scholarly journals BRAF in Melanoma: Pathogenesis, Diagnosis, Inhibition, and Resistance

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Ryan J. Sullivan ◽  
Keith T. Flaherty
Keyword(s):  
Standard Of Care ◽  
Diagnostic Techniques ◽  
Therapeutic Interventions ◽  
Molecular Testing ◽  
Braf Inhibitors ◽  
Testing Methods ◽  
Braf Mutations ◽  
Initial Discovery ◽  
Braf Mutant ◽  
Mutant Braf

Since the initial discovery that a subset of patients with cutaneous melanoma harbor BRAF mutations, substantial research has been focused on determining the pathologic consequences of BRAF mutations, optimizing diagnostic techniques to identify these mutations, and developing therapeutic interventions to inhibit the function of this target in mutation-bearing tumors. Recently, advances have been made which are revolutionizing the standard of care for patients with BRAF mutant melanoma. This paper provides an overview on the pathogenic ramifications of mutant BRAF signaling, the latest molecular testing methods to detect BRAF mutations, and the most recent clinical data of BRAF pathway inhibitors in patients with melanoma and BRAF mutations. Finally, emerging mechanisms of resistance to BRAF inhibitors and ways of overcoming this resistance are discussed.

Type II RAF inhibition predicts superior ERK suppression compared to type I RAF inhibition in different BRAF mutant types recurrently found in lung cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e23154-e23154
Author(s):  
Philippe Giron ◽  
Amir Noeparast ◽  
Sylvia De Brakeleer ◽  
Ulrike De Ridder ◽  
Erik Teugels ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Line ◽  
Single Agent ◽  
Mek Inhibitor ◽  
Expression Vectors ◽  
Type I ◽  
Type Ii ◽  
Braf Mutations ◽  
Braf Mutant ◽  
Mutant Braf

e23154 Background: Somatic driver BRAF mutations account for 6-8% of lung cancers. As opposed to melanoma in which V600E mutant BRAF predominates, the majority of lung cancer-derived BRAF mutations are non-V600. Yet, the efficacy of RAF-inhibitors and the possible resistance mechanisms in non-V600 BRAF mutant cells remain to be uncovered. Recently, we have shown that non-V600 BRAF mutations recurrently found in lung cancer predict sensitivity to the combination of type I RAF inhibitor Dabrafenib and a MEK inhibitor Trametinib. As a single agent, Dabrafenib shows only weak suppression of mutant BRAF-induced ERK signaling; moreover it can induce ERK paradoxical activation in CRAF overexpressing cells. Methods: Several recombinant BRAF expression vectors were generated by performing site-directed mutagenesis. We compared the effects of Dabrafenib and a type II RAF inhibitor (AZD-628) at clinically relevant dose as single agents or in combination with MEK inhibitor Trametinib on ERK activity in HEK293T cells expressing several tumor-derived BRAF mutants and a non-V600 BRAF mutant lung cancer cell line (H1666). Viability and caspase3/7 activation assays were performed using the H1666 cell line model. Results: In contrast to Dabrafenib, AZD-628 does not induce paradoxical ERK activation in CRAF expressing cells. Increased CRAF expression desensitizes BRAF-mutant expressing cells to Dabrafenib but not to AZD-628. Notably, AZD-628 has superior ERK-inhibitory effect in HEK293T cells co-expressing several different BRAF-mutants with CRAF and in H1666 cells. Combination of Trametinib and AZD-628 has superior MEK-inhibitory and pro-apoptotic effect in H1666 cells compared to combined Trametinib/Dabrafenib. Moreover, upon down titration of the RAF inhibitors with a steady dose of Trametinib, AZD-628 resulted in overall stronger effect on viability compared to Dabrafenib. Conclusions: In our in vitro model, we obtained strong indications that at conventional doses, type II RAF-inhibitor AZD628 is superior to type I RAF-inhibitor Dabrafenib in combination with MEK inhibitor Trametinib for the treatment of non-V600 BRAF mutant lung cancer.

Promising Strategies for Overcoming BRAF Inhibitor Resistance Based on Known Resistance Mechanisms

2020 ◽  
Vol 20 (12) ◽  
pp. 1415-1430 ◽  
Author(s):  
Qing-Shan Li ◽  
Bang-Nian Shen ◽  
Hua-Jian Xu ◽  
Ban-Feng Ruan
Keyword(s):  
Treatment Strategies ◽  
Braf Inhibitor ◽  
Resistance Mechanisms ◽  
Therapeutic Effects ◽  
Braf Inhibitors ◽  
Braf Mutations ◽  
Clinical Benefits ◽  
Melanoma Patients ◽  
Inhibitor Resistance ◽  
Braf Mutant

Background: Almost 50% of metastatic melanomas harbor BRAF mutations. Since 2011, BRAF inhibitors have exhibited striking clinical benefits in BRAF-mutant melanoma patients. Unfortunately, their therapeutic effects are often temporary. The resistance mechanisms vary and can be broadly classified as MAPK reactivation-dependent and -independent. Elucidation of these resistance mechanisms provides new insights into strategies for overcoming resistance. Indeed, several alternative treatment strategies, including changes in the mode of administration, combinations of BRAF and MEK inhibitors, and immunotherapy have been verified as beneficial to BRAF inhibitor-resistant melanoma patients. Prospect: In this review, we discuss promising strategies for overcoming drug resistance and highlighting the prospects for discovering strategies to counteract BRAF inhibitor resistance.

scholarly journals Ultrasensitive Detection of BRAF Mutations in Circulating Tumor DNA of Patients With Metastatic Thyroid Cancer

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A872-A873
Author(s):  
Mohamed A Gouda ◽  
Emily Ong ◽  
Helen J Huang ◽  
Laron McPhaul ◽  
Steve Yoon ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Thyroid Carcinoma ◽  
Liquid Biopsy ◽  
Braf V600e ◽  
Molecular Testing ◽  
Ultrasensitive Detection ◽  
Tumor Type ◽  
Proof Of Concept ◽  
Braf Mutations ◽  
Mutant Braf

Abstract Background: Liquid biopsy is a promising technology that can offer various advantages for molecular testing over tissue-based approaches. Most studies trying to address the utility of liquid biopsy in thyroid cancer have failed so far to achieve satisfactory rates of detection of relevant mutations. In this study, we examined a newly developed approach for ultrasensitive detection of oncogenic mutations in thyroid cancer using BRAF mutation as a proof-of-concept. In an exploratory analysis, we also correlated our findings with clinical outcomes and with levels of standard of care biomarkers. Methods: We included a group of patients with metastatic thyroid carcinoma. Cell free DNA (cfDNA) was isolated from an average of 2 ml of plasma and from matched formaldehyde fixed paraffin tissue blocks (FFPB) that were obtained from prior surgery. Extracted DNA was subject to preamplification of mutant copies using Q5 High-Fidelity PCR kit. Digital droplet PCR was performed on pre-amplified purified DNA where BRAF mutated allele frequencies (AF) were measured using BioRad ddPCR Qx200. Results: Thirty-three patients were included in our study with a median age at diagnosis of 62. Our method achieved a sensitivity of detection of 47.6% and a specificity of 80%. Mutant BRAF V600E was detected in cfDNA of 54.5% of patients (n=18) compared to 80.8% in isolated DNA from matched FFPB. Median overall survival (OS) was shorter in patients with wild type (WT) BRAF in both ctDNA and tissue (127m vs 218m, p=0.015; 116m vs 223m, p=0.004). Thyroglobulin (Tg) levels did not correlate with BRAF mutations either quantitatively or qualitatively. In the papillary thyroid carcinoma-classic variant cohort (n=20), however, patients with cfDNA mutant BRAF were more likely to have elevated Tg (90.9% versus 44.4% respectively, p=0.05). Conclusions: Our study provided a proof of concept for a newly developed technique to provide high sensitivity of mutation detection in thyroid cancer. The achieved sensitivity of detection is the highest to date using liquid biopsy in this tumor type. While we addressed only BRAF mutations in our study, the same approach can potentially be used for other mutations as well, likely changing the paradigm for use of liquid biopsy in thyroid cancer.

The next-generation pan-RAF inhibitor, KIN-2787, is active in class II and class III BRAF mutant models.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3116-3116
Author(s):  
Aleksandra Franovic ◽  
Nichol Miller ◽  
Paul Severson ◽  
Toufike Kanouni ◽  
Noelito Timple ◽  
...  
Keyword(s):  
Class Ii ◽  
Class I ◽  
Braf Inhibitors ◽  
Class Iii ◽  
Braf Gene ◽  
Braf Mutations ◽  
Braf Mutant ◽  
Gene Alterations

3116 Background: Oncogenic BRAF gene alterations, leading to aberrantly activated BRAF monomers (Class I mutations) or dimers (Class II and Class III mutations), are observed in approximately 6% of all human cancers. First-generation BRAF inhibitors targeting Class I BRAF mutants, including dabrafenib, encorafenib, and vemurafenib, provide significant clinical benefit to patients with BRAF V600 mutation-driven melanoma and select solid tumors as monotherapies or in combination with other targeted therapies. The currently approved BRAF inhibitors have not, however, proven to be effective in patients with Class II or III BRAF alterations which account for a large proportion (34%) of BRAF mutations. KIN-2787 is an orally available, potent and selective small molecule pan-RAF inhibitor specifically designed to inhibit Class II and III BRAF dimers, in addition to Class I mutants. Methods: The efficacy and tolerability of the pan-RAF inhibitor, KIN-2787, was evaluated in vitro and in vivo in Class I, II, and III BRAF mutation-driven human cancer models. Results: In biochemical assays, KIN-2787 showed low nanomolar to picomolar potency against RAF1, BRAF, and ARAF (IC50 0.06-3.46 nM) with minimal activity towards non-RAF kinases. In cell-based assays, KIN-2787 inhibited RAF activity, as measured by inhibition of downstream ERK phosphorylation (pERK), across multiple BRAF mutant cancer cell lines. Class II and III BRAF mutant cell lines were the most responsive when treated with KIN-2787 (IC50 < 50 nM); 19- and 7-fold more sensitive compared to cells harboring wild-type BRAF, respectively. Dose-dependent inhibition of A-375 (Class I), BxPC-3 (Class II), and WM3629 (Class III) BRAF mutant human xenograft tumor growth was attained with daily KIN-2787 treatment and was well-tolerated. A trend towards greater tumor responses was observed with twice daily (BID) compared to once daily (QD) dosing of KIN-2787; however, the two dosing regimens led to similar tumor growth inhibition (TGI) and regressions (mean TGI up to 101-118%; p ≤0.0001) at equivalent total daily doses. Furthermore, KIN-2787 led to a significant in vivo pharmacodynamic response using either regimen, however, prolonged target coverage, as measured by pERK, was achieved with BID dosing. The impact of KIN-2787 treatment on additional biomarkers, including transcriptional changes and MAPK pathway modulation in cell-based models and patient-derived samples, will be presented at the meeting. Conclusions: KIN-2787 is a next-generation pan-RAF inhibitor with pronounced in vitro and in vivo activity against human cancers driven by Class II and III BRAF mutations. A phase 1 dose escalation and expansion clinical trial evaluating the safety and efficacy of KIN-2787 monotherapy in patients with advanced or metastatic solid tumors harboring BRAF gene alterations, including Class II and III mutations, is expected to initiate in 2021.

scholarly journals Non-Invasive Biomarkers for Earlier Detection of Pancreatic Cancer—A Comprehensive Review

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2722
Author(s):  
Greta Brezgyte ◽  
Vinay Shah ◽  
Daria Jach ◽  
Tatjana Crnogorac-Jurcevic
Keyword(s):  
Clinical Setting ◽  
Selection Index ◽  
Reporting Quality ◽  
Standard Of Care ◽  
Therapeutic Interventions ◽  
Ductal Adenocarcinoma ◽  
Index Test ◽  
Delayed Presentation ◽  
Non Invasive ◽  
Study Selection

Pancreatic ductal adenocarcinoma (PDAC) carries a deadly diagnosis, due in large part to delayed presentation when the disease is already at an advanced stage. CA19-9 is currently the most commonly utilized biomarker for PDAC; however, it lacks the necessary accuracy to detect precursor lesions or stage I PDAC. Novel biomarkers that could detect this malignancy with improved sensitivity (SN) and specificity (SP) would likely result in more curative resections and more effective therapeutic interventions, changing thus the present dismal survival figures. The aim of this study was to systematically and comprehensively review the scientific literature on non-invasive biomarkers in biofluids such as blood, urine and saliva that were attempting earlier PDAC detection. The search performed covered a period of 10 years (January 2010—August 2020). Data were extracted using keywords search in the three databases: MEDLINE, Web of Science and Embase. The Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool was applied for study selection based on establishing the risk of bias and applicability concerns in Patient Selection, Index test (biomarker assay) and Reference Standard (standard-of-care diagnostic test). Out of initially over 4000 published reports, 49 relevant studies were selected and reviewed in more detail. In addition, we discuss the present challenges and complexities in the path of translating the discovered biomarkers into the clinical setting. Our systematic review highlighted several promising biomarkers that could, either alone or in combination with CA19-9, potentially improve earlier detection of PDAC. Overall, reviewed biomarker studies should aim to improve methodological and reporting quality, and novel candidate biomarkers should be investigated further in order to demonstrate their clinical usefulness. However, challenges and complexities in the path of translating the discovered biomarkers from the research laboratory to the clinical setting remain and would have to be addressed before a more realistic breakthrough in earlier detection of PDAC is achieved.

scholarly journals Optical Detection and Eradication of Dysplastic Barrett's Esophagus

2003 ◽  
Vol 2 (4) ◽  
pp. 289-302 ◽  
Author(s):  
Louis-Michel Wong Kee Song ◽  
Kenneth K. Wang
Keyword(s):  
Barrett’S Esophagus ◽  
Barrett's Esophagus ◽  
Sampling Error ◽  
Imaging Techniques ◽  
Standard Of Care ◽  
Diagnostic Techniques ◽  
Endoscopic Surveillance ◽  
Current Status ◽  
Delay In Diagnosis ◽  
Multiple Biopsies

Dysplastic Barrett's esophagus is a condition that offers multiple diagnostic and therapeutic challenges. The diagnosis of dysplasia within Barrett's esophagus currently relies on periodic endoscopic surveillance with multiple biopsies, a methodology limited by random sampling error, inconsistent histopathologic interpretation and delay in diagnosis. Optical spectroscopic and imaging techniques have the potential to identify dysplastic or early neoplastic lesions in real-time. These diagnostic modalities are needed to enhance the endoscopic surveillance of Barrett's esophagus in the future as well as help to define lesions for endoscopic therapy. Esophagectomy has been the standard of care for Barrett's esophagus with high-grade dysplasia although it is a procedure associated with significant morbidity and mortality. Minimally invasive endoscopic ablative therapies are attractive and less morbid alternatives to esophagectomy, with promising results obtained from the use of light-activated drugs (i.e., photodynamic therapy). The combination of novel optical diagnostic techniques and therapies will provide the endoscopist with much needed tools that can considerably enhance the management of patients with Barrett's esophagus. This article reviews the current status and future prospects of optical-based modalities for diagnosis and therapy of dysplastic Barrett's esophagus.

scholarly journals Cutaneous Side Effects of BRAF Inhibitors in Advanced Melanoma: Review of the Literature

2016 ◽  
Vol 2016 ◽  
pp. 1-6 ◽  
Author(s):  
Bilgen Gençler ◽  
Müzeyyen Gönül
Keyword(s):  
Side Effects ◽  
Metastatic Melanoma ◽  
Mapk Pathway ◽  
Case Reports ◽  
Mitogen Activated Protein Kinase ◽  
Braf V600e ◽  
Braf Inhibitors ◽  
Braf Mutations ◽  
Cutaneous Side Effects ◽  
Downstream Signaling

The incidence of melanoma has recently been increasing. BRAF mutations have been found in 40–60% of melanomas. The increased activity of BRAF V600E leads to the activation of downstream signaling through the mitogen-activated protein kinase (MAPK) pathway, which plays a key role as a regulator of cell growth, differentiation, and survival. The use of BRAF inhibitors in metastatic melanoma with BRAF mutation ensures clinical improvement of the disease. Vemurafenib and dabrafenib are two selective BRAF inhibitors approved by the Food and Drug Administration (FDA). Both drugs are well tolerated and successfully used in clinical practice. However, some adverse reactions have been reported in patients in the course of treatment. Cutaneous side effects are the most common adverse events among them with a broad spectrum. Both the case reports and several original clinical trials reported cutaneous reactions during the treatment with BRAF inhibitors. In this review, the common cutaneous side effects of BRAF inhibitors in the treatment of metastatic melanoma with BRAF V600E mutation were reviewed.

Evaluation of patients with surgically resected high-risk melanoma receiving adjuvant therapy in routine clinical practice in the United States.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9577-9577
Author(s):  
Michael B. Atkins ◽  
Cristina Julian ◽  
Matthew H. Secrest ◽  
Janet Lee ◽  
Ana Maria Abajo Guijarro ◽  
...  
Keyword(s):  
Adjuvant Therapy ◽  
Checkpoint Inhibitors ◽  
The United States ◽  
Distant Recurrence ◽  
Advanced Melanoma ◽  
Stage Iii ◽  
Braf Mutations ◽  
Stage Iii Melanoma ◽  
Resected Stage ◽  
Braf Mutant

9577 Background: The management of patients with resected stage III melanoma has changed in recent years, and real-world data on recurrence patterns and adjuvant therapy responses are scarce. This study assessed adjuvant treatment patterns and outcomes in patients with advanced melanoma by BRAF status and relapse location. Methods: Patients diagnosed with stage III advanced melanoma between January 2011 and February 2020 in the nationwide Flatiron Health electronic health record–derived deidentified database were included if they were ≥18 years, received approved first-line (1L) adjuvant therapy after January 2018 with checkpoint inhibitors (CPIs; eg, nivolumab, pembrolizumab) or targeted therapies (TTs; eg, dabrafenib/trametinib), had 6 months’ follow-up and had ≥1 visit after starting adjuvant therapy (Cohort 1). Patients from Cohort 1 were included in Cohort 2 if they had a recurrence following initiation of adjuvant therapy, and those from Cohort 2 were included in Cohort 3 if they had a distant recurrence and available documented BRAF status at any time. Time to next systemic treatment (TTNT), overall survival (OS) and relapse free survival (RFS) were estimated using Kaplan-Meier (KM) methods from adjuvant therapy start (Cohort 1), first recurrence date (Cohort 2) or first distant recurrence date (Cohort 3). Results: Cohort 1 included 447 patients receiving 1L adjuvant therapy; Cohort 2 included patients after first distant (n = 47) or local (n = 35) relapse; Cohort 3 included distant-recurrent patients with tumors that were BRAF wild type (WT) (n = 22) or BRAF mutant (n = 23). The majority of patients were aged < 65 years. Across cohorts, relative use of TTs vs CPIs was similar: Cohort 1 (4.5% vs 96%), Cohort 2 (2.4% vs 98%) and Cohort 3 (2.2% vs 98%). Nivolumab was the most frequent treatment used across cohorts (84%-88%). In Cohort 1, 1- and 2-year KM probabilities for OS, RFS and TTNT were 93.5%/83.8%, 83.2%/70.6% and 84.0%/62.4%, respectively. In Cohort 2, for patients with local recurrence, 6- and 12-month OS probabilities were 93.4% and 78.8%, respectively, which were substantially higher than those for patients with distant recurrence (64.5% and 46.9%). In Cohort 3, for patients with documented BRAF mutations, 6- and 12-month OS rates from disease recurrence were 79.1% and 49.4%, respectively, which were greater than for those with BRAF-WT tumors (54.1% and 46.3%). Conclusions: Early RFS and OS outcomes for patients with surgically resected Stage III melanoma appear comparable to those reported in randomized clinical studies. The majority of patients with advanced melanoma, including patients who experienced recurrence, initiated treatment with CPIs. OS rates were numerically greater for Cohort 3 patients with BRAF-mutant tumors. Outcomes for patients with distant recurrence after adjuvant therapy remain unfavorable and represent a continued unmet medical need.

Molecular Testing of Solid Tumors

2011 ◽  
Vol 135 (1) ◽  
pp. 67-82 ◽  
Author(s):  
Anne Igbokwe ◽  
Dolores H. Lopez-Terrada
Keyword(s):  
Solid Tumors ◽  
Solid Tumor ◽  
Unknown Origin ◽  
Standard Of Care ◽  
Soft Tissue Tumors ◽  
Molecular Diagnostic ◽  
Original Research ◽  
Molecular Testing ◽  
Neoplastic Disease ◽  
Therapeutic Decisions

Abstract Context—Molecular testing of solid tumors is steadily becoming a vital component of the contemporary anatomic pathologist's armamentarium. These sensitive and specific ancillary tools are useful for confirming ambiguous diagnoses suspected by light microscopy and for guiding therapeutic decisions, assessing prognosis, and monitoring patients for residual neoplastic disease after therapy. Objective—To review current molecular biomarkers and tumor-specific assays most useful in solid tumor testing, specifically of breast, colon, lung, thyroid, and soft tissue tumors, malignant melanoma, and tumors of unknown origin. A few upcoming molecular diagnostic assays that may become standard of care in the near future will also be discussed. Data Sources—Original research articles, review articles, and the authors' personal practice experience. Conclusions—Molecular testing in anatomic pathology is firmly established and will continue to gain ground as the need for more specific diagnoses and new targeted therapies evolve. Knowledge of the more common and clinically relevant molecular tests available for solid tumor diagnosis and management, and their indications and limitations, is necessary if anatomic pathologists are to optimally use these tests and act as consultants for fellow clinicians directly involved in patient care.

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