Identification and experimental validation of druggable epigenetic targets in hepatoblastoma

Clavería-Cabello, Alex; Herranz, José M.; Latasa, María U.; Arechederra, María; Uriarte, Iker; Pineda‐Lucena, Antonio; Prósper, Felipe; Berraondo, Pedro; Alonso, Cristina; Sangro, Bruno; Marin, José J.G.; Martínez‐Chantar, María Luz; Ciordia, Sergio; Corrales, Fernando J.; Francalanci, Paola; Alaggio, Rita; Zucman–Rossi, Jessica; Indersie, Emilie; Cairo, Stefano; Domingo-Sàbat, Montserrat; Zanatto, Laura; Sancho‐Bru, Pau; Armengol, Carolina; Berasain, Carmen; Fernández‐Barrena, Maite G.; Avila, Matı́as A.

doi:10.1016/j.jhep.2023.05.031

Cited by 16 publications

(14 citation statements)

References 55 publications

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“…In contrast, dual targeting of both G9a and DNMT1 by the small molecule CM-272 has been reported to show significant therapeutic efficacy in hematological malignancies 27 and most liver cancer types. 40 42 43 In agreement with these data, our study demonstrates a significant reduction in tumor cell viability on CM-272 exposure in pediatric liver cancer cell lines and HB PDX models, while healthy cells remained nonresponsive toward this epigenetic perturbation. Most notably, we identified higher synergy scores when CM-272 was combined with cisplatin rather than with doxorubicin, even at low nanomolar concentrations, thereby suggesting that the combination of CM-272 and cisplatin could be an effective treatment for patients with HB.…”

Section: Discussionsupporting

confidence: 88%

“…This has been achieved by comprehensively profiling PDX-derived HB cell lines, 36 which closely mirror the original tumors by expressing high levels of IFG2, as opposed to conventional HB cell lines grown on plastic for years that have been used in former studies. 21 43 Moreover, our functional assays as well as RNA sequencing data in PDX-derived HB cell lines, highlighted that the transcriptional downregulation of IGF2 by CM-272 results in a reduced proliferation capacity of HB cells with decreased levels of the proliferation marker Ki-67 and a strong upregulation of apoptosis with increased levels of the proapoptotic protein BCL2 interacting killer. Constitutive activation of the PI3K-AKT pathway 9 through epigenetic upregulation of IGF2 10 and downregulation of IGF binding proteins 47 is, along with the CTNNB1-mediated Wnt activation, the most important mechanism involved in HB development.…”

Section: Discussionmentioning

confidence: 86%

“…This is in line with previous work on liver cancers, which showed simultaneous activation of the respective complex partners in HCC, 40 cholangiocarcinoma, 42 and just recently patients with HB. 43 The clinical association between inferior patient survival and overexpression of the individual components of the UHRF1-DNMT1-G9a complex has been shown for many adult and pediatric cancers. 26 Our previous work has also established that elevated levels of UHRF1 are predominantly observed in patients with HB with poor outcomes and the so-called C2 subtype of the 16-gene signature, 21 which defines a more aggressive subtype of HB and is associated with poor prognosis.…”

Section: Discussionmentioning

confidence: 99%

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Targeting G9a/DNMT1 methyltransferase activity impedes IGF2-mediated survival in hepatoblastoma

Demir,

Razizadeh,

Indersie

et al. 2024

Hepatology Communications

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Background: As the variable clinical outcome of patients with hepatoblastoma (HB) cannot be explained by genetics alone, the identification of drugs with the potential to effectively reverse epigenetic alterations is a promising approach to overcome poor therapy response. The gene ubiquitin like with PHD and ring finger domains 1 (UHRF1) represents an encouraging epigenetic target due to its regulatory function in both DNA methylation and histone modifications and its clinical relevance in HB. Methods: Patient-derived xenograft in vitro and in vivo models were used to study drug response. The mechanistic basis of CM-272 treatment was elucidated using RNA sequencing and western blot experiments. Results: We validated in comprehensive data sets that UHRF1 is highly expressed in HB and associated with poor outcomes. The simultaneous pharmacological targeting of UHRF1-dependent DNA methylation and histone H3 methylation by the dual inhibitor CM-272 identified a selective impact on HB patient-derived xenograft cell viability while leaving healthy fibroblasts unaffected. RNA sequencing revealed downregulation of the IGF2-activated survival pathway as the main mode of action of CM-272 treatment, subsequently leading to loss of proliferation, hindered colony formation capability, reduced spheroid growth, decreased migration potential, and ultimately, induction of apoptosis in HB cells. Importantly, drug response depended on the level of IGF2 expression, and combination assays showed a strong synergistic effect of CM-272 with cisplatin. Preclinical testing of CM-272 in a transplanted patient-derived xenograft model proved its efficacy but also uncovered side effects presumably caused by its strong antitumor effect in IGF2-driven tumors. Conclusions: The inhibition of UHRF1-associated epigenetic traces, such as IGF2-mediated survival, is an attractive approach to treat high-risk HB, especially when combined with the standard-of-care therapeutic cisplatin.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

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Targeting G9a/DNMT1 methyltransferase activity impedes IGF2-mediated survival in hepatoblastoma

Demir,

Razizadeh,

Indersie

et al. 2024

Hepatology Communications

Self Cite

View full text Add to dashboard Cite

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“…Some studies indicate that there are differences in the transcriptomic signature and epigenetic machinery of HB with varied treatment responses. These findings contribute to a deeper understanding of HB development and therapeutic responses, offering potential predictive biomarkers for personalized therapy (Song et al 2022 ; Clavería-Cabello et al 2023 ). However, the development of a simple and practical predictive model for chemotherapy response in HB is still a challenge.…”

Section: Introductionmentioning

confidence: 98%

Predicting response of hepatoblastoma primary lesions to neoadjuvant chemotherapy through contrast-enhanced computed tomography radiomics

Yang,

Wang,

et al. 2024

J Cancer Res Clin Oncol

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Objective To investigate the clinical value of contrast-enhanced computed tomography (CECT) radiomics for predicting the response of primary lesions to neoadjuvant chemotherapy in hepatoblastoma. Methods Clinical and CECT imaging data were retrospectively collected from 116 children with hepatoblastoma who received neoadjuvant chemotherapy. Tumor response was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST). Subsequently, they were randomly stratified into a training cohort and a test cohort in a 7:3 ratio. The clinical model was constructed using univariate and multivariate logistic regression, while the radiomics model was developed based on selected radiomics features employing the support vector machine algorithm. The combined clinical–radiomics model incorporated both clinical and radiomics features. Results The area under the curve (AUC) for the clinical, radiomics, and combined models was 0.704 (95% CI: 0.563–0.845), 0.830 (95% CI: 0.704–0.959), and 0.874 (95% CI: 0.768–0.981) in the training cohort, respectively. In the validation cohort, the combined model achieved the highest mean AUC of 0.830 (95% CI 0.616–0.999), with a sensitivity, specificity, accuracy, precision, and f1 score of 72.0%, 81.1%, 78.5%, 57.2%, and 63.5%, respectively. Conclusion CECT radiomics has the potential to predict primary lesion response to neoadjuvant chemotherapy in hepatoblastoma.

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“…In light of the rapid advancement of high-throughput sequencing technology, gene chip, and RNA-seq have become integral tools for investigating the molecular mechanisms underlying various diseases, screening for new biomarkers, and identifying potential drug targets [ 9 , 10 ]. However, due to sample size limitations and inter-sample variation, sequencing results for the same disease may not be entirely consistent.…”

Section: Introductionmentioning

confidence: 99%

Identification and experimental validation of druggable epigenetic targets in hepatoblastoma

Cited by 16 publications

References 55 publications

Targeting G9a/DNMT1 methyltransferase activity impedes IGF2-mediated survival in hepatoblastoma

Targeting G9a/DNMT1 methyltransferase activity impedes IGF2-mediated survival in hepatoblastoma

Predicting response of hepatoblastoma primary lesions to neoadjuvant chemotherapy through contrast-enhanced computed tomography radiomics

Identification of novel potential drugs for the treatment and prevention of osteoarthritis

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