Targeting GPNMB in Melanoma
See article by Rose et al., p. 6088
BRAF and MEK inhibitors have improved the clinical management of BRAF-mutant melanoma; however, patients often develop drug resistance. MITF is a transcription factor required for melanoma formation. Rose and colleagues demonstrate that clinically approved MAPK inhibitors cause the MITF-dependent upregulation of GPNMB. GPNMB is the target of an antibody-drug conjugate (CDX-011) currently in clinical trials. Combining BRAF and/or MEK inhibitors with CDX-011 enhanced melanoma tumor regression and delayed emergence of acquired resistance when compared with treatment with MAPK pathway inhibitors alone. These findings support the initiation of clinical trials to assess the efficacy of MAPK pathway inhibitors combined with CDX-011 for the treatment of melanoma.
Impact of Blood Brain Barrier Integrity on Brain Metastases
See article by Osswald et al., p. 6078
Osswald and colleagues develop an in vivo two-photon microscopy approach to study blood brain barrier (BBB) permeability properties, tumor growth kinetics, and response to PI3K/mTOR inhibitors in metastatic melanoma of the brain. A BBB permeable inhibitor, but not an impermeable inhibitor, reduced the growth rate of impermeable metastases. These results provide evidence that nonpermeable brain micro- and macrometastases can effectively be targeted by drugs designed to cross the BBB.
Ex Vivo Culture of PDX Tissue Slices Predicts Pancreatic Ductal Adenocarcionma Outcome
See article by Roife et al., p. 6021
Patient-derived xenograft (PDX) models have been proved to be effective in prioritizing therapeutic regimens in personalized cancer medicine; however, establishing and testing transplantable tumorgrafts are expensive and time-consuming. In this study, Roife and colleagues developed an ex vivo drug efficacy testing method, Live Tissue Sensitivity Assay (LTSA), for patients with pancreatic ductal adenocarcionma. The test enables efficient testing of PDX tumor in 96-well plates against standard of care chemotherapeutic agents in 2 to 3 days. This system is highly reflective of patients' responses to conventional therapeutic agents and has significant potential for guiding personalized cancer treatment design.
D-2HG in the CSF of Glioma Patients with Mutated IDH
See article by Kalinina et al., p. 6256
There is a pressing need for biomarkers to assist with the clinical management of brain tumor patients. The majority of WHO grade II–III gliomas express mutant forms of Isocitrate Dehydrogenases (IDH) 1 and 2, resulting in excessive production of D-2-Hydroxyglutarate (D-2HG) in the tumor cells. Kalinina and colleagues examined whether this oncometabolite is shed into the cerebrospinal fluid (CSF) and if it can potentially serve as a biomarker. Using mass spectrometry the authors demonstrated high levels of D-2HG in the CSF of IDH1-mutant glioma patients, suggesting that this assay may be developed into a clinical test for diagnosis, prognosis, and follow-up of glioma patients.