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Targeting Metabolic Symbiosis to Overcome Resistance to Anti-angiogenic Therapy.

ABSTRACT: Despite the approval of several anti-angiogenic therapies, clinical results remain unsatisfactory, and transient benefits are followed by rapid tumor recurrence. Here, we demonstrate potent anti-angiogenic efficacy of the multi-kinase inhibitors nintedanib and sunitinib in a mouse model of breast cancer. However, after an initial regression, tumors resume growth in the absence of active tumor angiogenesis. Gene expression profiling of tumor cells reveals metabolic reprogramming toward anaerobic glycolysis. Indeed, combinatorial treatment with a glycolysis inhibitor (3PO) efficiently inhibits tumor growth. Moreover, tumors establish metabolic symbiosis, illustrated by the differential expression of MCT1 and MCT4, monocarboxylate transporters active in lactate exchange in glycolytic tumors. Accordingly, genetic ablation of MCT4 expression overcomes adaptive resistance against anti-angiogenic therapy. Hence, targeting metabolic symbiosis may be an attractive avenue to avoid resistance development to anti-angiogenic therapy in patients.

SUBMITTER: Pisarsky L

PROVIDER: S-EPMC4870473 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Targeting Metabolic Symbiosis to Overcome Resistance to Anti-angiogenic Therapy.

Pisarsky Laura L Bill Ruben R Fagiani Ernesta E Dimeloe Sarah S Goosen Ryan William RW Hagmann Jörg J Hess Christoph C Christofori Gerhard G

Cell reports 20160428 6

Despite the approval of several anti-angiogenic therapies, clinical results remain unsatisfactory, and transient benefits are followed by rapid tumor recurrence. Here, we demonstrate potent anti-angiogenic efficacy of the multi-kinase inhibitors nintedanib and sunitinib in a mouse model of breast cancer. However, after an initial regression, tumors resume growth in the absence of active tumor angiogenesis. Gene expression profiling of tumor cells reveals metabolic reprogramming toward anaerobic ...[more]

PMID: 27134168

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Project description:Amplification of chromosome 17q23 is a frequent genomic event that occurs in ~ 11% of human breast cancers. The 17q23 amplification is enriched in HER2+ breast cancers, which is significantly correlated with poor clinical outcomes. Previous studies have identified the oncogenic phosphatase WIP1 gene in the amplicon, which functions as a master inhibitor in DNA damage response. While the possibility of any other protein-coding oncogenes in the WIP1-containing 17q23 amplicon was ruled out, our analysis of human breast cancer genomics uncovered an oncogenic microRNA gene, MIR21, in a majority of the WIP1-containing amplicons. Interestingly, DEAD-box helicase 5 (DDX5), co-amplified with WIP1 and MIR21 in the 17q23 amplicon, facilitates the essential processing of primary miR-21 transcripts. Accordingly, the 17q23 amplification results in aberrant expression of WIP1 and miR-21, which not only promotes breast tumorigenesis, but also leads to resistance to anti-HER2 therapies. Inhibiting WIP1 and miR-21 using small molecular inhibitor against WIP1 (GSK2830371) and anti-miR-21 oligonucleotides selectively inhibits the proliferation, survival and tumorigenic potential of HER2+ breast cancer cells harboring 17q23 amplification. However, the in vivo bioavailability of the two agents in their free form is poor. To overcome the resistance of trastuzumab-based therapies in vivo, we developed pH-sensitive nanoparticles for specific co-delivery of the two agents into breast tumors. The nanoparticles consist of four materials approved by the Food and Drug Administration (FDA) for medical use: Poly (d,l-lactide-co-glycolide) (PLGA), Pluronic F127 (PF127), chitosan, and 1,2-dipalmitoyl-sn-glycerol-3-phosphocholine (DPPC). Moreover, chitosan was modified with guanidine to form chitosan-guanidine (CG), which not only can improve the encapsulation efficiency of anti-miR-21 oligonucleotides but also effectively capture carbon dioxide (CO2) into the nanoparticle to achieve the ‘nano-bomb’ effect for triggered drug release under the reduced pH in tumors. The two agents (inhibitors of miR-21 and WIP1)-laden nanoparticles can be used to efficiently kill trastuzumab-resistant HER2+ breast cancer cells, leading to a profound reduction of the tumor growth in vivo. These results demonstrate the great potential of the combined treatment of WIP1 and miR-21 inhibitors for the HER2+ breast cancers resistant to anti-HER2-based therapies.

Dataset Information

Targeting Metabolic Symbiosis to Overcome Resistance to Anti-angiogenic Therapy.

Publications

Targeting Metabolic Symbiosis to Overcome Resistance to Anti-angiogenic Therapy.

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