Combining APR-246 and HDAC-Inhibitors: A Novel Targeted Treatment Option for Neuroblastoma
APR-246 (Eprenetapopt/PRIMA-1<sup>Met</sup>) is a very potent anti-cancer drug in clinical trials and was initially developed as a p53 refolding agent. As an alternative mode of action, the elevation of reactive oxygen species (ROS) has been proposed. Through an in silico analysis, we in...
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doaj-4ce7352813a94cf9a0e11429e771f4482021-09-09T13:41:10ZengMDPI AGCancers2072-66942021-09-01134476447610.3390/cancers13174476Combining APR-246 and HDAC-Inhibitors: A Novel Targeted Treatment Option for NeuroblastomaMichael Müller0Lisa Rösch1Sara Najafi2Charlotte Gatzweiler3Johannes Ridinger4Xenia F. Gerloff5David T. W. Jones6Jochen Baßler7Sina Kreth8Sabine Stainczyk9Karen Frese10Benjamin Meder11Frank Westermann12Till Milde13Heike Peterziel14Olaf Witt15Ina Oehme16Hopp Children’s Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, GermanyHopp Children’s Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, GermanyHopp Children’s Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, GermanyHopp Children’s Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, GermanyHopp Children’s Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, GermanyHopp Children’s Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, GermanyHopp Children’s Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, GermanyBiochemistry Center, Heidelberg University, 69120 Heidelberg, GermanyHopp Children’s Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, GermanyHopp Children’s Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, GermanyInstitute for Cardiomyopathies Heidelberg, Heidelberg University, 69120 Heidelberg, GermanyInstitute for Cardiomyopathies Heidelberg, Heidelberg University, 69120 Heidelberg, GermanyHopp Children’s Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, GermanyHopp Children’s Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, GermanyHopp Children’s Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, GermanyHopp Children’s Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, GermanyHopp Children’s Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, GermanyAPR-246 (Eprenetapopt/PRIMA-1<sup>Met</sup>) is a very potent anti-cancer drug in clinical trials and was initially developed as a p53 refolding agent. As an alternative mode of action, the elevation of reactive oxygen species (ROS) has been proposed. Through an in silico analysis, we investigated the responses of approximately 800 cancer cell lines (50 entities; Cancer Therapeutics Response Portal, CTRP) to APR-246 treatment. In particular, neuroblastoma, lymphoma and acute lymphocytic leukemia cells were highly responsive. With gene expression data from the Cancer Cell Line Encyclopedia (CCLE; <i>n</i> = 883) and patient samples (<i>n</i> = 1643) from the INFORM registry study, we confirmed that these entities express low levels of <i>SLC7A11,</i> a previously described predictive biomarker for APR-246 responsiveness. Combining the CTRP drug response data with the respective CCLE gene expression profiles, we defined a novel gene signature, predicting the effectiveness of APR-246 treatment with a sensitivity of 90% and a specificity of 94%. We confirmed the predicted APR-246 sensitivity in 8/10 cell lines and in ex vivo cultures of patient samples. Moreover, the combination of ROS detoxification-impeding APR-246 with approved HDAC-inhibitors, known to elevate ROS, substantially increased APR-246 sensitivity in cell cultures and in vivo in two zebrafish neuroblastoma xenograft models. These data provide evidence that APR-246, in combination with HDAC-inhibitors, displays a novel potent targeted treatment option for neuroblastoma patients.https://www.mdpi.com/2072-6694/13/17/4476histone deacetylasesROSTP53small molecule inhibitorspediatric tumors of the nervous systemprecision medicine |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Michael Müller Lisa Rösch Sara Najafi Charlotte Gatzweiler Johannes Ridinger Xenia F. Gerloff David T. W. Jones Jochen Baßler Sina Kreth Sabine Stainczyk Karen Frese Benjamin Meder Frank Westermann Till Milde Heike Peterziel Olaf Witt Ina Oehme |
spellingShingle |
Michael Müller Lisa Rösch Sara Najafi Charlotte Gatzweiler Johannes Ridinger Xenia F. Gerloff David T. W. Jones Jochen Baßler Sina Kreth Sabine Stainczyk Karen Frese Benjamin Meder Frank Westermann Till Milde Heike Peterziel Olaf Witt Ina Oehme Combining APR-246 and HDAC-Inhibitors: A Novel Targeted Treatment Option for Neuroblastoma Cancers histone deacetylases ROS TP53 small molecule inhibitors pediatric tumors of the nervous system precision medicine |
author_facet |
Michael Müller Lisa Rösch Sara Najafi Charlotte Gatzweiler Johannes Ridinger Xenia F. Gerloff David T. W. Jones Jochen Baßler Sina Kreth Sabine Stainczyk Karen Frese Benjamin Meder Frank Westermann Till Milde Heike Peterziel Olaf Witt Ina Oehme |
author_sort |
Michael Müller |
title |
Combining APR-246 and HDAC-Inhibitors: A Novel Targeted Treatment Option for Neuroblastoma |
title_short |
Combining APR-246 and HDAC-Inhibitors: A Novel Targeted Treatment Option for Neuroblastoma |
title_full |
Combining APR-246 and HDAC-Inhibitors: A Novel Targeted Treatment Option for Neuroblastoma |
title_fullStr |
Combining APR-246 and HDAC-Inhibitors: A Novel Targeted Treatment Option for Neuroblastoma |
title_full_unstemmed |
Combining APR-246 and HDAC-Inhibitors: A Novel Targeted Treatment Option for Neuroblastoma |
title_sort |
combining apr-246 and hdac-inhibitors: a novel targeted treatment option for neuroblastoma |
publisher |
MDPI AG |
series |
Cancers |
issn |
2072-6694 |
publishDate |
2021-09-01 |
description |
APR-246 (Eprenetapopt/PRIMA-1<sup>Met</sup>) is a very potent anti-cancer drug in clinical trials and was initially developed as a p53 refolding agent. As an alternative mode of action, the elevation of reactive oxygen species (ROS) has been proposed. Through an in silico analysis, we investigated the responses of approximately 800 cancer cell lines (50 entities; Cancer Therapeutics Response Portal, CTRP) to APR-246 treatment. In particular, neuroblastoma, lymphoma and acute lymphocytic leukemia cells were highly responsive. With gene expression data from the Cancer Cell Line Encyclopedia (CCLE; <i>n</i> = 883) and patient samples (<i>n</i> = 1643) from the INFORM registry study, we confirmed that these entities express low levels of <i>SLC7A11,</i> a previously described predictive biomarker for APR-246 responsiveness. Combining the CTRP drug response data with the respective CCLE gene expression profiles, we defined a novel gene signature, predicting the effectiveness of APR-246 treatment with a sensitivity of 90% and a specificity of 94%. We confirmed the predicted APR-246 sensitivity in 8/10 cell lines and in ex vivo cultures of patient samples. Moreover, the combination of ROS detoxification-impeding APR-246 with approved HDAC-inhibitors, known to elevate ROS, substantially increased APR-246 sensitivity in cell cultures and in vivo in two zebrafish neuroblastoma xenograft models. These data provide evidence that APR-246, in combination with HDAC-inhibitors, displays a novel potent targeted treatment option for neuroblastoma patients. |
topic |
histone deacetylases ROS TP53 small molecule inhibitors pediatric tumors of the nervous system precision medicine |
url |
https://www.mdpi.com/2072-6694/13/17/4476 |
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