domatinostat (4SC-202)

To address the question of whether the IFNg can be analyzed using primary tumor material (P-IFNg) instead of LN-IFNg or, in the case of incongruencies, has a higher predictive value when combined with LN-IFNg, we analyzed the IFNg signature in paired samples (P and LN) from stage III melanoma pts. Paraffin primary tumor tissue from pts with stage III melanoma, treated in the OpACIN-neo, PRADO and DONIMI trials (neoadjuvant anti-PD1 +/- anti-CTLA4 +/- domatinostat), was retrospectively analyzed with the nanostring nCounter PanCancer immune profiling panel and compared to fresh frozen LN biopsies. Our results suggest that pts with concurrently high IFNg-signature expressions (high IFNg in P and LN) have a better outcome than LN-IFNg high pts only. If confirmed, these findings could inform treatment selection and prognosis.

P2, N=19, Completed, 4SC AG | Active, not recruiting --> Completed | Trial completion date: Dec 2024 --> Feb 2024

P1/2, N=44, Active, not recruiting, The Netherlands Cancer Institute

P1/2, N=44, Active, not recruiting, The Netherlands Cancer Institute | Phase classification: P1b --> P1/2

Preliminary drug screening data suggests that HDAC inhibitors, such as Domatinostat, have the potential to specifically target the MCs in order to inhibit metastasis in UPS... HDACs have been identified as potential therapeutic targets for metastatic UPS. Previous data has shown that a single subpopulation of cells is responsible for the formation of these distant lesions. Ongoing studies aim to identify which HDACs are important for metastasis in addition to elucidating their mechanism of disease progression and further analysis of the effect of pharmacological inhibition.

Cell viability, as well as protein and mRNA expression of FOXM1 and its transcriptional target survivin, was examined after domatinostat treatment of TOV21G and SKOV3 ovarian cancer cell lines in the absence or presence of cisplatin and paclitaxel. Survivin inhibition was sufficient to reduce the viability of ovarian cancer cells alone and in combination with the chemotherapeutic agents. Our findings suggest that domatinostat, which effectively targets the FOXM1-survivin axis required for the viability of ovarian cancer cells, is a promising option for the treatment of ovarian cancer.

P2, N=19, Active, not recruiting, 4SC AG | Trial completion date: Jul 2023 --> Dec 2024 | Trial primary completion date: Jul 2022 --> Feb 2024

Supplemental domatinostat (a class I histone deacetylase inhibitor) to neoadjuvant nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) was hypothesized to lead to an increased anti-tumor immune response due to its beneficial immune-modulating effects including IFN-γ signature expression increase. New ICI treatment strategies with supplemental drugs, targeting other immunosuppressive pathways such as domatinostat, may lead to unexpected dermatologic toxicities with thus far unknown mechanisms and different clinical presentations than ICI-associated dermatitis or classic drug reaction with eosinophilia and systematic symptoms (DRESS).

Our results demonstrate that the direct anti-tumor effect of HDACi domatinostat on MCC cells is at least in part mediated via decreased HES1 expression allowing the induction of IFNα, which in turn causes apoptosis.

Critically, we show that when given in combination, 4SC-202 and lapatinib exert synergistic effects on 2D cell proliferation and colony formation capacity. We therefore propose that co-treatment with 4SC-202 may prolong the clinical efficacy of lapatinib in HER2 breast cancer patients.

Neoadjuvant ipilimumab + nivolumab has demonstrated high pathologic response rates in stage III melanoma. At studied dose levels, domatinostat addition did not increase treatment efficacy. The baseline IFN-γ score adequately differentiated patients who were likely to benefit from nivolumab alone versus patients who require other therapies.

4SC-202 down-regulated the expression of PRLR and activities of PRLR-related pathways in the mouse model, displayed no effects on serum biochemical indicators and caused no toxicity to mouse organs. This finding suggests that 4SC-202 may serve as a novel therapeutic agent for CC.

Pharmacological inhibition of USP7 by P5091 phenocopies the shUSP7-induced senescent phenotype. We show that the bifunctional histone deacetylase (HDAC)/LSD1 inhibitor domatinostat has an additive antitumor effect, eliminating P5091-induced senescent cells, paving the way to a therapeutic combination for individuals with melanoma.

Thus, the goal of this study is to explore the molecular mechanisms behind promising epigenetic inhibitors in RMS, focusing on embryonal RMS, and to test these drugs in vivo in combination with vincristine. Our laboratory obtained a selection of epigenetic compounds from the Ontario Institute of Cancer Research (OICR) and Structural Genomics Consortium (SGC) that mainly target BET (BMS-986158, I-BET151, PLX51107) or HDAC (Apicidin, Domatinostat, Fimepinostat) proteins...Furthermore, the level of apoptosis in this cell line was higher after treatment with PLX51107 than after treatment with the positive control, doxorubicin (Figure 3)... Our data suggest that BET inhibitors may exploit an epigenetic weakness of ERMS, perhaps related to MYC amplification. In the future, we plan to conduct transcriptome assays to explore the mechanism of action of BET inhibitors in ERMS, and in vivo drug combination studies in an ERMS mosaic mouse model and patient-derived xenografts (PDXs).

Adjuvant NIVO or dabrafenib + trametinib started at week 12 for 52 weeks. Treatment regimen of arm D-exp was not feasible; DOM was stopped early in all arm D-exp pts. Addition of DOM did not increase the pRR in IFN-γ low pts.

P1b, N=44, Active, not recruiting, The Netherlands Cancer Institute | Recruiting --> Active, not recruiting | Trial primary completion date: Jun 2021 --> Jan 2022

P1b, N=40, Active, not recruiting, The Netherlands Cancer Institute | Recruiting --> Active, not recruiting

Bulk transcriptome (RNA) sequencing analyses of 4T1 tumors reveal changes in metastasis-related pathways in 4SC-202-treated tumors, including changes to expression levels of genes implicated in cell migration and cell motility. In summary, 4SC-202 treatment of tumors from a highly metastatic murine model of TNBC reduces metastasis and warrants further preclinical studies.

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.

P1b, N=40, Recruiting, The Netherlands Cancer Institute | Not yet recruiting --> Recruiting

P1b, N=40, Not yet recruiting, The Netherlands Cancer Institute

In conclusion, we identified an effective combination therapy involving class I histone deacetylase and mammalian target of rapamycin complex 1/2 inhibition that effectively blocked the EMT of tumor cells by upregulating FoxO1 expression to inhibit Twist1 transcription. These data have implications for developing new targets for early diagnosis and treatment of OSCC.

Pancreatic cancer (PCa) is the fourth leading cause of cancer-related death in developed countries, and, although chemotherapeutic regimens, such as FOLFIRINOX or gemcitabine combined with nab-paclitaxel (GP), improved overall survival in metastatic setting, the prognosis remains very poor with 5-year survival rate of 8%...We first demonstrated the synergistic/additive anti-tumor effects induced by domatinostat plus commonly used chemotherapeutics in PCa (i.e. gemcitabine, paclitaxel, irinotecan, oxaliplatin, fluoropyrimidines) or their combinations, in three PCa models (PANC1, PANC28 and ASPC1) by evaluating combination indexes (Chou and Talalay)...Finally, we found a correlation of FOXM1 expression with poor progression free survival in PCa chemotherapy-treated patients by analyzing TCGA PAAD data. Overall, we suggest a novel therapeutic strategy based on domatinostat to improve efficacy and to overcome resistance of commonly used chemotherapeutics in pancreatic cancer that warrant further clinical evaluation.

Furthermore, inhibition of STAT3 by S31-201 suppressed the expression of TWIST1 and led to a decline in migration and invasion of OSCC, while overexpression of TWIST1 attenuated these effects. Metformin and 4SC-202 suppressed the invasion and migration of OSCC through inhibition of STAT3/TWIST1, and this scheme can serve as a novel therapeutic strategy for OSCC.

Notably, and during this short period, there are four HDAC inhibitor hybrids have entered different phases of clinical trials for treatment of different types of blood and solid tumors, namely; CUDC-101, CUDC-907, Tinostamustine, and Domatinostat. The designed multitarget hybrids include topoisomerase inhibitors, kinase inhibitors, nitric oxide releasers, antiandrogens, FLT3 and JAC-2 inhibitors, PDE5-inhibitors, NAMPT-inhibitors, Protease inhibitors, BRD4-inhibitors and other targets. This review may help researchers in development and discovery of new horizons in cancer treatment.

The HDAC inhibitor domatinostat can be successfully combined with B7-H3 CAR T cells to enhance their anti-tumor activity. Its beneficial effect is likely mediated by the targeted tumor antigen upregulation on PDAC cells. Our ongoing studies are assessing the in vivo efficacy and safety of the combinatorial scheme.

To date, 7 patients have been enrolled. Clinical trial information NCT04133948

As a result, up-regulation HO-1 could partially attenuate 4SC-202-suppressed MDS cells growth in NOD/SCID mice. In conclusion, 4SC-202 could induce apoptosis via the NF-κB pathway, and our present finding may provide a novel therapeutic strategy for MDS.

P1b, N=45, Recruiting, The Netherlands Cancer Institute | Not yet recruiting --> Recruiting

Drug-induced changes to the systems biology landscape are also explored by multi-omics enrichment analyses. In summary, our data indicate that 4SC-202 has both cytotoxic and cytostatic effects on ATRT, targets specific cell sub-populations, including those with cancer stem-like features, and is an important potential cancer therapeutic to be investigated in vivo.

The first patient was enrolled on January 23th, 2020. Research Funding: 4SC

Among investigational SMO inhibitors, vismodegib and sonidegib are approved for the treatment of patients with BCC, and glasdegib is approved for the treatment of patients with acute myeloid leukemia (AML). GLI-DNA-interaction inhibitors (glabrescione B and GANT61), GLI2 destabilizers (arsenic trioxide and pirfenidone) and a GLI-deacetylation inhibitor (4SC-202) were shown to block GLI-dependent transcription and tumorigenesis in preclinical studies. By contrast, SMO inhibitors can remodel the immunosuppressive TME that is dominated by M2-like tumor-associated macrophages (M2-TAMs), myeloid-derived suppressor cells and regulatory T cells, and thus, a Phase I/II clinical trial of the immune checkpoint inhibitor pembrolizumab with or without vismodegib in BCC patients is ongoing.

Not yet recruiting