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https://www.readbyqxmd.com/read/28736627/personalized-and-precision-medicine-integrating-genomics-into-treatment-decisions-in-gastrointestinal-malignancies
#1
REVIEW
Trang H Au, Kai Wang, David Stenehjem, Ignacio Garrido-Laguna
The advent of next generation sequencing (NGS) technologies has advanced our understanding of the intrinsic biology of different gastrointestinal (GI) tumor types. The use of novel, more efficient sequencing platforms has improved turnaround times of sequencing results. This is providing real time opportunities to put precision medicine to the test. A number of early phase clinical trials are testing targeted therapies in unique molecularly characterized subsets of patients (baskets). While basket studies are gaining momentum, treatment failures serve to remind us that shifting from a histology-driven to a histology-agnostic approach is unlikely to be a failure-free strategy for a number of tumor types as recently learnt from vemurafenib failure in BRAF mutated metastatic colorectal cancer (mCRC)...
June 2017: Journal of Gastrointestinal Oncology
https://www.readbyqxmd.com/read/28724666/braf-inhibitors-amplify-the-pro-apoptotic-activity-of-mek-inhibitors-by-inducing-er-stress-in-nras-mutant-melanoma
#2
Heike Niessner, Tobias Sinnberg, Corinna Kosnopfel, Keiran S M Smalley, Daniela Beck, Christian Praetorius, Marion Mai, Stefan Beissert, Dagmar Kulms, Martin Schaller, Claus Garbe, Keith T Flaherty, Dana Westphal, Ines Wanke, Friedegund Meier
<p>NRAS mutations in malignant melanoma are associated with aggressive disease requiring rapid antitumor intervention, but there is no approved targeted therapy for this subset of patients. In clinical trials, the MEK inhibitor (MEKi) binimetinib displayed modest antitumor activity, making combinations a requisite. In a previous study, the BRAF inhibitor (BRAFi) vemurafenib was shown to induce endoplasmic reticulum (ER) stress that together with inhibition of the RAF-MEK-ERK (MAPK) pathway amplified its pro-apoptotic activity in BRAF-mutant melanoma...
July 19, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28722539/an-autophagy-driven-pathway-of-atp-secretion-supports-the-aggressive-phenotype-of-braf-v600e-inhibitor-resistant-metastatic-melanoma-cells
#3
Shaun Martin, Aleksandra M Dudek-Peric, Abhishek D Garg, Heleen Roose, Seyma Demirsoy, Sofie Van Eygen, Freya Mertens, Peter Vangheluwe, Hugo Vankelecom, Patrizia Agostinis
The ingrained capacity of melanoma cells to rapidly evolve towards an aggressive phenotype is manifested by their increased ability to develop drug-resistance, evident in the case of vemurafenib, a therapeutic-agent targeting BRAF(V600E). Previous studies indicated a tight correlation between heightened melanoma-associated macroautophagy/autophagy and acquired Vemurafenib resistance. However, how this vesicular trafficking pathway supports Vemurafenib resistance remains unclear. Here, using isogenic human and murine melanoma cell lines of Vemurafenib-resistant and patient-derived melanoma cells with primary resistance to the BRAF(V600E) inhibitor, we found that the enhanced migration and invasion of the resistant melanoma cells correlated with an enhanced autophagic capacity and autophagosome-mediated secretion of ATP...
July 19, 2017: Autophagy
https://www.readbyqxmd.com/read/28722363/-erdheim-chester-disease-a-differential-diagnosis-of-retroperitoneal-fibrosis
#4
Raphaël André, Jörg D Seebach
Erdheim-Chester disease is a rare multisystemic non-Langerhans histiocytosis with about 500 reported cases. Typical features include retroperitoneal and perirenal fibrosis (hairy kidney), periaortitis with a coated aorta, osteosclerosis of the lower limbs, and sometimes exophthalmia or diabetes insipidus. Histology is the cornerstone for diagnosis showing an infiltrate with foamy histiocytes and occasional multinucleated giant cells (Touton cells). There is no standard treatment regimen, current options include corticosteroids, interferon alpha, systemic chemotherapy, and radiation therapy ; however, a better understanding of the pathophysiological mechanisms has allowed the emergence of novel targeted treatments such as vemurafenib, imatinib, and anakinra...
April 5, 2017: Revue Médicale Suisse
https://www.readbyqxmd.com/read/28720543/involvement-of-the-bh3-only-pro-apoptotic-bik-nbk-in-braf-mek-inhibitor-induced-apoptosis-in-melanoma-cell-lines
#5
Andreas Borst, Sebastian Haferkamp, Johannes Grimm, Manuel Rösch, Guannan Zhu, Sen Guo, Chunying Li, Tianwen Gao, Svenja Meierjohann, David Schrama, Roland Houben
In patients with BRAF-mutated melanoma specific inhibitors of BRAF(V600E) and MEK1/2 frequently induce initial tumor reduction, frequently followed by relapse. As demonstrated previously, BRAF(V600E)-inhibition induces apoptosis only in a fraction of treated cells, while the remaining arrest and survive providing a source or a niche for relapse. To identify factors contributing to the differential initial response towards BRAF/MEK inhibition, we established M14 melanoma cell line-derived single cell clones responding to treatment with BRAF inhibitor vemurafenib and MEK inhibitor trametinib predominantly with either cell cycle arrest (CCA-cells) or apoptosis (A-cells)...
July 15, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28719434/primary-cutaneous-small-medium-cd4-t-cell-lymphoproliferative-disorder-occurring-in-a-patient-with-metastatic-melanoma
#6
Jonathan J Davick, Elizabeth Gaughan, Megan Barry, Alejandro A Gru
Therapeutic agents designed to stimulate the immune system are now cornerstones in the treatment of metastatic melanoma. These drugs promote lymphocyte growth and survival, which could plausibly result in clinical lymphoproliferative disorders. We report the case of a 62-year-old female with metastatic melanoma who developed primary cutaneous small/medium CD4 T-cell lymphoproliferative disorder (PC-SMTCL) after treatment with vemurafenib and recombinant high-dose interleukin-2 (IL-2). The patient developed a painless red papule behind the ear...
July 14, 2017: American Journal of Dermatopathology
https://www.readbyqxmd.com/read/28711086/the-new-paradigm-of-systemic-therapies-for-metastatic-melanoma
#7
REVIEW
Virginia O Volpe, Daniel M Klufas, Upendra Hegde, Jane M Grant-Kels
New treatments for metastatic melanoma work through distinct mechanisms: enhancing the immune response and blocking cellular proliferation. Agents that enhance the immune response include ipilimumab, pembrolizumb, and nivolumab; agents that block cellular proliferation include vemurafenib, dabrafenib, trametinib, cobimetinib, binimetinib, and selumetinib. The translational impact of laboratory discoveries has revolutionized management of metastatic melanoma and enhanced the prognosis of affected patients.
August 2017: Journal of the American Academy of Dermatology
https://www.readbyqxmd.com/read/28708099/role-played-by-signalling-pathways-in-overcoming-braf-inhibitor-resistance-in-melanoma
#8
REVIEW
Xian Yang Chan, Alamdeep Singh, Narin Osman, Terrence J Piva
The discovery of the BRAF(V600E) mutation led to the development of vemurafenib (PLX4032), a selective BRAF inhibitor specific to the kinase, for the treatment of metastatic melanomas. However, initial success of the drug was dampened by the development of acquired resistance. Melanoma was shown to relapse in patients following treatment with vemurafenib which eventually led to patients' deaths. It has been proposed that mechanisms of resistance can be due to (1) reactivation of the mitogen-activated protein kinase (MAPK) signalling pathway via secondary mutations, amplification or activation of target kinase(s), (2) the bypass of oncogenic pathway via activation of alternative signalling pathways, (3) other uncharacterized mechanisms...
July 14, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28699904/the-anti-apoptotic-bag3-protein-is-involved-in-braf-inhibitor-resistance-in-melanoma-cells
#9
Luana Guerriero, Giuseppe Palmieri, Margot De Marco, Antonio Cossu, Paolo Remondelli, Mario Capunzo, Maria Caterina Turco, Alessandra Rosati
BAG3 protein, a member of BAG family of co-chaperones, has a pro-survival role in several tumour types. BAG3 anti-apoptotic properties rely on its characteristic to bind several intracellular partners, thereby modulating crucial events such as apoptosis, differentiation, cell motility, and autophagy. In human melanomas, BAG3 positivity is correlated with the aggressiveness of the tumour cells and can sustain IKK-γ levels, allowing a sustained activation of NF-κB. Furthermore, BAG3 is able to modulate BRAFV600E levels and activity in thyroid carcinomas...
June 30, 2017: Oncotarget
https://www.readbyqxmd.com/read/28692456/focal-necrotizing-myopathy-with-dropped-head-syndrome-induced-by-cobimetinib-in-metastatic-melanoma
#10
Marie-Léa Gauci, Pauline Laly, Leonard-Louis Sarah, Anthony Behin, Jérémy Gottlieb, Isabelle Madelaine-Chambrin, Barouyr Baroudjian, Laetitia Da-Meda, Samia Mourah, Maxime Battistella, Nicole Basset Seguin, Martine Bagot, Cécile Pages, Laetitia Vercellino, Thierry Maisonobe, Céleste Lebbé
Therapeutic advances derived from targeted therapy and immune checkpoint inhibitors can improve melanoma prognosis. Since 2015, cobimetinib has been approved in combination with vemurafenib in the first-line treatment for BRAF-mutated melanoma. For NRAS-mutated melanomas, MEK inhibition seems to be a therapeutic target, and association with checkpoint inhibitor provides a further therapeutic perspective. Infraclinical creatine phosphokinase (CPK) elevation is an MEK inhibitor side effect. We describe a case of focal necrotizing myopathy with 'dropped-head syndrome' induced by cobimetinib, 1 month after its introduction...
July 7, 2017: Melanoma Research
https://www.readbyqxmd.com/read/28690524/erdheim-chester-disease-case-report-with-aggressive-multisystem-manifestations-and-review-of-the-literature
#11
Sultan Alotaibi, Osama Alhafi, Hatem Nasr, Khalid Eltayeb, Ghaleb Elyamany
Erdheim-Chester disease (ECD) is an extremely rare and aggressive form of non-Langerhans cell histiocytosis. ECD usually presents with bone pain in adults aged 40-60. Its etiology is unknown but it is thought to be either a reactive or neoplastic disorder. Recently, mutation of the proto-oncogene BRAF (BRAFV600E) has been found in more than 50% of cases. The multisystemic form of ECD is associated with significant morbidity, which may arise due to histiocytic infiltration of critical organ systems. The common sites of involvement are the skeleton, central nervous system, cardiovascular system, lungs, retroperitoneum, and skin...
May 2017: Case Reports in Oncology
https://www.readbyqxmd.com/read/28684402/braf-v600-inhibition-alters-the-microrna-cargo-in-the-vesicular-secretome-of-malignant-melanoma-cells
#12
Taral R Lunavat, Lesley Cheng, Berglind O Einarsdottir, Roger Olofsson Bagge, Somsundar Veppil Muralidharan, Robyn A Sharples, Cecilia Lässer, Yong Song Gho, Andrew F Hill, Jonas A Nilsson, Jan Lötvall
The BRAF inhibitors vemurafenib and dabrafenib can be used to treat patients with metastatic melanomas harboring BRAF(V600) mutations. Initial antitumoral responses are often seen, but drug-resistant clones with reactivation of the MEK-ERK pathway soon appear. Recently, the secretome of tumor-derived extracellular vesicles (EVs) has been ascribed important functions in cancers. To elucidate the possible functions of EVs in BRAF-mutant melanoma, we determined the RNA content of the EVs, including apoptotic bodies, microvesicles, and exosomes, released from such cancer cells after vemurafenib treatment...
July 6, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28677189/radiosensibilisierung-durch-braf-inhibitoren
#13
Sophia Boyoung Strobel, Sylvie Pätzold, Lisa Zimmer, Alexandra Jensen, Alexander Enk, Jessica Cecile Hassel
HINTERGRUND: In der letzten Zeit wurden in der Literatur vermehrt erhöhte Hauttoxizitäten während einer Kombinationstherapie mit BRAF Inhibitoren und Radiotherapie beschrieben. MATERIAL UND METHODIK: Wir berichten über sieben Melanompatienten in einem nicht resezierbaren Stadium III oder IV, die eine kombinierte Behandlung aus Bestrahlung und BRAF-Inhibitor erhielten. ERGEBNISSE: Bei allen Patienten konnte durch die Kombinationstherapie ein gutes lokales Ansprechen erreicht werden...
July 2017: Journal der Deutschen Dermatologischen Gesellschaft, Journal of the German Society of Dermatology: JDDG
https://www.readbyqxmd.com/read/28674996/characteristics-of-adverse-drug-reactions-in-a-vemurafenib-early-post-marketing-phase-vigilance-study-in-japan
#14
H Uhara, Y Kiyohara, A Tsuda, M Takata, N Yamazaki
BACKGROUND: Post-approval research or monitoring is important to determine real-world safety of new products; however, evidence is scant for vemurafenib in Japanese patients. In Japan, a unique system is officially obligated to investigate post-approval safety. Here we report the first adverse drug reaction (ADR) data from vemurafenib-treated Japanese patients with metastatic melanoma. Data were collected in an early post-marketing phase vigilance (EPPV) study. METHODS: ADRs were events for which a causal relationship with vemurafenib could not be ruled out or was unknown...
July 3, 2017: Clinical & Translational Oncology
https://www.readbyqxmd.com/read/28649441/clinical-responses-to-erk-inhibition-in-braf-v600e-mutant-colorectal-cancer-predicted-using-a-computational-model
#15
Daniel C Kirouac, Gabriele Schaefer, Jocelyn Chan, Mark Merchant, Christine Orr, Shih-Min A Huang, John Moffat, Lichuan Liu, Kapil Gadkar, Saroja Ramanujan
Approximately 10% of colorectal cancers harbor BRAF(V600E) mutations, which constitutively activate the MAPK signaling pathway. We sought to determine whether ERK inhibitor (GDC-0994)-containing regimens may be of clinical benefit to these patients based on data from in vitro (cell line) and in vivo (cell- and patient-derived xenograft) studies of cetuximab (EGFR), vemurafenib (BRAF), cobimetinib (MEK), and GDC-0994 (ERK) combinations. Preclinical data was used to develop a mechanism-based computational model linking cell surface receptor (EGFR) activation, the MAPK signaling pathway, and tumor growth...
2017: NPJ Systems Biology and Applications
https://www.readbyqxmd.com/read/28646893/clinical-features-of-serous-retinopathy-observed-with-cobimetinib-in-patients-with-braf-mutated-melanoma-treated-in-the-randomized-cobrim-study
#16
Luis de la Cruz-Merino, Lorenza Di Guardo, Jean-Jacques Grob, Alfredo Venosa, James Larkin, Grant A McArthur, Antoni Ribas, Paolo A Ascierto, Jeffrey T R Evans, Antonio Gomez-Escobar, Giulio Barteselli, Susan Eng, Jessie J Hsu, Anne Uyei, Brigitte Dréno
BACKGROUND: Serous chorioretinopathy has been associated with MEK inhibitors, including cobimetinib. We describe the clinical features of serous retinopathy observed with cobimetinib in patients with BRAF (V600)-mutated melanoma treated in the Phase III coBRIM study. METHODS: In the coBRIM study, 493 patients were treated in two randomly assigned treatment groups: cobimetinib and vemurafenib (n = 247) or vemurafenib (n = 246). All patients underwent prospective ophthalmic examinations at screening, at regular intervals during the study, and whenever ocular symptoms developed...
June 24, 2017: Journal of Translational Medicine
https://www.readbyqxmd.com/read/28628251/a-network-meta-analysis-of-short-and-long-term-efficacy-of-targeted-therapy-with-single-or-double-drug-regimens-in-the-treatment-of-stage-iii-iv-malignant-melanoma-based-on-16-randomized-controlled-trials
#17
Ting Xie, Chun-Yu Huang, Xu Kang, Jia-Sheng Luo, Xiao-Min Qin, Feng Han
For the treatment of stage III/IV malignant melanoma (MM), a network meta-analysis (NMA) was conducted to compare the short and long-term efficacy of targeted therapy with single or double-drug regimens. All conducted randomized controlled trials (RCTs) searched from PubMed and Cochrane Library were included in the study for direct and indirect comparison for MM. The odds ratio (OR) and surface under the cumulative ranking curves (SUCRA) value of the targeted therapy with single or double-drug regimens for treatment of stage III/IV MM were also analyzed...
June 19, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28622068/salmonella-typhimurium-a1-r-targeting-of-a-chemotherapy-resistant-braf-v600e-melanoma-in-a-patient-derived-orthotopic-xenograft-pdox-model-is-enhanced-in-combination-with-either-vemurafenib-or-temozolomide
#18
Kei Kawaguchi, Kentaro Igarashi, Takashi Murakami, Tasuku Kiyuna, Ming Zhao, Yong Zhang, Scott D Nelson, Tara A Russell, Sarah M Dry, Arun S Singh, Bartosz Chmielowski, Yunfeng Li, Michiaki Unno, Fritz C Eilber, Robert M Hoffman
A metastatic melanoma obtained from the right chest wall of a patient was previously established orthotopically in the right chest wall of nude mice as a patient-derived orthotopic xenograft (PDOX) model. We previously showed that the combination of tumor-targeting Salmonella typhimurium A1-R (S. typhimurium A1-R) and chemotherapy was highly effective against the melanoma PDOX. In the present study, we investigated the mechanism of the high efficacy of this combination. Two weeks after implantation, 40 PDOX mouse models were randomized into 4 groups of 10 mice each: untreated control (n = 10); treated with S...
July 3, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28614138/acute-exudative-paraneoplastic-polymorphous-vitelliform-maculopathy-during-vemurafenib-and-pembrolizumab-treatment-for-metastatic-melanoma
#19
Harpal S Sandhu, Anton M Kolomeyer, Marisa K Lau, Carol L Shields, Lynn M Schuchter, Charles W Nichols, Tomas S Aleman
PURPOSE: To describe a patient with BRAF mutation-positive cutaneous melanoma who developed acute exudative polymorphous vitelliform maculopathy during vemurafenib and pembrolizumab treatment for metastatic melanoma. METHODS: Retrospective case report documented with wide-field fundus imaging, spectral domain optical coherence tomography, and fundus autofluorescence imaging. RESULTS: A 55-year-old woman with bilateral ductal breast carcinoma and BRAF mutation-positive metastatic cutaneous melanoma complained of bilateral blurred vision within 5 days of starting vemurafenib (BRAF inhibitor)...
June 13, 2017: Retinal Cases & Brief Reports
https://www.readbyqxmd.com/read/28611627/panniculitis-associated-with-mek-inhibitor-therapy-an-uncommon-adverse-effect
#20
Miruna Negulescu, Florian Deilhes, Vincent Sibaud, Emilie Tournier, Laurence Lamant, Serge Boulinguez, Nicolas Meyer
The combination of MEK inhibitor (cobimetinib, trametinib) and BRAF inhibitor (vemurafenib, dabrafenib) is now the first-line treatment in patients with BRAF V600-mutated metastatic melanoma. This association reduces cutaneous adverse events induced by BRAF inhibitors alone, including photosensitivity, hand-foot syndrome, hyperkeratosis, alopecia, skin papillomas, keratoacanthomas, and squamous-cell carcinomas. While panniculitis has exceptionally been reported with BRAF inhibitors, this rare side effect has never been described with the use of MEK inhibitors...
January 2017: Case Reports in Dermatology
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