fimepinostat (CUDC-907)

TRIM21 may represent a therapeutic target for tumors, and inhibiting TRIM21 could be a potential strategy for tumor treatment.

Our study demonstrated most t-SCLC showed neuronal subtypes with low EGFR expression. DEGs analysis and t-SCLC preclinical models identified an epigenetic modifier as a promising treatment strategy for t-SCLC.

P1, N=26, Active, not recruiting, Dana-Farber Cancer Institute | Trial completion date: Jul 2024 --> Jan 2025 | Trial primary completion date: Jul 2024 --> Jan 2025

P1, N=26, Active, not recruiting, Dana-Farber Cancer Institute | Trial completion date: Jan 2024 --> Jul 2024 | Trial primary completion date: Jan 2024 --> Jul 2024

Reactivating this pathway using fimepinostat, which relieves inhibitory signaling directed at PTEN and increases FBXW7 expression, combined with inhibiting Aurora-A with alisertib, suppressed breast cancer cell proliferation in culture and tumor growth in vivo. The findings demonstrate a therapeutically exploitable, tumor-suppressive role for eEF1A2 in breast cancer.

Through the utilization of western blotting analyses, targeted inhibitors, and ectopic overexpression, we propose that the downregulation of Wee1, CHK1, RNR, and c-Myc are the potential mechanisms. Our data support the development of ADA in combination with CUDC-907 for the treatment of AML.

Fimepinostat therapy was also associated with the suppression of lineage transcription factors including AR in ARPC and Achaete-scute homolog 1 (ASCL1) in NEPC. Together, these results indicate that fimepinostat represents a novel therapeutic that may be effective against both ARPC and NEPC through CRPC subtype-dependent and -independent mechanisms.

Our results showed that CUDC-907 had powerful anti-tumor effects on OC, which could provide a theoretical and experimental basis for the application of CUDC-907 in the therapy of OC.

Upregulation of the NET by CUDC-907 lead to a better internalization of mIBG in vitro and in vivo.

P1, N=26, Active, not recruiting, Dana-Farber Cancer Institute | Trial primary completion date: Jul 2023 --> Jan 2024

MYC is a potent driver of platinum resistance in SCLC that is effectively treated with fimepinostat.

P1, N=26, Active, not recruiting, Dana-Farber Cancer Institute | Recruiting --> Active, not recruiting | N=44 --> 26

Our lab has previously demonstrated the promising outlook for CUDC-907, a dual inhibitor of PI3K and HDAC, in combination with venetoclax (VEN), against AML both in vitro and in vivo at least partially through suppression of c-Myc...CUDC-907 synergized with VEN in inducing apoptosis in the AraC-resistant AML cells. In conclusion, the CUDC-907 and VEN combination induces metabolic and transcriptomic reprograming and sup-pression of OXPHOS in AML, which provides additional mechanisms underlying the synergy between the two agents.

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).

Our findings suggested the clinical development and administration of CUDC-907 might act as a novel treatment strategy for ESCC. A more in-depth understanding of the anti-tumor effect of CUDC-907 in ESCC will benefit the clinically targeted treatment of ESCC.

P1, N=44, Recruiting, Dana-Farber Cancer Institute | Trial completion date: Dec 2022 --> Dec 2023 | Trial primary completion date: Jul 2022 --> Jul 2023

Its efficacy correlated with basal phospho-HDAC2 levels. CUDC907 has cytotoxic activity in NF2 schwannoma models and primary VS cells and is a candidate for clinical trials.

Mechanistically, we demonstrated that EWS-FLI1 protein levels were mainly regulated by fimepinostat's HDAC activity. Our study demonstrates that HTS combined to GPS is a reliable approach to identify drug candidates able to modulate stability of EWS-FLI1 and lays new ground for the development of novel therapeutic strategies aimed to reduce Ewing sarcoma tumor progression.

P1, N=44, Recruiting, Dana-Farber Cancer Institute | Trial completion date: Jun 2022 --> Dec 2022 | Trial primary completion date: Dec 2021 --> Jul 2022

Furthermore, CUDC-907 significantly inhibits NB tumor growth in a 3D spheroid tumor model that recapitulates the in vivo tumor growth. Overall, our findings highlight that the dual inhibition of PI3K and HDAC by CUDC-907 is an effective therapeutic strategy for NB and other MYC-dependent cancers.

Prolonged durations of response were achieved by patients with MYC-altered R/R DLBCL/HGBL treated with single-agent fimepinostat. Combination therapies and/or biomarker-based patient selection strategies may lead to higher response rates in future clinical trials.

P1, N=44, Recruiting, Dana-Farber Cancer Institute | Trial primary completion date: Jun 2021 --> Dec 2021

In addition, the combined treatment results in cooperative downregulation of cellular metabolites and persisting antileukemic effects. CUDC-907 plus gilteritinib shows synergistic antileukemic activity against FLT3-ITD AML in vitro and in vivo, demonstrating strong translational therapeutic potential.

P1, N=106, Completed, Curis, Inc. | Active, not recruiting --> Completed | N=180 --> 106

The combination of an HDAC and an Akt inhibitor represents a promising approach for the treatment of relapsed/refractory MM.

Our previous work demonstrated that a novel dual inhibitor of PI3K and HDAC, CUDC-907, synergizes with venetoclax by overcoming these resistance mechanisms in bulk AML cells and suppressing c-Myc expression and mTOR activity. Finally we will confirm that these two drugs when combined, reduce the number of LSCs in primary patient samples with a PDX model and flow cytometry for known LSC markers, CD38, CD34 & CD123. The results of this study will form a solid foundation for the clinical evaluation of this promising combination therapy for the treatment of AML and potentially reduce the incidence of relapse.

Data from this study suggested that the administration of CUDC-907 might be a powerful strategy against myeloma cells, to enhance the cytotoxic effects of proteasome inhibitors.

Interestingly, we discovered that L1CAM expression could be induced in the 22Rv1 cell line in response to treatment with the pan-histone deacetylase (HDAC) inhibitor fimepinostat... Our work indicates that L1CAM CAR T cells demonstrate antigen-specific activation and killing of SCNPC in vitro. In addition, pan-HDAC inhibition of 22Rv1 provokes L1CAM expression—likely through epithelial-to-mesenchymal transition—and induces a vulnerability to L1CAM CAR T cell therapy. Characterization of the activity of L1CAM CAR T cells in disseminated tumor models of SCNPC in vivo is ongoing.

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.

Our study uncovers that dual PI3K and HDAC inhibition by CUDC-907 exerts significant single-agent activity and strong synergistic effects with PARP inhibitor olaparib in SCLC, which thus provides a rational combination treatment strategy for SCLC clinical investigation.

P1, N=44, Recruiting, Dana-Farber Cancer Institute | Trial completion date: Oct 2022 --> Jun 2022 | Trial primary completion date: Oct 2020 --> Jun 2021

CUDC-907 may be a potential therapeutic agent for ATL.

In addition, CUDC-907 treatment decreases leukemia progenitor cells in primary acute myeloid leukemia samples ex vivo, while also sparing normal hematopoietic progenitor cells. These findings support the clinical development of CUDC-907 for the treatment of acute myeloid leukemia.

Our data indicate that, apart from its known functions, CUDC-907 blocks multiple pro-survival pathways to overcome microenvironment protection in CLL cells. This provides a rationale to evaluate the clinical relevance of CUDC-907 in combination therapies with other targeted inhibitors.

In the LuCaP 35CR PDX model, treatment with CUDC-907 resulted in significant inhibition of tumour growth. These findings support the clinical development of CUDC-907 for the treatment of prostate cancer.

This study sought to identify differences in transcript-level signatures of gene networks in pre-treatment tumor samples associated with future clinical response to F. Among 105 patients (pts) with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) treated in phase 1/2 clinical trials of F (± rituximab), 33 pts had pre-treatment tumor biopsy samples available for molecular testing. GSEA analysis of genes upregulated in the F-treated responder DLBCL pts are consistent with preclinical data showing that F functions to suppress MYC in tumor cells. F is currently undergoing active clinical study in combination with venetoclax for the treatment of R/R DLBCL or high grade B-cell lymphoma (HGBL): NCT01742988. Research Funding: Curis, Inc.

P1, N=180, Active, not recruiting, Curis, Inc. | Recruiting --> Active, not recruiting

In summary, CUDC-907 shows potent cytotoxicity against breast cancer cells and facilitates TRAIL-mediated apoptosis through DR5 upregulation. The combination of CUDC-907 and TRAIL may be a promising therapeutic approach in the treatment of breast cancer.

Interestingly, we found that venetoclax treatment enhances CUDC-907-induced DNA damage potentially through inhibition of DNA repair. In vivo results show that CUDC-907 enhances venetoclax efficacy in an acute myeloid leukemia cell line derived xenograft mouse model, supporting the development of CUDC-907 in combination with venetoclax for the treatment of acute myeloid leukemia.

P1, N=180, Recruiting, Curis, Inc. | Phase classification: P1/2 --> P1

Lenalidomide (Len) selectively binds to cereblon (CRBN), which mediates recruitment of specific substrates like IKZF1 to E3 ubiquitin ligase and subsequent degradation, resulting in downregulation of IRF-4 and c-Myc...We observed that ADCC activity of both daratumumab and elotuzumab against MM cells was enhanced in the presence of HDAC inhibitors, which was compatible with our previous data that HDAC inhibitors upregulated MICA mRNA expression via inhibition of IKZF1 (ASH2018 abstract #4435)...Afuresertib, an AKT inhibitor, suppressed GSK-3 phosphorylation (p-GSK-3) with or without ACY-1215, an HDAC inhibitor, leading to a substantial decrease of c-Myc (Figure 2)...Bortezomib, doxorubicin, and dexamethasone resistant MM cell lines were also sensitive to CUDC-907...Furthermore, CUDC-907 was effective on primary MM cells which were resistant to bortezomib and Len (Figure 5). Thus, dual inhibition of HDAC and AKT with or without monoclonal antibodies is a promising therapeutic approach to multi-drug resistant MM.