scholarly journals The BRAF-inhibitor PLX4720 inhibits CXCL8 secretion in BRAFV600E mutated and normal thyroid cells: a further anti-cancer effect of BRAF-inhibitors

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Francesca Coperchini ◽  
Laura Croce ◽  
Marco Denegri ◽  
Oriana Awwad ◽  
Samuel Tata Ngnitejeu ◽  
...  
Keyword(s):  
Braf Inhibitor ◽  
Braf Inhibitors ◽  
Thyroid Cells ◽  
Normal Thyroid ◽  
Cxcl8 Secretion ◽  
Anti Cancer

scholarly journals PTEN Loss-of-Function Alterations Are Associated With Intrinsic Resistance to BRAF Inhibitors in Metastatic Melanoma

2017 ◽  
pp. 1-15 ◽  
Author(s):  
Federica Catalanotti ◽  
Donavan T. Cheng ◽  
Alexander N. Shoushtari ◽  
Douglas B. Johnson ◽  
Katherine S. Panageas ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Tumor Regression ◽  
Braf Inhibitor ◽  
Molecular Signature ◽  
Braf Inhibitors ◽  
Next Generation ◽  
Loss Of Function ◽  
Intrinsic Resistance ◽  
Braf Mutant ◽  
Generation Sequencing

Purpose The clinical use of BRAF inhibitors in patients with melanoma is limited by intrinsic and acquired resistance. We asked whether next-generation sequencing of pretreatment tumors could identify coaltered genes that predict for intrinsic resistance to BRAF inhibitor therapy in patients with melanoma as a prelude to rational combination strategies. Patients and Methods We analyzed 66 tumors from patients with metastatic BRAF-mutant melanoma collected before treatment with BRAF inhibitors. Tumors were analyzed for > 250 cancer-associated genes using a capture-based next-generation sequencing platform. Antitumor responses were correlated with clinical features and genomic profiles with the goal of identifying a molecular signature predictive of intrinsic resistance to RAF pathway inhibition. Results Among the 66 patients analyzed, 11 received a combination of BRAF and MEK inhibitors for the treatment of melanoma. Among the 55 patients treated with BRAF inhibitor monotherapy, objective responses, as assessed by Response Evaluation Criteria in Solid Tumors (RECIST), were observed in 30 patients (55%), with five (9%) achieving a complete response. We identified a significant association between alterations in PTEN that would be predicted to result in loss of function and reduced progression-free survival, overall survival, and response grade, a metric that combines tumor regression and duration of treatment response. Patients with melanoma who achieved an excellent response grade were more likely to have an elevated BRAF-mutant allele fraction. Conclusion These results provide a rationale for cotargeting BRAF and the PI3K/AKT pathway in patients with BRAF-mutant melanoma when tumors have concurrent loss-of-function mutations in PTEN. Future studies should explore whether gain of the mutant BRAF allele and/or loss of the wild-type allele is a predictive marker of BRAFi sensitivity.

scholarly journals In silico evaluation of some 4-(quinolin-2-yl)pyrimidin-2-amine derivatives as potent V600E-BRAF inhibitors with pharmacokinetics ADMET and drug-likeness predictions

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Abdullahi Bello Umar ◽  
Adamu Uzairu ◽  
Gideon Adamu Shallangwa ◽  
Sani Uba
Keyword(s):  
Molecular Docking ◽  
Side Effects ◽  
Oral Bioavailability ◽  
In Silico ◽  
Braf Inhibitor ◽  
Docking Studies ◽  
Pharmacological Properties ◽  
Braf Inhibitors ◽  
Docking Analysis ◽  
Risk Parameters

Abstract Background The resistance of V600E-BRAF to the vemurafenib and the side effects of the identified inhibitors trigger the research for a novel and more potent anti-melanoma agents. In this study, virtual docking screening along with pharmacokinetics ADMET and drug-likeness predictions were combined to evaluate some 4-(quinolin-2-yl)pyrimidin-2-amine derivatives as potent V600E-BRAF inhibitors. Results Some of the selected compounds exhibited better binding scores and favorable interaction with the V600E-BRAF enzyme. Out of the screened compounds, two most potent (5 and 9) having good Rerank scores (− 128.011 and − 126.258) emerged as effective and potent V600E-BRAF inhibitors that outperformed the FDA-approved V600E-BRAF inhibitor (vemurafenib, − 118.607). Thus, the molecular docking studies revealed that the studied compounds showed competing for inhibition of V600E-BRAF with vemurafenib at the binding site and possessed better pharmacological parameters based on the drug-likeness rules filters for the oral bioavailability, and ADMET risk parameters. Conclusion The docking analysis, drug-likeness rules filters, and ADMET study identified compounds (5 and 9) as the best hits against V600E-BRAF kinase with enhanced pharmacological properties. This recommends that these compounds may be developed as potent anti-melanoma agents.

Incidence of New Primary Melanomas After Diagnosis of Stage III and IV Melanoma

2014 ◽  
Vol 32 (8) ◽  
pp. 816-823 ◽  
Author(s):  
Lisa Zimmer ◽  
Lauren E. Haydu ◽  
Alexander M. Menzies ◽  
Richard A. Scolyer ◽  
Richard F. Kefford ◽  
...  
Keyword(s):  
Cumulative Incidence ◽  
Braf Inhibitor ◽  
Stage Iv ◽  
Incidence Rates ◽  
Stage Iii ◽  
Prior History ◽  
Braf Inhibitors ◽  
History Of ◽  
Stage Iii Melanoma ◽  
Stage Iv Melanoma

Purpose New primary melanomas (NPMs) have developed in some patients with metastatic melanoma treated with BRAF inhibitors. We sought to determine the background incidence of spontaneous NPMs after a diagnosis of American Joint Committee on Cancer/International Union Against Cancer stage III or IV melanoma in patients not treated with a BRAF inhibitor. Patients and Methods Patients diagnosed with stage III or IV melanoma at Melanoma Institute Australia between 1983 and 2008 were analyzed, and those who received a BRAF inhibitor were excluded. Results Two hundred twenty-nine (5%) of 4,215 patients with stage III melanoma and 43 (1%) of 3,563 patients with stage IV melanoma had at least one NPM after diagnosis of stage III or IV disease. The 6-month, 1-year, and 10-year cumulative incidence rates of developing an NPM after stage III melanoma were 1.2% (95% CI, 0.86% to 1.51%), 1.8% (95% CI, 1.44% to 2.26%), and 5.9% (95% CI, 5.08% to 6.74%), respectively. The 3-month, 6-month, and 1-year cumulative incidence rates of NPM after diagnosis of stage IV melanoma were 0.2% (95% CI, 0.07% to 0.36%), 0.3% (95% CI, 0.15% to 0.51%), and 0.4% (95% CI, 0.25% to 0.7%), respectively. In both patients with stage III and stage IV melanoma, male patients and patients with a prior history of multiple primaries had a higher incidence of NPM. Conclusion Patients with stage III and stage IV melanoma remain at risk for development of further primary melanomas, particularly if they have a history of multiple primary melanomas before stage III or IV disease. The incidence rates are lower than those reported in patients receiving BRAF inhibitors. However, the results must be compared with caution because dermatologic assessment is more frequent in BRAF inhibitor trials.

scholarly journals Combining Targeted Therapy With Immunotherapy in BRAF-Mutant Melanoma: Promise and Challenges

2014 ◽  
Vol 32 (21) ◽  
pp. 2248-2254 ◽  
Author(s):  
Siwen Hu-Lieskovan ◽  
Lidia Robert ◽  
Blanca Homet Moreno ◽  
Antoni Ribas
Keyword(s):  
Targeted Therapy ◽  
Braf Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Braf Inhibitors ◽  
Oncogenic Signaling ◽  
Pathway Activation ◽  
Prolonged Duration ◽  
Trial Testing ◽  
Mitogen Activated Protein ◽  
Braf Mutant

Recent breakthroughs in the treatment of advanced melanoma are based on scientific advances in understanding oncogenic signaling and the immunobiology of this cancer. Targeted therapy can successfully block oncogenic signaling in BRAFV600-mutant melanoma with high initial clinical responses, but relapse rates are also high. Activation of an immune response by releasing inhibitory check points can induce durable responses in a subset of patients with melanoma. These advances have driven interest in combining both modes of therapy with the goal of achieving high response rates with prolonged duration. Combining BRAF inhibitors and immunotherapy can specifically target the BRAFV600 driver mutation in the tumor cells and potentially sensitize the immune system to target tumors. However, it is becoming evident that the effects of paradoxical mitogen-activated protein kinase pathway activation by BRAF inhibitors in non–BRAF-mutant cells needs to be taken into account, which may be implicated in the problems encountered in the first clinical trial testing a combination of the BRAF inhibitor vemurafenib with ipilimumab (anti-CTLA4), with significant liver toxicities. Here, we present the concept and potential mechanisms of combinatorial activity of targeted therapy and immunotherapy, review the literature for evidence to support the combination, and discuss the potential challenges and future directions for rational conduct of clinical trials.

scholarly journals P.109 Increased survival when combining BRAF inhibitors and stereotactic radiosurgery in patients with melanoma brain metastases

2016 ◽  
Vol 43 (S2) ◽  
pp. S45-S46
Author(s):  
A Wolf ◽  
A Pavlick ◽  
M Wilson ◽  
J Silverman ◽  
D Kondziolka
Keyword(s):  
Overall Survival ◽  
Brain Metastases ◽  
Stereotactic Radiosurgery ◽  
Systemic Disease ◽  
Braf Inhibitor ◽  
Braf Inhibitors ◽  
Actuarial Survival ◽  
Early Management ◽  
Melanoma Brain Metastases ◽  
The Impact

Background: The purpose of the study was to evaluate the impact of BRAF inhibitors on survival outcomes in patients receiving stereotactic radiosurgery (SRS) for melanoma brain metastases. Methods: We prospectively collected treatment outcomes for 80 patients with melanoma brain metastases who underwent SRS. Thirty-five patients harbored the BRAF mutation (BRAF-M) and 45 patients did not (BRAF-WT). Results: The median overall survival from first SRS procedure was 11.2 months if treated with a BRAF inhibitor and 4.5 months for BRAF-WT. Actuarial survival rates for BRAF-M patients on an inhibitor were 54% and 41% at 6 and 12 months after radiosurgery, in contrast to 28% and 19% for BRAF-WT. Overall survival was extended for patients on a BRAF inhibitor if initiated at or after the first SRS. The local control rate did not differ based on BRAF status and was over 90%. Patients with higher KPS, fewer treated metastases, controlled systemic disease, RPA class 1 and BRAF-M patients had extended overall survival. Conclusions: Patients with BRAF-M treated with both SRS and BRAF inhibitors, at or after SRS, have increased overall survival. As patients live longer due to more effective systemic and local therapies, close surveillance and early management of intracranial disease with SRS will become increasingly important.

Sequential presentation of a case of hyperthyroidism with autonomously functioning nodules and Graves' disease in the presence of IgG thyroid stimulators

1988 ◽  
Vol 118 (4) ◽  
pp. 474-478 ◽  
Author(s):  
P. P. A. Smyth ◽  
D. Neylan ◽  
N. M. McMullan ◽  
D. F. Smith ◽  
T.J. McKenna
Keyword(s):  
Thyroid Hormones ◽  
Graves Disease ◽  
Sequential Presentation ◽  
Rare Occurrence ◽  
Thyroid Cells ◽  
Normal Thyroid ◽  
Thyroid Stimulating Immunoglobulins ◽  
Short Loop ◽  
Cytochemical Bioassay ◽  
Loop Feedback

Abstract. The rare occurrence of hyperthyroidism with an autonomously functioning nodule which following 131I therapy presented as toxic diffuse goitre (Graves' disease) is described in a 60 year old male. This progression was characterised by the presence of varying concentrations of IgG thyroid stimulators, thyroid stimulating immunoglobulins and thyroid growth stimulating immunoglobulins, as measured by cytochemical bioassay. It is postulated that the presence of the nodule and its associated hypersecretion of thyroid hormones may have protected the gland from the effects of IgG stimulators by bringing about inhibitory short-loop feedback on normal thyroid cells. It is further suggested that following therapeutic ablation of the nodule, normal thyroid cells became sensitive to the thyroid stimulators with the evolution of typical features of toxic diffuse goitre.

scholarly journals Low-Dose BRAF-Inhibitors in the Treatment of Histiocytic Disorders with the BRAF-V600E Mutation

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5895-5895
Author(s):  
Gordon Ruan ◽  
Gaurav Goyal ◽  
Jithma P. Abeykoon ◽  
N. Nora Bennani ◽  
Karen Rech ◽  
...  
Keyword(s):  
Median Time ◽  
Low Dose ◽  
Braf Inhibitor ◽  
Brain Parenchyma ◽  
Advisory Board ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Braf Inhibitors ◽  
Starting Dose ◽  
Dose Reductions

Introduction: The landmark VE-BASKET trial demonstrated that Erdheim-Chester disease (ECD) patients with the BRAF-V600E mutation can be effectively treated with vemurafenib 1920 mg/day. However, all patients required dose reductions due to adverse effects. The efficacy of low dose BRAF-inhibitors is not well established in ECD. Further, as Langerhans cell histiocytosis (LCH) also harbors BRAF-V600E mutations in 50-60% of patients, BRAF-inhibitors may be effective in this disease as well. In this study, we evaluated the efficacy of low dose BRAF-inhibitors (vemurafenib and dabrafenib) in the treatment of ECD and LCH. Methods: We conducted a retrospective study of ECD and LCH patients who were seen at our institution from January 1998 to July 2018. All patients had a diagnosis of ECD and LCH determined by clinical criteria in conjunction with histopathologic findings. Based on the standard doses approved for malignant melanoma and ECD, patients were categorized into the low dose BRAF-inhibitor group if they were treated with vemurafenib < 960 mg/day or dabrafenib ≤ 150mg/day at any point in time. We used a simple response criteria that defined clinical progressive disease (PD) as worsening of symptoms attributed to ECD/LCH or radiologic PD as a progression or worsening of proven or suspected lesions due to ECD/LCH. The minimum duration for symptom improvement to be considered a response was set at 3 months. Results: A total of 89 ECD patients and 186 LCH patients were identified. Within the ECD cohort, 24 of 44 (55%) patients who were tested had the BRAF-V600E mutation. Eight patients were included in the low dose BRAF-inhibitor group. The median age at diagnosis was 57 years (range 37-74) and 5 (63%) were male. The most common areas of involvement included bone (88%), cardiovascular system (63%), kidneys (63%), and brain parenchyma (50%). The median time of follow up was 66 months (range 23-165) and the median time on low-dose BRAF-inhibitor was 10 months (range 1-27) [Table 1]. Three patients had a starting dose of vemurafenib 1920 mg/day, 4 had 960 mg/day, and 1 had 480 mg/day. All patients required dose reductions and 50% of the patients ultimately discontinued vemurafenib due to side effects. Side effects included fatigue, pruritus, nausea, facial swelling, blisters, papillomas, and/or subcutaneous nodules. Four patients were able to remain on low-dose vemurafenib for a median follow up time of 24.5 months (range 12-28) with ongoing response and no signs of clinical or radiologic PD. Within the LCH cohort, 18 of 31 tested (58%) patients had the BRAF-V600E mutation. Four patients were included in the low dose BRAF-inhibitor group. The median age at diagnosis of this cohort was 43 years (range 34-69) and 2 (50%) were male. Areas of involvement included bone (100%), brain parenchyma (hypothalamus/optic stalk and pons; 50%), and skin (25%). The median time of follow up was 31 months (range 21-46) and the median time on low-dose BRAF-inhibitor was 4 months (range 3-24) [Table 2]. Two patients had a starting dose of vemurafenib 960mg/day. The patients with brain parenchymal involvement had a starting dose of dabrafenib 150mg/day or 100mg/day. All patients taking vemurafenib 960mg/day required dose reductions and one patient discontinued treatment due to skin blistering in her feet. In the patients taking dabrafenib, no side effects have yet been reported. 3 patients had an ongoing response and did not have clinical or radiologic PD. Patient #10 however, had clinical and radiologic PD after being on vemurafenib 720mg/day for 22 months. Conclusion: Our study suggests a potential role for lower doses of BRAF-inhibitors in ECD and LCH patients harboring BRAF-V600E mutations. Dabrafenib was found to be particularly efficacious and well-tolerated in LCH involving the brain parenchyma. However, patients who undergo dose reductions should be closely monitored due to the risk of disease progression. Careful balance of toxicities and efficacy is needed for optimizing patient outcomes with targeted therapies. Disclosures Bennani: Adicet Bio: Other: Advisory board; Kite Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Purdue Pharma: Other: Advisory board; Adicet Bio: Other: Advisory board; Kite Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Adicet Bio: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Seattle Genetics: Other: Advisory board. OffLabel Disclosure: Vemurafenib and dabrafenib for Langerhans cell histiocytosis. Vemurafenib dosage for Erdheim-Chester disease is less than the approved dose of 960mg every 12 hours.

scholarly journals T-Type Calcium Channels: A Potential Novel Target in Melanoma

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 391 ◽  
Author(s):  
Carla Barceló ◽  
Pol Sisó ◽  
Oscar Maiques ◽  
Inés de la Rosa ◽  
Rosa M. Martí ◽  
...  
Keyword(s):  
Calcium Channels ◽  
Therapeutic Potential ◽  
Therapeutic Option ◽  
Acquired Resistance ◽  
Braf Inhibitor ◽  
Braf Inhibitors ◽  
Promising Therapeutic Approach ◽  
Novel Target ◽  
And Migration

T-type calcium channels (TTCCs) are overexpressed in several cancers. In this review, we summarize the recent advances and new insights into TTCC biology, tumor progression, and prognosis biomarker and therapeutic potential in the melanoma field. We describe a novel correlation between the Cav3.1 isoform and the increased basal autophagy in BRAFV600E-mutant melanomas and after acquired resistance to BRAF inhibitors. Indeed, TTCC blockers reduce melanoma cell viability and migration/invasion in vitro and tumor growth in mice xenografts in both BRAF-inhibitor-sensitive and -resistant scenarios. These studies open a new, promising therapeutic approach for disseminated melanoma and improved treatment in BRAFi relapsed melanomas, but further validation and clinical trials are needed for it to become a real therapeutic option.

Sequential treatment with ipilimumab and BRAF inhibitors in patients with metastatic melanoma: Data from the Italian cohort of ipilimumab expanded access programme (EAP).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 9035-9035 ◽  
Author(s):  
Paolo Antonio Ascierto ◽  
Ester Simeone ◽  
Vanna Chiarion-Sileni ◽  
Paola Queirolo ◽  
Michele Del Vecchio ◽  
...  
Keyword(s):  
Overall Survival ◽  
Metastatic Melanoma ◽  
Disease Progression ◽  
Median Overall Survival ◽  
Therapeutic Option ◽  
Braf Inhibitor ◽  
Stage Iv ◽  
Sequential Treatment ◽  
Braf Inhibitors ◽  
A Prospective Study

9035 Background: Ipilimumab and vemurafenib have recently been approved as single agents for the treatment of unresectable or metastatic melanoma. Currently, limited data exist on the sequential treatment with these agents in patients (pts) with the BRAF mutation; here we evaluate the efficacy outcomes of pts enrolled in the EAP in Italy who sequentially received a BRAF-inhibitor and ipilimumab, or vice versa. Methods: Ipilimumab was available upon physician request for pts aged ≥16 years with unresectable stage III/stage IV melanoma who had either failed systemic therapy or were intolerant to ≥1 systemic treatment and for whom no other therapeutic option was available. Ipilimumab 3 mg/kg was administered intravenously every 3 weeks for 4 doses. Tumour assessments were conducted at baseline and after completion of induction therapy using immune-related response criteria. Patients were considered for this analysis if they tested positive for the BRAF mutation and had received a BRAF-inhibitor before or after ipilimumab treatment. Results: In total, 855 Italian pts participated in the EAP from June 2010 to January 2012 across 55 centres. Out of 173 BRAF positive pts, 93 (53.7%) were treated sequentially with both treatments: 48 pts received a BRAF inhibitor upon disease progression with ipilimumab and 45 pts received ipilimumab upon disease progression with a BRAF inhibitor. As of December 2012, median overall survival was 14.5 months (11.1-17.9) and 9.7 months (4.6-14.9) for the two groups, respectively (p=0.01). Among the 45 BRAF inhibitors pretreated pts, 18 (40%) had rapid disease progression (median overall survival: 5.8 months) and were unable to complete all four induction doses of ipilimumab, while the remaining 27 (60%) pts had slower disease progression (median overall survival: 19.3 months) and were able to complete the therapy with ipilimumab. Conclusions: These preliminary results suggest that, in BRAF-mutated pts, to start the sequential treatment with ipilimumab can provide a better survival than the reverse sequence. These findings deserve confirmation in a prospective study.

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