Effective inhibition of MYC-amplified group 3 medulloblastoma by FACT-targeted curaxin drug CBL0137

Abstract

Medulloblastoma (MB) is the most common malignant pediatric brain tumor that can be categorized into four major molecular subgroups. Group 3 MB with MYC amplification (MYCamp-G3-MB) has been shown to be highly aggressive and exhibited worst prognosis, indicating the need for novel effective therapy most urgently. A few epigenetic targeted therapeutic strategies have recently been proven to effectively treat preclinical models of MYCamp-G3-MB, including BET inhibition, HDAC inhibition and SETD8 inhibition, unveiling a promising direction for further investigation. In this study, we carried out systemic bioinformatic analyses of public-available MB datasets as well as functional genomic screening datasets of primary MYCamp-G3-MB lines to search for other potential therapeutic targets within epigenetic modulators. We identified SSRP1, a subunit of histone-chaperone FACT complex, to be the top drug target candidate as it is highly cancer-dependent in whole-genome CRISPR-Cas9 screening across multiple MYCamp-G3-MB lines; significantly upregulated in MYCamp-G3-MB compared to normal cerebellum and most of the rest MB subtypes; its higher expression is correlated with worse prognosis; and it has a blood-brain-barrier penetrable targeted drug that has entered early phase human clinical trials already. Then we utilized RNA-interference approach to verify the cancer-dependency of SSRP1 in multiple MYCamp-G3-MB lines and further confirmed the therapeutic efficacy of FACT-targeted curaxin drug CBL0137 on treating preclinical models of MYCamp-G3-MB in vitro and in vivo, including an orthotopic intracranial xenograft model. Mechanistically, transcriptome analyses showed CBL0137 preferentially suppressed cell-cycle and DNA-repair related biological processes. Moreover, it selectively disrupted transcription of MYC and NEUROD1, two critical oncogenic transcription factors of MYCamp-G3-MB, via depleting FACT complex from their promoter regions. In summary, our study demonstrates FACT-targeted CBL0137 works effectively on treating MYCamp-G3-MB, presenting another promising epigenetic-targeted therapeutic strategy against the most devastating form of MB.

Exploring the Interaction of Curaxin CBL0137 with G-Quadruplex DNA Oligomers

“…The relative small dimension of the flat aromatic portion of the molecule favors the entrance between the base pairs promoting the exchange among different sites. Overall, the results are in agreement with the literature’s available cellular data [ 4 , 14 , 15 , 17 ] and suggest that the interaction with G-quadruplex DNA may play a role in the anticancer activity of curaxin CBL0137. The molecular models here built for the complexes with DNA G-quadruplex structures could be a precious source of inspiration for the design of curaxin-related more active and selective DNA-binding ligands.…”

“…In particular, numerous in vivo and in vitro experimental evidences, including inhibition of c-MYC expression, DNA methyltransferase inhibition, and chromatin remodelling, could be consistent with curaxin DNA G-quadruplex binding [ 4 , 14 , 15 , 17 , 18 , 19 ].…”

“…Among curaxins, CBL0137 ( Figure 1 ), appeared the most suitable for further development, on the basis of its metabolic stability, solubility and activity in vivo. CBL0137 suppressed tumor growth in xenograft models of colon (DLD-1), renal cell carcinoma (Caki-1) [ 3 ], medulloblastoma [ 4 ], small-cell lung cancer [ 5 , 6 ], melanoma (Mel-7) and transplanted surgical samples from patients with pancreatic ductal adenocarcinoma [ 7 ].…”

Kidney cancer biomarkers and targets for therapeutics: survivin (BIRC5), XIAP, MCL-1, HIF1α, HIF2α, NRF2, MDM2, MDM4, p53, KRAS and AKT in renal cell carcinoma

“…Since then, the research rapidly expanded into other human cancers in the preclinical studies for the small molecule drug CBLC137 (CBL0137). This includes human pancreatic cancer [ 145 ]; neuroblastoma [ 146 ]; glioblastoma [ 147 – 149 ]; extremity melanomas [ 150 ]; small cell lung cancer [ 151 , 152 ]; hepatocellular carcinoma [ 153 ]; leukemia [ 154 ]; and medulloblastoma [ 155 ]. Importantly, a phase 1 clinical trial result of CBL0137 from cancer patients with solid tumors was communicated at the ASCO 2020 Annual meeting [ 156 ].…”

Relapsed Medulloblastoma in Pre-Irradiated Patients: Current Practice for Diagnostics and Treatment

“…The underlying molecular drivers for MB Group3 and MB Group4 remain to be fully characterised and therefore no specific targeted treatments are currently available. Indirectly targeting MYC continues to be explored in MB Group3 with therapies such as bromodomain inhibitors [ 182 , 183 , 184 , 185 , 186 ]. For MB Group4 there may be a role for epigenetic-based therapies such as demethylating agents (decitabine and azacitidine) and histone deacetylase inhibitors (vorinostat and panobinostat) [ 182 , 187 , 188 ].…”