A novel treatment strategy utilizing panobinostat for high-risk and treatment-refractory hepatoblastoma

Espinoza, Andres F.; Patel, Roma H.; Patel, Kalyani R.; Badachhape, Andrew A.; Whitlock, Richard; Srivastava, Rohit K.; Govindu, Saiabhiroop R.; Duong, Ashley; Kona, Abhishek; Kureti, Pavan; Armbruster, Bryan; Kats, Dina; Srinivasan, Ramakrishnan R.; Dobrolecki, Lacey E.; Yu, Xinjian; Najaf Panah, Mohammad J.; Zorman, Barry; Sarabia, Stephen F.; Urbicain, Martin; Major, Angela; Bissig, Karl-Dimiter; Keller, Charles; Lewis, Michael T.; Heczey, Andras; Sumazin, Pavel; López-Terrada, Dolores H.; Woodfield, Sarah E.; Vasudevan, Sanjeev A.

doi:10.1016/j.jhep.2024.01.003

Cited by 4 publications

(2 citation statements)

References 33 publications

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“…These findings are consistent with previous studies showing that the HDAC inhibition by SAHA in HepG2 cells increased cisplatin's ability to eliminate cancer cells [22]. Further, Espinoza et al have recently reported that the inhibited HDAC activity by panobinostat suppresses tumor growth in patient-derived spheroids and in PDX models [23]. Panobinostat likely utilizes similar molecular mechanisms, including the inhibition of HDAC1-Sp5 and the elevation of p21.…”

Section: Discussionsupporting

confidence: 91%

“…In this regard, examinations of precise molecular mechanisms of HDAC-dependent epigenetic alterations in HBL patients revealed that HDAC1 and transcription factor Sp5 are elevated in HBL, form HDAC1-Sp5 complexes, and repress the expression of hepatocyte markers and inhibitor of proliferation p21 [10]. In agreement, it has been shown that inhibited HDAC activity in patient-derived xenograft (PDX) models inhibits the growth of implanted tumors [23]. Despite progress being made in the study of HDAC activity within pediatric liver cancers, little is known about the metastatic cancer cells that are potentially driven by HDAC signaling.…”

Section: Introductionmentioning

confidence: 82%

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Inhibition of Histone Deacetylase Activity Increases Cisplatin Efficacy to Eliminate Metastatic Cells in Pediatric Liver Cancers

Gulati,

Fleifil,

Jennings

et al. 2024

Cancers

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The pediatric liver cancers, hepatoblastoma and hepatocellular carcinoma, are dangerous cancers which often spread to the lungs. Although treatments with cisplatin significantly improve outcomes, cisplatin may not eliminate metastasis-initiating cells. Our group has recently shown that the metastatic microenvironments of hepatoblastoma contain Cancer Associated Fibroblasts (CAFs) and neuron-like cells, which initiate cancer spread from liver to lungs. In this study, we found that these cells express high levels of HDAC1; therefore, we examined if histone deacetylase inhibition improves cisplatin anti-proliferative effects and reduces the formation of tumor clusters in pediatric liver cancer metastatic microenvironments. Methods: New cell lines were generated from primary hepatoblastoma liver tumors (hbl) and lung metastases (LM) of HBL patients. In addition, cell lines were generated from hepatocellular neoplasm, not otherwise specified (HCN-NOS) tumor samples, and hcc cell lines. Hbl, LM and hcc cells were treated with cisplatin, SAHA or in combination. The effect of these drugs on the number of cells, formation of tumor clusters and HDAC1-Sp5-p21 axis were examined. Results: Both HBL and HCC tissue specimens have increased HDAC1-Sp5 pathway activation, recapitulated in cell lines generated from the tumors. HDAC inhibition with vorinostat (SAHA) increases cisplatin efficacy to eliminate CAFs in hbl and in hcc cell lines. Although the neuron-like cells survive the combined treatments, proliferation was inhibited. Notably, combining SAHA with cisplatin overcame cisplatin resistance in an LM cell line from an aggressive case with multiple metastases. Underlying mechanisms of this enhanced inhibition include suppression of the HDAC1-Sp5 pathway and elevation of an inhibitor of proliferation p21. Similar findings were found with gemcitabine treatments suggesting that elimination of proliferative CAFs cells is a key event in the inhibition of mitotic microenvironment. Conclusions: Our studies demonstrate the synergistic benefits of HDAC inhibition and cisplatin to eliminate metastasis-initiating cells in pediatric liver cancers.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 82%

Inhibition of Histone Deacetylase Activity Increases Cisplatin Efficacy to Eliminate Metastatic Cells in Pediatric Liver Cancers

Gulati,

Fleifil,

Jennings

et al. 2024

Cancers

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Worldwide burden of liver cancer across childhood and adolescence, 2000–2021: a systematic analysis of the Global Burden of Disease Study 2021

Wu,

Xia,

Wang

et al. 2024

eClinicalMedicine

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An indocyanine green-based liquid biopsy test for circulating tumor cells for pediatric liver cancer

Espinoza,

Kureti,

Patel

et al. 2024

Hepatology Communications

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Background: Hepatoblastoma and HCC are the most common malignant hepatocellular tumors seen in children. The aim of this study was to develop a liquid biopsy test for circulating tumor cells (CTCs) for these tumors that would be less invasive and provide real-time information about tumor response to therapy. Methods: For this test, we utilized indocyanine green (ICG), a far-red fluorescent dye used clinically to identify malignant liver cells during surgery. We assessed ICG accumulation in cell lines using fluorescence microscopy and flow cytometry. For our CTC test, we developed a panel of liver tumor-specific markers, including ICG, Glypican-3, and DAPI, and tested it with cell lines and noncancer control blood samples. We then used this panel to analyze whole-blood samples for CTC burden with a cohort of 15 patients with hepatoblastoma and HCC and correlated with patient characteristics and outcomes. Results: We showed that ICG accumulation is specific to liver cancer cells, compared to nonmalignant liver cells, non-liver solid tumor cells, and other nonmalignant cells, and can be used to identify liver tumor cells in a mixed population of cells. Experiments with the ICG/Glypican-3/DAPI panel showed that it specifically tagged malignant liver cells. Using patient samples, we found that CTC burden from sequential blood samples from the same patients mirrored the patients’ responses to therapy. Conclusions: Our novel ICG-based liquid biopsy test for CTCs can be used to specifically detect and quantify CTCs in the blood of pediatric patients with liver cancer.

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A novel treatment strategy utilizing panobinostat for high-risk and treatment-refractory hepatoblastoma

Cited by 4 publications

References 33 publications

Inhibition of Histone Deacetylase Activity Increases Cisplatin Efficacy to Eliminate Metastatic Cells in Pediatric Liver Cancers

Inhibition of Histone Deacetylase Activity Increases Cisplatin Efficacy to Eliminate Metastatic Cells in Pediatric Liver Cancers

Worldwide burden of liver cancer across childhood and adolescence, 2000–2021: a systematic analysis of the Global Burden of Disease Study 2021

An indocyanine green-based liquid biopsy test for circulating tumor cells for pediatric liver cancer

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