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Metabolic reprogramming is linked to cancer cell growth and proliferation, metastasis, and therapeutic resistance in a multitude of cancers. Targeting dysregulated metabolic pathways to overcome resistance, an urgent clinical need in all relapsed/refractory cancers, remains difficult. Through genomic analyses of clinical specimens, we show that metabolic reprogramming toward oxidative phosphorylation (OXPHOS) and glutaminolysis is associated with therapeutic resistance to the Bruton's tyrosine kinase inhibitor ibrutinib in mantle cell lymphoma (MCL), a B cell lymphoma subtype with poor clinical outcomes. Inhibition of OXPHOS with a clinically applicable small molecule, IACS-010759, which targets complex I of the mitochondrial electron transport chain, results in marked growth inhibition in vitro and in vivo in ibrutinib-resistant patient-derived cancer models. This work suggests that targeting metabolic pathways to subvert therapeutic resistance is a clinically viable approach to treat highly refractory malignancies., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

The plasticity of a preexisting regulatory circuit compromises the effectiveness of targeted therapies, and leveraging genetic vulnerabilities in cancer cells may overcome such adaptations. Hereditary leiomyomatosis renal cell carcinoma (HLRCC) is characterized by oxidative phosphorylation (OXPHOS) deficiency caused by fumarate hydratase (FH) nullizyogosity. To identify metabolic genes that are synthetically lethal with OXPHOS deficiency, we conducted a genetic loss-of-function screen and found that phosphogluconate dehydrogenase (PGD) inhibition robustly blocks the proliferation of FH mutant cancer cells both in vitro and in vivo. Mechanistically, PGD inhibition blocks glycolysis, suppresses reductive carboxylation of glutamine, and increases the NADP + /NADPH ratio to disrupt redox homeostasis. Furthermore, in the OXPHOS-proficient context, blocking OXPHOS using the small-molecule inhibitor IACS-010759 enhances sensitivity to PGD inhibition in vitro and in vivo. Together, our study reveals a dependency on PGD in OXPHOS-deficient tumors that might inform therapeutic intervention in specific patient populations., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

Lung cancer is a devastating disease that remains a top cause of cancer mortality. Despite improvements with targeted and immunotherapies, the majority of patients with lung cancer lack effective therapies, underscoring the need for additional treatment approaches. Genomic studies have identified frequent alterations in components of the SWI/SNF chromatin remodeling complex including SMARCA4 and ARID1A. To understand the mechanisms of tumorigenesis driven by mutations in this complex, we developed a genetically engineered mouse model of lung adenocarcinoma by ablating Smarca4 in the lung epithelium. We demonstrate that Smarca4 acts as a bona fide tumor suppressor and cooperates with p53 loss and Kras activation. Gene expression analyses revealed the signature of enhanced oxidative phosphorylation (OXPHOS) in SMARCA4 mutant tumors. We further show that SMARCA4 mutant cells have enhanced oxygen consumption and increased respiratory capacity. Importantly, SMARCA4 mutant lung cancer cell lines and xenograft tumors have marked sensitivity to inhibition of OXPHOS by a novel small molecule, IACS-010759, that is under clinical development. Mechanistically, we show that SMARCA4-deficient cells have a blunted transcriptional response to energy stress creating a therapeutically exploitable synthetic lethal interaction. These findings provide the mechanistic basis for further development of OXPHOS inhibitors as therapeutics against SWI/SNF mutant tumors.

Metabolic reprograming is an emerging hallmark of tumor biology and an actively pursued opportunity in discovery of oncology drugs. Extensive efforts have focused on therapeutic targeting of glycolysis, whereas drugging mitochondrial oxidative phosphorylation (OXPHOS) has remained largely unexplored, partly owing to an incomplete understanding of tumor contexts in which OXPHOS is essential. Here, we report the discovery of IACS-010759, a clinical-grade small-molecule inhibitor of complex I of the mitochondrial electron transport chain. Treatment with IACS-010759 robustly inhibited proliferation and induced apoptosis in models of brain cancer and acute myeloid leukemia (AML) reliant on OXPHOS, likely owing to a combination of energy depletion and reduced aspartate production that leads to impaired nucleotide biosynthesis. In models of brain cancer and AML, tumor growth was potently inhibited in vivo following IACS-010759 treatment at well-tolerated doses. IACS-010759 is currently being evaluated in phase 1 clinical trials in relapsed/refractory AML and solid tumors.

Glioblastoma (GBM) is the most prevailing malignant primary brain tumor, and the precise diagnosis of GBM has always been a challenge. Gboxin is a recently developed drug efficiently inhibiting the oxidative phosphorylation in GBM cells, and both the chlorotoxin (CLTX) and GBM cell membrane coating are capable of GBM targeting and tumor homing. Herein, the near‐infrared (NIR) persistent luminescence (PL) nanoparticle, CUDZG, with a dual function of imaging and therapy is developed based on ZnGa2O4:Cr3+,Sn4+. CUDZG exhibits superior rechargeable NIR PL for at least 48 h with excellent tissue penetration in vivo, which enables the longstanding autofluorescence‐free imaging of the orthotopic GBM. The tumor growth of both the orthotropic and subcutaneous GBM‐bearing mice are significantly suppressed by CUDZG. This is the first‐time report of 1) the integration of CLTX and cell membrane coating for drug delivery, 2) diselenide‐based trigger release for anti‐GBM therapy, and 3) the systemic delivery of Gboxin. This study also offers an example of the highly promising blood‐brain penetrable drug carriers for precise diagnosis and therapy of central nervous system diseases. [ABSTRACT FROM AUTHOR]

• A stimuli-responsive drug-loaded particle was formed to treat glioblastoma (GBM). • Gboxin and cannabidiol were co-delivered through blood–brain barrier (BBB). • Chlorotoxin and cannabidiol were integrated for BBB penetration and GBM targeting. • The receptor-mediated pathways of BBB penetration of CLTX were investigated. Glioblastoma (GBM) is the most common and aggressive primary brain tumor. Effective treatment for GBM is limited by the presence of the blood–brain barrier (BBB) and low specificity of tumor targeting. Gboxin is a recently developed drug that effectively inhibits the oxidative phosphorylation of GBM cells, and cannabidiol (CBD) is one kind of cannabinoids showing anti-GBM effects. Herein, a dual receptor-mediated BBB penetrable carrier GZCX co-loaded with Gboxin and CBD was developed for the treatment of GBM. The surface conjugated chlorotoxin (CLTX) facilitated the BBB penetration and GBM targeting, while CBD also promoted the BBB penetration. 10-fold enhanced Gboxin accumulation in the brain was achieved by GZCX. Treatment of GBM-bearing mice with GZCX lead to increased apoptosis and reduced angiogenesis that correlated with a 3.7-fold decrease in tumor burden and corresponding increase in survival. This is the first-time report of 1) the co-delivery of Gboxin and CBD, 2) the integration of CLTX and CBD for BBB penetration and GBM targeting, and 3) the receptor-mediated pathways of BBB penetration of CLTX. This study also offers an example of the highly promising BBB penetrable drug carriers for precise diagnosis and therapy of central nervous system diseases. [ABSTRACT FROM AUTHOR]

Tumors lack a well-regulated vascular supply of O2 and often fail to balance O2 supply and demand. Net O2 tension within many tumors may not only depend on O2 delivery but also depend strongly on O2 demand. Thus, tumor O2 consumption rates may influence tumor hypoxia up to true anoxia. Recent reports have shown that many human tumors in vivo depend primarily on oxidative phosphorylation (OxPhos), not glycolysis, for energy generation, providing a driver for consumptive hypoxia and an exploitable vulnerability. In this regard, IACS-010759 is a novel high affinity inhibitor of OxPhos targeting mitochondrial complex-I that has recently completed a Phase-I clinical trial in leukemia. However, in solid tumors, the effective translation of OxPhos inhibitors requires methods to monitor pharmacodynamics in vivo. Herein, 18F-fluoroazomycin arabinoside ([18F]FAZA), a 2-nitroimidazole-based hypoxia PET imaging agent, was combined with a rigorous test-retest imaging method for non-invasive quantification of the reversal of consumptive hypoxia in vivo as a mechanism-specific pharmacodynamic (PD) biomarker of target engagement for IACS-010759. Neither cell death nor loss of perfusion could account for the IACS-010759-induced decrease in [18F]FAZA retention. Notably, in an OxPhos-reliant melanoma tumor, a titration curve using [18F]FAZA PET retention in vivo yielded an IC50 for IACS-010759 (1.4 mg/kg) equivalent to analysis ex vivo. Pilot [18F]FAZA PET scans of a patient with grade IV glioblastoma yielded highly reproducible, high-contrast images of hypoxia in vivo as validated by CA-IX and GLUT-1 IHC ex vivo. Thus, [18F]FAZA PET imaging provided direct evidence for the presence of consumptive hypoxia in vivo, the capacity for targeted reversal of consumptive hypoxia through the inhibition of OxPhos, and a highly-coupled mechanism-specific PD biomarker ready for translation. [ABSTRACT FROM AUTHOR]