Biguanides, such as the diabetes therapeutics metformin and phenformin, have shown antitumor activity both in vitro and in vivo. However, their potential effects on the tumor microenvironment are largely unknown. Here we report that phenformin selectively inhibits granulocytic myeloid-derived suppressor cells in spleens of tumor-bearing mice and ex vivo. Phenformin induces production of reactive oxygen species in granulocytic myeloid-derived suppressor cells, whereas the antioxidant N-acetylcysteine attenuates the inhibitory effects of phenformin. Co-treatment of phenformin enhances the effect of anti-PD-1 antibody therapy on inhibiting tumor growth in the BRAF V600E/PTEN-null melanoma mouse model. Combination of phenformin and anti PD-1 cooperatively induces CD8 T-cell infiltration and decreases levels of proteins that are critical for immune suppressive activities of myeloid-derived suppressor cells. Our findings show a selective, inhibitory effect of phenformin on granulocytic myeloid-derived suppressor cell-driven immune suppression and support that phenformin improves the anti-tumor activity of PD-1 blockade immunotherapy in melanoma.

Metabolic rearrangements subsequent to malignant transformation are not well characterized in endometrial cancer. Identification of altered metabolites could facilitate imaging-guided diagnosis, treatment surveillance, and help to identify new therapeutic options. Here, we used high-resolution magic angle spinning magnetic resonance mass spectroscopy on endometrial cancer surgical specimens and normal endometrial tissue to investigate the key modulators that might explain metabolic changes, incorporating additional investigations using qRT-PCR, Western blotting, tissue microarrays (TMA), and uptake assays of [ 3 H]-labeled choline. Lipid metabolism was severely dysregulated in endometrial cancer with various amino acids, inositols, nucleobases, and glutathione also altered. Among the most important lipid-related alterations were increased phosphocholine levels (increased 70% in endometrial cancer). Mechanistic investigations revealed that changes were not due to altered choline transporter expression, but rather due to increased expression of choline kinase a (CHKA) and an activated deacylation pathway, as indicated by upregulated expression of the catabolic enzymes LYPLA1, LYPLA2, and GPCPD1. We confirmed the significance of CHKA overexpression on a TMA, including a large series of endometrial hyperplasia, atypical hyperplasia, and adenocarcinoma tissues, supporting a role for CHKA in malignant transformation.

Background:This study investigates whether a histone deacetylase subtype 6 (HDAC6) inhibitor could be used in the treatment of solid tumours.Methods:We evaluated the effect of a novel inhibitor, C1A, on HDAC6 biochemical activity and cell growth. We further examined potential of early noninvasive imaging of cell proliferation by [18F]fluorothymidine positron emission tomography ([18F]FLT-PET) to detect therapy response.Results:C1A induced sustained acetylation of HDAC6 substrates, α-tubulin and HSP90, compared with current clinically approved HDAC inhibitor SAHA. C1A induced apoptosis and inhibited proliferation of a panel of human tumour cell lines from different origins in the low micromolar range. Systemic administration of the drug inhibited the growth of colon tumours in vivo by 78%. The drug showed restricted activity on gene expression with <0.065% of genes modulated during 24 h of treatment. C1A treatment reduced tumour [18F]FLT uptake by 1.7-fold at 48 h, suggesting that molecular imaging could provide value in future studies of this compound.Conclusion:C1A preferentially inhibits HDAC6 and modulates HDAC6 downstream targets leading to growth inhibition of a diverse set of cancer cell lines. This property together with the favourable pharmacokinetics and efficacy in vivo makes it a candidate for further pre-clinical and clinical development.