- |||||||||| macrocyclic peptide / UCB, Merck (MSD), Zelboraf (vemurafenib) / Roche
Journal: Design and Synthesis of Type-IV Inhibitors of BRAF Kinase That Block Dimerization and Overcome Paradoxical MEK/ERK Activation. (Pubmed Central) - Jun 10, 2020
The proof of concept for a structure-guided approach targeting the dimerization interface is described through the design and synthesis of macrocyclic peptides that bind with high affinity to BRAF and that block paradoxical signaling in malignant melanoma cells occurring through this drug target. The lead compounds identified are type-IV kinase inhibitors and represent an ideal framework for conversion into next-generation BRAF inhibitors through macrocyclic drug discovery.
- |||||||||| Braftovi (encorafenib) / Ono Pharma, Pierre Fabre, Pfizer, Mektovi (binimetinib) / Ono Pharma, Pierre Fabre, Pfizer
Journal, Adverse events: Adverse events associated with encorafenib plus binimetinib in the COLUMBUS study: incidence, course and management. (Pubmed Central) - Jun 10, 2020
P3
The lead compounds identified are type-IV kinase inhibitors and represent an ideal framework for conversion into next-generation BRAF inhibitors through macrocyclic drug discovery. Encorafenib+binimetinib is generally well tolerated and has a low discontinuation rate in patients with BRAFV600-mutant melanoma, with a distinct safety profile as compared with other anti-BRAF/MEK targeted therapies.
- |||||||||| Biomarker, Journal, PD(L)-1 Biomarker: Progress in rare central nervous system tumors. (Pubmed Central) - Jun 10, 2020
There is a need for dedicated clinical trials with strong correlative component in patients of all ages with rare CNS tumors. Critical research questions include relevance of the selected target for specific tumor types, persistence of the actionable biomarker at recurrence, blood-brain barrier penetration, and analysis of mechanisms of primary and acquired resistance.
- |||||||||| PLX4720 / Daiichi Sankyo, Zelboraf (vemurafenib) / Roche
Preclinical, Journal: Molecular alterations associated with acquired resistance to BRAFV600E targeted therapy in melanoma cells. (Pubmed Central) - Jun 8, 2020
In summary, we identified new genomic alterations and characterized the protein expression patterns associated with the resistant phenotype. Although several proteins have been shown to be associated with BRAF resistance, our study is the first to describe the association of VCAM-1 and osteopontin with BRAF resistance.
- |||||||||| Cotellic (cobimetinib) / Exelixis, Roche, Tafinlar (dabrafenib) / Novartis, Zelboraf (vemurafenib) / Roche
Clinical, Journal: Two cases of pneumonitis induced by targeted therapy. (Pubmed Central) - Jun 8, 2020
To the best of our knowledge, it appears that cases of targeted-therapy-induced pneumonitis are predominantly an MEK-inhibitor effect. We, therefore, propose a management strategy of discontinuing targeted therapy, introducing steroid treatment and switching to dabrafenib.
- |||||||||| Journal: The Medical Therapy of Craniopharyngiomas: The Way Ahead. (Pubmed Central) - Jun 8, 2020
The identification of specific genetic alterations in patients with craniopharyngiomas has expanded the therapeutic options, providing evidence for a a customized approach using newer molecular agents. More studies including a larger number of carefully selected patients are required to evaluate the response to currently available and evolving agents alone and in combination.
- |||||||||| Torisel (temsirolimus) / Pfizer, Zelboraf (vemurafenib) / Roche
Trial completion, Trial completion date, Trial primary completion date, Combination therapy, Metastases: Vemurafenib in Combination With Everolimus or Temsirolimus With Advanced Cancer (clinicaltrials.gov) - Jun 4, 2020
P1, N=27, Completed,
Active, not recruiting --> Recruiting Active, not recruiting --> Completed | Trial completion date: Dec 2020 --> Jun 2020 | Trial primary completion date: Dec 2020 --> Jun 2020
- |||||||||| Tafinlar (dabrafenib) / Novartis, Zelboraf (vemurafenib) / Roche
Journal: Pharmacological STING Activation Is a Potential Alternative to Overcome Drug-Resistance in Melanoma. (Pubmed Central) - Jun 3, 2020
Therefore, we investigated if STING agonists such as the newly developed dimeric aminobenzimidazole (diABZI) could sensitize melanoma cells to the clinically used BRAF inhibitors. Our results reveal that pharmacological activation of STING by diABZI, down regulates NRF2-dependent anti-oxidative responses and potentiates cell-death in melanoma cells when used in combination with BRAF inhibitors.
- |||||||||| Tafinlar (dabrafenib) / Novartis, Zelboraf (vemurafenib) / Roche
Journal: Quantitative Interrogation of the Human Kinome Perturbed by Two BRAF Inhibitors. (Pubmed Central) - May 29, 2020
Furthermore, we confirmed that vemurafenib could compromise the ATP binding capacity of MAP2K5 in vitro and inhibit its kinase activity in cells. Together, our targeted quantitative proteomic methods revealed profound changes in expression levels of kinase proteins in cultured melanoma cells upon treatment with clinically used BRAF inhibitors and led to the discovery of novel putative target kinases for these inhibitors.
- |||||||||| Zelboraf (vemurafenib) / Roche, XL888 / Exelixis, Merck (MSD)
Trial completion date: Study of XL888 With Vemurafenib for Patients With Unresectable BRAF Mutated Stage III/IV Melanoma (clinicaltrials.gov) - May 28, 2020
P1, N=21, Active, not recruiting,
Together, our targeted quantitative proteomic methods revealed profound changes in expression levels of kinase proteins in cultured melanoma cells upon treatment with clinically used BRAF inhibitors and led to the discovery of novel putative target kinases for these inhibitors. Trial completion date: Apr 2020 --> Dec 2020
- |||||||||| Zelboraf (vemurafenib) / Roche
Journal, Pan tumor: BRAF Inhibition in BRAF-Mutant Gliomas: Results From the VE-BASKET Study. (Pubmed Central) - May 27, 2020
Vemurafenib demonstrated evidence of durable antitumor activity in some patients with BRAF-mutant gliomas, although efficacy seemed to vary qualitatively by histologic subtype. Additional study is needed to determine the optimal use of vemurafenib in patients with primary brain tumors and to identify the mechanisms driving differential responses across histologic subsets.
- |||||||||| Zelboraf (vemurafenib) / Roche
Preclinical, Journal: 3D co-culture models underline metastatic melanoma cell sensitivity to vemurafenib. (Pubmed Central) - May 25, 2020
The heterotypic 3D melanoma model we have established summarizes paracrine signalization by stromal cells and type I collagen matrix, mimicking the natural microenvironment of cutaneous metastatic melanoma. This model could be a powerful tool for predicting drug efficiency.
- |||||||||| Zelboraf (vemurafenib) / Roche
Journal: BRAF inhibitor and hairy cell leukemia-related transient acantholytic dermatosis. (Pubmed Central) - May 25, 2020
Combination therapy with a MEK inhibitor appears to prevent BRAF-induced GD. Given that there is a higher prevalence of GD in patients with hematologic malignancy, a direct causal relationship between the initiation of vemurafenib therapy and development of GD in this case may be difficult to establish.
- |||||||||| Zelboraf (vemurafenib) / Roche
Journal: Vemurafenib-induced histiocytoid neutrophilic panniculitis simulating myeloid leukaemia cutis. (Pubmed Central) - May 21, 2020
We describe a novel variant of neutrophilic panniculitis with histiocytoid myeloid cells in an early lesion from a patient treated with vemurafenib in combination with an anti-EGFR (epidermal growth factor receptor) agent for metastatic colon carcinoma, three weeks after initiation of therapy. Recognizing this variant of panniculitis associated to BRAFi can avoid misinterpretation of the atypical subcutaneous infiltrate as myeloid leukaemia cutis.
- |||||||||| Zelboraf (vemurafenib) / Roche
Journal: BRAF in the cross-hairs. (Pubmed Central) - May 21, 2020
Areas covered: Herein the authors review the role of BRAF V600E and RAF-MEK-ERK signaling in the pathogenesis of HCL, anecdotal clinical reports of BRAF inhibitor monotherapy in management of relapsed or refractory HCL, larger phase 2 trials investigating efficacy of BRAF inhibitor therapy for HCL, adverse effects commonly associated with BRAF inhibitor therapy, including cutaneous toxicity, and mechanisms of therapeutic resistance. Expert opinion: Ongoing and planned studies will help to optimize the use of BRAF inhibitor therapy for HCL by determining efficacy of BRAF inhibition in combination with other antigen targeted or molecularly targeted therapies, and more broadly, to determine how hematologists can best utilize and sequence emerging diagnostic and therapeutic modalities in the care of patients with newly diagnosed and relapsed or refractory HCL.
- |||||||||| mirdametinib (PD-0325901) / SpringWorks Therap, BeiGene, lifirafenib (BGB-283) / BeiGene, EMD Serono
RAF dimer inhibitor lifirafenib enhances the antitumor activity of MEK inhibitor mirdametinib in RAS mutant tumors (Virtual Meeting II: E-Posters) - May 16, 2020 - Abstract #AACRII2020AACR-II_510;
P1b
Pharmacodynamic analysis supported the role of synergistic phospho-ERK blockade in enhancing the antitumor activity in the K-RAS mutant models. These findings support the rationale to combine a RAF dimer inhibitor and a MEK inhibitor to treat K-RAS-mutated cancers and led to the ongoing a Phase Ib/II clinical trial of lifirafenib and mirdametinib in patients with K-RAS mutations or other MAPK pathway aberrations (Clinical Trial ID: NCT03905148).
- |||||||||| Zelboraf (vemurafenib) / Roche
Loss of Spry1 reduces growth of BRAFV600-mutant cutaneous melanoma and improves response to targeted therapy (Virtual Meeting II: E-Posters) - May 16, 2020 - Abstract #AACRII2020AACR-II_403;
Indeed, treatment with the BRAFi vemurafenib down-regulated Spry1 levels in parental CM cell lines, indicating that Spry1 expression is sustained by MAPK/ERK signaling pathway in a positive feedback loop that safeguards cells from the potentially toxic effects of ERK1/2 hyperactivation. All together, our data strongly suggest that targeting Spry1 might offer a treatment strategy for BRAFV600-mutant CM by inducing the toxic effects of ERK-mediated signaling.
- |||||||||| ABM-1310 / ABM Therap, Erbitux (cetuximab) / Eli Lilly, EMD Serono
ABM-1310, A novel BRAF Inhibitor, combined with EGFR and MEK inhibitors, inhibits colorectal tumor growth and increases overall survival in vivo (Virtual Meeting II: E-Posters) - May 16, 2020 - Abstract #AACRII2020AACR-II_3818;
In the HT-29 colon intracranial model, ABM-1310 also demonstrated significant tumor inhibition effect and increased animal overall survival. Compared with vehicle or marketed BRAF inhibitor vemurafenib, the median survival time of ABM-1310 group was >90 days vs 51 days (vemurafenib) and 38 days (vehicle), respectively.In Summary, ABM-1310, as a novel small molecule BRAF inhibitor, combined with EGFR and MEK inhibitors, has shown strong anti-tumor effect in preclinical in vivo models of colon cancer with BRAFv600 mutation, especially with brain metastasis.
- |||||||||| Tafinlar (dabrafenib) / Novartis, Zelboraf (vemurafenib) / Roche
Specific detection of mutant Ras oncoproteins in cell and tissue lysates by multiplex immunoassay (Virtual Meeting II: E-Posters) - May 16, 2020 - Abstract #AACRII2020AACR-II_3396;
These exosomal preparations yielded detectable signal for Total Ras and phospho-BRAF. Our data demonstrate the utility of studying the effects of Ras oncoproteins by multiplex immunoassay in multiple sample types, including cell, tissue, and exosomal lysates.
- |||||||||| Temporal inhibition of ERK is sufficient for tumor growth inhibition in KRAS-mutant or BRAF-mutant tumors (Virtual Meeting II: E-Posters) - May 16, 2020 - Abstract #AACRII2020AACR-II_3326;
The combination of BRAF and MEK inhibitors have been clinically studied, and three different combinations (dabrafenib plus trametinib, vemurafenib plus cobimetinib and encorafenib plus binimetinib) are approved by the FDA for treatment of melanoma patients with BRAF V600E mutation...We have tested the PK-PD-efficacy of MEK inhibitors trametinib and cobimetinib, as well as ERK inhibitors BVD-523, GDC-0994 and LY3214996 in BRAF V600E or KRAS mutant xenograft models including A375 BRAF V600E melanoma, Colo205 BRAF V600E colorectal carcinoma and HCT116 KRAS G13D colorectal carcinoma...LY3214996 is in Phase 1 clinical development and the preliminary PK profile in patients looks as predicted from preclinical data. Therefore, we believe that the PK profile of LY3214996 offers flexibility with dose and schedule to balance efficacy and safety, and to achieve a better therapeutic index in combination therapy for RAS/MAPK pathway altered cancers.
- |||||||||| Zelboraf (vemurafenib) / Roche
Discovery of small molecule Mcl-1 and Bfl-1 inhibitors (Virtual Meeting II: E-Posters) - May 16, 2020 - Abstract #AACRII2020AACR-II_3231;
Overall, this work contributes to the drug discovery efforts of Bcl-2 family inhibitors and provides novel dual Mcl-1/Bfl-1 selective inhibitors. Further optimization of these dual inhibitors may provide valuable therapeutics to help combat acquired resistance in melanoma, where Mcl-1 and Bfl-1 play prominent functional roles, as determined by BH3 profiling.
- |||||||||| Zelboraf (vemurafenib) / Roche
Extracellular lipid starvation modulates the effects of BRAF inhibitors in melanoma (Virtual Meeting II: E-Posters) - May 16, 2020 - Abstract #AACRII2020AACR-II_3125;
Two matched pairs of sensitive and PLX4032-resistant cell lines (LM16 and LM36) were used...These findings suggest that lipid starvation redirects lipid pathways toward cholesterol synthesis (acetate-cholesterol) by increasing ACSS2, HMGCR as well as DHCR24 levels. Thus, extracellular lipid availability may influence tumor cell response to treatment, a finding to be considered in the frame of a personalized therapy tailored to the specific characteristics of each patient.
- |||||||||| 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.
|
