Conservation and divergence of metabolic phenotypes between patient tumours and matched xenografts.

Patient-derived xenografts (PDXs) are frequently used as preclinical models, but their recapitulation of tumour metabolism in patients has not been closely examined. We developed a parallel workflow to analyse [U-C]glucose tracing and metabolomics data from patient melanomas and matched PDXs. Melanomas from patients have substantial TCA cycle labelling, similar to levels in human brain tumours.

Long-term clinical outcomes of bevacizumab for treatment of stereotactic radiosurgery-induced radiation necrosis in patients with brain metastases.

Purpose: Radiation necrosis (RN) is a potentially debilitating complication of stereotactic radiosurgery (SRS) for brain metastases (BrM). Bevacizumab, a monoclonal antibody against vascular endothelial growth factor A, is increasingly used for treating symptomatic RN. This multi-institutional retrospective study examines its longitudinal efficacy, toxicity, and steroid-sparing effect in BrM patients with SRS-induced RN over an extended follow-up.

Sensitivity to immune checkpoint inhibitors in BRAF/MEK inhibitor refractory melanoma.

Background: Resistance to BRAF and MEK inhibitors (BRAFi/MEKi) in metastatic melanoma frequently results in cross-resistance to immune checkpoint inhibitors (ICI), limiting effective treatment options. However, a subset of BRAFi/MEKi-resistant patients remains responsive to second-line ICI, suggesting heterogeneous underlying resistance mechanisms. This study aimed to explore the tumor immune microenvironment in BRAFi/MEKi-resistant melanoma to uncover factors influencing sensitivity to second-line ICI therapy.

Assessing cancer therapeutic efficacy in vivo using [H]glucose deuterium metabolic imaging.

Metabolic imaging produces powerful visual assessments of organ function in vivo. Current techniques can be improved by safely increasing metabolic contrast. The gold standard, 2-[F]fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging, is limited by radioactive exposure and sparse assessment of metabolism beyond glucose uptake and retention.

High Glucose Contribution to the TCA Cycle Is a Feature of Aggressive Non-Small Cell Lung Cancer in Patients.

Intraoperative 13C-glucose infusions in patients with NSCLC show that tumors with high labeling of TCA cycle intermediates progress rapidly, resulting in metastasis and early death. Blocking this pathway suppresses metastasis of human NSCLC cells in mice.

In vivo characterization of glutamine metabolism identifies therapeutic targets in clear cell renal cell carcinoma.

Targeting metabolic vulnerabilities has been proposed as a therapeutic strategy in renal cell carcinoma (RCC). Here, we analyzed the metabolism of patient-derived xenografts (tumorgrafts) from diverse subtypes of RCC. Tumorgrafts from -mutant clear cell RCC (ccRCC) retained metabolic features of human ccRCC and engaged in oxidative and reductive glutamine metabolism.

In vivo isotope tracing reveals a requirement for the electron transport chain in glucose and glutamine metabolism by tumors.

In mice and humans with cancer, intravenous C-glucose infusion results in C labeling of tumor tricarboxylic acid (TCA) cycle intermediates, indicating that pyruvate oxidation in the TCA cycle occurs in tumors. The TCA cycle is usually coupled to the electron transport chain (ETC) because NADH generated by the cycle is reoxidized to NAD by the ETC. However, C labeling does not directly report ETC activity, and other pathways can oxidize NADH, so the ETC's role in these labeling patterns is unverified.

Adaptive translational reprogramming of metabolism limits the response to targeted therapy in BRAF melanoma.

Despite the success of therapies targeting oncogenes in cancer, clinical outcomes are limited by residual disease that ultimately results in relapse. This residual disease is often characterized by non-genetic adaptive resistance, that in melanoma is characterised by altered metabolism. Here, we examine how targeted therapy reprograms metabolism in BRAF-mutant melanoma cells using a genome-wide RNA interference (RNAi) screen and global gene expression profiling.

A Short Isoform of Spermatogenic Enzyme GAPDHS Functions as a Metabolic Switch and Limits Metastasis in Melanoma.

Unlabelled: Despite being the leading cause of cancer deaths, metastasis remains a poorly understood process. To identify novel regulators of metastasis in melanoma, we performed a large-scale RNA sequencing screen of 48 samples from patient-derived xenograft (PDX) subcutaneous melanomas and their associated metastases. In comparison with primary tumors, expression of glycolytic genes was frequently decreased in metastases, whereas expression of some tricarboxylic acid (TCA) cycle genes was increased in metastases.

Regulation of PRMT5-MDM4 axis is critical in the response to CDK4/6 inhibitors in melanoma.

Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are an established treatment in estrogen receptor-positive breast cancer and are currently in clinical development in melanoma, a tumor that exhibits high rates of CDK4 activation. We analyzed melanoma cells with acquired resistance to the CDK4/6 inhibitor palbociclib and demonstrate that the activity of PRMT5, a protein arginine methyltransferase and indirect target of CDK4, is essential for CDK4/6 inhibitor sensitivity. By indirectly suppressing PRMT5 activity, palbociclib alters the pre-mRNA splicing of MDM4, a negative regulator of p53, leading to decreased MDM4 protein expression and subsequent p53 activation.

Targeting metabolic reprogramming as a potential therapeutic strategy in melanoma.

Metabolic reprogramming is a recognized hallmark of cancer. In order to support continued proliferation and growth, tumor cells must metabolically adapt to balance their bioenergetic and biosynthetic needs. To achieve this, cancer cells switch from mitochondrial oxidative phosphorylation to predominantly rely on glycolysis, a process known as the "Warburg effect".

Activity of trametinib in K601E and L597Q BRAF mutation-positive metastatic melanoma.

BRAF and MEK inhibitors are not established treatments for non-V600 mutation-positive metastatic melanoma. We carried out a retrospective analysis of efficacy and safety in four patients with BRAF K601E and one patient with L597Q mutation-positive metastatic melanoma treated with the MEK inhibitor trametinib. Three patients achieved a RECIST partial response, including the patient with an L597Q mutation.