences the susceptibility of non-small cell lung cancer (NSCLC) cells to NK cell mediated cytotoxicity. We found radiation treatment increased expression of programmed cell death ligand 1 (PD-L1), but decreased NK group 2, member D (NKG2D) ligand expressions in A549 and H157 NSCLC cells. Both types of changes would have protected tumor cells from the cytotoxic action of NK cells. Consistently, we detected similar alteration in these molecules in radioresistant A549R26-1 and H157R24-1 subline cells...
July 12, 2017: Oncotarget
https://www.readbyqxmd.com/read/28724377/combination-therapy-for-melanoma-with-braf-mek-inhibitor-and-immune-checkpoint-inhibitor-a-mathematical-model
#13
Xiulan Lai, Avner Friedman
BACKGROUND: The B-raf gene is mutated in up to 66% of human malignant melanomas, and its protein product, BRAF kinase, is a key part of RAS-RAF-MEK-ERK (MAPK) pathway of cancer cell proliferation. BRAF-targeted therapy induces significant responses in the majority of patients, and the combination BRAF/MEK inhibitor enhances clinical efficacy, but the response to BRAF inhibitor and to BRAF/MEK inhibitor is short lived. On the other hand, treatment of melanoma with an immune checkpoint inhibitor, such as anti-PD-1, has lower response rate but the response is much more durable, lasting for years...
July 19, 2017: BMC Systems Biology
https://www.readbyqxmd.com/read/28690075/tumor-microenvironment-changes-leading-to-resistance-of-immune-checkpoint-inhibitors-in-metastatic-melanoma-and-strategies-to-overcome-resistance
#14
REVIEW
Bhargavi Pulluri, Abhijeet Kumar, Montaser Shaheen, Joanne Jeter, Srinath Sundararajan
Immunotherapy with checkpoint inhibitors targeting CTLA-4 and/or PD-1 receptors independent of the BRAF mutational status and targeted therapy with BRAF and MEK inhibitors in BRAF V600 mutated patients have taken the forefront of advanced melanoma treatment. The main advantage of immunotherapy is its ability to provide durable responses in a subset of patients. However, significant proportions of patients either do not respond or have progression after initial response to immunotherapies. Multiple changes in the tumor microenvironment, such as down regulation of immune checkpoint ligands by tumor, alteration in interferon signaling, and activation of alternate immune suppressive pathways, have been identified as possible reasons for failure of immune checkpoint therapy...
July 6, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28658669/shp2-negatively-regulates-hla-abc-and-pd-l1-expression-via-stat1-phosphorylation-in-prostate-cancer-cells
#15
Zhuqing Liu, Yu Zhao, Juemin Fang, Ran Cui, Yuanyuan Xiao, Qing Xu
Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2) is a ubiquitous protein tyrosine phosphatase that activates the signal transduction pathways of several growth factors and cytokines. In our study, SHP2 expression was very high in prostate cancer (PCa) cell lines, and the expression of phospho-signal transducer and activator of transcription 1 (p-STAT1) and STAT1 was very low. SHP2 knockdown upregulated the expression of p-STAT1 and downregulated phospho-extracellular signal regulated kinase (p-ERK)...
June 21, 2017: Oncotarget
https://www.readbyqxmd.com/read/28634084/drug-delivery-to-melanoma-brain-metastases-can-current-challenges-lead-to-new-opportunities
#16
Gautham Gampa, Shruthi Vaidhyanathan, Jann N Sarkaria, William F Elmquist
Melanoma has a high propensity to metastasize to the brain, and patients with melanoma brain metastases (MBM) have an extremely poor prognosis. The recent approval of several molecularly-targeted agents (e.g., BRAF, MEK inhibitors) and biologics (anti-CTLA-4, anti-PD-1 and anti-PD-L1 antibodies) has brought new hope to patients suffering from this formerly untreatable and lethal disease. Importantly, there have been recent reports of success in some clinical studies examining the efficacy of both targeted agents and immunotherapies that show similar response rates in both brain metastases and extracranial disease...
September 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28622036/molecular-targeted-drugs-and-treatment-of-colorectal-cancer-recent-progress-and-future-perspectives
#17
Fang Geng, Zheng Wang, Hang Yin, Junxian Yu, Bangwei Cao
Nowadays, colorectal cancer is the fourth most common type of tumor all over the world. When diagnosed, ∼50%-60% of tumors have metastasized, thus resulting in a grim prognosis. Chemotherapy is regarded as standard treatment for patients with colorectal cancer, however, limitations of chemotherapy cannot be ignored, such as low selectivity, insufficient concentrations in tumor tissues, and systemic toxicity. Recently, six targeted drugs have been approved by the U.S. Food and Drug Administration (FDA) for treatment of metastatic colorectal cancer (mCRC), including bevacizumab, aflibercept, regorafenib, cetuximab, and panitumumab...
June 2017: Cancer Biotherapy & Radiopharmaceuticals
https://www.readbyqxmd.com/read/28601879/outcomes-in-melanoma-patients-treated-with-braf-mek-directed-therapy-or-immune-checkpoint-inhibition-stratified-by-clinical-trial-versus-standard-of-care
#18
Chloe Goldman, Jeremy Tchack, Eric M Robinson, Sung Won Han, Una Moran, David Polsky, Russell S Berman, Richard L Shapiro, Patrick A Ott, Iman Osman, Hua Zhong, Anna C Pavlick, Melissa Ann Wilson
OBJECTIVES: Since 2011, metastatic melanoma treatment has evolved with commercial approval of BRAF- and MEK-targeted therapy and CTLA-4- and PD-1-blocking antibodies (immune checkpoint inhibitors, ICI). While novel therapies have demonstrated improved prognosis in clinical trials, few studies have examined the evolution of prognosis and toxicity of these drugs among an unselected population. We assess whether survival and toxicity reported in trials, which typically exclude most patients with brain metastases and poor performance status, are recapitulated within a commercial access population...
2017: Oncology
https://www.readbyqxmd.com/read/28537004/mek-inhibitors-in-the-treatment-of-metastatic-melanoma-and-solid-tumors
#19
REVIEW
Antonio M Grimaldi, Ester Simeone, Lucia Festino, Vito Vanella, Martina Strudel, Paolo A Ascierto
The mitogen-activated protein kinase (MAPK) cascade is an intracellular signaling pathway involved in the regulation of cellular proliferation and the survival of tumor cells. Several different mutations, involving BRAF or NRAS, exert an oncogenic effect by activating the MAPK pathway, resulting in an increase in cellular proliferation. These mutations have become targets for new therapeutic strategies in melanoma and other cancers. Selective MEK inhibitors have the ability to inhibit growth and induce cell death in BRAF- and NRAS-mutant melanoma cell lines...
May 23, 2017: American Journal of Clinical Dermatology
https://www.readbyqxmd.com/read/28463413/a-systematic-review-and-network-meta-analysis-of-immunotherapy-and-targeted-therapy-for-advanced-melanoma
#20
Joao Paulo da Silveira Nogueira Lima, Mina Georgieva, Benjamin Haaland, Gilberto de Lima Lopes
Immune and BRAF-targeted therapies have changed the therapeutic scenario of advanced melanoma, turning the clinical decision-making a challenging task. This Bayesian network meta-analysis assesses the role of immunotherapies and targeted therapies for advanced melanoma. We retrieved randomized controlled trials testing immune, BRAF- or MEK-targeted therapies for advanced melanoma from electronic databases. A Bayesian network model compared therapies using hazard ratio (HR) for overall survival (OS), progression-free survival (PFS), and odds ratio (OR) for response rate (RR), along with 95% credible intervals (95% CrI), and probabilities of drugs outperforming others...
June 2017: Cancer Medicine
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