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11 pages, 282 KiB

Open AccessArticle

Therapeutic Targeting of ALK in Neuroblastoma: Experience of Italian Precision Medicine in Pediatric Oncology

by Fabio Pastorino, Mario Capasso, Chiara Brignole, Vito A. Lasorsa, Veronica Bensa, Patrizia Perri, Sueva Cantalupo, Serena Giglio, Massimo Provenzi, Marco Rabusin, Elvira Pota, Monica Cellini, Annalisa Tondo, Maria A. De Ioris, Angela R. Sementa, Alberto Garaventa, Mirco Ponzoni and Loredana Amoroso

Cancers 2023, 15(3), 560; https://doi.org/10.3390/cancers15030560 - 17 Jan 2023

Cited by 4 | Viewed by 2545

Abstract

Neuroblastoma (NB) is the most common extracranial solid tumor in childhood. Patients with relapsed/refractory disease have a poor prognosis, and additional therapeutic options are needed. Mutations and amplifications in the ALK (Anaplastic Lymphoma Kinase) gene constitute a key target for treatment. Our goal, [...] Read more.

Neuroblastoma (NB) is the most common extracranial solid tumor in childhood. Patients with relapsed/refractory disease have a poor prognosis, and additional therapeutic options are needed. Mutations and amplifications in the ALK (Anaplastic Lymphoma Kinase) gene constitute a key target for treatment. Our goal, within the Italian project of PeRsonalizEdMEdicine (PREME), was to evaluate the genomic status of patients with relapsed/refractory NB and to implement targeted therapies in those with targetable mutations. From November 2018 to November 2021, we performed Whole Exome Sequencing or Targeted Gene Panel Sequencing in relapsed/refractory NB patients in order to identify druggable variants. Activating mutations of ALK were identified in 8(28.57%) of 28 relapsed/refractory NB patients. The mutation p.F1174L was found in six patients, whereas p.R1275Q was found in one and the unknown mutation p.S104R in another. Three patients died before treatment could be started, while five patients received crizotinib: two in monotherapy (one with p.F1174L and the other with p.S104R) and three (with p.F1174L variant) in combination with chemotherapy. All treated patients showed a clinical improvement, and one had complete remission after two cycles of combined treatment. The most common treatment-related toxicities were hematological. ALK inhibitors may play an important role in the treatment of ALK-mutated NB patients. Full article

(This article belongs to the Special Issue Targeted Therapies for Pediatric Solid Tumors)

18 pages, 4441 KiB

Open AccessArticle

Quantum Dot-Based Screening Identifies F3 Peptide and Reveals Cell Surface Nucleolin as a Therapeutic Target for Rhabdomyosarcoma

by Dzhangar Dzhumashev, Andrea Timpanaro, Safa Ali, Andrea J. De Micheli, Kamel Mamchaoui, Ilaria Cascone, Jochen Rössler and Michele Bernasconi

Cancers 2022, 14(20), 5048; https://doi.org/10.3390/cancers14205048 - 14 Oct 2022

Cited by 4 | Viewed by 2690

Abstract

Active drug delivery by tumor-targeting peptides is a promising approach to improve existing therapies for rhabdomyosarcoma (RMS), by increasing the therapeutic effect and decreasing the systemic toxicity, e.g., by drug-loaded peptide-targeted nanoparticles. Here, we tested 20 different tumor-targeting peptides for their ability to [...] Read more.

Active drug delivery by tumor-targeting peptides is a promising approach to improve existing therapies for rhabdomyosarcoma (RMS), by increasing the therapeutic effect and decreasing the systemic toxicity, e.g., by drug-loaded peptide-targeted nanoparticles. Here, we tested 20 different tumor-targeting peptides for their ability to bind to two RMS cell lines, Rh30 and RD, using quantum dots Streptavidin and biotin-peptides conjugates as a model for nanoparticles. Four peptides revealed a very strong binding to RMS cells: NCAM-1-targeting NTP peptide, nucleolin-targeting F3 peptide, and two Furin-targeting peptides, TmR and shTmR. F3 peptide showed the strongest binding to all RMS cell lines tested, low binding to normal control myoblasts and fibroblasts, and efficient internalization into RMS cells demonstrated by the cytoplasmic delivery of the Saporin toxin. The expression of the nucleophosphoprotein nucleolin, the target of F3, on the surface of RMS cell lines was validated by competition with the natural ligand lactoferrin, by colocalization with the nucleolin-binding aptamer AS1411, and by the marked sensitivity of RMS cell lines to the growth inhibitory nucleolin-binding N6L pseudopeptide. Taken together, our results indicate that nucleolin-targeting by F3 peptide represents a potential therapeutic approach for RMS. Full article

(This article belongs to the Special Issue Targeted Therapies for Pediatric Solid Tumors)

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19 pages, 6233 KiB

Open AccessArticle

Oncogenic Role of ADAM32 in Hepatoblastoma: A Potential Molecular Target for Therapy

by Takahiro Fukazawa, Keiji Tanimoto, Emi Yamaoka, Masato Kojima, Masami Kanawa, Nobuyuki Hirohashi and Eiso Hiyama

Cancers 2022, 14(19), 4732; https://doi.org/10.3390/cancers14194732 - 28 Sep 2022

Cited by 2 | Viewed by 2655

Abstract

Outcomes of pediatric hepatoblastoma (HBL) have improved, but refractory cases still occur. More effective and safer drugs are needed that are based on molecular mechanisms. A disintegrin and metalloproteases (ADAMs) are expressed with high frequency in various human carcinomas and play an important [...] Read more.

Outcomes of pediatric hepatoblastoma (HBL) have improved, but refractory cases still occur. More effective and safer drugs are needed that are based on molecular mechanisms. A disintegrin and metalloproteases (ADAMs) are expressed with high frequency in various human carcinomas and play an important role in cancer progression. In this study, we analyzed expression of ADAMs in HBL with a cDNA microarray dataset and found that the expression level of ADAM32 is particularly high. To investigate the role of ADAM32 in cancer, forced expression or knockdown experiments were conducted with HepG2 and HBL primary cells. Colony formation, cell migration and invasion, and cell viability were increased in HepG2 expressing ADAM32, whereas knockdown of ADAM32 induced a decrease in these cellular functions. Quantitative RT-PCR demonstrated an association between ADAM32 expression and the expression of genes related to cancer stem cells and epithelial–mesenchymal transition (EMT), suggesting a role of ADAM32 in cancer stemness and EMT. Furthermore, knockdown of ADAM32 increased cisplatin-induced apoptosis, and this effect was attenuated by a caspase-8 inhibitor, suggesting that ADAM32 plays a role in extrinsic apoptosis signaling. We conclude that ADAM32 plays a crucial role in progression of HBL, so it might be a promising molecular target in anticancer therapy. Full article

(This article belongs to the Special Issue Targeted Therapies for Pediatric Solid Tumors)

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10 pages, 1293 KiB

Open AccessArticle

Blood-Derived Liquid Biopsies Using Foundation One^® Liquid CDx for Children and Adolescents with High-Risk Malignancies: A Monocentric Experience

by Fanny Cahn, Gabriel Revon-Riviere, Victoria Min, Angélique Rome, Pauline Filaine, Annick Pelletier, Sylvie Abed, Jean-Claude Gentet, Arnauld Verschuur and Nicolas André

Cancers 2022, 14(11), 2774; https://doi.org/10.3390/cancers14112774 - 2 Jun 2022

Cited by 7 | Viewed by 2569

Abstract

Precision oncology requires tumor molecular profiling to identify actionable targets. Tumor biopsies are considered as the gold standard, but their indications are limited by the burden of procedures in children. Blood-derived liquid biopsy (LB) is a potential alternative that is not yet documented [...] Read more.

Precision oncology requires tumor molecular profiling to identify actionable targets. Tumor biopsies are considered as the gold standard, but their indications are limited by the burden of procedures in children. Blood-derived liquid biopsy (LB) is a potential alternative that is not yet documented in real-world settings, especially in pediatric oncology. We performed a retrospective analysis of children and teenagers with a relapsing or refractory disease, upon whom LB was performed using the Foundation One® liquid CDx from 1 January 2020 to 31 December 2021 in a single center. Forty-five patients (27 boys) were included, with a median age of 9 years of age (range: 1.5–17 years old). Underlying malignancies were neuroblastoma (12 patients), bone sarcoma (12), soft tissue sarcoma (9), brain tumors (7), and miscellaneous tumors (5). Forty-three patients had metastatic disease. Six patients had more than one biopsy because of a failure in first LB. Median time to obtain results was 13 days. Overall, analysis was successful for 33/45 patients. Eight patients did not present any molecular abnormalities. Molecular alterations were identified in 25 samples with a mean of 2.1 alterations per sample. The most common alterations concerned TP53 (7 pts), EWS-FLI1 (5), ALK (3), MYC (3), and CREBBP (2). TMB was low in all cases. Six patients received treatment based on the results from LB analysis and all were treated off-trial. Three additional patients were included in early phase clinical trials. Mean duration of treatment was 85 days, with one patient with stable disease after eight months. Molecular profiling using Foundation One® Liquid CDx was feasible in pediatric patients with high-risk solid tumors and lead to identification of targetable mutations in a subset of patients. Full article

(This article belongs to the Special Issue Targeted Therapies for Pediatric Solid Tumors)

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24 pages, 4303 KiB

Open AccessArticle

Upregulation of the Mevalonate Pathway through EWSR1-FLI1/EGR2 Regulatory Axis Confers Ewing Cells Exquisite Sensitivity to Statins

by Charlie Buchou, Karine Laud-Duval, Wietske van der Ent, Sandrine Grossetête, Sakina Zaidi, Géraldine Gentric, Maxime Corbé, Kévin Müller, Elaine Del Nery, Didier Surdez and Olivier Delattre

Cancers 2022, 14(9), 2327; https://doi.org/10.3390/cancers14092327 - 8 May 2022

Cited by 10 | Viewed by 3309

Abstract

Ewing sarcoma (EwS) is an aggressive primary bone cancer in children and young adults characterized by oncogenic fusions between genes encoding FET-RNA-binding proteins and ETS transcription factors, the most frequent fusion being EWSR1-FLI1. We show that EGR2, an Ewing-susceptibility gene and an essential [...] Read more.

Ewing sarcoma (EwS) is an aggressive primary bone cancer in children and young adults characterized by oncogenic fusions between genes encoding FET-RNA-binding proteins and ETS transcription factors, the most frequent fusion being EWSR1-FLI1. We show that EGR2, an Ewing-susceptibility gene and an essential direct target of EWSR1-FLI1, directly regulates the transcription of genes encoding key enzymes of the mevalonate (MVA) pathway. Consequently, Ewing sarcoma is one of the tumors that expresses the highest levels of mevalonate pathway genes. Moreover, genome-wide screens indicate that MVA pathway genes constitute major dependencies of Ewing cells. Accordingly, the statin inhibitors of HMG-CoA-reductase, a rate-limiting enzyme of the MVA pathway, demonstrate cytotoxicity in EwS. Statins induce increased ROS and lipid peroxidation levels, as well as decreased membrane localization of prenylated proteins, such as small GTP proteins. These metabolic effects lead to an alteration in the dynamics of S-phase progression and to apoptosis. Statin-induced effects can be rescued by downstream products of the MVA pathway. Finally, we further show that statins impair tumor growth in different Ewing PDX models. Altogether, the data show that statins, which are off-patent, well-tolerated, and inexpensive compounds, should be strongly considered in the therapeutic arsenal against this deadly childhood disease. Full article

(This article belongs to the Special Issue Targeted Therapies for Pediatric Solid Tumors)

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11 pages, 901 KiB

Open AccessArticle

Handheld PET Probe for Pediatric Cancer Surgery

by Hannah N. Rinehardt, Sadie Longo, Ryan Gilbert, Jennifer N. Shoaf, Wilson B. Edwards, Gary Kohanbash and Marcus M. Malek

Cancers 2022, 14(9), 2221; https://doi.org/10.3390/cancers14092221 - 29 Apr 2022

Cited by 6 | Viewed by 3141

Abstract

18F-fluorodeoxyglucose (FDG) is a glucose analog that acts as a marker for glucose uptake and metabolism. FDG PET scans are used in monitoring pediatric cancers. The handheld PET probe localization of FDG-avid lesions is an emerging modality for radio-guided surgery (RGS). We sought [...] Read more.

18F-fluorodeoxyglucose (FDG) is a glucose analog that acts as a marker for glucose uptake and metabolism. FDG PET scans are used in monitoring pediatric cancers. The handheld PET probe localization of FDG-avid lesions is an emerging modality for radio-guided surgery (RGS). We sought to assess the utility of PET probe in localizing occult FDG-avid tumors in pediatric patients. PET probe functionality was evaluated by using a PET/CT scan calibration phantom. The PET probe was able to detect FDG photon emission from simulated tumors with an expected decay of the radioisotope over time. Specificity for simulated tumor detection was lower in a model that included background FDG. In a clinical model, eight pediatric patients with FDG-avid primary, recurrent or metastatic cancer underwent a tumor excision, utilizing IV FDG and PET probe survey. Adequate tissue for diagnosis was present in 16 of 17 resected specimens, and pathology was positive for malignancy in 12 of the 17 FDG-avid lesions. PET probe gamma counts per second were higher in tumors compared with adjacent benign tissue in all operations. The median ex vivo tumor-to-background ratio (TBR) was 4.0 (range 0.9–12). The PET probe confirmed the excision of occult FDG-avid tumors in eight pediatric patients. Full article

(This article belongs to the Special Issue Targeted Therapies for Pediatric Solid Tumors)

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21 pages, 6512 KiB

Open AccessArticle

Antiangiogenic Compound Axitinib Demonstrates Low Toxicity and Antitumoral Effects against Medulloblastoma

by Marina Pagnuzzi-Boncompagni, Vincent Picco, Valérie Vial, Victor Planas-Bielsa, Ashaina Vandenberghe, Thomas Daubon, Marie-Alix Derieppe, Christopher Montemagno, Jérôme Durivault, Renaud Grépin, Sonia Martial, Jérôme Doyen, Julie Gavard and Gilles Pagès

Cancers 2022, 14(1), 70; https://doi.org/10.3390/cancers14010070 - 24 Dec 2021

Cited by 9 | Viewed by 4220

Abstract

Background: Despite the improvement of medulloblastoma (MB) treatments, survivors face severe long-term adverse effects and associated morbidity following multimodal treatments. Moreover, relapses are fatal within a few months. Therefore, chemotherapies inducing fewer adverse effects and/or improving survival at relapse are key for MB [...] Read more.

Background: Despite the improvement of medulloblastoma (MB) treatments, survivors face severe long-term adverse effects and associated morbidity following multimodal treatments. Moreover, relapses are fatal within a few months. Therefore, chemotherapies inducing fewer adverse effects and/or improving survival at relapse are key for MB patients. Our purpose was to evaluate the last-generation antiangiogenic drugs for their relevance in the therapeutic arsenal of MB. Methods: We screened three EMA- and FDA-approved antiangiogenic compounds (axitinib, cabozantinib and sunitinib) for their ability to reduce cell viability of five MB cell lines and their low toxicity towards two normal cell lines in vitro. Based on this screening, single-agent and combination therapies were designed for in vivo validation. Results: Axitinib, cabozantinib and sunitinib decreased viability of all the tested tumor cells. Although sunitinib was the most efficient in tumor cells, it also impacted normal cells. Therefore, axitinib showed the highest selectivity index for MB cells as compared to normal cells. The compound did not lead to acute toxicity in juvenile rats and crossed the blood–brain barrier. Moreover, axitinib efficiently reduced the growth rate of experimental brain tumors. Analysis of public databases showed that high expression of axitinib targets correlates with poor prognosis. Conclusion: Our results suggest that axitinib is a compelling candidate for MB treatment. Full article

(This article belongs to the Special Issue Targeted Therapies for Pediatric Solid Tumors)

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17 pages, 3059 KiB

Open AccessArticle

Increased Replication Stress Determines ATR Inhibitor Sensitivity in Neuroblastoma Cells

by David King, Harriet E. D. Southgate, Saskia Roetschke, Polly Gravells, Leona Fields, Jessica B. Watson, Lindi Chen, Devon Chapman, Daniel Harrison, Daniel Yeomanson, Nicola J. Curtin, Deborah A. Tweddle and Helen E. Bryant

Cancers 2021, 13(24), 6215; https://doi.org/10.3390/cancers13246215 - 10 Dec 2021

Cited by 7 | Viewed by 4215

Abstract

Despite intensive high-dose multimodal therapy, high-risk neuroblastoma (NB) confers a less than 50% survival rate. This study investigates the role of replication stress in sensitivity to inhibition of Ataxia telangiectasia and Rad3-related (ATR) in pre-clinical models of high-risk NB. Amplification of the oncogene [...] Read more.

Despite intensive high-dose multimodal therapy, high-risk neuroblastoma (NB) confers a less than 50% survival rate. This study investigates the role of replication stress in sensitivity to inhibition of Ataxia telangiectasia and Rad3-related (ATR) in pre-clinical models of high-risk NB. Amplification of the oncogene MYCN always imparts high-risk disease and occurs in 25% of all NB. Here, we show that MYCN-induced replication stress directly increases sensitivity to the ATR inhibitors VE-821 and AZD6738. PARP inhibition with Olaparib also results in replication stress and ATR activation, and sensitises NB cells to ATR inhibition independently of MYCN status, with synergistic levels of cell death seen in MYCN expressing ATR- and PARP-inhibited cells. Mechanistically, we demonstrate that ATR inhibition increases the number of persistent stalled and collapsed replication forks, exacerbating replication stress. It also abrogates S and G2 cell cycle checkpoints leading to death during mitosis in cells treated with an ATR inhibitor combined with PARP inhibition. In summary, increased replication stress through high MYCN expression, PARP inhibition or chemotherapeutic agents results in sensitivity to ATR inhibition. Our findings provide a mechanistic rationale for the inclusion of ATR and PARP inhibitors as a potential treatment strategy for high-risk NB. Full article

(This article belongs to the Special Issue Targeted Therapies for Pediatric Solid Tumors)

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21 pages, 2895 KiB

Open AccessArticle

PPM1D Is a Therapeutic Target in Childhood Neural Tumors

by Jelena Milosevic, Diana Treis, Susanne Fransson, Gabriel Gallo-Oller, Baldur Sveinbjörnsson, Nina Eissler, Keiji Tanino, Kazuyasu Sakaguchi, Tommy Martinsson, Malin Wickström, Per Kogner and John Inge Johnsen

Cancers 2021, 13(23), 6042; https://doi.org/10.3390/cancers13236042 - 30 Nov 2021

Cited by 7 | Viewed by 3526

Abstract

Childhood medulloblastoma and high-risk neuroblastoma frequently present with segmental gain of chromosome 17q corresponding to aggressive tumors and poor patient prognosis. Located within the 17q-gained chromosomal segments is PPM1D at chromosome 17q23.2. PPM1D encodes a serine/threonine phosphatase, WIP1, that is a negative regulator [...] Read more.

Childhood medulloblastoma and high-risk neuroblastoma frequently present with segmental gain of chromosome 17q corresponding to aggressive tumors and poor patient prognosis. Located within the 17q-gained chromosomal segments is PPM1D at chromosome 17q23.2. PPM1D encodes a serine/threonine phosphatase, WIP1, that is a negative regulator of p53 activity as well as key proteins involved in cell cycle control, DNA repair and apoptosis. Here, we show that the level of PPM1D expression correlates with chromosome 17q gain in medulloblastoma and neuroblastoma cells, and both medulloblastoma and neuroblastoma cells are highly dependent on PPM1D expression for survival. Comparison of different inhibitors of WIP1 showed that SL-176 was the most potent compound inhibiting medulloblastoma and neuroblastoma growth and had similar or more potent effects on cell survival than the MDM2 inhibitor Nutlin-3 or the p53 activator RITA. SL-176 monotherapy significantly suppressed the growth of established medulloblastoma and neuroblastoma xenografts in nude mice. These results suggest that the development of clinically applicable compounds inhibiting the activity of WIP1 is of importance since PPM1D activating mutations, genetic gain or amplifications and/or overexpression of WIP1 are frequently detected in several different cancers. Full article

(This article belongs to the Special Issue Targeted Therapies for Pediatric Solid Tumors)

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15 pages, 6084 KiB

Open AccessArticle

The Role of BiP and the IRE1α–XBP1 Axis in Rhabdomyosarcoma Pathology

by Mahmoud Aghaei, Ahmad Nasimian, Marveh Rahmati, Philip Kawalec, Filip Machaj, Jakub Rosik, Bhavya Bhushan, S. Zahra Bathaie, Negar Azarpira, Marek J. Los, Afshin Samali, David Perrin, Joseph W. Gordon and Saeid Ghavami

Cancers 2021, 13(19), 4927; https://doi.org/10.3390/cancers13194927 - 30 Sep 2021

Cited by 13 | Viewed by 3254

Abstract

Background: Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in children, and is associated with a poor prognosis in patients presenting with recurrent or metastatic disease. The unfolded protein response (UPR) plays pivotal roles in tumor development and resistance to therapy, including RMS. [...] Read more.

Background: Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in children, and is associated with a poor prognosis in patients presenting with recurrent or metastatic disease. The unfolded protein response (UPR) plays pivotal roles in tumor development and resistance to therapy, including RMS. Methods: In this study, we used immunohistochemistry and a tissue microarray (TMA) on human RMS and normal skeletal muscle to evaluate the expression of key UPR proteins (GRP78/BiP, IRE1α and cytosolic/nuclear XBP1 (spliced XBP1-sXBP1)) in the four main RMS subtypes: alveolar (ARMS), embryonal (ERMS), pleomorphic (PRMS) and sclerosing/spindle cell (SRMS) RMS. We also investigated the correlation of these proteins with the risk of RMS and several clinicopathological indices, such as lymph node involvement, distant metastasis, tumor stage and tumor scores. Results: Our results revealed that the expression of BiP, sXBP1, and IRE1α, but not cytosolic XBP1, are significantly associated with RMS (BiP and sXBP1 p-value = 0.0001, IRE1 p-value = 0.001) in all of the studied types of RMS tumors (n = 192) compared to normal skeletal muscle tissues (n = 16). In addition, significant correlations of BiP with the lymph node score (p = 0.05), and of IRE1α (p value = 0.004), cytosolic XBP1 (p = 0.001) and sXBP1 (p value = 0.001) with the stage score were observed. At the subtype level, BiP and sXBP1 expression were significantly associated with all subtypes of RMS, whereas IRE1α was associated with ARMS, PRMS and ERMS, and cytosolic XBP1 expression was associated with ARMS and SRMS. Importantly, the expression levels of IRE1α and sXBP1 were more pronounced in ARMS than in any of the other subtypes. The results also showed correlations of BiP with the lymph node score in ARMS (p value = 0.05), and of sXBP1 with the tumor score in PRMS (p value = 0.002). Conclusions: In summary, this study demonstrates that the overall UPR is upregulated and, more specifically, that the IRE1/sXBP1 axis is active in RMS. The subtype and stage-specific dependency on the UPR machinery in RMS may open new avenues for the development of novel targeted therapeutic strategies and the identification of specific tumor markers in this rare but deadly childhood and young-adult disease. Full article

(This article belongs to the Special Issue Targeted Therapies for Pediatric Solid Tumors)

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23 pages, 14922 KiB

Open AccessArticle

Combining APR-246 and HDAC-Inhibitors: A Novel Targeted Treatment Option for Neuroblastoma

by 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 and Ina Oehme

Cancers 2021, 13(17), 4476; https://doi.org/10.3390/cancers13174476 - 5 Sep 2021

Cited by 10 | Viewed by 4741

Abstract

APR-246 (Eprenetapopt/PRIMA-1^Met) 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, [...] Read more.

APR-246 (Eprenetapopt/PRIMA-1^Met) 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; n = 883) and patient samples (n = 1643) from the INFORM registry study, we confirmed that these entities express low levels of SLC7A11, 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. Full article

(This article belongs to the Special Issue Targeted Therapies for Pediatric Solid Tumors)

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20 pages, 5794 KiB

Open AccessArticle

HLA-G and HLA-E Immune Checkpoints Are Widely Expressed in Ewing Sarcoma but Have Limited Functional Impact on the Effector Functions of Antigen-Specific CAR T Cells

by Bianca Altvater, Sareetha Kailayangiri, Lina F. Pérez Lanuza, Katja Urban, Lea Greune, Maike Flügge, Jutta Meltzer, Nicole Farwick, Simone König, Dennis Görlich, Wolfgang Hartmann and Claudia Rossig

Cancers 2021, 13(12), 2857; https://doi.org/10.3390/cancers13122857 - 8 Jun 2021

Cited by 15 | Viewed by 4551

Abstract

Immune-inhibitory barriers in the tumor microenvironment of solid cancers counteract effective T cell therapies. Based on our finding that Ewing sarcomas (EwS) respond to chimeric antigen receptor (CAR) gene-modified effector cells through upregulation of human leukocyte antigen G (HLA-G), we hypothesized that nonclassical [...] Read more.

Immune-inhibitory barriers in the tumor microenvironment of solid cancers counteract effective T cell therapies. Based on our finding that Ewing sarcomas (EwS) respond to chimeric antigen receptor (CAR) gene-modified effector cells through upregulation of human leukocyte antigen G (HLA-G), we hypothesized that nonclassical HLA molecules, HLA-G and HLA-E, contribute to immune escape of EwS. Here, we demonstrate that HLA-G isotype G1 expression on EwS cells does not directly impair cytolysis by G_D2-specific CAR T cells (CART), whereas HLA-G1 on myeloid bystander cells reduces CART degranulation responses against EwS cells. HLA-E was induced in EwS cells by IFN-γ stimulation in vitro and by G_D2-specific CART treatment in vivo and was detected on tumor cells or infiltrating myeloid cells in a majority of human EwS biopsies. Interaction of HLA-E-positive EwS cells with G_D2-specific CART induced upregulation of HLA-E receptor NKG2A. However, HLA-E expressed by EwS tumor cells or by myeloid bystander cells both failed to reduce antitumor effector functions of CART. We conclude that non-classical HLA molecules are expressed in EwS under inflammatory conditions, but have limited functional impact on antigen-specific T cells, arguing against a relevant therapeutic benefit from combining CART therapy with HLA-G or HLA-E checkpoint blockade in this cancer. Full article

(This article belongs to the Special Issue Targeted Therapies for Pediatric Solid Tumors)

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24 pages, 1458 KiB

Open AccessArticle

Exploiting Gangliosides for the Therapy of Ewing’s Sarcoma and H3K27M-Mutant Diffuse Midline Glioma

by Arthur Wingerter, Khalifa El Malki, Roger Sandhoff, Larissa Seidmann, Daniel-Christoph Wagner, Nadine Lehmann, Nadine Vewinger, Katrin B. M. Frauenknecht, Clemens J. Sommer, Frank Traub, Thomas Kindler, Alexandra Russo, Henrike Otto, André Lollert, Gundula Staatz, Lea Roth, Claudia Paret and Jörg Faber

Cancers 2021, 13(3), 520; https://doi.org/10.3390/cancers13030520 - 29 Jan 2021

Cited by 22 | Viewed by 5841

Abstract

The ganglioside GD2 is an important target in childhood cancer. Nevertheless, the only therapy targeting GD2 that is approved to date is the monoclonal antibody dinutuximab, which is used in the therapy of neuroblastoma. The relevance of GD2 as a target in other [...] Read more.

The ganglioside GD2 is an important target in childhood cancer. Nevertheless, the only therapy targeting GD2 that is approved to date is the monoclonal antibody dinutuximab, which is used in the therapy of neuroblastoma. The relevance of GD2 as a target in other tumor entities remains to be elucidated. Here, we analyzed the expression of GD2 in different pediatric tumor entities by flow cytometry and tested two approaches for targeting GD2. H3K27M-mutant diffuse midline glioma (H3K27M-mutant DMG) samples showed the highest expression of GD2 with all cells strongly positive for the antigen. Ewing’s sarcoma (ES) samples also showed high expression, but displayed intra- and intertumor heterogeneity. Osteosarcoma had low to intermediate expression with a high percentage of GD2-negative cells. Dinutuximab beta in combination with irinotecan and temozolomide was used to treat a five-year-old girl with refractory ES. Disease control lasted over 12 months until a single partially GD2-negative intracranial metastasis was detected. In order to target GD2 in H3K27M-mutant DMG, we blocked ganglioside synthesis via eliglustat, since dinutuximab cannot cross the blood–brain barrier. Eliglustat is an inhibitor of glucosylceramide synthase, and it is used for treating children with Gaucher’s disease. Eliglustat completely inhibited the proliferation of primary H3K27M-mutant DMG cells in vitro. In summary, our data provide evidence that dinutuximab might be effective in tumors with high GD2 expression. Moreover, disrupting the ganglioside metabolism in H3K27M-mutant DMG could open up a new therapeutic option for this highly fatal cancer. Full article

(This article belongs to the Special Issue Targeted Therapies for Pediatric Solid Tumors)

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Review

Jump to: Research

21 pages, 812 KiB

Open AccessReview

Novel Targeted Therapeutic Strategies for Ewing Sarcoma

by Daria Fayzullina, Sergey Tsibulnikov, Mikhail Stempen, Brett A. Schroeder, Naveen Kumar, Rajesh Kumar Kharwar, Arbind Acharya, Peter Timashev and Ilya Ulasov

Cancers 2022, 14(8), 1988; https://doi.org/10.3390/cancers14081988 - 14 Apr 2022

Cited by 7 | Viewed by 4660

Abstract

Ewing sarcoma (ES) is an uncommon cancer that arises in mesenchymal tissues and represents the second most widespread malignant bone neoplasm after osteosarcoma in children. Amplifications in genomic, proteomic, and metabolism are characteristics of sarcoma, and targeting altered cancer cell molecular processes has [...] Read more.

Ewing sarcoma (ES) is an uncommon cancer that arises in mesenchymal tissues and represents the second most widespread malignant bone neoplasm after osteosarcoma in children. Amplifications in genomic, proteomic, and metabolism are characteristics of sarcoma, and targeting altered cancer cell molecular processes has been proposed as the latest promising strategy to fight cancer. Recent technological advancements have elucidated some of the underlying oncogenic characteristics of Ewing sarcoma. Offering new insights into the physiological basis for this phenomenon, our current review examines the dynamics of ES signaling as it related to both ES and the microenvironment by integrating genomic and proteomic analyses. An extensive survey of the literature was performed to compile the findings. We have also highlighted recent and ongoing studies integrating metabolomics and genomics aimed at better understanding the complex interactions as to how ES adapts to changing biochemical changes within the tumor microenvironment. Full article

(This article belongs to the Special Issue Targeted Therapies for Pediatric Solid Tumors)

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15 pages, 1969 KiB

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Chromosome Imbalances in Neuroblastoma—Recent Molecular Insight into Chromosome 1p-deletion, 2p-gain, and 11q-deletion Identifies New Friends and Foes for the Future

by Jikui Guan, Bengt Hallberg and Ruth H. Palmer

Cancers 2021, 13(23), 5897; https://doi.org/10.3390/cancers13235897 - 24 Nov 2021

Cited by 18 | Viewed by 4715

Abstract

Neuroblastoma is the most common extracranial solid pediatric tumor, with around 15% childhood cancer-related mortality. High-risk neuroblastomas exhibit a range of genetic, morphological, and clinical heterogeneities, which add complexity to diagnosis and treatment with existing modalities. Identification of novel therapies is a high [...] Read more.

Neuroblastoma is the most common extracranial solid pediatric tumor, with around 15% childhood cancer-related mortality. High-risk neuroblastomas exhibit a range of genetic, morphological, and clinical heterogeneities, which add complexity to diagnosis and treatment with existing modalities. Identification of novel therapies is a high priority in high-risk neuroblastoma, and the combination of genetic analysis with increased mechanistic understanding—including identification of key signaling and developmental events—provides optimism for the future. This focused review highlights several recent findings concerning chromosomes 1p, 2p, and 11q, which link genetic aberrations with aberrant molecular signaling output. These novel molecular insights contribute important knowledge towards more effective treatment strategies for neuroblastoma. Full article

(This article belongs to the Special Issue Targeted Therapies for Pediatric Solid Tumors)

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18 pages, 820 KiB

Open AccessReview

N-of-1 Trials in Pediatric Oncology: From a Population-Based Approach to Personalized Medicine—A Review

by Michal Kyr, Adam Svobodnik, Radka Stepanova and Renata Hejnova

Cancers 2021, 13(21), 5428; https://doi.org/10.3390/cancers13215428 - 29 Oct 2021

Cited by 6 | Viewed by 2907

Abstract

Pediatric oncology is a critical area where the more efficient development of new treatments is urgently needed. The speed of approval of new drugs is still limited by regulatory requirements and a lack of innovative designs appropriate for trials in children. Childhood cancers [...] Read more.

Pediatric oncology is a critical area where the more efficient development of new treatments is urgently needed. The speed of approval of new drugs is still limited by regulatory requirements and a lack of innovative designs appropriate for trials in children. Childhood cancers meet the criteria of rare diseases. Personalized medicine brings it even closer to the horizon of individual cases. Thus, not all the traditional research tools, such as large-scale RCTs, are always suitable or even applicable, mainly due to limited sample sizes. Small samples and traditional versus subject-specific evidence are both distinctive issues in personalized pediatric oncology. Modern analytical approaches and adaptations of the paradigms of evidence are warranted. We have reviewed innovative trial designs and analytical methods developed for small populations, together with individualized approaches, given their applicability to pediatric oncology. We discuss traditional population-based and individualized perspectives of inferences and evidence, and explain the possibilities of using various methods in pediatric personalized oncology. We find that specific derivatives of the original N-of-1 trial design adapted for pediatric personalized oncology may represent an optimal analytical tool for this area of medicine. We conclude that no particular N-of-1 strategy can provide a solution. Rather, a whole range of approaches is needed to satisfy the new inferential and analytical paradigms of modern medicine. We reveal a new view of cancer as continuum model and discuss the “evidence puzzle”. Full article

(This article belongs to the Special Issue Targeted Therapies for Pediatric Solid Tumors)

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16 pages, 749 KiB

Open AccessReview

Chimeric Antigen Receptor T cell Therapy and the Immunosuppressive Tumor Microenvironment in Pediatric Sarcoma

by Rachael L. Terry, Deborah Meyran, Emmy D. G. Fleuren, Chelsea Mayoh, Joe Zhu, Natacha Omer, David S. Ziegler, Michelle Haber, Phillip K. Darcy, Joseph A. Trapani, Paul J. Neeson and Paul G. Ekert

Cancers 2021, 13(18), 4704; https://doi.org/10.3390/cancers13184704 - 20 Sep 2021

Cited by 15 | Viewed by 4975

Abstract

Sarcomas are a diverse group of bone and soft tissue tumors that account for over 10% of childhood cancers. Outcomes are particularly poor for children with refractory, relapsed, or metastatic disease. Chimeric antigen receptor T (CAR T) cells are an exciting form of [...] Read more.

Sarcomas are a diverse group of bone and soft tissue tumors that account for over 10% of childhood cancers. Outcomes are particularly poor for children with refractory, relapsed, or metastatic disease. Chimeric antigen receptor T (CAR T) cells are an exciting form of adoptive cell therapy that potentially offers new hope for these children. In early trials, promising outcomes have been achieved in some pediatric patients with sarcoma. However, many children do not derive benefit despite significant expression of the targeted tumor antigen. The success of CAR T cell therapy in sarcomas and other solid tumors is limited by the immunosuppressive tumor microenvironment (TME). In this review, we provide an update of the CAR T cell therapies that are currently being tested in pediatric sarcoma clinical trials, including those targeting tumors that express HER2, NY-ESO, GD2, EGFR, GPC3, B7-H3, and MAGE-A4. We also outline promising new CAR T cells that are in pre-clinical development. Finally, we discuss strategies that are being used to overcome tumor-mediated immunosuppression in solid tumors; these strategies have the potential to improve clinical outcomes of CAR T cell therapy for children with sarcoma. Full article

(This article belongs to the Special Issue Targeted Therapies for Pediatric Solid Tumors)

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18 pages, 3698 KiB

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Development of a Selective Tumor-Targeted Drug Delivery System: Hydroxypropyl-Acrylamide Polymer-Conjugated Pirarubicin (P-THP) for Pediatric Solid Tumors

by Atsushi Makimoto, Jun Fang and Hiroshi Maeda

Cancers 2021, 13(15), 3698; https://doi.org/10.3390/cancers13153698 - 23 Jul 2021

Cited by 5 | Viewed by 3139

Abstract

Most pediatric cancers are highly chemo-sensitive, and cytotoxic chemotherapy has always been the mainstay of treatment. Anthracyclines are highly effective against most types of childhood cancer, such as neuroblastoma, hepatoblastoma, nephroblastoma, rhabdomyosarcoma, Ewing sarcoma, and so forth. However, acute and chronic cardiotoxicity, one [...] Read more.

Most pediatric cancers are highly chemo-sensitive, and cytotoxic chemotherapy has always been the mainstay of treatment. Anthracyclines are highly effective against most types of childhood cancer, such as neuroblastoma, hepatoblastoma, nephroblastoma, rhabdomyosarcoma, Ewing sarcoma, and so forth. However, acute and chronic cardiotoxicity, one of the major disadvantages of anthracycline use, limits their utility and effectiveness. Hydroxypropyl acrylamide polymer-conjugated pirarubicin (P-THP), which targets tumor tissue highly selectively via the enhanced permeability and retention (EPR) effect, and secondarily releases active pirarubicin molecules quickly into the acidic environment surrounding the tumor. Although, the latter rarely occurs in the non-acidic environment surrounding normal tissue. This mechanism has the potential to minimize acute and chronic toxicities, including cardiotoxicity, as well as maximize the efficacy of chemotherapy through synergy with tumor-targeting accumulation of the active molecules and possible dose-escalation. Simply replacing doxorubicin with P-THP in a given regimen can improve outcomes in anthracycline-sensitive pediatric cancers with little risk of adverse effects, such as cardiotoxicity. As cancer is a dynamic disease showing intra-tumoral heterogeneity during its course, continued parallel development of cytotoxic agents and molecular targeting agents is necessary to find potentially more effective treatments. Full article

(This article belongs to the Special Issue Targeted Therapies for Pediatric Solid Tumors)

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22 pages, 385 KiB

Open AccessReview

Pursuing Precision: Receptor Tyrosine Kinase Inhibitors for Treatment of Pediatric Solid Tumors

by Andrew J. Bellantoni and Lars M. Wagner

Cancers 2021, 13(14), 3531; https://doi.org/10.3390/cancers13143531 - 14 Jul 2021

Cited by 10 | Viewed by 2773

Abstract

Receptor tyrosine kinases are critical for the growth and proliferation of many different cancers and therefore represent a potential vulnerability that can be therapeutically exploited with small molecule inhibitors. Over forty small molecule inhibitors are currently approved for the treatment of adult solid [...] Read more.

Receptor tyrosine kinases are critical for the growth and proliferation of many different cancers and therefore represent a potential vulnerability that can be therapeutically exploited with small molecule inhibitors. Over forty small molecule inhibitors are currently approved for the treatment of adult solid tumors. Their use has been more limited in pediatric solid tumors, although an increasing number of single-agent and combination studies are now being performed. These agents have been quite successful in certain clinical contexts, such as the treatment of pediatric tumors driven by kinase fusions or activating mutations. By contrast, only modest activity has been observed when inhibitors are used as single agents for solid tumors that do not have genetically defined alterations in the target genes. The absence of predictive biomarkers has limited the wider applicability of these drugs and much work remains to define the appropriate patient population and clinical situation in which receptor tyrosine kinase inhibitors are most beneficial. In this manuscript, we discuss these issues by highlighting past trials and identifying future strategies that may help add precision to the use of these agents for pediatric extracranial solid tumors. Full article

(This article belongs to the Special Issue Targeted Therapies for Pediatric Solid Tumors)

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