- |||||||||| Zelboraf (vemurafenib) / Roche
Implications of HVEM/BTLA/LIGHT signaling in anaplastic thyroid cancer (Virtual Meeting II: E-Posters) - May 16, 2020 - Abstract #AACRII2020AACR-II_238; Currently we are conducting co-culture experiments to validate its role in immunomodulation and trying to understand its regulation in case of acquired resistance against small molecule inhibitors, like vemurafenib. We believe our study has identified HVEM as an immunotherapeutic target, soluble form of which could be a potential biomarker in ATC patients.
- |||||||||| Erbitux (cetuximab) / Eli Lilly, EMD Serono
The NEDD8 and EGFR pathways are independent therapeutic targets in colorectal cancer (Virtual Meeting II: E-Posters) - May 16, 2020 - Abstract #AACRII2020AACR-II_1291; Furthermore, we considered the depletion of constructs targeting BRAF, a member of EGFR pathway, observed in WIDR BRAF-mutant cells: we found an additive effect of BRAF inhibitor vemurafenib and pevonedistat in reducing in vitro cell growth. Altogether our results suggest that the concomitant pharmacological inhibition of NEDD8 and EGFR-pathway could be a novel effective approach to treat clinically aggressive CRCs, worthy of further characterization.
- |||||||||| ulixertinib (BVD-523) / BioMed Valley Discoveries, Tafinlar (dabrafenib) / Novartis, Zelboraf (vemurafenib) / Roche
Clinical, Journal, IO biomarker: Mutations in RAS-BRAF-MAPK-ERK pathway define a specific subgroup of patients with adverse clinical features and provide new therapeutic options in chronic lymphocytic leukemia. (Pubmed Central) - May 13, 2020 In contrast, ulixertinib, a pan-ERK inhibitor, decreased phospho-ERK levels. In conclusion, although larger series of patients are needed to corroborate these findings, our results suggest that RAS-BRAF-MAPK-ERK pathway is one of the core cellular processes affected by novel mutations in chronic lymphocytic leukemia, it is associated with adverse clinical features and it could be pharmacologically inhibited.
- |||||||||| Zelboraf (vemurafenib) / Roche
Clinical, Journal, Tumor Mutational Burden: Longitudinal assessment of peripheral blood BRAFV600E levels in patients with Langerhans cell histiocytosis. (Pubmed Central) - May 13, 2020 In conclusion, although larger series of patients are needed to corroborate these findings, our results suggest that RAS-BRAF-MAPK-ERK pathway is one of the core cellular processes affected by novel mutations in chronic lymphocytic leukemia, it is associated with adverse clinical features and it could be pharmacologically inhibited. Our data support the view that single-agent treatment with an RAF inhibitor reduces disease activity but does not cure LCH.
- |||||||||| Zelboraf (vemurafenib) / Roche
Journal: RNA sequencing data of Vemurafenib-resistant melanoma cells and parental cells. (Pubmed Central) - May 10, 2020 For more insight please see Transcripts 202 and 205 of IL-6 confer resistance to Vemurafenib by reactivating the MAPK pathway in BRAF(V600E) mutant melanoma cells [1]. RNA-seq data has been uploaded to Sequence Read Archive (SRA), which allows researchers to obtain RNA sequence data for these cells.
- |||||||||| Zelboraf (vemurafenib) / Roche
Journal: Cell surface CD63 increased by up-regulated polylactosamine modification sensitizes human melanoma cells to the BRAF inhibitor PLX4032. (Pubmed Central) - May 9, 2020 CD63 overexpression in PLX4032-resistant cells, in which CD63 levels were lower and cell surface polylactosamine levels were higher than those in parental cells, effectively suppressed proliferation. Our study shows the potential of CD63 to sensitize melanoma cells to PLX4032 and to reduce the proliferation of PLX4032-resistant cells.-Kudo, K., Yoneda, A., Sakiyama, D., Kojima, K., Miyaji, T., Yamazaki, M., Yaita, S., Hyodo, T., Satow, R., Fukami, K. Cell surface CD63 increased by up-regulated polylactosamine modification sensitizes human melanoma cells to the BRAF inhibitor PLX4032.
- |||||||||| Review, Journal, IO Biomarker: BRAF in malignant melanoma progression and metastasis: potentials and challenges. (Pubmed Central) - May 6, 2020
This review delineates the current role of BRAF in melanoma progression and metastasis. It discusses targeted therapies and resistance mechanisms to BRAF inhibitors, and illustrates strategies to overcome this mechanism with recently approved agents.
- |||||||||| Zelboraf (vemurafenib) / Roche
Journal: Trying for a BRAF Slam Dunk. (Pubmed Central) - May 3, 2020 The first basket clinical trial testing the BRAF inhibitor vemurafenib resulted in evidence of activity in 13 unique cancer types with BRAF mutations, but the response rates were variable. Therefore, different cancer histologies with the same driver oncogene display different degrees of oncogenic pathway addiction.See related article by Subbiah et al., p. 657.
- |||||||||| PIK-75 / Pathway Therapeutics, Tafinlar (dabrafenib) / Novartis, Zelboraf (vemurafenib) / Roche
Journal: Joint action of miR-126 and MAPK/PI3K inhibitors against metastatic melanoma. (Pubmed Central) - May 1, 2020 Finally, the synergistic role played by miR-126 in combination with vemurafenib and/or PIK-75 was demonstrated in vivo in mouse xenograft models, in which tumor growth inhibition was associated with increased apoptosis. All together, these results not only show the efficacy of PIK-75 and vemurafenib co-treatment, but also indicate that restoration of miR-126 expression in advanced melanoma can enhance their antitumor activity, which may possibly allow dose reduction to decrease adverse events without reducing the therapeutic benefits.
- |||||||||| Tecentriq (atezolizumab) / Roche
Trial completion date, Trial primary completion date: IMbrella B: A Study in Patients Previously Enrolled in a Genentech and/or F. Hoffmann-La Roche Ltd Sponsored Atezolizumab Study (clinicaltrials.gov) - May 1, 2020 P4, N=1000, Recruiting, All together, these results not only show the efficacy of PIK-75 and vemurafenib co-treatment, but also indicate that restoration of miR-126 expression in advanced melanoma can enhance their antitumor activity, which may possibly allow dose reduction to decrease adverse events without reducing the therapeutic benefits. Trial completion date: Dec 2028 --> Jul 2028 | Trial primary completion date: Dec 2028 --> Jul 2028
- |||||||||| Zelboraf (vemurafenib) / Roche
Journal: Functional Genomic Screening Independently Identifies CUL3 as a Mediator of Vemurafenib Resistance via Src-Rac1 Signaling Axis. (Pubmed Central) - Apr 30, 2020 Our results also indicated that the loss of CUL3 does not promote the activation of RAC1 through stabilization, suggesting that CUL3 is involved in the stability of upstream regulators of RAC1. Collectively, our study identifies the loss of CUL3 as a driver of MAPKi resistance through activation of RAC1 and demonstrates that inhibition of the Src family can suppress the MAPKi resistance phenotype in CUL3 cells by inactivating RAC1 protein.
- |||||||||| Zelboraf (vemurafenib) / Roche
Journal: Synergy from gene expression and network mining (SynGeNet) method predicts synergistic drug combinations for diverse melanoma genomic subtypes. (Pubmed Central) - Apr 29, 2020 Finally, we prospectively validated the drug combination for BRAF-mutant melanoma that was top ranked by our approach, vemurafenib (BRAF inhibitor) + tretinoin (retinoic acid receptor agonist), using both in vitro and in vivo models of BRAF-mutant melanoma and RNA-sequencing analysis of drug-treated melanoma cells to validate the predicted mechanisms. Our approach is applicable to a wide range of disease domains, and, importantly, can model disease-relevant protein subnetworks in precision medicine contexts.
- |||||||||| Zelboraf (vemurafenib) / Roche
Journal: Inhibition of mitochondrial respiration prevents BRAF-mutant melanoma brain metastasis. (Pubmed Central) - Apr 24, 2020 Large-scale analyses of human melanoma brain metastases indicated a significant role of mitochondrial complex I compared to brain metastases from other cancers. Finally, we observed completely abrogated BRAF inhibitor resistance when vemurafenib was combined with either β-sitosterol or a functional knockdown of mitochondrial complex I. In conclusion, based on its favorable tolerability, excellent brain bioavailability, and capacity to inhibit mitochondrial respiration, β-sitosterol represents a promising adjuvant to BRAF inhibitor therapy in patients with, or at risk for, melanoma brain metastases.
- |||||||||| Erbitux (cetuximab) / Eli Lilly, Zelboraf (vemurafenib) / Roche
Trial primary completion date, Metastases: Cetuximab and Vemurafenib Plus FOLFIRI for BRAF V600E Mutated Advanced Colorectal Cancer (IMPROVEMENT) (clinicaltrials.gov) - Apr 20, 2020 P2, N=30, Recruiting, Finally, we observed completely abrogated BRAF inhibitor resistance when vemurafenib was combined with either β-sitosterol or a functional knockdown of mitochondrial complex I. In conclusion, based on its favorable tolerability, excellent brain bioavailability, and capacity to inhibit mitochondrial respiration, β-sitosterol represents a promising adjuvant to BRAF inhibitor therapy in patients with, or at risk for, melanoma brain metastases. Trial primary completion date: Aug 2019 --> Dec 2020
- |||||||||| Opdivo (nivolumab) / Ono Pharma, BMS
Clinical, Journal, PD(L)-1 Biomarker: Two cases of BRAF-mutated, bulbar conjunctival melanoma with review of the published literature. (Pubmed Central) - Apr 19, 2020 The patient died due to metastases to the liver and multiple vertebrae, despite therapy with nivolumab and combination therapy with dabrafenib plus trametinib...After adjuvant cryotherapy, periodic mitomycin C eye drops, and excision of the superficial portion of the right parotid gland and the dissection of cervical lymph nodes, adjuvant combination therapy with dabrafenib plus trametinib was administered. Dermatologists should be familiar with BRAF-mutated conjunctival melanoma, which is usually located on the bulbar conjunctiva and associated with more frequent distant metastasis.
- |||||||||| Braftovi (encorafenib) / Ono Pharma, Pierre Fabre, Pfizer, Mektovi (binimetinib) / Ono Pharma, Pierre Fabre, Pfizer
Clinical, Review, Journal: Encorafenib with Binimetinib for the Treatment of Patients with BRAF V600 Mutation-Positive Unresectable or Metastatic Melanoma: An Evidence Review Group Perspective of a NICE Single Technology Appraisal. (Pubmed Central) - Apr 16, 2020 As part of the Single Technology Appraisal process, the National Institute for Health and Care Excellence (NICE) invited Pierre Fabre to submit evidence for the clinical and cost-effectiveness of encorafenib with binimetinib (Enco + Bini) versus dabrafenib with trametinib (Dab + Tram) as a first-line treatment for advanced (unresectable or metastatic) BRAF V600 mutation-positive melanoma...The main clinical evidence in the CS was derived from the COLUMBUS trial and focused on the efficacy of Enco + Bini (encorafenib 450 mg per day plus binimetinib 45 mg twice daily) compared to vemurafenib...However, as the numerical differences in outcomes generated by the company's networks were small, the AC did not have a preferred approach and considered that both the company's and the ERG's methods of incorporating outcome estimates into the economic model were suitable for decision making. The NICE AC recommended Enco + Bini as a first-line treatment for unresectable or metastatic melanoma with a BRAF V600 mutation.
- |||||||||| Leustatin (cladribine) / J&J, Rituxan (rituximab) / Roche, Biogen, Zenyaku Kogyo
Journal, IO Biomarker: No Loose Ends: A Review of the Pharmacotherapy of Hairy Cell and Hairy Cell Leukemia Variant. (Pubmed Central) - Apr 16, 2020 HCL and HCLv are uncommon lymphoid neoplasms that lead to a characteristic constellation of symptoms. The emergence of PAs and novel targeted agents have improved the likelihood and durability of responses for these patients.
- |||||||||| Cotellic (cobimetinib) / Exelixis, Roche, Tavalisse (fostamatinib) / Rigel, Zelboraf (vemurafenib) / Roche
Journal: The role of polo-like kinase 3 in the response of BRAF-mutant cells to targeted anticancer therapies. (Pubmed Central) - Apr 14, 2020 In PLK3-expressing cells, R406, a kinase inhibitor whose targets include PLK3, recapitulates the sensitizing effects of genetic PLK3 inhibitors. The findings support a role for PLK3 as a predictor of BRAFi efficacy and suggest suppression of PLK3 as a way to improve the efficacy of targeted therapy.
- |||||||||| Zelboraf (vemurafenib) / Roche
[VIRTUAL] A systematic analysis of BRAF mutations and their sensitivity to different BRAF inhibitors (Virtual Meeting: All Session Times Are U.S. EDT) - Apr 13, 2020 - Abstract #AACRI2020AACR-I_28; Using a high throughput method for functional annotation of MAPK activity, we profiled 151 different BRAF mutations identified in the AACR Project GENIE dataset, and their response to 4 different BRAF inhibitors- vemurafenib and 3 different exploratory 2nd generation inhibitors...Our results show that the number of activating variants is large and that they possess differential sensitivity to different types of direct inhibitors. This data can serve as a basis for rational drug design as well as more accurate treatment options for patients.
- |||||||||| JQ-1 / Roche, Farydak (panobinostat) / Novartis, Zelboraf (vemurafenib) / Roche
Journal: Identifying drug targets in tissues and whole blood with thermal-shift profiling. (Pubmed Central) - Apr 12, 2020 Blood-TPP analysis of panobinostat confirmed its binding to known targets and also revealed thermal stabilization of the zinc-finger transcription factor ZNF512. These methods will help to elucidate the mechanisms of drug action in vivo.
- |||||||||| Zelboraf (vemurafenib) / Roche
Trial completion date, Trial primary completion date: Vemurafenib With Lymphodepletion Plus Adoptive Cell Transfer & High Dose IL-2 Metastatic Melanoma (clinicaltrials.gov) - Apr 10, 2020 P2, N=17, Active, not recruiting, Combined, our results support that inclusion of proteomics can predict drug response and identify co-therapies in a basket setting. Trial completion date: Dec 2020 --> Dec 2022 | Trial primary completion date: Apr 2020 --> Dec 2020
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