المؤلفون: Farah, Chantale, Mignion, Lionel, Jordan, Bénédicte

المساهمون: UCL - SSS/LDRI - Louvain Drug Research Institute

المصدر: International journal of molecular sciences, Vol. 25, no.3, p. 1725 (2024)

مصطلحات موضوعية: Humans, Melanoma, Immunotherapy, Biomarkers, Signal Transduction, Positron-Emission Tomography, Molecular Targeted Therapy, Proto-Oncogene Proteins B-raf, BRAF-targeted therapy, immune checkpoint inhibitors, metabolic imaging, response to treatment

الوصف: There is currently no consensus to determine which advanced melanoma patients will benefit from targeted therapy, immunotherapy, or a combination of both, highlighting the critical need to identify early-response biomarkers to advanced melanoma therapy. The goal of this review is to provide scientific rationale to highlight the potential role of metabolic imaging to assess response to targeted and/or immune therapy in melanoma cancer. For that purpose, a brief overview of current melanoma treatments is provided. Then, current knowledge with respect to melanoma metabolism is described with an emphasis on major crosstalks between melanoma cell metabolism and signaling pathways involved in BRAF-targeted therapy as well as in immune checkpoint inhibition therapies. Finally, preclinical and clinical studies using metabolic imaging and/or profiling to assess response to melanoma treatment are summarized with a particular focus on PET (Positron Emission Tomography) imaging and C-MRS (Magnetic Resonance Spectroscopy) methods.

العلاقة: boreal:285363; http://hdl.handle.net/2078.1/285363Test; info:pmid/; info:pmid/38339003; urn:EISSN:1422-0067

الإتاحة: https://doi.org/10.3390/ijms25031725Test
http://hdl.handle.net/2078.1/285363Test

المؤلفون: LJ Jenkins, IY Luk, F Chionh, T Tan, K Needham, J Ayton, CM Reehorst, N Vukelic, OM Sieber, D Mouradov, P Gibbs, DS Williams, NC Tebbutt, J Desai, F Hollande, Amardeep Dhillon, EF Lee, D Merino, WD Fairlie, JM Mariadason

مصطلحات موضوعية: Biological sciences, Biochemistry and cell biology, Biomedical and clinical sciences, Oncology and carcinogenesis, Animals, Antineoplastic Agents, Apoptosis, bcl-X Protein, Carbamates, Colorectal Neoplasms, Humans, Mice, Myeloid Cell Leukemia Sequence 1 Protein, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, Sulfonamides

الوصف: Metastatic BRAFV600E colorectal cancer (CRC) carries an extremely poor prognosis and is in urgent need of effective new treatments. While the BRAFV600E inhibitor encorafenib in combination with the EGFR inhibitor cetuximab (Enc+Cet) was recently approved for this indication, overall survival is only increased by 3.6 months and objective responses are observed in only 20% of patients. We have found that a limitation of Enc+Cet treatment is the failure to efficiently induce apoptosis in BRAFV600E CRCs, despite inducing expression of the pro-apoptotic protein BIM and repressing expression of the pro-survival protein MCL-1. Here, we show that BRAFV600E CRCs express high basal levels of the pro-survival proteins MCL-1 and BCL-XL, and that combining encorafenib with a BCL-XL inhibitor significantly enhances apoptosis in BRAFV600E CRC cell lines. This effect was partially dependent on the induction of BIM, as BIM deletion markedly attenuated BRAF plus BCL-XL inhibitor-induced apoptosis. As thrombocytopenia is an established on-target toxicity of BCL-XL inhibition, we also examined the effect of combining encorafenib with the BCL-XL -targeting PROTAC DT2216, and the novel BCL-2/BCL-XL inhibitor dendrimer conjugate AZD0466. Combining encorafenib with DT2216 significantly increased apoptosis induction in vitro, while combining encorafenib with AZD0466 was well tolerated in mice and further reduced growth of BRAFV600E CRC xenografts compared to either agent alone. Collectively, these findings demonstrate that combined BRAF and BCL-XL inhibition significantly enhances apoptosis in pre-clinical models of BRAFV600E CRC and is a combination regimen worthy of clinical investigation to improve outcomes for these patients.

العلاقة: http://hdl.handle.net/10779/DRO/DU:25546591.v2Test; https://figshare.com/articles/journal_contribution/BCL-XL_inhibitors_enhance_the_apoptotic_efficacy_of_BRAF_inhibitors_in_BRAF_sup_V600E_sup_colorectal_cancer/25546591Test

الإتاحة: http://hdl.handle.net/10779/DRO/DU:25546591.v2Test
https://figshare.com/articles/journal_contribution/BCL-XL_inhibitors_enhance_the_apoptotic_efficacy_of_BRAF_inhibitors_in_BRAF_sup_V600E_sup_colorectal_cancer/25546591Test

المؤلفون: Berrocal, A., Arance, A., Castellón, V. E., Cruz Merino, Luis de la, Espinosa, E., Cao, M. G., Larriba, J. L. G., Marquez-Rodas, I., Soria, A., Algarra, S. M.

المساهمون: Universidad de Sevilla. Departamento de Medicina, Universidad de Sevilla. CTS151: Bioquímica médica.

مصطلحات موضوعية: Melanoma, Metastatic, Adjuvant, Immunotherapy, B-RAF

الوصف: All melanoma suspected patients must be con firmed histologically and resected. Sentinel node biopsy must be done when tumor is over 1 mm or if less with high-risk factors. Adjuvant therapy with interferon could be offered for patients with high-risk melanoma and in selected cases radiotherapy can be added. Metastatic mel anoma treatment is guided by mutational BRAF status. BRAF wild type patients must receive anti-PD1 containing therapy and BRAF mutated patients BRAF/MEK inhibitors or anti-PD1 containing therapy. Up to 10 years follow up is reasonable for melanoma patients with dermatologic examinations and physical exams

العلاقة: Clinical and Translational Oncology, 20 (1), 69-74.; https://link.springer.com/article/10.1007/s12094-017-1768-1Test; https://idus.us.es/handle//11441/156158Test

الإتاحة: https://idus.us.es/handle//11441/156158Test

المؤلفون: Reinhard Büttner, Sibel Elif Gültekin, Carina Heydt, Lucia Nogova, Sonja Meemboor, Matthias Kreppel, Reem Aziz-Heiloun

المصدر: Heliyon, Vol 9, Iss 12, Pp e23206- (2023)

مصطلحات موضوعية: Ameloblastoma, B-RAF-/MEK-Inhibitors, Neoadjuvant therapy, Science (General), Q1-390, Social sciences (General), H1-99

الوصف: Background: Ameloblastoma is a benign but locally invasive and aggressive odontogenic tumor harboring activating BRAF V600E mutations in about two thirds of the cases. Case presentation: Neoadjuvant therapy with Dabrafenib and Trametinib was given to a 42-year-old male patient with recurrent ameloblastoma of the right mandible with a BRAF V600E mutation for 18 months. The patient manifested an excellent response to the therapy with remarkable reduction in tumor size from 72.6 mm to 55.9 mm. Histopathologically, the tumor underwent significant degenerative changes with only a few sparse vital residuals revealing 0 % Ki67 proliferative index. Conclusions: Neoadjuvant therapy with BRAF-inhibitors or BRAF-MEK-inhibitors is an effective means to reduce the size of mandibulary ameloblastomas. We propose the consideration of neoadjuvant therapy in future treatment modalities to minimize post-surgical morbidity and facial deformations.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S2405844023104142Test; https://doaj.org/toc/2405-8440Test

الوصول الحر: https://doaj.org/article/08ac69f5c490454a93d3679fb0643f00Test

المؤلفون: Davari, Danielle R, Orlow, Irene, Kanetsky, Peter A, Luo, Li, Edmiston, Sharon N, Conway, Kathleen, Parrish, Eloise A, Hao, Honglin, Busam, Klaus J, Sharma, Ajay, Kricker, Anne, Cust, Anne E, Anton-Culver, Hoda, Gruber, Stephen B, Gallagher, Richard P, Zanetti, Roberto, Rosso, Stefano, Sacchetto, Lidia, Dwyer, Terence, Ollila, David W, Begg, Colin B, Berwick, Marianne, Thomas, Nancy E, Group, on behalf of the GEM Study

المصدر: Cancer Epidemiology Biomarkers & Prevention. 30(12)

مصطلحات موضوعية: Clinical Research, Human Genome, Cardiovascular, Cancer, Genetics, Diabetes, Heart Disease, Heart Disease - Coronary Heart Disease, Aged, Cyclin-Dependent Kinase Inhibitor p15, Female, GTP Phosphohydrolases, Genome-Wide Association Study, Humans, Lymphocytes, Tumor-Infiltrating, Male, Melanoma, Membrane Proteins, Middle Aged, Mutation, Proto-Oncogene Proteins B-raf, Skin Neoplasms, coronary artery disease, coronary artery calci fi cation, myocardial, GEM Study Group, Medical and Health Sciences, Epidemiology

الوصف: BackgroundGenome-wide association studies have reported that genetic variation at ANRIL (CDKN2B-AS1) is associated with risk of several chronic diseases including coronary artery disease, coronary artery calcification, myocardial infarction, and type 2 diabetes mellitus. ANRIL is located at the CDKN2A/B locus, which encodes multiple melanoma tumor suppressors. We investigated the association of these variants with melanoma prognostic characteristics.MethodsThe Genes, Environment, and Melanoma Study enrolled 3,285 European origin participants with incident invasive primary melanoma. For each of ten disease-associated SNPs at or near ANRIL, we used linear and logistic regression modeling to estimate, respectively, the per allele mean changes in log of Breslow thickness and ORs for presence of ulceration and tumor-infiltrating lymphocytes (TIL). We also assessed effect modification by tumor NRAS/BRAF mutational status.ResultsRs518394, rs10965215, and rs564398 passed false discovery and were each associated (P ≤ 0.005) with TILs, although only rs564398 was independently associated (P = 0.0005) with TILs. Stratified by NRAS/BRAF mutational status, rs564398*A was significantly positively associated with TILs among NRAS/BRAF mutant, but not wild-type, cases. We did not find SNP associations with Breslow thickness or ulceration.ConclusionsANRIL rs564398 was associated with TIL presence in primary melanomas, and this association may be limited to NRAS/BRAF-mutant cases.ImpactPathways related to ANRIL variants warrant exploration in relationship to TILs in melanoma, especially given the impact of TILs on immunotherapy and survival.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/7ck2z7drTest

المؤلفون: Hirata, Amanda S, Rezende-Teixeira, Paula, Machado-Neto, João Agostinho, Jimenez, Paula C, Clair, James J La, Fenical, William, Costa-Lotufo, Leticia V

المصدر: Molecules (Basel, Switzerland). 26(23)

مصطلحات موضوعية: Cell Line, Tumor, Humans, Melanoma, Quinones, GTP Phosphohydrolases, Proto-Oncogene Proteins B-raf, Serine, Membrane Proteins, Antineoplastic Agents, Apoptosis, Mutation, Autophagy, Drug Discovery, antitumor agent, apoptosis, autophagy, dermcidin, drug discovery, marine pharmacology, natural products, Cancer, 5.1 Pharmaceuticals, Medicinal and Biomolecular Chemistry, Organic Chemistry, Theoretical and Computational Chemistry

الوصف: Isolated from the marine bacteria Serinicoccus sp., seriniquinone (SQ1) has been characterized by its selective activity in melanoma cell lines marked by its modulation of human dermcidin and induction of autophagy and apoptosis. While an active lead, the lack of solubility of SQ1 in both organic and aqueous media has complicated its preclinical evaluation. In response, our team turned its effort to explore analogues with the goal of returning synthetically accessible materials with comparable selectivity and activity. The analogue SQ2 showed improved solubility and reached a 30-40-fold greater selectivity for melanoma cells. Here, we report a detailed comparison of the activity of SQ1 and SQ2 in SK-MEL-28 and SK-MEL-147 cell lines, carrying the top melanoma-associated mutations, BRAFV600E and NRASQ61R, respectively. These studies provide a definitive report on the activity, viability, clonogenicity, dermcidin expression, autophagy, and apoptosis induction following exposure to SQ1 or SQ2. Overall, these studies showed that SQ1 and SQ2 demonstrated comparable activity and modulation of dermcidin expression. These studies are further supported through the evaluation of a panel of basal expression of key-genes related to autophagy and apoptosis, providing further insight into the role of these mutations. To explore this rather as a survival or death mechanism, autophagy inhibition sensibilized BRAF mutants to SQ1 and SQ2, whereas the opposite happened to NRAS mutants. These data suggest that the seriniquinones remain active, independently of the melanoma mutation, and suggest the future combination of their application with inhibitors of autophagy to treat BRAF-mutated tumors.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/9034947xTest

المؤلفون: Hendifar, Andrew, Blais, Edik M, Wolpin, Brian, Subbiah, Vivek, Collisson, Eric, Singh, Isha, Cannon, Timothy, Shaw, Kenna, Petricoin, Emanuel F, Klempner, Samuel, Lyons, Emily, Wang-Gillam, Andrea, Pishvaian, Michael J, O'Reilly, Eileen M

المصدر: JCO Precision Oncology. 5(5)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Rare Diseases, Pancreatic Cancer, Clinical Research, Genetics, Orphan Drug, Digestive Diseases, 2.1 Biological and endogenous factors, Aetiology, Good Health and Well Being, Aged, Exons, Female, Humans, MAP Kinase Signaling System, Male, Middle Aged, Mutation, Neoplasm Metastasis, Pancreatic Neoplasms, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, Retrospective Studies, Survival Analysis, Oncology and carcinogenesis

الوصف: PurposeIn pancreatic cancer (PC), the RAF family alterations define a rare subset of patients that may predict response to inhibition of the BRAF/MEK/ERK signaling pathway. A comprehensive understanding of the molecular and clinical characteristics of RAF-mutated PC may support future development of RAF-directed strategies.MethodsClinical outcomes were assessed across a multi-institutional case series of 81 patients with RAF family-mutated PC. Mutational subgroups were defined on the basis of RAF alteration hotspots and therapeutic implications.ResultsThe frequency of RAF alterations in PC was 2.2% (84 of 3,781) within a prevalence cohort derived from large molecular databases where BRAF V600E (Exon 15), BRAF ΔNVTAP (Exon 11), and SND1-BRAF fusions were the most common variants. In our retrospective case series, we identified 17 of 81 (21.0%) molecular profiles with a BRAF V600/Exon 15 mutation without any confounding drivers, 25 of 81 (30.9%) with BRAF or RAF1 fusions, and 18 of 81 (22.2%) with Exon 11 mutations. The remaining 21 of 81 (25.9%) profiles had atypical RAF variants and/or multiple oncogenic drivers. Clinical benefit from BRAF/MEK/ERK inhibitors was observed in 3 of 3 subjects within the V600 subgroup (two partial responses), 4 of 6 with fusions (two partial responses), 2 of 6 with Exon 11 mutations (one partial response), and 0 of 3 with confounding drivers. Outcomes analyses also suggested a trend favoring fluorouracil-based regimens over gemcitabine/nab-paclitaxel within the fusion subgroup (P = .027).ConclusionProspective evaluation of RAF-directed therapies is warranted in RAF-mutated PC; however, differential responses to targeted agents or standard regimens for each mutational subgroup should be a consideration when designing clinical trials.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/3nh7g6n9Test

المؤلفون: Mengyao Ye, Shan Wu, Qi Zhou, Fang Wang, Xiaojun Chen, Xiaohua Gong, Wenjun Wu

المصدر: World Journal of Surgical Oncology, Vol 21, Iss 1, Pp 1-7 (2023)

مصطلحات موضوعية: Thyroid nodule, Papillary thyroid carcinoma, Macrocalcification, Fine needle aspiration biopsy, Proto-Oncogene Proteins B-raf V600E, Surgery, RD1-811, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Abstract Background Microcalcifications are suggested to be an indicator of thyroid malignancy, especially for papillary thyroid carcinoma (PTC), nonetheless, the association between macrocalcification and PTC is underexplored. Furthermore, screening methods like ultrasonography and ultrasound-guided fine needle aspiration biopsy (US-FNAB) are limited in evaluating macro-calcified thyroid nodules. Thus, we aimed to investigate the relationship between macrocalcification and PTC. We also explored the diagnostic efficiency of US-FNAB and proto-Oncogene Proteins B-raf V600E (BRAF V600E) mutation in macro-calcified thyroid nodules evaluation. Methods A retrospective research of 2645 thyroid nodules from 2078 participants was performed and divided into three groups as non-, micro-, and macro-calcified for further PTC incidence comparison. Besides, a total of 100 macro-calcified thyroid nodules with both results of US-FNAB and BRAF V600E mutation were screened out for subsequent evaluation of diagnostic efficiency. Results Compared to non-calcification, macrocalcification showed a significantly higher incidence of PTC (31.5% vs. 23.2%, P

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1477-7819Test

الوصول الحر: https://doaj.org/article/df8c4965bc6e49cebb777a2441738517Test

المؤلفون: Ascierto, Paolo A, Dréno, Brigitte, Larkin, James, Ribas, Antoni, Liszkay, Gabriella, Maio, Michele, Mandalà, Mario, Demidov, Lev, Stroyakovskiy, Daniil, Thomas, Luc, de la Cruz-Merino, Luis, Atkinson, Victoria, Dutriaux, Caroline, Garbe, Claus, Hsu, Jessie, Jones, Surai, Li, Haocheng, McKenna, Edward, Voulgari, Athina, McArthur, Grant A

المصدر: Clinical Cancer Research. 27(19)

مصطلحات موضوعية: Clinical Research, Clinical Trials and Supportive Activities, Cancer, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Antineoplastic Combined Chemotherapy Protocols, Azetidines, Follow-Up Studies, Humans, Melanoma, Mutation, Piperidines, Proto-Oncogene Proteins B-raf, Skin Neoplasms, Vemurafenib, Oncology and Carcinogenesis, Oncology & Carcinogenesis

الوصف: PurposeThe randomized phase III coBRIM study (NCT01689519) demonstrated improved progression-free survival (PFS) and overall survival (OS) with addition of cobimetinib to vemurafenib compared with vemurafenib in patients with previously untreated BRAFV600 mutation-positive advanced melanoma. We report long-term follow-up of coBRIM, with at least 5 years since the last patient was randomized.Patients and methodsEligible patients were randomized 1:1 to receive either oral cobimetinib (60 mg once daily on days 1-21 in each 28-day cycle) or placebo in combination with oral vemurafenib (960 mg twice daily).Results495 patients were randomized to cobimetinib plus vemurafenib (n = 247) or placebo plus vemurafenib (n = 248). Median follow-up was 21.2 months for cobimetinib plus vemurafenib and 16.6 months for placebo plus vemurafenib. Median OS was 22.5 months (95% CI, 20.3-28.8) with cobimetinib plus vemurafenib and 17.4 months (95% CI, 15.0-19.8) with placebo plus vemurafenib; 5-year OS rates were 31% and 26%, respectively. Median PFS was 12.6 months (95% CI, 9.5-14.8) with cobimetinib plus vemurafenib and 7.2 months (95% CI, 5.6-7.5) with placebo plus vemurafenib; 5-year PFS rates were 14% and 10%, respectively. OS and PFS were longest in patients with normal baseline lactate dehydrogenase levels and low tumor burden, and in those achieving complete response. The safety profile remained consistent with previously published reports.ConclusionsExtended follow-up of coBRIM confirms the long-term clinical benefit and safety profile of cobimetinib plus vemurafenib compared with vemurafenib monotherapy in patients with BRAFV600 mutation-positive advanced melanoma.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/1g1197j5Test

المؤلفون: Lacouture, Mario E, Wainberg, Zev A, Patel, Anisha B, Anadkat, Milan J, Stemmer, Salomon M, Shacham-Shmueli, Einat, Medina, Egmidio, Zelinger, Galit, Shelach, Noa, Ribas, Antoni

المصدر: Cancer Discovery. 11(9)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Clinical Research, Colo-Rectal Cancer, Digestive Diseases, Cancer, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Skin, Adult, Aged, Female, Humans, Male, Middle Aged, Acneiform Eruptions, Administration, Cutaneous, Antineoplastic Agents, Immunological, Cetuximab, Colorectal Neoplasms, Dermatologic Agents, ErbB Receptors, Panitumumab, Proto-Oncogene Proteins B-raf, Treatment Outcome, Biochemistry and cell biology, Oncology and carcinogenesis

الوصف: Treatment of cancer with EGFR inhibitors is limited by on-target skin toxicities induced by inhibition of the MAPK pathway. BRAF inhibitors are known to paradoxically activate the MAPK downstream of EGFR, which we confirmed using human skin keratinocytes. We then conducted a phase I clinical trial testing the hypothesis that topical therapy with the BRAF inhibitor LUT014 could improve skin toxicities induced by EGFR inhibitors. Ten patients with metastatic colorectal cancer who had developed acneiform rash while being treated with cetuximab or panitumumab were enrolled in three cohorts. LUT014 was well tolerated, and there were no dose-limiting toxicities. The acneiform rash improved in the 6 patients who started with grade 2 rash in the low and intermediate cohorts. We conclude that topical LUT014 is safe and efficacious in improving rash from EGFR inhibitors, consistent with the mechanism of action inducting paradoxical MAPK activation. SIGNIFICANCE: BRAF inhibitor topical therapy could avoid dose reductions of EGFR inhibitors, locally treating the main dose-limiting skin toxicity of this class of agents.This article is highlighted in the In This Issue feature, p. 2113.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/96m7v784Test