Author: Janji, Bassam ; Timson, Mary Jane ; Simeon, Jodi ; Yu, Yasmin ; Silvander, Camilla ; De Milito, Angelo ; Lindström, Johan ; Alexeyenko, Andrey ; Trésaugues, Lionel ; Parpal, Santiago ; Bogdan, Madhumita ; Flynn, Daniel L ; Noman, Muhammad Zaeem ; Al-Hashimi, Hikmat ; Pokrovskaja Tamm, Katja ; Smith, Bryan D ; Andersson, Martin ; Kleinendorst, Simone Caroline ; Bilgrav Saether, Kristine ; Martinsson, Jessica ; Bartolini, Elisabetta ; Van Moer, Kris ; Viklund, Jenny

An immunosuppressive tumor microenvironment promotes tumor growth and is one of the main factors limiting the response to cancer immunotherapy. We have previously reported that inhibition of vacuolar protein sorting 34 (VPS34), a crucial lipid kinase in the autophagy/endosomal trafficking pathway, decreases tumor growth in several cancer models, increases infiltration of immune cells and sensitizes tumors to anti‐programmed cell death protein 1/programmed cell death 1 ligand 1 therapy by upregulation of C‐C motif chemokine 5 (CCL5) and C‐X‐C motif chemokine 10 (CXCL10) chemokines. The purpose of this study was to investigate the signaling mechanism leading to the VPS34‐dependent chemokine increase. NanoString gene expression analysis was applied to tumors from mice treated with the VPS34 inhibitor SB02024 to identify key pathways involved in the anti‐tumor response. We showed that VPS34 inhibitors increased the secretion of T‐cell‐recruitment chemokines in a cyclic GMP‐AMP synthase (cGAS)/stimulator of interferon genes protein (STING)‐dependent manner in cancer cells. Both pharmacological and small interfering RNA (siRNA)‐mediated VPS34 inhibition increased cGAS/STING‐mediated expression and secretion of CCL5 and CXCL10. The combination of VPS34 inhibitor and STING agonist further induced cytokine release in both human and murine cancer cells as well as monocytic or dendritic innate immune cells. Finally, the VPS34 inhibitor SB02024 sensitized B16‐F10 tumor‐bearing mice to STING agonist treatment and significantly improved mice survival. These results show that VPS34 inhibition augments the cGAS/STING pathway, leading to greater tumor control through immune‐mediated mechanisms. We propose that pharmacological VPS34 inhibition may synergize with emerging therapies targeting the cGAS/STING pathway.

01 Oct 2018·Cancer LettersQ1 · MEDICINE

Targeting autophagy by small molecule inhibitors of vacuolar protein sorting 34 (Vps34) improves the sensitivity of breast cancer cells to Sunitinib

Q1 · MEDICINE

Article

Author: Yasmin Yu ; Jessica Martinsson ; Aine Brigette Henley ; Jenny Viklund ; Tiago Braga ; Angelo De Milito ; Krister Wennerberg ; Dan Grandér ; Magdalena Otrocka ; Santiago Parpal ; Henric Zazzi ; Matheus Dyczynski ; Mikael Lerner ; Katja Pokrovskaja Tamm

Resistance to chemotherapy is a challenging problem for treatment of cancer patients and autophagy has been shown to mediate development of resistance. In this study we systematically screened a library of 306 known anti-cancer drugs for their ability to induce autophagy using a cell-based assay. 114 of the drugs were classified as autophagy inducers; for 16 drugs, the cytotoxicity was potentiated by siRNA-mediated knock-down of Atg7 and Vps34. These drugs were further evaluated in breast cancer cell lines for autophagy induction, and two tyrosine kinase inhibitors, Sunitinib and Erlotinib, were selected for further studies. For the pharmacological inhibition of autophagy, we have characterized here a novel highly potent selective inhibitor of Vps34, SB02024. SB02024 blocked autophagy in vitro and reduced xenograft growth of two breast cancer cell lines, MDA-MB-231 and MCF-7, in vivo. Vps34 inhibitor significantly potentiated cytotoxicity of Sunitinib and Erlotinib in MCF-7 and MDA-MB-231 in vitro in monolayer cultures and when grown as multicellular spheroids. Our data suggests that inhibition of autophagy significantly improves sensitivity to Sunitinib and Erlotinib and that Vps34 is a promising therapeutic target for combination strategies in breast cancer.

01 Feb 2014·Tropical Animal Health and ProductionQ3 · AGRICULTURAL & FORESTRY SCIENCE

Genotypic characterization by spoligotyping and VNTR typing of Mycobacterium bovis and Mycobacterium caprae isolates from cattle of Tunisia

Q3 · AGRICULTURAL & FORESTRY SCIENCE

Article

Author: Hela Lamine-Khemiri ; Imed Khazri ; Mohammed Salah Abassi ; Remigio Martínez ; Maria Cortés ; Javier Hermoso-de-Mendoza ; Jose Manuel Benítez-Medina ; Inés Hurtado ; Waldo Luis García-Jiménez ; Mohammed Benzarti

This work is an approach to the molecular epidemiology of Mycobacterium tuberculosis complex (MTBC) bovine infections in Tunisia. A total of 35 MTBC isolates from both lateral retropharyngeal lymph node samples of cattle slaughtered in different Tunisian regions were genotyped by spoligotyping and variable number tandem repeat typing (VNTR)-typing. Spoligotyping allowed to identify two profiles not previously registered, namely SB2024, a Mycobacterium caprae isolate from Nabeul Region (North East Tunisia), the first description of this species in the country, and SB2025 (Mycobacterium bovis) from Sfax Region (Southern Tunisia). A second M. caprae isolate with a spoligotyping profile previously described in Europe mainland, SB0418, was also isolated from a bovine of Sfax region. Both isolates suggest the possibility of a widespread distribution of this species in the country. The predominant spoligotype was SB0120, present in all Tunisian regions selected for the study but Nabeul. Molecular typing also allowed to describe a mixed infection caused by two different M. bovis isolates (SB0120 and SB0848) in the same animal. VNTR typing was highly discriminant by testing a panel of six loci. Loci QUB3232 and QUB11b were the most discriminant, whereas ETR-D and QUB11a had the lower diversity index. The value of allelic diversity can significantly vary among countries; thus, it is important to standardize a panel of loci for future inter-laboratory comparisons. Although VNTR typing proved to be useful for an efficient discrimination among MTBC isolates, especially in combination with spoligotyping, further studies are needed in order to assess the genetic diversity of the MTBC in Tunisia.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	SE	Sprint Bioscience AB	30 Apr 2020

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