Volasertib preclinical activity in high-risk hepatoblastoma

Kats, Dina; Ricker, Cora A.; Berlow, Noah; Noblet, Bénédicte; Nicolle, Delphine; Mevel, Katell; Branchereau, Sophie; Judde, Jean-Gabriel; Stiverson, Cody D; Stiverson, Christina L; Svalina, Matthew N.; Settelmeyer, Teagan P.; Matlock, Kevin; Lathara, Melvin; Mussini, Charlotte; Geller, James I.; Noakes, Christopher; Sloma, Ido; Bharathy, Narendra; Cairo, Stefano; Keller, Charles

doi:10.18632/oncotarget.27237

Cited by 21 publications

(24 citation statements)

References 46 publications

(67 reference statements)

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“…These intriguing findings deserve further preclinical exploration and a deeper investigation for a clinical trial concept. 104 Enhancer of Zeste homolog 2 (EZH2) is a histone-lysine N-methyltransferase participating in histone methylation and transcriptional repression. 105,106 Perturbations of EZH2 levels have been described in many forms of cancer.…”

Section: Igf Pathwaymentioning

confidence: 99%

Molecular Mechanisms of Hepatoblastoma

et al. 2021

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Hepatoblastoma (HB) is the predominant primary liver tumor in children. While the prognosis is favorable when the tumor can be resected, the outcome is dismal for patients with progressed HB. Therefore, a better understanding of the molecular mechanisms responsible for HB is imperative for early detection and effective treatment. Sequencing analysis of human HB specimens unraveled the pivotal role of Wnt/β-catenin pathway activation in this disease. Nonetheless, β-catenin activation alone does not suffice to induce HB, implying the need for additional alterations. Perturbations of several pathways, including Hippo, Hedgehog, NRF2/KEAP1, HGF/c-Met, NK-1R/SP, and PI3K/AKT/mTOR cascades and aberrant activation of c-MYC, n-MYC, and EZH2 proto-oncogenes, have been identified in HB, although their role requires additional investigation. Here, we summarize the current knowledge on HB molecular pathogenesis, the relevance of the preclinical findings for the human disease, and the innovative therapeutic strategies that could be beneficial for the treatment of HB patients.

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Section: Igf Pathwaymentioning

confidence: 99%

Molecular Mechanisms of Hepatoblastoma

et al. 2021

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“…Spheroids mimic 3D architecture of solid tumors and offer tissue-like environment for cancer drug research (55). The patient-derived HB models used here recapitulate the characteristics of advanced and aggressive original HB tumors (50). Taken together, our results demonstrate decreased cell viability and activation of apoptotic cell death as response to CQ treatment in these HB cell models.…”

Section: Discussionmentioning

confidence: 58%

“…Since traditional 2D cell cultures do not accurately represent the architecture and interactions of solid tumors, we assayed the effect of CQ treatment using 3D HB spheroid models. Six of the cell lines used in this study were established from aggressive HB tumors (Clinical details in Table 1) thus representing a situation of an unfavorable treatment outcome for first line therapy (50). The seventh cell line, HUH6, is a gold standard in HB research.…”

Section: Hb Spheroids Treated With Cq Show Decreased Atp Availabilitymentioning

confidence: 99%

Chloroquine Triggers Cell Death and Inhibits PARPs in Cell Models of Aggressive Hepatoblastoma

Eloranta

Cairo²,

Liljeström

et al. 2020

Front. Oncol.

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Background: Hepatoblastoma (HB) is the most common pediatric liver malignancy. Despite advances in chemotherapeutic regimens and surgical techniques, the survival of patients with advanced HB remains poor, underscoring the need for new therapeutic approaches. Chloroquine (CQ), a drug used to treat malaria and rheumatologic diseases, has been shown to inhibit the growth and survival of various cancer types. We examined the antineoplastic activity of CQ in cell models of aggressive HB. Methods: Seven human HB cell models, all derived from chemoresistant tumors, were cultured as spheroids in the presence of relevant concentrations of CQ. Morphology, viability, and induction of apoptosis were assessed after 48 and 96 h of CQ treatment. Metabolomic analysis and RT-qPCR based Death Pathway Finder array were used to elucidate the molecular mechanisms underlying the CQ effect in a 2-dimensional cell culture format. Quantitative western blotting was performed to validate findings at the protein level. Results: CQ had a significant dose and time dependent effect on HB cell viability both in spheroids and in 2-dimensional cell cultures. Following CQ treatment HB spheroids exhibited increased caspase 3/7 activity indicating the induction of apoptotic cell death. Metabolomic profiling demonstrated significant decreases in the concentrations of NAD + and aspartate in CQ treated cells. In further investigations, oxidation of NAD + decreased as consequence of CQ treatment and NAD + /NADH balance shifted toward NADH. Aspartate supplementation rescued cells from CQ induced cell death. Additionally, downregulated expression of PARP1 and PARP2 was observed. Conclusions: CQ treatment inhibits cell survival in cell models of aggressive HB, presumably by perturbing NAD + levels, impairing aspartate bioavailability, and inhibiting PARP expression. CQ thus holds potential as a new agent in the management of HB.

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“…48 Investigators used volasertib to inhibit PLK-1 function in HB cells, leading to decreased viability and proliferation. 50 Volasertib also showed synergistic effects on tumor growth inhibition in mice when combined with irinotecan. 50 Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase that has been explored in HB.…”

Section: Kinases and Phosphatasesmentioning

confidence: 99%

“…50 Volasertib also showed synergistic effects on tumor growth inhibition in mice when combined with irinotecan. 50 Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase that has been explored in HB. 51 PP2A, a tumor suppressor, has been shown to be inactivated in a number of cancers.…”

Section: Kinases and Phosphatasesmentioning

confidence: 99%

Novel therapeutics in hepatoblastoma

Wadhwani

Marayati

Beierle

2020

MRAJ

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Hepatoblastoma is the most common primary liver malignancy in children less than 5 years of age. The incidence of this cancer is increasing but therapy for hepatoblastoma has not significantly changed and it is primarily managed with combinations of surgery and chemotherapy. Conventional chemotherapy regimens include cisplatin, as it is currently the most effective agent for this tumor. Unfortunately, with the current modalities, the prognosis for advanced-stage disease remains poor due to the high rate of recurrence and/or the development of chemoresistance. As the understanding of the pathophysiology of hepatoblastoma deepens, there is a burgeoning interest in developing novel therapeutic agents for hepatoblastoma, including targeted therapies. In the current review, we discuss the use of major signaling pathways and their effector molecules such as βcatenin, c-MET, mTOR, PIM kinases, and PLK1 as therapeutic targets. In addition, we explore various alternative pre-clinical approaches that have been described in hepatoblastoma, including immunotherapy, differentiation agents, micro-RNAs, and targeted drug delivery. Finally, we outline the therapies currently under investigation in pre-clinical and clinical settings that show promising preliminary results for hepatoblastoma treatment.

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Volasertib preclinical activity in high-risk hepatoblastoma

Cited by 21 publications

References 46 publications

Molecular Mechanisms of Hepatoblastoma

Molecular Mechanisms of Hepatoblastoma

Chloroquine Triggers Cell Death and Inhibits PARPs in Cell Models of Aggressive Hepatoblastoma

Novel therapeutics in hepatoblastoma

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