MEK and Autophagy Inhibition in Metastatic/Locally Advanced, Unresectable Neuroblastoma RAS (NRAS) Melanoma

MEK and Autophagy Inhibition in Metastatic/Locally Advanced, Unresectable Neuroblastoma RAS (NRAS) Melanoma

Publication date: Jun 07, 2019

Patients with metastatic Neuroblastoma RAS (NRAS) melanoma are currently treated with first line immune checkpoint inhibitors (nivolumab, pembrolizumab). Thus far, no targeted therapy has been approved in NRAS mutated melanoma as a second line treatment, because although the use of a MEK inhibitor (binimetinib) alone was superior to the gold standard chemotherapy (dacarbazine) in a phase 3 trial, the progression free survival gain was very modest. In vitro and in vivo work from the study team’s lab (McMAHON, Huntsman Cancer Institute (HCI), Salt Lake City), as well as, Ravi Amaravardi and Jean Mulchey-Levy suggests that the activation of autophagy is a mechanism of resistance to BRAF and MEK inhibitors in RAS and RAF mutated cancers, such as melanoma, pediatric brain tumors and pancreatic adenocarcinoma. The study team has shown in vivo, in four different NRAS mutated melanoma Patient Derived Xenograft (PDX) models that the combination of the MEK inhibitor trametinib and the autophagy inhibitor chloroquine results in a more dramatic tumor regression and inhibition than trametinib or chloroquine used as single agents (Nat Med. 2019 Apr;25(4):620-627. doi: 10.1038/s41591-019-0367-9. Epub 2019 Mar 4). In two of the PDX models, the combination resulted in almost complete tumor regression (quasi disappearance) that was not observed in the single agent treatment arms. Trametinib (MEKINISTR) is an orally available MEK inhibitor that is currently approved in combination with the BRAF inhibitor dabrafenib (TAFINLARR) to treat BRAF mutated metastatic melanoma at the standard dosing of 2 milligrams (mg) once a day. Hydroxychloroquine (PLAQUENILR) is an orally available autophagy inhibitor that has been used for many years to treat autoimmune diseases like lupus, sarcoidosis and rheumatoid arthritis at the standard dosing of 400-600mg/day. For this study, the investigating team would like to evaluate the safety and tolerability of the combination of hydroxychloroquine and trametinib in a phase I trial in patients with NRAS mutated metastatic melanoma.

Concepts Keywords
Adenocarcinoma Nonmelanoma tumors
Adjuvant Complete tumor
Alanine Diarrhea malabsorption syndrome
ALAT Active Hepatitis infection
Albumin Severe hypersensitivity
ANC Vomiting
Antibodies HIV active Hepatitis
Antineoplastic Symptomatic brain metastases
ASAT Tumors
Aspartate Aminotransferase Tumor
Asymptomatic Pregnancy testing protocol
Autoimmune Diseases Baseline tumor
Autophagy Autoimmune diseases
Bilirubin Radiation therapy
Biopsies Antineoplastic therapy
Biopsy Contraception
Bone Marrow Major surgery
BRAF Investigational therapy
BRAF Inhibitor Chemotherapy
Brain Tumors Radiotherapy
Cardiac Arrhythmias Immunotherapy
Chemotherapy Clinical medicine
Chloroquine Cancer treatments
Cognitive Antineoplastic drugs
Common Melanoma
Computed Tomography Breakthrough therapy
Congestive Heart Failure Bristol-Myers Squibb
Contraception Targeted therapy
Contraceptive Nivolumab
Contraindicate Pembrolizumab
Cooperative Group MEK inhibitor
Creatine Ipilimumab
Creatinine Clearance Radiation
Diarrhea Tomography
Ejection Fraction Antibodies
EKG Pregnancy testing protocol
Electrocardiogram Chemotherapy
Epidural Ultra sound
Formula
G6PD Deficiency
Gastrointestinal
Gestation
Glaucoma
Glucose
Gold Standard
Gonadotropin
HCG
Hemoglobin
Heterosexual
Histologically
HIV
Hydroxychloroquine
Hypersensitivity
Hypertension
Immunotherapy
Infection
Informed Consent
Inhibitor
Ipilimumab
Ischemic
Lactating
Liver
Lupus
LVEF
Lyon
Macular Degeneration
Malabsorption Syndrome
Malignancies
Malignant Melanoma
MEK
Melanoma
Metastatic
Mitomycin C
Monoclonal Antibodies
Mutation
Myocardial Infarction
Nausea
NCI
Neuroblastoma
Neuromuscular Disorders
Nursing
Occlusion
Ocular Hypertension
Pediatric
Phosphate
Platelet
Pregnancy
Pregnancy Test
Protocol
QTc Interval
Radiation Therapy
Radiotherapy
RAF
RAS
Regression
Renal
Retinal
Retinal Degeneration
Rheumatoid Arthritis
Risk Factor
Salt Lake City
Sarcoidosis
Serology
Serum
Small Bowel
Targeted Therapy
Tolerability
Toxin
Tumor
Unstable Angina
Urine
Uveitis
Vascular Disorders
Ventricular
Vivo
Vomiting
Xenograft

Semantics

Type Source Name
gene UNIPROT MAP2K7
disease MESH Neuroblastoma
disease DOID Neuroblastoma
drug DRUGBANK Rasagiline
gene UNIPROT NRAS
disease MESH Melanoma
disease DOID Melanoma
pathway BSID Melanoma
drug DRUGBANK Nivolumab
drug DRUGBANK Pembrolizumab
drug DRUGBANK Binimetinib
drug DRUGBANK Gold
drug DRUGBANK Dacarbazine
gene UNIPROT LAT2
disease MESH Cancer
disease DOID Cancer
gene UNIPROT TIMP1
gene UNIPROT BRAF
gene UNIPROT ZHX2
disease MESH brain tumors
disease DOID pancreatic adenocarcinoma
gene UNIPROT IRF1
drug DRUGBANK Pralatrexate
gene UNIPROT KIDINS220
drug DRUGBANK Trametinib
drug DRUGBANK Dabrafenib
drug DRUGBANK Hydroxychloroquine
disease MESH autoimmune diseases
disease DOID lupus
disease MESH sarcoidosis
disease DOID sarcoidosis
disease MESH rheumatoid arthritis
disease DOID rheumatoid arthritis
pathway BSID Rheumatoid arthritis
drug DRUGBANK Ipilimumab
disease MESH separated
disease MESH renal
disease DOID ASAT
gene UNIPROT ABCB7
drug DRUGBANK L-Alanine
drug DRUGBANK Creatinine
disease MESH Electrocardiogram
disease MESH ventricular ejection fraction
drug DRUGBANK Mitomycin
disease MESH metastasis
disease MESH multiple
disease DOID degenerative disease
disease MESH retinal degeneration
disease DOID retinal degeneration
disease MESH age-related macular degeneration
disease DOID age-related macular degeneration
disease MESH uveitis
disease DOID uveitis
disease MESH Retinal Vein Occlusion
disease DOID Retinal Vein Occlusion
disease MESH risk factor
disease MESH glaucoma
disease DOID glaucoma
disease MESH ocular hypertension
disease DOID ocular hypertension
disease MESH Congestive heart failure
disease DOID Congestive heart failure
disease MESH unstable angina
disease DOID unstable angina
disease MESH cardiac arrhythmias
disease MESH hypertension
disease DOID hypertension
disease MESH Stroke
disease DOID Stroke
disease MESH myocardial infarction
disease DOID myocardial infarction
drug DRUGBANK Glucose-6-Phosphate
gene UNIPROT UBL4A
gene UNIPROT G6PD
drug DRUGBANK Creatine
disease MESH gastrointestinal disease
disease DOID gastrointestinal disease
disease DOID diarrhea
disease MESH malabsorption syndrome
disease MESH Hepatitis B
disease DOID Hepatitis B
pathway BSID Hepatitis B
disease DOID Hepatitis C infection
drug DRUGBANK Chorionic Gonadotropin (Human)
gene UNIPROT CGA
disease MESH hypersensitivity
disease DOID hypersensitivity
gene UNIPROT NR4A2
gene UNIPROT ALG3

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