443P EMERGE: A phase II trial assessing the efficacy of domatinostat plus avelumab in patients with previously treated advanced mismatch repair proficient oesophagogastric and colorectal cancers – phase IIA dose finding

Cartwright, Edward; Turkes, F.; Saffery, Claire; Tran, Amina; Smith, Gillian; Moreno, Shanti; Hatt, S.; Renn, Alexandra; Johnston, E.; Kohoutová, Darina; Begum, Ruwaida; Smyth, E.; Peckitt, Clare; Fribbens, Charlotte; S, Rao; Watkins, David; Starling, Naureen; Cunningham, David

doi:10.1016/j.annonc.2021.08.964

Cited by 6 publications

(1 citation statement)

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“…Domatinostat, currently in clinical development in both in hematological and solid malignancies, has shown a good safety profile also in combination treatments [ 43 – 46 ]. In this regard, in our study we demonstrated a selective anti-tumour effect of domatinostat on tumor cells and a good tolerability of treatment in combination with chemotherapy in mice preclinical model.…”

Section: Discussionmentioning

confidence: 99%

HDAC class I inhibitor domatinostat sensitizes pancreatic cancer to chemotherapy by targeting cancer stem cell compartment via FOXM1 modulation

Roca

Moccia

Iannelli

et al. 2022

J Exp Clin Cancer Res

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Background Pancreatic ductal adenocarcinoma (PDAC) represents an unmet clinical need due to the very poor prognosis and the lack of effective therapy. Here we investigated the potential of domatinostat (4SC-202), a new class I histone deacetylase (HDAC) inhibitor, currently in clinical development, to sensitize PDAC to first line standard gemcitabine (G)/taxol (T) doublet chemotherapy treatment. Methods Synergistic anti-tumor effect of the combined treatment was assessed in PANC1, ASPC1 and PANC28 PDAC cell lines in vitro as well as on tumor spheroids and microtissues, by evaluating combination index (CI), apoptosis, clonogenic capability. The data were confirmed in vivo xenograft models of PANC28 and PANC1 cells in athymic mice. Cancer stem cells (CSC) targeting was studied by mRNA and protein expression of CSC markers, by limiting dilution assay, and by flow cytometric and immunofluorescent evaluation of CSC mitochondrial and cellular oxidative stress. Mechanistic role of forkhead box M1 (FOXM1) and downstream targets was evaluated in FOXM1-overexpressing PDAC cells. Results We showed that domatinostat sensitized in vitro and in vivo models of PDAC to chemotherapeutics commonly used in PDAC patients management and particularly to GT doublet, by targeting CSC compartment through the induction of mitochondrial and cellular oxidative stress. Mechanistically, we showed that domatinostat hampers the expression and function of FOXM1, a transcription factor playing a crucial role in stemness, oxidative stress modulation and DNA repair. Domatinostat reduced FOXM1 protein levels by downregulating mRNA expression and inducing proteasome-mediated protein degradation thus preventing nuclear translocation correlated with a reduction of FOXM1 target genes. Furthermore, by overexpressing FOXM1 in PDAC cells we significantly reduced domatinostat-inducing oxidative mitochondrial and cellular stress and abolished GT sensitization, both in adherent and spheroid cells, confirming FOXM1 crucial role in the mechanisms described. Finally, we found a correlation of FOXM1 expression with poor progression free survival in PDAC chemotherapy-treated patients. Conclusions Overall, we suggest a novel therapeutic strategy based on domatinostat to improve efficacy and to overcome resistance of commonly used chemotherapeutics in PDAC that warrant further clinical evaluation.

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Section: Discussionmentioning

confidence: 99%