- |||||||||| Mekinist (trametinib) / Novartis, Zelboraf (vemurafenib) / Roche
Validation of the interaction between a candidate compound and the intended drug target by a phenotypic rescue approach (Board 21: Level 2 - Hall D) - Sep 18, 2019 - Abstract #AACRNCIEORTC2019AACR_NCI_EORTC_453;
Mimicking the tumor microenvironment increases the knowledge about “drug-ability” of a target and sustainability of the target modulation at an early time point in the development process. Such early in-depth validation of the relationship between a compound and the drug target is vital to mitigate the risk of failure at later steps of drug development.
- |||||||||| Ibrance (palbociclib) / Pfizer, Mekinist (trametinib) / Novartis, Zelboraf (vemurafenib) / Roche
Uncoupling of the cell cycle pathway from the MAPK pathway in BRAF/MEK inhibitor resistant melanoma (Board 76: Level 2 - Hall D) - Sep 18, 2019 - Abstract #AACRNCIEORTC2019AACR_NCI_EORTC_309;
Both BRAFi/MEKi resistant patient samples were established as patient-derived xenograft (PDX) models to test the in vivo efficacy of trametinib (MEKi) and palbociclib (CDK4/6i) as single agents and in combination...To study the mechanism of response to the combination of MEKi and CDK4/6i in the context of BRAFi acquired resistance, we generated an in vitro resistance model using a panel of BRAF-V600 mutant cutaneous melanoma cell lines constantly treated with the BRAF inhibitor, vemurafenib, to generate a resistant cell population...Whereas, the BRAFi resistance cells are the opposite and require a lower concentration of CDK4/6i, and a higher concentration of MEKi, to have a durable response. Taken together, this data supports the observation that upon BRAFi resistance, the cell cycle pathway is uncoupled from the MAPK pathway, and cell cycle reactivation may represent a common acquired resistance mechanism to MEKi.
- |||||||||| Zelboraf (vemurafenib) / Roche
Evaluation of synergetic effect of drug combination by high-resolution diffusion-weighted imaging (HR-DWMRI) in BRAFV600E mutant thyroid cancer (Board 39: Level 2 - Hall D) - Sep 18, 2019 - Abstract #AACRNCIEORTC2019AACR_NCI_EORTC_266;
Although PLX4032 has been known as a highly potent inhibitor of BRAF activity, we have confirmed by RTK array that signaling pathways underlying drug resistance were amplified in cells which survived after PLX4032 treatment...Furthermore, DWI/ADC imaging was found to be a remarkable technique for predicting drug response, and we could confirm the cellularity and viscosity of the tumor by ADC intensity mapping against the tumor area. DWI could be used as an imaging-based evaluation system for therapeutic effects, as well as drug reactivity prediction.
- |||||||||| Afinitor (everolimus) / Novartis, Cabometyx (cabozantinib tablet) / Takeda, Exelixis, Ipsen, Unituxin (dinutuximab) / United Therapeutics
Successes and failures of targeted drug development in pediatric tumors (Level 3 - Ballroom AB) - Sep 18, 2019 - Abstract #AACRNCIEORTC2019AACR_NCI_EORTC_5;
Selumetinib has been FDA approved for the treatment of plexiform neurofibromas in children with neurofibromatosis type 1 and may have activity in children and adolescents with solid tumors harboring MAP kinase aberrations...Crizotinib is approved for the treatment of ALK-positive metastatic NSCLC and has activity in children with refractory Anaplastic Large Cell Lymphoma (ALCL) and inflammatory myofibroblastic tumors, both associated with ALK fusions...Clinical trials of multi-targeted kinase inhibitors including cabozantinib, regorafenib, sorafenib and vandetanib have demonstrated activity in a variety of solid tumors...To date, multi-targeted kinase inhibitors and drugs that target fusion oncoproteins that are histology-agnostic oncogenic drivers in cancers that occur in both child and adults have been most successful. Understanding the characteristics of successful target- drug pairs is critically important to the prioritization of new drugs and clinical trials in children as well as the development of new therapies for pediatric specific targets.
- |||||||||| Tafinlar (dabrafenib) / Novartis, Zelboraf (vemurafenib) / Roche
Clinical, Journal: Treating malignant melanoma when a rare BRAF V600M mutation is present: case report and literature review. (Pubmed Central) - Sep 18, 2019
We present the evolution of a patient with malignant melanoma with a rare V600M mutation in the BRAF gene, that was eventually treated with vemurafenib. Also we present a brief review of the major phase III trials that showed benefit with tyrosine-kinase inhibitors in BRAF mutated melanoma, with respect to the BRAF mutations included.
- |||||||||| Zelboraf (vemurafenib) / Roche
Preclinical, Journal, IO Biomarker: Telmisartan induces melanoma cell apoptosis and synergizes with vemurafenib in vitro by altering cell bioenergetics. (Pubmed Central) - Sep 15, 2019
Telmisartan altered the cell bioenergetics, thereby synergizing with vemurafenib in vitro, and even sensitized vemurafenib-resistant cells to the treatment. Given that the effective doses of telmisartan examined in our study can be administered to patients and that telmisartan is a widely used and safe antihypertensive drug, our findings provide the scientific rationale for testing its efficacy in treatment of melanoma progression.
- |||||||||| Zelboraf (vemurafenib) / Roche
Journal: COP1-DET1-ETS axis regulates ERK transcriptome and sensitivity to MAPK inhibitors. (Pubmed Central) - Sep 12, 2019
Two melanoma patients had de novo DET1 mutations arising after vemurafenib treatment. These observations indicate that MAPK signaling-dependent regulation of Pea3-ETS protein stability is a key signaling node in oncogenesis and therapeutic resistance to MAPK pathway inhibition.
- |||||||||| Cotellic (cobimetinib) / Exelixis, Roche, Zelboraf (vemurafenib) / Roche, Tecentriq (atezolizumab) / Roche
Trial completion date, Trial primary completion date, Combination therapy, PD(L)-1 Biomarker, IO biomarker, Metastases: A Phase 1b Study of Atezolizumab in Combination With Vemurafenib or Vemurafenib Plus Cobimetinib in Participants With BRAFV600-Mutation Positive Metastatic Melanoma (clinicaltrials.gov) - Sep 6, 2019
P1b, N=67, Active, not recruiting,
In summary, we show that 4-NC is a compound with activity against cutaneous melanoma, including resistant cells to clinically approved therapies. Trial completion date: Jun 2019 --> Sep 2020 | Trial primary completion date: Jun 2019 --> Sep 2020
- |||||||||| Cotellic (cobimetinib) / Exelixis, Roche, Zelboraf (vemurafenib) / Roche, Tecentriq (atezolizumab) / Roche
Trial completion date, Trial primary completion date, PD(L)-1 Biomarker, IO biomarker, Metastases: ImmunoCobiVem: Evaluating the Efficacy and Safety of a Sequencing Schedule of Cobimetinib Plus Vemurafenib Followed by Immunotherapy With an Anti- PD-L1 Antibody in Patients With Unresectable or Metastatic BRAF V600 Mutant Melanoma (clinicaltrials.gov) - Sep 6, 2019
P2, N=176, Recruiting,
Trial completion date: Jun 2019 --> Sep 2020 | Trial primary completion date: Jun 2019 --> Sep 2020 Trial completion date: Dec 2021 --> Jun 2022 | Trial primary completion date: Sep 2021 --> Mar 2022
- |||||||||| Zelboraf (vemurafenib) / Roche
5T105 Histiocytic Disorders: Don’t Miss New Drugs (B308) - Sep 3, 2019 - Abstract #ACRARHP2019ACR_669;
This in-depth session will present novel diagnostic approaches and new targeted treatment options for histiocytic disorders. Learning Objectives:Describe the family of histiocytic disorders and their new classificationExplain the novel diagnostic approaches including evaluating M AP and BR AF gene mutationsIdentify the new targeted treatment options for histiocytic disorders
- |||||||||| Enrollment open, PD(L)-1 Biomarker: Serial Measurements of Molecular and Architectural Responses to Therapy (SMMART) PRIME Trial (clinicaltrials.gov) - Sep 3, 2019
P1, N=52, Recruiting,
Learning Objectives:Describe the family of histiocytic disorders and their new classificationExplain the novel diagnostic approaches including evaluating M AP and BR AF gene mutationsIdentify the new targeted treatment options for histiocytic disorders Not yet recruiting --> Recruiting
- |||||||||| Review, Journal: BRAF Mutations and the Utility of RAF and MEK Inhibitors in Primary Brain Tumors. (Pubmed Central) - Aug 31, 2019
While class II and III BRAF mutations are found in primary brain tumors, further research is necessary to determine their sensitivity to third-generation RAF inhibitors and/or MEK inhibitors. We recommend that the neuro-oncologist consider using these drugs primarily in the setting of a clinical trial for patients with BRAF-altered glioma in order to advance our knowledge of their efficacy in this patient population.
- |||||||||| Zelboraf (vemurafenib) / Roche
Clinical, Journal: Severe panuveitis in a metastatic cutaneous melanoma patient treated with vemurafenib (Pubmed Central) - Aug 30, 2019
We recommend that the neuro-oncologist consider using these drugs primarily in the setting of a clinical trial for patients with BRAF-altered glioma in order to advance our knowledge of their efficacy in this patient population. No abstract available
- |||||||||| Revlimid (lenalidomide) / Celgene, Zelboraf (vemurafenib) / Roche
Journal: Synthesis and Cytotoxic Evaluation of Kojic Acid Derivatives with Inhibitory Activity on Melanogenesis in Human Melanoma Cells. (Pubmed Central) - Aug 28, 2019
Melanogenesis inhibition assay was performed to observe the ability of the drugs to inhibit melanin production and certain compounds were shown to be capable of actively inhibiting melanin production in melanoma cells. In conclusion, Mannich bases of kojic acid derivatives may be promising therapeutic agents, since some have more potent effects on melanoma cells than previously FDA-approved drugs for the treatment of malignant melanoma.
- |||||||||| Cotellic (cobimetinib) / Exelixis, Roche, Zelboraf (vemurafenib) / Roche
Trial completion, Metastases: A Study to Detect V-Raf Murine Sarcoma Viral Oncogene Homolog B1 (BRAF) V600 Mutation on Cell-Free Deoxyribonucleic Acid (cfDNA) From Plasma in Participants With Advanced Melanoma (clinicaltrials.gov) - Aug 28, 2019
P2, N=40, Completed,
In conclusion, Mannich bases of kojic acid derivatives may be promising therapeutic agents, since some have more potent effects on melanoma cells than previously FDA-approved drugs for the treatment of malignant melanoma. Active, not recruiting --> Completed
- |||||||||| Zelboraf (vemurafenib) / Roche
Retrospective data, Journal: Genome-Wide Meta-analysis identifies three novel loci associated with stroke. (Pubmed Central) - Aug 28, 2019
...We identified an exonic polymorphism in NOS3 (rs1799983, p.Glu298Asp; p = 2.2E-8, odds ratio [OR] = 1.05, 95% confidence interval [CI] = 1.04-1.07) and variants in an intron of COL4A1 (rs9521634; p = 3.8E-8, OR = 1.04, 95% CI = 1.03-1.06) and near DYRK1A (rs720470; p = 6.1E-9, OR = 1.05, 95% CI = 1.03-1.07) at genome-wide significance for stroke...Effect sizes of known stroke loci were highly correlated between UKB and MEGASTROKE. Using Mendelian Randomization we further show that genetic variation in the nitric oxide synthase (NOS) - nitric oxide (NO) pathway in part affects stroke risk via variation in blood pressure.
- |||||||||| Actemra IV (tocilizumab) / Roche, JW Pharma
Journal: IL6/STAT3 axis mediates resistance to BRAF inhibitors in thyroid carcinoma cells. (Pubmed Central) - Aug 25, 2019
Consistently, the dual blockade of STAT3 (by siRNA or pharmacological inhibition) or IL6 signaling (by the humanized anti-human IL6 receptor antibody, tocilizumab) and BRAF (by PLX4032) improved the inhibition of cell cycle progression compared to PLX4032 single agent. These data support the role of IL6/STAT3 signaling pathway in modulating TC cell response to PLX4032 and candidate IL6 targeting as a strategy to improve the activity of PLX4032 in BRAF V600E TC cells.
- |||||||||| Tasigna (nilotinib) / Novartis, Inhibikase, Zydelig (idelalisib) / Gilead, Zelboraf (vemurafenib) / Roche
Journal: Re-positioning of known drugs for Pim-1 kinase target using molecular docking analysis. (Pubmed Central) - Aug 23, 2019
Therefore, it is of interest to re-profile known drugs against the Pim-1 kinase target using molecular docking analysis. Results show that known drugs such as nilotinib, vemurafenib, Idelalisib, and other small kinases inhibitors have high binding ability with Pim-1 kinase for consideration as potential inhibitors.
- |||||||||| Cotellic (cobimetinib) / Exelixis, Roche, Zelboraf (vemurafenib) / Roche
Trial completion, Enrollment change: Prevention of Phototoxicities in Patients Undergoing Vemurafenib Treatment (clinicaltrials.gov) - Aug 22, 2019
P=N/A, N=30, Completed,
Results show that known drugs such as nilotinib, vemurafenib, Idelalisib, and other small kinases inhibitors have high binding ability with Pim-1 kinase for consideration as potential inhibitors. Recruiting --> Completed | N=222 --> 30
- |||||||||| Cotellic (cobimetinib) / Exelixis, Roche, Zelboraf (vemurafenib) / Roche
Clinical, Journal: Cobimetinib/vemurafenib-associated bilateral serous retinopathy: a case report (Pubmed Central) - Aug 21, 2019
In the case presented the progress of bilateral serous retinopathy was documented by optical coherence tomography (OCT). After therapy discontinuation, subfoveal fluid levels varied until remission was reached six months later.
- |||||||||| Cabometyx (cabozantinib tablet) / Takeda, Exelixis, Ipsen
Journal: Mortalin (GRP75/HSPA9) Promotes Survival and Proliferation of Thyroid Carcinoma Cells. (Pubmed Central) - Aug 21, 2019
Intriguingly, Mito-CP-induced cell death was partially rescued by mortalin overexpression, suggesting that Mito-CP may inactivate a mechanism that requires mortalin function. These findings support the significance of mortalin and mitochondrial activity in a broad spectrum of thyroid cancer.
- |||||||||| Zelboraf (vemurafenib) / Roche
Journal: Inhibition of peptidyl-prolyl isomerase (PIN1) and BRAF signaling to target melanoma. (Pubmed Central) - Aug 10, 2019
Combinatorial treatment of melanoma cells is with Vemurafenib as a common therapeutic option for BRAF-mutated melanoma and inhibitor 37 resulted in a strong, synergistic effect on apoptosis of melanoma cell lines. In summary, targeting PIN1 offers a promising therapeutic approach to simultaneously downregulate multiple cancer-driving pathways in cancer.
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