====== Trametinib ======

Trametinib is a [[MEK]] inhibitor approved for treatment of [[melanoma]]. Therapeutic responses with Talimogene laherparepvec (T-VEC) are often limited, and BRAF/MEK inhibition is complicated by drug resistance. 

Bommareddy et al., from [[Rutgers New Jersey Medical School]], Rush University Medical Center, [[Rush University Medical Center]], [[Massachusetts General Hospital]], observed that the combination of T-VEC and trametinib resulted in enhanced melanoma [[cell death]] [[in vitro]]. Further, combination treatment resulted in delayed tumor growth and improved survival in mouse models. Tumor regression was dependent on activated CD8+ T cells and Batf3+ dendritic cells. They also observed antigen spreading and induction of an inflammatory [[gene signature]], including increased expression of PD-L1. Triple therapy with the combination of T-VEC, MEK  inhibition, and anti-PD-1 antibody further augmented responses. These data support clinical development of combination oncolytic viruses, MEK inhibitors, and checkpoint blockade in patients with melanoma
((Bommareddy PK, Aspromonte S, Zloza A, Rabkin SD, Kaufman HL. MEK inhibition
enhances oncolytic virus immunotherapy through increased tumor cell killing and T
cell activation. Sci Transl Med. 2018 Dec 12;10(471). pii: eaau0417. doi:
10.1126/scitranslmed.aau0417. PubMed PMID: 30541787.
)).
===== Case reports =====
A clinical phase I study reported significant shrinkage of plexiform neurofibromas following treatment with the MEK inhibitor [[selumetinib]]. 

Vaassen et al., reported an 11-year-old NF1 patient with a large plexiform neurofibroma of the neck that had led to a sharp-angled kinking of the cervical spine and subsequent myelopathy. Although surgical stabilization of the cervical vertebral column was urgently recommended, the vertebral column was inaccessible due to extensive tumor growth. In this situation, treatment with the MEK inhibitor [[trametinib]] was initiated which resulted in a 22% reduction in tumor volume after 6 months of therapy and finally enabled surgery. These data show that MEK inhibitors may not lead to complete disappearance of NF1-associated plexiform neurofibromas but can be an essential step in a multimodal therapeutic approach for these tumors. The course of our patient suggests that MEK inhibitors are likely to play a significant role in providing a cure for one of the most devastating manifestations of NF1
((Vaassen P, Dürr N, Röhrig A, Willing R, Rosenbaum T. Trametinib Induces
Neurofibroma Shrinkage and Enables Surgery. Neuropediatrics. 2019 May 29. doi:
10.1055/s-0039-1691830. [Epub ahead of print] PubMed PMID: 31141829.
)).

----

Hussain et al., present the case of an [[Anaplastic Pleomorphic Xanthoastrocytoma]] initially treated with the BRAF inhibitor [[vemurafenib]]. After progression trametinib was added to the regimen leading to radiographic improvement
((Hussain F, Horbinski CM, Chmura SJ, Yamini B, Lukas RV. Response to BRAF/MEK
Inhibition After Progression With BRAF Inhibition in a Patient With Anaplastic
Pleomorphic Xanthoastrocytoma. Neurologist. 2018 Sep;23(5):163-166. doi:
10.1097/NRL.0000000000000194. PubMed PMID: 30169370.
)).
----
Kondyli et al., described six children with sporadic pediatric low-grade glioma who were treated with trametinib, following progression under conventional therapies. 

The median age at diagnosis was 2.3 years (y) old [range 11 months (m)-8.5 y old]. KIAA1549-BRAF fusion was identified in five cases, and hotspot FGFR1/NF1/PTPN11 mutations in one. All patients received at least one previous line of chemotherapy (range 1-4). The median time on treatment was 11 m (range 4-20). Overall, we observed two partial responses and three minor responses as best response; three of these patients are still on therapy. Treatment was discontinued in the patient with progressive disease. The most frequent
toxicities were minor to moderately severe skin rash and gastro-intestinal symptoms. Two patients had dose reduction due to skin toxicity. Quality of life was excellent with decreased hospital visits and a close to normal life.

Trametinib appears to be a suitable option for refractory  pediatric low-grade glioma and warrants further investigations in case of progression
((Kondyli M, Larouche V, Saint-Martin C, Ellezam B, Pouliot L, Sinnett D,
Legault G, Crevier L, Weil A, Farmer JP, Jabado N, Perreault S. Trametinib for
progressive pediatric low-grade gliomas. J Neurooncol. 2018 Nov;140(2):435-444.
doi: 10.1007/s11060-018-2971-9. Epub 2018 Aug 10. PubMed PMID: 30097824.
)).
----
A 5-month-old boy who presented with giant congenital melanocytic nevus and hydrocephalus. MR imaging and CSF immunohistochemistry confirmed leptomeningeal melanosis. 

The patient required placement of a right-sided ventriculoperitoneal shunt to control hydrocephalus. The patient tolerated the procedure well and was discharged home with normal neurological function. A presumptive diagnosis of NCM was made based on the MR characteristics, CSF cytology and clinical presentation.
He received trametinib, a MAPK/Erk kinase inhibitor for 7 months. At 30 months of age, he developed left-sided weakness and status epilepticus requiring paediatric intensive care unit admission and ventilator support. The patient eventually succumbed to malignant transformation of leptomeningeal disease.

Cutaneous manifestations of NCM are usually congenital, and neurological manifestations develop early in life. Patients with large or multiple congenital nevi should therefore be investigated early to facilitate
treatment. MR imaging is the investigation of choice which can further assist in performing biopsy. Symptomatic NCM is refractory to radiotherapy and chemotherapy and has a poor prognosis. A multidisciplinary approach is necessary in the management of NCM patients
((Sharouf F, Zaben M, Lammie A, Leach P, Bhatti MI. Neurocutaneous melanosis
presenting with hydrocephalus and malignant transformation: case-based update.
Childs Nerv Syst. 2018 Aug;34(8):1471-1477. doi: 10.1007/s00381-018-3851-5. Epub 
2018 Jun 12. PubMed PMID: 29948137; PubMed Central PMCID: PMC6060827.
)).
----


5. Clin Cancer Res. 2018 Dec 15;24(24):6483-6494. doi:
10.1158/1078-0432.CCR-17-3384. Epub 2018 Jun 14.

Dual MAPK Inhibition Is an Effective Therapeutic Strategy for a Subset of Class
II BRAF Mutant Melanomas.

Dankner M(1)(2), Lajoie M(1)(3), Moldoveanu D(1)(4), Nguyen TT(1)(3), Savage
P(1)(2), Rajkumar S(1)(3), Huang X(5), Lvova M(5), Protopopov A(5), Vuzman
D(5)(6)(7), Hogg D(8), Park M(1)(2)(3), Guiot MC(9)(10), Petrecca K(9),
Mihalcioiu C(11), Watson IR(1)(3), Siegel PM(1)(2)(3), Rose AAN(12).

Author information: 
(1)Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada.
(2)Department of Medicine, McGill University, Montréal, Québec, Canada.
(3)Department of Biochemistry, McGill University, Montréal, Québec, Canada.
(4)Department of General Surgery, McGill University, Montréal, Québec, Canada.
(5)KEW Inc., Cambridge, Massachusetts.
(6)Division of Genetics, Department of Medicine, Brigham and Women's Hospital and
Harvard Medical School, Boston, Massachusetts.
(7)Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
(8)Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
(9)Department of Neurology and Neurosurgery, McGill University, Montréal, Québec,
Canada.
(10)Department of Pathology, McGill University, Montréal, Québec, Canada.
(11)McGill University Health Centre, McGill University, Montréal, Québec, Canada.
(12)Division of Medical Oncology, Department of Medicine, University of Toronto, 
Toronto, Ontario, Canada. april.rose@uhn.ca.

PURPOSE: Dual MAPK pathway inhibition (dMAPKi) with BRAF and MEK inhibitors
improves survival in BRAF V600E/K mutant melanoma, but the efficacy of dMAPKi in 
non-V600 BRAF mutant tumors is poorly understood. We sought to characterize the
responsiveness of class II (enhanced kinase activity, dimerization dependent)
BRAF mutant melanoma to dMAPKi.
EXPERIMENTAL DESIGN: Tumors from patients with BRAF wild-type (WT), V600E (class 
I), and L597S (class II) metastatic melanoma were used to generate
patient-derived xenografts (PDX). We assembled a panel of melanoma cell lines
with class IIa (activation segment) or IIb (p-loop) mutations and compared these 
with WT or V600E/K BRAF mutant cells. Cell lines and PDXs were treated with BRAFi
(vemurafenib, dabrafenib, encorafenib, and LY3009120), MEKi (cobimetinib,
trametinib, and binimetinib), or the combination. We identified 2 patients with
BRAF L597S metastatic melanoma who were treated with dMAPKi.
RESULTS: BRAFi impaired MAPK signaling and cell growth in class I and II BRAF
mutant cells. dMAPKi was more effective than either single MAPKi at inhibiting
cell growth in all class II BRAF mutant cells tested. dMAPKi caused tumor
regression in two melanoma PDXs with class II BRAF mutations and prolonged
survival of mice with class II BRAF mutant melanoma brain metastases. Two
patients with BRAF L597S mutant melanoma clinically responded to dMAPKi.
CONCLUSIONS: Class II BRAF mutant melanoma is growth inhibited by dMAPKi.
Responses to dMAPKi have been observed in 2 patients with class II BRAF mutant
melanoma. These data provide rationale for clinical investigation of dMAPKi in
patients with class II BRAF mutant metastatic melanoma.See related commentary by 
Johnson and Dahlman, p. 6107.

©2018 American Association for Cancer Research.

DOI: 10.1158/1078-0432.CCR-17-3384 
PMID: 29903896 


6. J Pediatr Hematol Oncol. 2018 Oct;40(7):553-554. doi:
10.1097/MPH.0000000000001170.

Encephalocraniocutaneous Lipomatosis.

Bavle A(1), Shah R(2), Gross N(3), Gavula T(1), Ruiz-Elizalde A(4), Wierenga
K(5), McNall-Knapp R(1).

Author information: 
(1)Jimmy Everest Section of Pediatric Hematology/Oncology.
(2)Section of Hematology/Oncology, Department of Pediatrics, Baylor College of
Medicine, Houston, TX.
(3)Departments of Neurosurgery.
(4)Surgery.
(5)Section of Genetics, Department of Pediatrics, University of Oklahoma Health
Sciences Center, Oklahoma City, OK.

A 5-year-old boy presented with worsening headaches for 3 months. On examination,
he was found to have a hairless fatty tissue nevus of the scalp (nevus
psiloliparus), subcutaneous soft tissue masses on the right side of his face,
neck, mandible and right buttock and epibulbar dermoid of the right eye
(choristoma) (). Magnetic resonance imaging revealed a large suprasellar mass,
which was debulked and found to be a pilocytic astrocytoma. Testing was not
performed for the BRAF/KIAA1549 fusion or BRAFV600E mutation. Seven years later, 
he was started on adjuvant chemotherapy for gradual tumor progression. Over the
ensuing 3 years, he had further disease progression despite treatment with 3
frontline chemotherapy regimens: vinblastine, carboplatin/vincristine, and
irinotecan/bevacizumab. Targeted sequencing of tissue from the right gluteal
mass, revealed a mosaic activating FGFR1 c.1966A>G (p.Lys656Glu) mutation, absent
in normal left gluteal tissue, confirming the diagnosis of
encephalocraniocutaneous lipomatosis (ECCL), belonging to the family of
RASopathies (including neurofibromatosis type I, Noonan syndrome, Costello
syndrome), with constitutive activation of the mitogen-activated protein kinase
(MAPK) pathway, and an increased risk of developing neoplasms. He was started on 
trametinib, a MEK inhibitor, off-label, targeting the MAPK pathway downstream
from FGFR1, with stable tumor size at last follow-up, after 6 months on therapy.

DOI: 10.1097/MPH.0000000000001170 
PMID: 29683947 


7. Acta Neuropathol. 2018 May;135(5):757-777. doi: 10.1007/s00401-018-1830-2. Epub
2018 Mar 14.

Tumour compartment transcriptomics demonstrates the activation of inflammatory
and odontogenic programmes in human adamantinomatous craniopharyngioma and
identifies the MAPK/ERK pathway as a novel therapeutic target.

Apps JR(1)(2), Carreno G(3), Gonzalez-Meljem JM(3)(4), Haston S(3), Guiho R(3),
Cooper JE(3), Manshaei S(3), Jani N(5), Hölsken A(6), Pettorini B(7), Beynon
RJ(8), Simpson DM(8), Fraser HC(3), Hong Y(9), Hallang S(10), Stone TJ(3)(11),
Virasami A(11), Donson AM(12), Jones D(13), Aquilina K(14), Spoudeas H(15), Joshi
AR(16), Grundy R(17), Storer LCD(17), Korbonits M(18), Hilton DA(19), Tossell
K(20), Thavaraj S(21), Ungless MA(20), Gil J(20), Buslei R(6)(22), Hankinson
T(12), Hargrave D(23), Goding C(24), Andoniadou CL(25)(26), Brogan P(9)(27),
Jacques TS(3)(11), Williams HJ(5), Martinez-Barbera JP(28).

Author information: 
(1)Developmental Biology and Cancer Programme, Birth Defects Research Centre, UCL
Great Ormond Street Institute of Child Health, University College London, London,
UK. j.apps@ucl.ac.uk.
(2)Histopathology Department, Great Ormond Street Hospital NHS Trust, London, UK.
j.apps@ucl.ac.uk.
(3)Developmental Biology and Cancer Programme, Birth Defects Research Centre, UCL
Great Ormond Street Institute of Child Health, University College London, London,
UK.
(4)Basic Research Department, National Institute of Geriatrics, Mexico City,
Mexico.
(5)Centre for Translational Omics-GOSgene, Genetics and Genomic Medicine
Programme, UCL Institute of Child Health, University College London, London, UK.
(6)Department of Neuropathology, Friedrich-Alexander University Erlangen-Nürnberg
(FAU), Erlangen, Germany.
(7)Alder Hey Children's Hospital NHS Foundation Trust, Liverpool, UK.
(8)Centre for Proteome Research, Institute of Integrative Biology, University of 
Liverpool, Liverpool, UK.
(9)Infection, Immunity and Inflammation Programme, UCL Great Ormond Street
Institute of Child Health, University College London, London, UK.
(10)Centre for Craniofacial and Regenerative Biology, King's College London,
London, UK.
(11)Histopathology Department, Great Ormond Street Hospital NHS Trust, London,
UK.
(12)Department of Pediatrics, University of Colorado Anschutz Medical Campus,
Aurora, CO, USA.
(13)German Cancer Research Center (DKFZ), Heidelberg, Germany.
(14)Neurosurgery Department, Great Ormond Street Hospital NHS Trust, London, UK.
(15)Endocrinology Department, Great Ormond Street Hospital NHS Trust, London, UK.
(16)Laboratory Medicine, Royal Victoria Infirmary, Newcastle, UK.
(17)Children's Brain Tumour Research Centre, University of Nottingham,
Nottingham, UK.
(18)William Harvey Research Institute, Barts and the London School of Medicine
and Dentistry, Queen Mary University, London, UK.
(19)Pathology Department, Plymouth Hospitals NHS Trust, Plymouth, UK.
(20)MRC London Institute of Medical Sciences, Imperial College London, London,
UK.
(21)Head and Neck Pathology, Dental Institute, King's College London, London, UK.
(22)Institute of Pathology, Klinikum Sozialstiftung Bamberg, Bamberg, Germany.
(23)Haematology and Oncology Department, Great Ormond Street Hospital NHS Trust, 
London, UK.
(24)Ludwig Institute for Cancer Research, Oxford University, Old Road Campus,
Headington, Oxford, UK.
(25)Centre for Craniofacial and Regenerative Biology, King's College London,
Guy's Hospital, Floor 27 Tower Wing, London, UK.
(26)Department of Internal Medicine III, Technische Universität Dresden,
Fetscherstaße 74, 01307, Dresden, Germany.
(27)Rheumatology Department, Great Ormond Street Hospital NHS Trust, London, UK.
(28)Developmental Biology and Cancer Programme, Birth Defects Research Centre,
UCL Great Ormond Street Institute of Child Health, University College London,
London, UK. j.martinez-barbera@ucl.ac.uk.

Adamantinomatous craniopharyngiomas (ACPs) are clinically challenging tumours,
the majority of which have activating mutations in CTNNB1. They are
histologically complex, showing cystic and solid components, the latter comprised
of different morphological cell types (e.g. β-catenin-accumulating cluster cells 
and palisading epithelium), surrounded by a florid glial reaction with immune
cells. Here, we have carried out RNA sequencing on 18 ACP samples and integrated 
these data with an existing ACP transcriptomic dataset. No studies so far have
examined the patterns of gene expression within the different cellular
compartments of the tumour. To achieve this goal, we have combined laser capture 
microdissection with computational analyses to reveal groups of genes that are
associated with either epithelial tumour cells (clusters and palisading
epithelium), glial tissue or immune infiltrate. We use these human ACP molecular 
signatures and RNA-Seq data from two ACP mouse models to reveal that cell
clusters are molecularly analogous to the enamel knot, a critical signalling
centre controlling normal tooth morphogenesis. Supporting this finding, we show
that human cluster cells express high levels of several members of the FGF, TGFB 
and BMP families of secreted factors, which signal to neighbouring cells as
evidenced by immunostaining against the phosphorylated proteins pERK1/2, pSMAD3
and pSMAD1/5/9 in both human and mouse ACP. We reveal that inhibiting the
MAPK/ERK pathway with trametinib, a clinically approved MEK inhibitor, results in
reduced proliferation and increased apoptosis in explant cultures of human and
mouse ACP. Finally, we analyse a prominent molecular signature in the glial
reactive tissue to characterise the inflammatory microenvironment and uncover the
activation of inflammasomes in human ACP. We validate these results by
immunostaining against immune cell markers, cytokine ELISA and proteome analysis 
in both solid tumour and cystic fluid from ACP patients. Our data support a new
molecular paradigm for understanding ACP tumorigenesis as an aberrant mimic of
natural tooth development and opens new therapeutic opportunities by revealing
the activation of the MAPK/ERK and inflammasome pathways in human ACP.

DOI: 10.1007/s00401-018-1830-2 
PMCID: PMC5904225
PMID: 29541918 


8. Pediatr Blood Cancer. 2018 May;65(5):e26969. doi: 10.1002/pbc.26969. Epub 2018
Jan 30.

Response to the BRAF/MEK inhibitors dabrafenib/trametinib in an adolescent with a
BRAF V600E mutated anaplastic ganglioglioma intolerant to vemurafenib.

Marks AM(1), Bindra RS(2), DiLuna ML(3), Huttner A(4), Jairam V(2), Kahle KT(5), 
Kieran MW(6).

Author information: 
(1)Department of Pediatric Hematology/Oncology, Yale University School of
Medicine, New Haven, Connecticut.
(2)Department of Radiation Oncology, Yale University School of Medicine, New
Haven, Connecticut.
(3)Department of Neurosurgery, Yale University School of Medicine, New Haven,
Connecticut.
(4)Department of Pathology, Yale University School of Medicine, New Haven,
Connecticut.
(5)Department of Neurosurgery, Yale University School of Medicine.
(6)Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston,
Massachusetts.

Efficacy of BRAF V600E targeted therapies in brain tumors harboring the mutation 
has been shown in several case reports and is currently being studied in larger
clinical trials. Monotherapy with vemurafenib has been associated with
significant side effects, including rashes, papillomas, and squamous cell
carcinomas. Here we describe an adolescent female with anaplastic ganglioglioma
and significant skin reaction to vemurafenib with subsequent tumor response and
tolerance to the BRAF/MEK inhibitor combination of dabrafenib and trametinib
without recurrence of previous reaction.

© 2018 Wiley Periodicals, Inc.

DOI: 10.1002/pbc.26969 
PMID: 29380516 


9. Pediatr Blood Cancer. 2018 May;65(5):e26917. doi: 10.1002/pbc.26917. Epub 2018
Jan 25.

Targeted therapy for infants with diencephalic syndrome: A case report and review
of management strategies.

Wagner LM(1), Myseros JS(2), Lukins DE(3), Willen CM(4), Packer RJ(5)(6).

Author information: 
(1)Division of Pediatric Hematology/Oncology, Kentucky Children's Hospital,
University of Kentucky, Lexington, Kentucky.
(2)Division of Neurosurgery, Children's National Health System, George Washington
University, Washington, District of Columbia.
(3)Department of Radiology, Kentucky Children's Hospital, University of Kentucky,
Lexington, Kentucky.
(4)Department of Ophthalmology, Kentucky Children's Hospital, University of
Kentucky, Lexington, Kentucky.
(5)Department of Neurology, Children's National Health System, George Washington 
University, Washington, District of Columbia.
(6)Center for Neuroscience and Behavioral Medicine, Children's National Health
System, George Washington University, Washington, District of Columbia.

Young children with emaciation caused by a hypothalamic glioma are considered to 
have diencephalic syndrome (DS), which is often poorly controlled with
conventional treatment. We describe an infant with DS whose tumor progressed
following chemotherapy. Biopsy was performed for molecular testing and
demonstrated a BRAF fusion. Treatment with the MEK inhibitor trametinib for
18 months resulted in reduction of tumor size, normalization of his weight curve,
and marked neurodevelopmental improvement. Our results build on earlier reports
of using targeted agents for low-grade glioma, and we review the evolving
management strategy for such patients in the era of precision medicine.

© 2018 Wiley Periodicals, Inc.

DOI: 10.1002/pbc.26917 
PMID: 29369501 


10. J Pediatr Hematol Oncol. 2018 Aug;40(6):478-482. doi:
10.1097/MPH.0000000000001032.

Sustained Response to Targeted Therapy in a Patient With Disseminated Anaplastic 
Pleomorphic Xanthoastrocytoma.

Amayiri N(1), Swaidan M(2), Al-Hussaini M(3), Halalsheh H(1), Al-Nassan A(1),
Musharbash A(4), Tabori U(5), Hawkins C(6), Bouffet E(5).

Author information: 
(1)Division of Pediatric Hematology/Oncology.
(2)Division of Radiology.
(3)Division of Pathology.
(4)Division of Neurosurgery, King Hussein Cancer Center, Amman, Jordan.
(5)Division of Hematology/Oncology.
(6)Division of Pathology, The Hospital for Sick Children, Toronto, ON, Canada.

Pleomorphic xanthoastrocytoma is a rare brain tumor with unique high frequency of
BRAF V600E mutation which is plausible for targeted therapy. The anaplastic
variant has generally worse prognosis. We present an adolescent patient with a
disseminated relapse of anaplastic pleomorphic xanthoastrocytoma following
surgery, radiotherapy, and chemotherapy. She had a dramatic and prolonged
response to a BRAF inhibitor (Dabrafinib) and later to addition of a MEK
inhibitor (Trametinib) on tumor progression. With minimal side effects and a good
quality of life, the patient is alive more than 2 years after initiation of
targeted therapy. This experience confirms the potential role of targeted
treatments in high-grade BRAF-mutated brain tumors.

DOI: 10.1097/MPH.0000000000001032 
PMID: 29200156 


11. Oncotarget. 2017 Sep 15;8(49):84697-84713. doi: 10.18632/oncotarget.20949.
eCollection 2017 Oct 17.

Overcoming resistance to single-agent therapy for oncogenic BRAF gene fusions via
combinatorial targeting of MAPK and PI3K/mTOR signaling pathways.

Jain P(1)(2)(3), Silva A(1), Han HJ(2), Lang SS(1)(2), Zhu Y(1)(3), Boucher
K(1)(2)(3), Smith TE(1)(2)(3), Vakil A(4), Diviney P(5), Choudhari N(1)(2)(3),
Raman P(3)(6)(7), Busch CM(8), Delaney T(1)(2)(3), Yang X(9), Olow AK(10),
Mueller S(9)(11)(12), Haas-Kogan D(13), Fox E(8), Storm PB(1)(2)(3), Resnick
AC(1)(2)(3)(6), Waanders AJ(3)(8)(14).

Author information: 
(1)Division of Neurosurgery, The Children's Hospital of Philadelphia,
Philadelphia, PA, USA.
(2)Department of Neurosurgery, University of Pennsylvania Perelman School of
Medicine, Philadelphia, PA, USA.
(3)Center for Data Driven Discovery in Biomedicine (D3b), The Children's Hospital
of Philadelphia, Philadelphia, PA, USA.
(4)The Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
(5)Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, 
PA, USA.
(6)Department of Biomedical and Health Informatics, The Children's Hospital of
Philadelphia, Philadelphia, PA, USA.
(7)Center for Childhood Cancer Research, Children's Hospital of Philadelphia,
Philadelphia, PA, USA.
(8)Division of Oncology, Department of Pediatrics, The Children's Hospital of
Philadelphia, Philadelphia, PA, USA.
(9)Division of Neurology, University of California, San Francisco, CA, USA.
(10)Amgen, South San Francisco, CA, USA.
(11)Department of Neurosurgery, University of California, San Francisco, CA, USA.
(12)Department of Pediatrics, University of California, San Francisco, CA, USA.
(13)Department of Radiation Oncology, Harvard Medical School, Boston, MA, USA.
(14)Department of Pediatrics, Perelman School of Medicine at the University of
Pennsylvania, Philadelphia, PA, USA.

Pediatric low-grade gliomas (PLGGs) are frequently associated with activating
BRAF gene fusions, such as KIAA1549-BRAF, that aberrantly drive the mitogen
activated protein kinase (MAPK) pathway. Although RAF inhibitors (RAFi) have been
proven effective in BRAF-V600E mutant tumors, we have previously shown how the
KIAA1549-BRAF fusion can be paradoxically activated by RAFi. While newer classes 
of RAFi, such as PLX8394, have now been shown to inhibit MAPK activation by
KIAA1549-BRAF, we sought to identify alternative MAPK pathway targeting
strategies using clinically relevant MEK inhibitors (MEKi), along with potential 
escape mechanisms of acquired resistance to single-agent MAPK pathway therapies. 
We demonstrate effectiveness of multiple MEKi against diverse BRAF-fusions with
novel N-terminal partners, with trametinib being the most potent. However,
resistance to MEKi or PLX8394 develops via increased RTK expression causing
activation of PI3K/mTOR pathway in BRAF-fusion expressing resistant clones. To
circumvent acquired resistance, we show potency of combinatorial targeting with
trametinib and everolimus, an mTOR inhibitor (mTORi) against multiple
BRAF-fusions. While single-agent mTORi and MEKi PLGG clinical trials are
underway, our study provides preclinical rationales for using MEKi and mTORi
combinatorial therapy to stave off or prevent emergent drug-resistance in
BRAF-fusion driven PLGGs.

DOI: 10.18632/oncotarget.20949 
PMCID: PMC5689567
PMID: 29156677 

Conflict of interest statement: CONFLICTS OF INTEREST None of the authors declare
any conflict of interest.


12. CNS Oncol. 2017 Oct;6(4):291-296. doi: 10.2217/cns-2017-0006. Epub 2017 Oct 6.

Dabrafenib and trametinib in BRAFV600E mutated glioma.

Brown NF(1)(2), Carter T(1)(2), Kitchen N(3), Mulholland P(1)(2).

Author information: 
(1)Department of Oncology, University College London Hospitals, 250 Euston Road, 
London, NW1 2PG, UK.
(2)UCL Cancer Institute, University College London, 72 Huntley Street, London,
WC1E 6DD, UK.
(3)Department of Neurosurgery, National Hospital for Neurology & Neurosurgery,
Queen Square, London, WC1N 3BG, UK.

BRAFV600E mutations have been identified in a number of glioma subtypes, most
frequently in pleomorphic xanthoastrocytoma, ganglioglioma, pilocytic
astrocytoma, and epithelioid glioblastoma. Although the development of BRAF
inhibitors has dramatically improved the clinical outcome for patients with
BRAFV600E mutant tumors, resistance develops in a majority of patients due to
reactivation of the MAPK pathway. Addition of MEK inhibition to BRAF inhibition
improves survival. Here we report successful treatment of two patients with
BRAFV600E mutant pleomorphic xanthoastrocytoma using the BRAF inhibitor
dabrafenib in combination with the MEK inhibitor trametinib.

DOI: 10.2217/cns-2017-0006 
PMCID: PMC6004887
PMID: 28984141  [Indexed for MEDLINE]


13. Int J Cancer. 2018 Jan 15;142(2):381-391. doi: 10.1002/ijc.31052. Epub 2017 Oct
4.

The impact of P-glycoprotein and breast cancer resistance protein on the brain
pharmacokinetics and pharmacodynamics of a panel of MEK inhibitors.

de Gooijer MC(1)(2), Zhang P(1)(2)(3), Weijer R(1)(2), Buil LCM(1)(2), Beijnen
JH(1)(4)(5), van Tellingen O(1)(2).

Author information: 
(1)Division of Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121,
Amsterdam, 1066, CX, The Netherlands.
(2)Mouse Cancer Clinic, The Netherlands Cancer Institute, Plesmanlaan 121,
Amsterdam, 1066, CX, The Netherlands.
(3)Department of Neurosurgery, Qilu Hospital, Shandong University, Wenhua Xi Road
107, Jinan, 250012, People's Republic of China.
(4)Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/MC
Slotervaart Hospital, Louwesweg 6, Amsterdam, 1066, EC, The Netherlands.
(5)Division of Pharmacoepidemiology and Clinical Pharmacology, Department of
Pharmaceutical Sciences, Faculty of Science, Utrecht University, Universiteitsweg
99, Utrecht, 3584, CG, The Netherlands.

Mitogen/extracellular signal-regulated kinase (MEK) inhibitors have been tested
in clinical trials for treatment of intracranial neoplasms, including
glioblastoma (GBM), but efficacy of these drugs has not yet been demonstrated.
The blood-brain barrier (BBB) is a major impediment to adequate delivery of drugs
into the brain and may thereby also limit the successful implementation of MEK
inhibitors against intracranial malignancies. The BBB is equipped with a range of
ATP-dependent efflux transport proteins, of which P-gp (ABCB1) and BCRP (ABCG2)
are the two most dominant for drug efflux from the brain. We investigated their
impact on the pharmacokinetics and target engagement of a panel of clinically
applied MEK inhibitors, in order to select the most promising candidate for brain
cancers in the context of clinical pharmacokinetics and inhibitor
characteristics. To this end, we used in vitro drug transport assays and
conducted pharmacokinetic and pharmacodynamic studies in wildtype and
ABC-transporter knockout mice. PD0325901 displayed more promising characteristics
than trametinib (GSK1120212), binimetinib (MEK162), selumetinib (AZD6244), and
pimasertib (AS703026): PD0325901 was the weakest substrate of P-gp and BCRP in
vitro, its brain penetration was only marginally higher in Abcb1a/b;Abcg2-/-
mice, and efficient target inhibition in the brain could be achieved at
clinically relevant plasma levels. Notably, target inhibition could also be
demonstrated for selumetinib, but only at plasma levels far above levels in
patients receiving the maximum tolerated dose. In summary, our study recommends
further development of PD0325901 for the treatment of intracranial neoplasms.

© 2017 UICC.

DOI: 10.1002/ijc.31052 
PMID: 28921565  [Indexed for MEDLINE]


14. Acta Neurochir (Wien). 2017 Nov;159(11):2217-2221. doi:
10.1007/s00701-017-3311-0. Epub 2017 Sep 16.

Recurrent papillary craniopharyngioma with BRAFV600E mutation treated with
neoadjuvant-targeted therapy.

Rostami E(1), Witt Nyström P(2)(3), Libard S(4)(5), Wikström J(6), Casar-Borota
O(4)(5), Gudjonsson O(7).

Author information: 
(1)Section of Neurosurgery, Department of Neuroscience, Uppsala University,
SE-751 85, Uppsala, Sweden. Elham.rostami@neuro.uu.se.
(2)Department of Immunology, Genetics and Pathology, Clinical and experimental
Oncology, Uppsala University, Uppsala, Sweden.
(3)Skandionkliniken, Uppsala, Sweden.
(4)Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala,
Sweden.
(5)Department of Clinical Pathology, Uppsala University Hospital, Uppsala,
Sweden.
(6)Department of Radiology, Uppsala University, Uppsala, Sweden.
(7)Section of Neurosurgery, Department of Neuroscience, Uppsala University,
SE-751 85, Uppsala, Sweden.

Craniopharyngiomas are histologically benign but locally aggressive tumors in the
sellar region that may cause devastating neurological and endocrine deficits.
They tend to recur following surgery with high morbidity; hence, postoperative
radiotherapy is recommended following sub-total resection. BRAFV600E mutation is 
the principal oncogenic driver in the papillary variant of craniopharyngiomas.
Recently, a dramatic tumor reduction has been reported in a patient with
BRAFV600E mutated, multiply recurrent papillary craniopharyngioma using a
combination therapy of BRAF inhibitor dabrafenib and MEK inhibitor trametinib.
Here, we report on near-radical reduction of a growing residual BRAFV600E
craniopharyngioma using the same neoadjuvant therapy.

DOI: 10.1007/s00701-017-3311-0 
PMCID: PMC5636852
PMID: 28918496  [Indexed for MEDLINE]


15. Expert Rev Anticancer Ther. 2017 Apr;17(4):347-356. doi:
10.1080/14737140.2017.1296764. Epub 2017 Mar 1.

Radiosurgery/stereotactic radiotherapy in combination with immunotherapy and
targeted agents for melanoma brain metastases.

Trino E(1), Mantovani C(2), Badellino S(2), Ricardi U(1)(2), Filippi AR(1)(3).

Author information: 
(1)a Department of Oncology , University of Torino , Torino , Italy.
(2)b Radiation Oncology , Città della Salute e della Scienza University Hospital 
, Torino , Italy.
(3)c Radiation Oncology , San Luigi Gonzaga University Hospital , Orbassano ,
Italy.

INTRODUCTION: The clinical landscape of advanced melanoma drastically changed
after the introduction of both targeted therapies and immunotherapy. This rapid
development in systemic therapies led to a change in the management of patients
with brain metastases, with the subsequent need to re-assess the role of local
therapies, in particular stereotactic radiosurgery (SRS). Areas covered: In this 
non-systematic review, we report on the current knowledge on the use of SRS in
combination with immunotherapy and BRAF/MEK inhibitors for patients with melanoma
brain metastases, as well as ongoing trials in this field. Expert commentary: It 
is now more common to observe patients with melanoma brain metastases with better
performance status and prolonged life expectancy. A combination of targeted
therapy and immunotherapy, in different sequences, has been shown to be feasible 
and well tolerable, on the basis of retrospective reports. Additional data from
ongoing prospective trials are however needed to confirm or not these findings
and better explore the efficacy of the combination.

DOI: 10.1080/14737140.2017.1296764 
PMID: 28277101  [Indexed for MEDLINE]


16. Cancer Treat Rev. 2017 Feb;53:25-37. doi: 10.1016/j.ctrv.2016.11.013. Epub 2016
Dec 19.

Toxicity of concurrent stereotactic radiotherapy and targeted therapy or
immunotherapy: A systematic review.

Kroeze SG(1), Fritz C(2), Hoyer M(3), Lo SS(4), Ricardi U(5), Sahgal A(6), Stahel
R(7), Stupp R(7), Guckenberger M(2).

Author information: 
(1)Department of Radiation Oncology, University Hospital Zurich, Rämistrasse 100,
8091 Zurich, Switzerland. Electronic address: Stephanie.kroeze@usz.ch.
(2)Department of Radiation Oncology, University Hospital Zurich, Rämistrasse 100,
8091 Zurich, Switzerland.
(3)Danish Center for Particle Therapy, Aarhus University, Palle Juul-Jensens
Boulevard, 8200 Aarhus, Denmark.
(4)Department of Radiation Oncology, University of Washington School of Medicine,
1959 N.E. Pacific Street, Box 356043, Seattle, USA.
(5)Department of Oncology, University of Turin, Regione Gonzole 10, 10043
Orbassano, Italy.
(6)Department of Radiation Oncology, University of Toronto, 27 King's College
Circle Toronto, Ontario M5S 1A1, Canada.
(7)Department of Oncology, University Hospital Zurich, Rämistrasse 100, 8091
Zurich, Switzerland.

BACKGROUND AND PURPOSE: Both stereotactic radiotherapy (SRT) and immune- or
targeted therapy play an increasingly important role in personalized treatment of
metastatic disease. Concurrent application of both therapies is rapidly expanding
in daily clinical practice. In this systematic review we summarize severe
toxicity observed after concurrent treatment.
MATERIAL AND METHODS: PubMed and EMBASE databases were searched for English
literature published up to April 2016 using keywords "radiosurgery", "local
ablative therapy", "gamma knife" and "stereotactic", combined with "bevacizumab",
"cetuximab", "crizotinib", "erlotinib", "gefitinib", "ipilimumab", "lapatinib",
"sorafenib", "sunitinib", "trastuzumab", "vemurafenib", "PLX4032", "panitumumab",
"nivolumab", "pembrolizumab", "alectinib", "ceritinib", "dabrafenib",
"trametinib", "BRAF", "TKI", "MEK", "PD1", "EGFR", "CTLA-4" or "ALK". Studies
performing SRT during or within 30days of targeted/immunotherapy, reporting
severe (⩾Grade 3) toxicity were included.
RESULTS: Concurrent treatment is mostly well tolerated in cranial SRT, but high
rates of severe toxicity were observed for the combination with BRAF-inhibitors. 
The relatively scarce literature on extra-cranial SRT shows a potential risk of
increased toxicity when SRT is combined with EGFR-targeting tyrosine kinase
inhibitors and bevacizumab, which was not observed for cranial SRT.
CONCLUSIONS: This review gives a best-possible overview of current knowledge and 
its limitations and underlines the need for a timely generation of stronger
evidence in this rapidly expanding field.

Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.

DOI: 10.1016/j.ctrv.2016.11.013 
PMID: 28056412  [Indexed for MEDLINE]


17. J Neurosurg Pediatr. 2017 Mar;19(3):319-324. doi: 10.3171/2016.9.PEDS16328. Epub 
2016 Dec 23.

Report of effective trametinib therapy in 2 children with progressive
hypothalamic optic pathway pilocytic astrocytoma: documentation of volumetric
response.

Miller C(1), Guillaume D(1), Dusenbery K(2), Clark HB(3), Moertel C(4).

Author information: 
(1)Departments of 1 Neurosurgery.
(2)Radiation Oncology.
(3)Pathology, and.
(4)Pediatric Hematology/Oncology, University of Minnesota, Minneapolis,
Minnesota.

Brain tumors are the most common solid tumor in childhood, and astrocytomas
account for the largest proportion of these tumors. Increasing sophistication in 
genetic testing has allowed for the detection of specific mutations within tumor 
subtypes that may represent targets for individualized tumor treatment. The
mitogen-activating protein kinase (MAPK) pathway and, more specifically, BRAF
mutations have been shown to be prevalent in pediatric pilocytic astrocytomas and
may represent one such area to target. Herein, the authors describe 2 cases of
inoperable, chemotherapy-resistant pediatric pilocytic astrocytomas with a
documented response to trametinib, an MAPK pathway inhibitor. While these cases
were not treated in the setting of a clinical trial, their data support further
ongoing clinical trial investigation to evaluate the safety and efficacy of this 
agent in pediatric low-grade gliomas.

DOI: 10.3171/2016.9.PEDS16328 
PMID: 28009226  [Indexed for MEDLINE]


18. J Neurooncol. 2016 Oct;130(1):211-219. Epub 2016 Aug 16.

Clinical utility and treatment outcome of comprehensive genomic profiling in high
grade glioma patients.

Blumenthal DT(1)(2), Dvir A(3), Lossos A(4), Tzuk-Shina T(5), Lior T(6), Limon
D(7), Yust-Katz S(8)(7), Lokiec A(5), Ram Z(8)(9), Ross JS(10)(11), Ali SM(10),
Yair R(3), Soussan-Gutman L(3), Bokstein F(12)(8).

Author information: 
(1)Division of Oncology, Neuro-Oncology Service, Tel Aviv Sourasky Medical
Center, 6 Weizman Street, 64239, Tel Aviv, Israel. deborahblumenthal@gmail.com.
(2)Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
deborahblumenthal@gmail.com.
(3)Oncotest-Teva Pharmaceuticals, Petah Tikva, Israel.
(4)Department of Oncology, Leslie and Michael Gaffin Center for Neuro-Oncology,
Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
(5)Department of Oncology, Rambam Health Care Campus, Haifa, Israel.
(6)Oncology Institute, Chaim Sheba Medical Center, Tel Hashomer, Israel.
(7)Oncology Institute, Davidoff Center, Rabin Medical Center, Petah Tikva,
Israel.
(8)Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
(9)Department of Neurosurgery, Tel Aviv Sourasky Medical Center, Tel Aviv,
Israel.
(10)Foundation Medicine, Cambridge, MA, USA.
(11)Albany Medical College, Albany, NY, USA.
(12)Division of Oncology, Neuro-Oncology Service, Tel Aviv Sourasky Medical
Center, 6 Weizman Street, 64239, Tel Aviv, Israel.

Genomic research of high grade glioma (HGG) has revealed complex biology with
potential for therapeutic impact. However, the utilization of this information
and impact upon patient outcome has yet to be assessed. We performed
capture-based next generation sequencing (NGS) genomic analysis assay of 236/315 
cancer-associated genes, with average depth of over 1000 fold, to guide treatment
in HGG patients. We reviewed clinical utility and response rates in correlation
to NGS results. Forty-three patients were profiled: 34 glioblastomas, 8
anaplastic astrocytomas, and one patient with anaplastic oligodendroglioma.
Twenty-five patients were profiled with the 315 gene panel. The median number of 
identified genomic alterations (GAs) per patient was 4.5 (range 1-23). In 41
patients (95 %) at least one therapeutically-actionable GA was detected, most
commonly in EGFR [17 (40 %)]. Genotype-directed treatments were prescribed in 13 
patients, representing a 30 % treatment decision impact. Treatment with targeted 
agents included everolimus as a single agent and in combination with erlotinib;
erlotinib; afatinib; palbociclib; trametinib and BGJ398. Treatments targeted
various genomic findings including EGFR alterations, mTOR activation, cell cycle 
targets and FGFR1 mutations. None of the patients showed response to respective
biologic treatments. In this group of patients with HGG, NGS revealed a high
frequency of GAs that lead to targeted treatment in 30 % of the patients. The
lack of response suggests that further study of mechanisms of resistance in HGG
is warranted before routine use of biologically-targeted agents based on NGS
results.

DOI: 10.1007/s11060-016-2237-3 
PMID: 27531351  [Indexed for MEDLINE]


19. World J Surg Oncol. 2016 Sep 1;14(1):235. doi: 10.1186/s12957-016-0965-7.

Primary cerebral malignant melanoma in insular region with extracranial
metastasis: case report and review literature.

Troya-Castilla M(1), Rocha-Romero S(2), Chocrón-González Y(2), Márquez-Rivas
FJ(2).

Author information: 
(1)Neurosurgery Department, University Hospital Virgen del Rocío, Av Manuel
Siurot s/n, 410013, Seville, Spain. Martta.troya@gmail.com.
(2)Neurosurgery Department, University Hospital Virgen del Rocío, Av Manuel
Siurot s/n, 410013, Seville, Spain.

BACKGROUND: Primary brain melanomas are very infrequent and metastasis outside
central nervous system very uncommon. There are some cases in the literature
about primary melanoma in the temporal lobe; nevertheless, the insular location
has never been described.
CASE PRESENTATION: The patient presented as left insular intraparenchymal
hematoma with multiple bleedings. Complementary tests did not show any tumoral
nor vascular pattern in relation with these bleedings. A complete surgical
resection was performed, and the diagnosis of malignant melanoma, with BRAF
mutation, was obtained after histology exam. Extension studies were negative for 
skin or mucous melanoma. 18F-FDG PET/CT was performed and a metastatic lymph node
was found. The diagnosis was primary brain melanoma with extracerebral
metastasis. Dabrafenib 150 mg/12 h was the only chemotherapy during 5 months.
After that, Trametinib 2 mg/24 h was added to the treatment. Eighteen months
after surgery, the patient is independent, with stable situation, and without new
metastasis.
CONCLUSIONS: Although malignant melanomas have poor prognosis, total surgical
resection and new therapies are increasing the overall survival and improving
quality of life. In a patient with suspected brain melanoma, in spite of having
extracerebral metastasis, aggressive treatment may be considered.

DOI: 10.1186/s12957-016-0965-7 
PMCID: PMC5009555
PMID: 27586680  [Indexed for MEDLINE]


20. Melanoma Res. 2016 Aug;26(4):382-6. doi: 10.1097/CMR.0000000000000250.

Initial experience with combined BRAF and MEK inhibition with stereotactic
radiosurgery for BRAF mutant melanoma brain metastases.

Patel BG(1), Ahmed KA, Johnstone PA, Yu HH, Etame AB.

Author information: 
(1)aMorsani College of Medicine, University of South Florida Departments of
bRadiation Oncology cNeuro-Oncology, H. Lee Moffitt Cancer Center and Research
Institute, Tampa, Florida, USA.

The combined use of the BRAF inhibitor dabrafenib and MEK inhibitor trametinib
has been found to improve survival over dabrafenib alone. The management of
melanoma brain metastases continues to present challenges. In this study, we
report our initial experience in the management of melanoma brain metastases with
stereotactic radiosurgery (SRS) with the use of BRAF and MEK inhibitors. We
identified six patients treated with SRS for 17 brain metastases within 3 months 
of BRAF and MEK inhibitor administration. The median planning target volume was
0.42 cm (range: 0.078-2.08 cm). The median treatment dose was 21 Gy (range
18-24 Gy). The median follow-up of all lesions from SRS was 10.6 months (range
5.8-28.5 months). One lesion was found to undergo local failure 21.7 months
following SRS treatment. The median overall survival was 20.0 months (range
6.1-31.8 months) from the time of SRS treatment and 23.1 months (range: 12.1-30.9
months) from the date of BRAFi and MEKi administration. There was no evidence of 
increased nor unexpected toxicity with the two modalities combined. In this
initial experience of melanoma brain metastases treated with BRAF and MEK
inhibition with SRS, we find the two modalities can be combined safely. These
outcomes should be assessed further in prospective evaluations.

DOI: 10.1097/CMR.0000000000000250 
PMID: 26926151  [Indexed for MEDLINE]


21. J Natl Cancer Inst. 2015 Oct 23;108(2). pii: djv310. doi: 10.1093/jnci/djv310.
Print 2016 Feb.

Dramatic Response of BRAF V600E Mutant Papillary Craniopharyngioma to Targeted
Therapy.

Brastianos PK(1), Shankar GM(1), Gill CM(1), Taylor-Weiner A(1), Nayyar N(1),
Panka DJ(1), Sullivan RJ(1), Frederick DT(1), Abedalthagafi M(1), Jones PS(1),
Dunn IF(1), Nahed BV(1), Romero JM(1), Louis DN(1), Getz G(1), Cahill DP(1),
Santagata S(1), Curry WT Jr(1), Barker FG 2nd(1).

Author information: 
(1)Department of Medicine (PKB, RS), Department of Neurology (PKB, CMG),
Department of Neurosurgery (GMS, PJ, BN, DPC, WTC, FGB), Department of Surgical
Oncology (DTF), Department of Pathology (GG, DNL), Cancer Center (PKB, CMG, NN,
DNL), Department of Radiology (JR) Massachusetts General Hospital, Harvard
Medical School, Boston, MA; Broad Institute (ATW, GG), Department of Pathology,
(MA, SS) and Department of Neurosurgery, Brigham and Women's Hospital (IFD),
Boston, MA; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard
Medical School, Boston, MA (DJP).

We recently reported that BRAF V600E is the principal oncogenic driver of
papillary craniopharyngioma, a highly morbid intracranial tumor commonly
refractory to treatment. Here, we describe our treatment of a man age 39 years
with multiply recurrent BRAF V600E craniopharyngioma using dabrafenib (150mg,
orally twice daily) and trametinib (2mg, orally twice daily). After 35 days of
treatment, tumor volume was reduced by 85%. Mutations that commonly mediate
resistance to MAPK pathway inhibition were not detected in a post-treatment
sample by whole exome sequencing. A blood-based BRAF V600E assay detected
circulating BRAF V600E in the patient's blood. Re-evaluation of the existing
management paradigms for craniopharyngioma is warranted, as patient morbidity
might be reduced by noninvasive mutation testing and neoadjuvant-targeted
treatment.

© The Author 2015. Published by Oxford University Press. All rights reserved. For
Permissions, please e-mail: journals.permissions@oup.com.

DOI: 10.1093/jnci/djv310 
PMCID: PMC4862417
PMID: 26498373  [Indexed for MEDLINE]


22. Am J Case Rep. 2014 Oct 12;15:441-3. doi: 10.12659/AJCR.890875.

A case of intracranial hemorrhage caused by combined dabrafenib and trametinib
therapy for metastatic melanoma.

Lee le M(1), Feun L(2), Tan Y(3).

Author information: 
(1)Department of Internal Medicine, University of Miami, Miami, USA.
(2)Department of Hematology and Oncology, University of Miami, Miami, USA.
(3)Department of Pathology, University of Miami, Miami, USA.

BACKGROUND: Combination therapy with BRAF V600E inhibitor dabrafenib and MEK
inhibitor trametinib significantly improves progression-free survival of patients
with BRAF V600-positive metastatic melanoma, but their use can be associated with
life-threatening toxicities. We report the case of a patient receiving dabrafenib
and trametinib for metastatic melanoma who developed intracranial hemorrhage
while on therapy. Combination therapy with dabrafenib and trametinib improves
progression-free survival of patients with BRAF V600-positive metastatic
melanoma. Nevertheless, it is associated with an increased incidence and severity
of any hemorrhagic event. To the best of our knowledge, this is the first report 
of intracranial hemorrhage with pathological confirmation.
CASE REPORT: We present the case of a 48-year-old man with metastatic melanoma of
unknown primary site. He had metastases to the right clavicle, brain, liver,
adrenal gland, and the right lower quadrant of the abdomen. He progressed on
treatment with alpha-interferon. He was found to have a 4.5-cm mass in the left
frontotemporal lobe and underwent gross total resection followed by adjuvant
CyberKnife stereotactic irradiation. He was subsequently started on ipilimumab.
Treatment was stopped due to kidney injury. He was then placed on dabrafenib and 
trametinib. He returned for follow-up complaining of severe headache and
developed an episode of seizure. MRI showed a large area of edema at the left
frontal lobe with midline shift. Emergency craniotomy was performed. Intracranial
hemorrhage was found intra-operatively. Pathology from surgery did not find tumor
cells, reported as organizing hemorrhage and necrosis with surrounding gliosis;
immunohistochemistry for S100 and HMB45 were negative.
CONCLUSIONS: This case demonstrates the life-threatening adverse effects that can
be seen with the newer targeted biological therapies. It is therefore crucial to 
maintain a high index of suspicion when patients on this combination therapy
present with new neurologic symptoms.

DOI: 10.12659/AJCR.890875 
PMCID: PMC4206477
PMID: 25305754  [Indexed for MEDLINE]