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Combination of CDK4/6 with BET-bromodomain and PI3K/mTOR inhibitors in medulloblastoma in vitro and in vivo

ABSTRACT: Despite improvement in the treatment of medulloblastoma (MB) over the last years, numerous patients with MYC- and MYCN-driven tumors still fail the current therapeutic regimen. The retinoblastoma (RB) pathway is often compromised in MB with RB remaining intact suggesting that CDK4/6 inhibition might represent a therapeutic strategy for which drug combination remains understudied. Using tumor lines grown in stem cell conditions referred as tumorspheres as well as tumor cells freshly dissociated from the brain of mice harboring intracranial patient-derived xenografts (PDX) of Group3 (G3) and Sonic Hedgehog (SHH) MB, we conducted high throughput drug combination screens using the CDK4/6 inhibitor (CDK4/6i) ribociclib as an anchor and 87 oncology drugs approved by FDA or currently in clinical trials. Bromodomain and extra terminal (BET) and PI3K/mTOR inhibitors potentiated ribociclibÃ¢Â€Â™s inhibition of proliferation in G3 and SHH MB. A reverse combination screen using BET inhibitor JQ1 as the anchor, revealed the three FDA approved CDK4/6i as the most potentiating drugs. Those synergistic combinations were tested in vivo in mice intracranially implanted with G3 and SHH MB tumor cells. Ribociclib showed single agent activity in several in vivo MB models. However, despite in vitro synergy, combinations of ribociclib with JQ1 and ribociclib with the PI3K/mTOR inhibitor paxalisib failed to improve the survival of MB bearing mice compared to ribociclib alone. Our data illustrates the difficulty in translating in vitro findings to in vivo for brain tumors partly due to insufficient free brain concentration and altered signaling pathways activation in vitro compared to in vivo.

PROVIDER: EGAS00001006286 | EGA |

REPOSITORIES: EGA

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Combination ofÃ‚Â ribociclibÃ‚Â andÃ‚Â gemcitabineÃ‚Â forÃ‚Â theÃ‚Â treatment ofÃ‚Â medulloblastoma

Project description:Group 3 (G3) medulloblastoma (MB) is one of the deadliest forms of the disease for which novel treatment is desperately needed. Here we evaluate ribociclib, a highly selective CDK4/6 inhibitor, with gemcitabine in mouse and human G3 MBs. Ribociclib CNS penetration was assessed by in vivo microdialysis and by immunohistochemistry and gene expression studies. Survival studies to determine the efficacy of ribociclib and gemcitabine combination were performed on mice orthotopically implanted with luciferase labelled mouse and human G3 MB. Pharmacokinetic-pharmacodynamic outcomes and univariable survival models were analyzed to estimate survival. Gene activity inference using NetBID and tumor differentiation analysis investigated the effects of the combination after short and long-term treatments. Tumors from mice treated with oral ribociclib displayed inhibited RB phosphorylation, downregulated E2F target genes, and decreased proliferation. Treatment of mice with the combination of ribociclib and gemcitabine was well tolerated, slowed tumor progression and metastatic spread, and increased survival. Molecular analysis of treated versus untreated tumors showed a significant decrease in the activity and expression of genes involved in cell cycle progression and DNA damage response, and an increase in activity and expression of genes implicated in neuronal identity and neuronal differentiation. Ribociclib is CNS-penetrant. When administered/combined with gemcitabine in orthotopic G3 MB models resulted in improved survival. Our findings, with both mouse and human patient-derived-orthotopic xenograft models, suggest that this combination therapy has promise for children with G3 MB and may represent an effective treatment strategy for other CNS malignancies.

| EGAS00001006001 | EGA

Proteomic research on effect of EIF4A1 inhibition in MYC-amplified Group 3 medulloblastoma

Project description:As the most life-threatening subtype of pediatric medulloblastoma (MB), MYC-amplified Group 3 (G3) MB lacks effective and selective therapeutics. We tried to indirectly target MYC (oncogenic driver and cancer-dependent molecule) production via inhibiting translational machinery. Through multiple datasets analyses on components of eIF4F (eukaryotic translation initiation factor 4F) complex, we found that EIF4A1 (major component with RNA helicase activity) has relatively higher expression level and the closest positive correlation with MYC in G3-MB among normal control and other 3 subtypes (e.g., WNT, SHH and G4). Both in vitro and in vivo experiments with MYC-amplified G3-MB cell lines showed effective growth inhibition upon EIF4A1 knockout or inhibitor treatment. Further FACS analysis found decreased cell proliferation and enhanced apoptosis on EIF4A1 inhibitor treatment. To explore the mechanisms of EIF4A1 inhibition on arresting MYC-amplified G3-MB, we performed the whole proteome analyses on corresponding MB cells treated with EIF4A1 inhibitor.

2020-10-15 | PXD022014 |

Spatial transcriptomic analysis of Sonic Hedgehog Medulloblastoma identified that loss of heterogeneity and promotion of differentiation underlies the response to CDK4/6 inhibition

Project description:We used spatially resolved transcriptomics to define the cellular diversity within a sonic hedgehog (SHH) patient-derived model of Medulloblastoma (MB) and identify how cells specific to a transcriptional state or spatial location are pivotal in responses to treatment with the CDK4/6 inhibitor, Palbociclib. Our analysis reveals that SHH tumour in the mouse brain contains multiple malignant transcriptional states, recapitulating the extent of intratumoural cellular diversity identified in primary human SHH MB. Our study offers new insight into the previously described features of CDK4/6 inhibition in MB, with Palbociclib treatment inducing neuronal differentiation across all remaining cell types comprising the bulk of the SHH patient-derived orthotropic xenograft model. This study is, to the best of our knowledge, the first spatially resolved gene expression atlas of SHH PDOX MB and acts as proof-of-principle for the use of ST-seq in identifying spatially-organised tumour heterogeneity of MB.

2022-06-16 | E-MTAB-11720 | biostudies-arrayexpress

HDAC5 loss impairs RB repression of oncogenic related genes and confers CDK4/6 inhibitor resistance in cancer [ChIP-seq]

Project description:The tumor suppressor protein RB acts as a transcription repressor via the interaction of its pocket domain with an L/IXCXE motif in HDAC proteins such as HDAC1. Here we demonstrated that while lacking an L/IXCXE motif, HDAC5 interacts with both RB-N (via an FXXXV motif) and RB-C segments and this interaction is diminished by RB serine-249/threonine-252 and threonine-821 phosphorylation. HDAC5 gene is frequently downregulated or deleted in human cancers such as prostate cancer. Loss of HDAC5 increases histone H3 lysine 27 acetylation (H3K27-ac) and circumvents RB-mediated repression of cell cycle-related oncogenic genes. Accordingly, HDAC5 loss confers resistance to the CDK4/6 inhibitors such as Palbociclib in prostate cancer cells in vitro and in mice, but this effect is overcome by the BET-CBP/p300 dual inhibitor NEO2734. Our findings reveal an unknown role of HDAC5 in RB-mediated histone deacetylation and gene repression and a mechanism modulating CDK4/6 inhibitor therapeutic sensitivity in cancer cells.

2021-07-24 | GSE155003 | GEO

HDAC5 loss impairs RB repression of oncogenic related genes and confers CDK4/6 inhibitor resistance in cancer [RNA-seq]

2021-07-24 | GSE155001 | GEO

Inhibition of CK1e potentiates the therapeutic efficacy of CDK4/6 inhibitor in breast cancer

Project description:In this study, we found that combination treatment of breast cells with CK1 inihbitor (D 4476) and CDK4/6 inhibitor (Ribociclib) exhibited greatly enhanced therapeutic efficacy than CDK4/6 inhiitor single treatment

2021-08-10 | GSE177054 | GEO

Myc and N-myc induce distinct medulloblastoma subgroups via Miz1

Project description:Medulloblastomas (MBs) are cerebellar tumors that can be classified into molecularly distinct subgroups that differ in pathology and prognosis. The mechanisms that underlie subgroup specification are largely unknown. While human SHH MBs express MYCN, Group3 (G3) MBs are associated with c-MYC (MYC) overexpression and often show metastasis that confers a poor prognosis. Although MYC proteins are thought to be functionally exchangeable, ectopic expression of Myc or N-myc in Trp53-/-;Cdkn2c-/- cerebellar granule neuron progenitors (GNPs) induces G3 and SHH MBs, respectively, demonstrating that each Myc protein has distinct biological properties. We now show that Myc and N-myc differ in their affinity to Miz1 and that Myc, but not N-myc, effectively recruits Miz1 to its target sites on chromatin. The interaction of Myc with Miz1 is required for the genesis of G3 MB. Myc suppresses ciliogenesis and “reprograms” the transcriptome of SHH-dependent GNPs to stem-like cells by repressing genes highly expressed in SHH MB via Miz1. Consistently, target genes of Myc/Miz1 are repressed in human G3 MBs but not in other MB subgroups. Collectively, the data show that the interaction of Myc with Miz1 is a defining hallmark of G3 MB development.

2016-01-21 | GSE66093 | GEO

Rb and the APC/C coactivator FZR1 determine CDK4/6-Cyclin D requirement in C. elegans and human cancer cells

Project description:Cyclin dependent kinase 4 and 6 (CDK4/6) in complex with D-type cyclins promote cell cycle entry, at least in part through phosphorylation of the retinoblastoma tumor suppressor protein (Rb). The CDK4/6-cyclin D-Rb pathway is commonly deregulated in human cancer, often through CDK4/6 or D-type cyclin overexpression, or inactivation of the CDK4/6 antagonist p16/CDKN2A. Importantly, a substantial fraction of cancers depend on continuous CDK4/6-cyclin D kinase activity and are sensitive to CDK4/6-specific inhibitors. Here, we investigate critical CDK4/6-cyclin D functions that may determine the sensitivity to CDK4/6 inhibitors, making use of the essential roles of CDK4/6 (CDK-4) and cyclin D (CYD-1) in the nematode C. elegans. In an unbiased screen, we found that simultaneous loss of C. elegans Rb (lin-35) and down-regulation of the APC/C substrate specificity factor FZR1/Cdh1 completely overcomes CDK-4/CYD-1 requirement. Furthermore, CDK-4/CYD-1 phosphorylates specific residues in the LIN-35 Rb spacer domain and FZR-1 N-terminus that correspond to inactivating phosphorylations of the human homologs. Thus, CDK-4/CYD-1 appears to promote cell cycle entry by antagonizing not only transcriptional repression by LIN-35 Rb but also protein degradation by APC/CFZR-1. Simultaneous knockdown of Rb and FZR1 in human breast cancer cells synergistically overcomes arrest by the CDK4/6-specific inhibitor PD 00332991. These results reveal APC/CFZR1 as a putative CDK4/6-Cyclin D target and important contributing factor in the response to CDK4/6-inhibitor treatment.

2016-07-05 | PXD001501 | Pride

SAR-096: Phase II clinical trial of ribociclib in combination with everolimus in advanced dedifferentiated liposarcoma (DDL), and leiomyosarcoma (LMS)

Project description:Purpose: DDL and LMS are two common subtypes of soft tissue sarcoma, a rare group of diseases for which new treatments are needed. Chemotherapy remains the standard option for advanced disease. Targeting CDK4/6 in DDL and mTOR in LMS is of biologic interest. When combined, the CDK4 inhibitor ribociclib and the mTOR inhibitor everolimus, have shown synergistic growth inhibition in multiple tumor models, suggesting that this combination could be beneficial in patients.Methods: This was a single arm, open label, multi-center phase II study of the combination of ribociclib and everolimus. Patients were enrolled into one of two cohorts: DDL or LMS with intact Rb. The primary endpoint was progression free rate (PFR) at 16 weeks. Secondary endpoints included progression free (PFS) and overall survival, safety and biomarker analyses. Results: In the DDL cohort, 33.3% (95% CI 15.6%-55.3%) of patients were progression free at 16 weeks. Median PFS in this cohort was 15.4 weeks (95% CI, 8-36 weeks) with 2 partial responses. In the LMS cohort the PFR at 16 weeks was 29.2% (95% CI 12.6%-51.1%). Median PFS in this cohort was 15.7 weeks (95% CI 7.7-NA). Most common toxicities included fatigue (66.7%), anorexia (43.8%) and hyperglycemia (43.8%). Concordance between Rb testing methodologies was poor.Conclusions: The combination of ribociclib and everolimus demonstrates activity in DDL with prolonged stable disease (≥16 weeks) meeting the primary endpoint. Notably partial responses were observed. The primary endpoint was not reached in the LMS cohort. The combination was well tolerated with expected side effects.

2023-11-09 | GSE247026 | GEO

The MYC-MIZ1 interaction defines tumor identity

Project description:Medulloblastoma (MB) is the most common malignant brain tumor. MB is a cerebellar tumor that occurs mostly in children between the ages of 3-7 years but also in adults. Human MBs are classified into four subgroups: Wingless (WNT), Sonic Hedgehog (SHH), Group 3 (G3) and G4, each of which with distinct molecular signatures. SHH MBs with MYCN amplification and TP53 mutations and G3 MBs characterized by C-MYC (MYC) overexpression in ~17% of cases from gene amplification with stem like properties, are the most aggressive and least curable with current therapeutic regimen. Using an orthotopic transplant approach, we found that enforced expression of MYCN in cerebellar granule neural progenitors (CGNPs) from 5-7 days old Trp53-null mice induced SHH MBs after transfer in the cortices or cerebella of naive recipient mice. In contrast, overexpression of MYC induced G3 MBs. Because MYCN and MYC bind to the same E-box DNA sequences, we hypothesized that the difference between MYC and MYCN-induced gene expression and tumor identity might be due to their interaction with different partners in CGNPs. In this study, we investigated the role of the Myc interacting zinc finger protein 1 (MIZ1). We found that MIZ1 binds with higher affinity to MYC than to MYCN and that MIZ1 and MYC co-occupy thousands of promoters in G3 MB. Remarkably, enforced expression of a MYC mutant (MYCV394D) that no longer binds to MIZ1 in Trp53-null CGNPs or expression of wild type MYC in CGNPs that lack functional Miz1 resulted in massive changes of the resulting tumor’s transcriptional program. Tumors differed from both SHH and G3 medulloblastoma and had a later time of onset compared to MYC-driven G3 medulloblastoma. Our data demonstrate that interaction of MYC with MIZ1 is required for the development of G3 medulloblastoma.

2016-01-21 | GSE64425 | GEO

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