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Mek pd-1

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https://www.readbyqxmd.com/read/29750425/increased-infiltration-of-macrophages-to-radioresistant-lung-cancer-cells-contributes-to-the-development-of-the-additional-resistance-of-tumor-cells-to-the-cytotoxic-effects-of-nk-cells
#1
Mingjing Shen, Yongbing Chen, Lijun Xu, Rongying Zhu, Xiang Xue, Ying Tsai, Peter C Keng, Soo Ok Lee, Yuhchyau Chen
In this study, in order to investigate the effects of increased macrophage infiltration to radioresistant lung tumors in regulating natural killer (NK) cell-mediated immunity, we examined whether the treatment of radioresistant cells with conditioned medium (CM) from phorbol myristate acetate (PMA)/interleukin (IL)-4 treated THP-1 cells (used as a tumor-associated macrophage source) leads to the development of the additional resistance of tumor cells to NK cell cytotoxicity. We found that the susceptibility of THP-1 CM-treated radioresistant cells to NK cell cytotoxicity was decreased compared to the non-treated cells...
May 4, 2018: International Journal of Oncology
https://www.readbyqxmd.com/read/29721378/a-phase-ii-study-of-combined-therapy-with-a-braf-inhibitor-vemurafenib-and-interleukin-2-aldesleukin-in-patients-with-metastatic-melanoma
#2
Meghan J Mooradian, Alexandre Reuben, Peter A Prieto, Mehlika Hazar-Rethinam, Dennie T Frederick, Brandon Nadres, Adriano Piris, Vikram Juneja, Zachary A Cooper, Arlene H Sharpe, Ryan B Corcoran, Keith T Flaherty, Donald P Lawrence, Jennifer A Wargo, Ryan J Sullivan
Background : Approximately 50% of melanomas harbor BRAF mutations. Treatment with BRAF +/- MEK inhibition is associated with favorable changes in the tumor microenvironment thus providing the rationale for combining targeted agents with immunotherapy. Methods : Patients with unresectable Stage III or IV BRAFV600E mutant melanoma were enrolled in a single-center prospective study (n = 6). Patients were eligible to receive two courses of HD-IL-2 and vemurafenib twice daily. The primary endpoint was progression-free survival (PFS) with secondary objectives including overall survival (OS), response rates (RR), and safety of combination therapy as compared to historical controls...
2018: Oncoimmunology
https://www.readbyqxmd.com/read/29703161/survival-and-clinical-outcomes-of-patients-with-melanoma-brain-metastasis-in-the-era-of-checkpoint-inhibitors-and-targeted-therapies
#3
Elham Vosoughi, Jee Min Lee, James R Miller, Mehdi Nosrati, David R Minor, Roy Abendroth, John W Lee, Brian T Andrews, Lewis Z Leng, Max Wu, Stanley P Leong, Mohammed Kashani-Sabet, Kevin B Kim
BACKGROUND: Melanoma brain metastasis is associated with an extremely poor prognosis, with a median overall survival of 4-5 months. Since 2011, the overall survival of patients with stage IV melanoma has been significantly improved with the advent of new targeted therapies and checkpoint inhibitors. We analyze the survival outcomes of patients diagnosed with brain metastasis after the introduction of these novel drugs. METHODS: We performed a retrospective analysis of our melanoma center database and identified 79 patients with brain metastasis between 2011 and 2015...
April 27, 2018: BMC Cancer
https://www.readbyqxmd.com/read/29682188/imaging-markers-of-response-to-combined-braf-and-mek-inhibition-in-braf-mutated-vemurafenib-sensitive-and-resistant-melanomas
#4
Stefania Acciardo, Lionel Mignion, Nicolas Joudiou, Caroline Bouzin, Jean-François Baurain, Bernard Gallez, Bénédicte F Jordan
A majority of patients with a V600x melanoma respond quickly to BRAF/MEK inhibition (BRAFi/MEKi) and have an obvious clinical benefit. Nearly all the patients after this initial phase will develop resistance. Therefore, non-invasive early markers of response/non-response are needed in order to identify those patients who, due to intrinsic or acquired resistance, do not respond to treatment and would be eligible for alternative treatments. The aim of this study was to investigate the value of magnetic resonance spectroscopy (1 H-MRS) of choline and diffusion-weighted magnetic resonance imaging (DW-MRI) as early markers of response to BRAF inhibition (BRAFi) with vemurafenib alone or in combination with MEK inhibition (MEKi) with trametinib, in BRAFi-sensitive and BRAFi-resistant melanoma xenografts...
March 30, 2018: Oncotarget
https://www.readbyqxmd.com/read/29510196/pd-l1-confers-glioblastoma-multiforme-malignancy-via-ras-binding-and-ras-erk-emt-activation
#5
Xin Yao Qiu, Dian Xing Hu, Wen-Qiang Chen, Ruo Qiao Chen, Shi Rui Qian, Chun Yang Li, Yuan Jun Li, Xin Xin Xiong, Di Liu, Feng Pan, Shang Bin Yu, Xiao Qian Chen
Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor due to the lack of effective therapeutic drugs. Cancer therapy targeting programmed cell death protein 1 (PD-1) or programmed death ligand-1 (PD-L1) is of revolutionary. However, the role of intrinsic PD-L1, which determines immune-therapy outcomes, remains largely unclear. Here we demonstrated an oncogenic role of PD-L1 via binding and activating Ras in GBM cells. RNA-sequencing transcriptome data revealed that PD-L1 significantly altered gene expression enriched in cell growth/migration/invasion pathways in human GBM cells...
May 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29509940/multiplexed-immunofluorescence-reveals-potential-pd-1-pd-l1-pathway-vulnerabilities-in-craniopharyngioma
#6
Shannon Coy, Rumana Rashid, Jia-Ren Lin, Ziming Du, Andrew M Donson, Todd C Hankinson, Nicholas K Foreman, Peter E Manley, Mark W Kieran, David A Reardon, Peter K Sorger, Sandro Santagata
Background: Craniopharyngiomas are neoplasms of the sellar/parasellar region that are classified into adamantinomatous (ACP) and papillary (PCP) subtypes. Surgical resection of craniopharyngiomas is challenging, and recurrence is common, frequently leading to profound morbidity. BRAF V600E mutations render PCP susceptible to BRAF/MEK inhibitors, but effective targeted therapies are needed for ACP. We explored the feasibility of targeting the PD-1/PD-L1 immune checkpoint pathway in ACP and PCP...
March 2, 2018: Neuro-oncology
https://www.readbyqxmd.com/read/29500411/astrocytic-jwa-deletion-exacerbates-dopaminergic-neurodegeneration-by-decreasing-glutamate-transporters-in-mice
#7
Rihua Wang, Xue Zhao, Jin Xu, Yifan Wen, Aiping Li, Ming Lu, Jianwei Zhou
Astrocytic JWA exerts neuroprotective roles by alleviating oxidative stress and inhibiting inflammation. However, the molecular mechanisms of how astrocytic JWA is involved in dopaminergic neurodegeneration in Parkinson's disease (PD) remain largely unknown. In this study, we found that astrocyte-specific JWA knockout mice (JWA CKO) exacerbated dopamine (DA) neuronal loss and motor dysfunction, and reduced the levels of DA and its metabolites in a 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine/probenecid (MPTP/p)-induced PD model...
March 2, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29471699/atezolizumab-for-the-treatment-of-colorectal-cancer-the-latest-evidence-and-clinical-potential
#8
Gonzalo Tapia Rico, Timothy J Price
Atezolizumab is a fully humanized, engineered monoclonal antibody that specifically targets PD-L1, key molecule in the cancer-immunity pathway. Atezolizumab is currently approved for the treatment of metastatic non-small-cell lung cancer and advanced urothelial carcinomas. Areas covered: In this review, we will present the available data supporting the efficacy of atezolizumab for the treatment of metastatic colorectal cancer (mCRC). We will also provide an update on the ongoing/future clinical trials evaluating the role of atezolizumab for the treatment of CRC in different settings (alone or in combination with other checkpoint inhibitors and/or targeted therapies)...
April 2018: Expert Opinion on Biological Therapy
https://www.readbyqxmd.com/read/29471676/results-and-challenges-of-immune-checkpoint-inhibitors-in-colorectal-cancer
#9
Sheik Emambux, Gaelle Tachon, Audelaure Junca, David Tougeron
Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide and clinical outcome has improved substantially during the last two decades with targeted therapies. The immune system has a major role in cancers, especially the CD8 + T cells specific to tumor antigens. However, tumors can escape immune response by different mechanisms including upregulation of inhibitory immune checkpoint receptors, such as well-known Programmed cell Death protein-1 (PD-1)/Programmed cell Death Ligand 1 (PD-L1) interaction, leading CD8 + T cells to a state of anergy...
February 28, 2018: Expert Opinion on Biological Therapy
https://www.readbyqxmd.com/read/29317734/combined-sep-and-anti-pd-l1-antibody-produces-a-synergistic-antitumor-effect-in-b16-f10-melanoma-bearing-mice
#10
Zhengping Hu, Liang Ye, Yingying Xing, Jinhang Hu, Tao Xi
The increased PD-L1 induces poorer prognosis in melanoma. The treatment with PD-1/PD-L1 antibodies have a low response rate. The combination immunotherapies are the encouraging drug development strategy to receive maximal therapeutic benefit. In this study, we investigated the enhanced antitumor and immunomodulatory activity of combined SEP and αPD-L1 in B16-F10 melanoma-bearing mice. The results shown that combined SEP and αPD-L1 presented significant synergistic antitumor effects, increased the frequency of CD8+ and CD4+ T cells in spleen and tumor, cytotoxic activity of CTL in spleen, and IL-2 and IFN-γ levels in splenocytes and tumor...
January 9, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29276997/cancer-immunotherapy-in-a-neglected-population-the-current-use-and-future-of-t-cell-mediated-checkpoint-inhibitors-in-organ-transplant-patients
#11
REVIEW
Young Kwang Chae, Carlos Galvez, Jonathan F Anker, Wade T Iams, Manali Bhave
Although the indications for immune checkpoint inhibitors continue to grow, organ transplant recipients with advanced malignancies have been largely excluded from clinical trials testing the safety and efficacy of these therapies given their need for chronic immunosuppression and the risk of allograft rejection. With the rapid growth of transplant medicine and the increased risk of malignancy associated with chronic immunosuppression, it is critical that we systematically analyze the available data describing immune checkpoint blockade in the organ transplant population...
February 2018: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/29204524/distant-intracranial-failure-in-melanoma-brain-metastases-treated-with-stereotactic-radiosurgery-in-the-era-of-immunotherapy-and-targeted-agents
#12
Sahaja Acharya, Mustafaa Mahmood, Daniel Mullen, Deshan Yang, Christina I Tsien, Jiayi Huang, Stephanie M Perkins, Keith Rich, Michael Chicoine, Eric Leuthardt, Joshua Dowling, Gavin Dunn, Jesse Keller, Clifford G Robinson, Christopher Abraham
Purpose: Stereotactic radiosurgery (SRS) in combination with immunotherapy (IMT) or targeted therapy is increasingly being used in the setting of melanoma brain metastases (MBMs). The synergistic properties of combination therapy are not well understood. We compared the distant intracranial failure rates of intact MBMs treated with SRS, SRS + IMT, and SRS + targeted therapy. Methods and materials: Combination therapy was defined as delivery of SRS within 3 months of IMT (anti-CTLA-4 /anti-PD-1 therapy) or targeted therapy (BRAF/MEK inhibitors)...
October 2017: Advances in Radiation Oncology
https://www.readbyqxmd.com/read/29195116/pd-l1-status-does-not-predict-the-outcome-of-braf-inhibitor-therapy-in-metastatic-melanoma
#13
Katrin Schaper-Gerhardt, Steven Okoye, Rudolf Herbst, Jens Ulrich, Patrick Terheyden, Claudia Pföhler, Jochen S Utikal, Alexander Kreuter, Peter Mohr, Edgar Dippel, Imke Satzger, Antje Sucker, Dirk Schadendorf, Selma Ugurel, Ralf Gutzmer
BACKGROUND: Targeted therapies with BRAF plus MEK inhibitors (BRAFi; MEKi) represent the major treatment strategy for patients with BRAF-mutated metastatic melanoma (MM). Previous analyses suggested a correlation between programmed death-ligand 1 (PD-L1) expression in tumour tissues and the outcome of targeted therapies. This study investigated PD-L1 as a potential predictive biomarker of BRAFi-based targeted therapies in MM patients. PATIENTS AND METHODS: We analysed two independent cohorts of BRAF V600-mutated MM patients undergoing BRAFi-based therapies for PD-L1 expression in pre-treatment tumour tissues...
January 2018: European Journal of Cancer
https://www.readbyqxmd.com/read/29181212/uncommon-braf-mutations-associated-with-durable-response-to-immunotherapy-in-patients-with-metastatic-melanoma
#14
Brenen P Swofford, Jade Homsi
Melanoma is a disease process which has been increasing in incidence over the past three decades and metastatic melanoma carries a poor prognosis. Through genetic studies of this disease, it has been determined that the BRAF V600 mutation plays a major role in the pathophysiology of the disease and this has led to the utilization of targeted therapy (BRAF and MEK inhibitors) in its treatment. Other BRAF mutations (non-V600 mutations) are rare in melanoma and targeted therapy is not indicated for patients with these mutations due to reduced response rates...
2017: Case Reports in Oncological Medicine
https://www.readbyqxmd.com/read/29164492/advanced-melanoma-current-treatment-options-biomarkers-and-future-perspectives
#15
REVIEW
Elisa A Rozeman, Tim J A Dekker, John B A G Haanen, Christian U Blank
Malignant melanoma accounts for the highest number of deaths from skin cancer, and the prognosis of patients with stage IV disease has historically been poor. Novel insights into both mutations driving tumorigenesis and immune escape mechanisms of these tumors have led to effective treatment options that have revolutionized the treatment of this disease. Targeting the MAPK kinase pathway (with BRAF and MEK inhibitors), as well as targeting checkpoints, such as cytotoxic T-lymphocyte associated protein 4 (CTLA-4) or programmed death 1 (PD-1), have improved overall survival in patients with late-stage melanoma, and biomarker research for personalized therapy is ongoing for each of these treatment modalities...
November 21, 2017: American Journal of Clinical Dermatology
https://www.readbyqxmd.com/read/29156488/association-of-programmed-death-ligand-1-pd-l1-expression-with-treatment-outcomes-in-patients-with-braf-mutation-positive-melanoma-treated-with-vemurafenib-or-cobimetinib-combined-with-vemurafenib
#16
Matthew J Wongchenko, Antoni Ribas, Brigitte Dréno, Paolo A Ascierto, Grant A McArthur, Jorge D Gallo, Isabelle A Rooney, Jessie Hsu, Hartmut Koeppen, Yibing Yan, James Larkin
The prognostic significance of programmed death ligand-1 (PD-L1) on treatment outcomes in patients receiving BRAF with or without MEK inhibitors is not well understood. This retrospective exploratory analysis evaluated the association of tumour PD-L1 expression with progression-free survival (PFS) and overall survival (OS) among 210 patients in the coBRIM trial treated with cobimetinib plus vemurafenib or placebo plus vemurafenib. In the vemurafenib cohort, there was a trend of increased PFS and OS in those with PD-L1+ melanoma, with hazard ratios (HRs; PD-L1+ vs...
November 20, 2017: Pigment Cell & Melanoma Research
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
#17
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
#18
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...
December 2017: Targeted Oncology
https://www.readbyqxmd.com/read/29050517/the-safety-and-efficacy-of-dabrafenib-and-trametinib-for-the-treatment-of-melanoma
#19
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
#20
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
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