|
1
|
Zhou X, Wang X, Li N, Guo Y, Yang X, Lei Y. Therapy resistance in neuroblastoma: Mechanisms and reversal strategies. Front Pharmacol 2023; 14:1114295. [PMID: 36874032 PMCID: PMC9978534 DOI: 10.3389/fphar.2023.1114295] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Accepted: 02/06/2023] [Indexed: 02/18/2023] Open
Abstract
Neuroblastoma is one of the most common pediatric solid tumors that threaten the health of children, accounting for about 15% of childhood cancer-related mortality in the United States. Currently, multiple therapies have been developed and applied in clinic to treat neuroblastoma including chemotherapy, radiotherapy, targeted therapy, and immunotherapy. However, the resistance to therapies is inevitable following long-term treatment, leading to treatment failure and cancer relapse. Hence, to understand the mechanisms of therapy resistance and discover reversal strategies have become an urgent task. Recent studies have demonstrated numerous genetic alterations and dysfunctional pathways related to neuroblastoma resistance. These molecular signatures may be potential targets to combat refractory neuroblastoma. A number of novel interventions for neuroblastoma patients have been developed based on these targets. In this review, we focus on the complicated mechanisms of therapy resistance and the potential targets such as ATP-binding cassette transporters, long non-coding RNAs, microRNAs, autophagy, cancer stem cells, and extracellular vesicles. On this basis, we summarized recent studies on the reversal strategies to overcome therapy resistance of neuroblastoma such as targeting ATP-binding cassette transporters, MYCN gene, cancer stem cells, hypoxia, and autophagy. This review aims to provide novel insight in how to improve the therapy efficacy against resistant neuroblastoma, which may shed light on the future directions that would enhance the treatment outcomes and prolong the survival of patients with neuroblastoma.
Collapse
Affiliation(s)
- Xia Zhou
- Shenzhen Hospital of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Xiaokang Wang
- Department of Pharmacy, Shenzhen Longhua District Central Hospital, Shenzhen, China.,Guangdong Provincial Key Laboratory of Research and Development of Natural Drugs, School of Pharmacy, Guangdong Medical University, Dongguan, China.,The Marine Biomedical Research Institute of Guangdong Zhanjiang, Zhanjiang, China
| | - Nan Li
- School of Traditional Chinese Medicine, Jinan University, Guangzhou, China
| | - Yu Guo
- School of Traditional Chinese Medicine, Jinan University, Guangzhou, China
| | - Xiaolin Yang
- Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yuhe Lei
- Shenzhen Hospital of Guangzhou University of Chinese Medicine, Shenzhen, China
| |
Collapse
|
|
2
|
Design, synthesis and anti-tumor efficacy of novel phenyl thiazole/triazole derivatives as selective TrkA inhibitors. Bioorg Med Chem 2022; 72:116995. [PMID: 36095945 DOI: 10.1016/j.bmc.2022.116995] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 08/23/2022] [Accepted: 08/29/2022] [Indexed: 11/20/2022]
Abstract
Aiming to develop novel tropomyosin receptor kinase A (TrkA) inhibitors, a scaffold hopping strategy was utilized by transforming the fused indazole of Entrectinib to phenyl triazole/thiazole skeleton to obtain compounds 7a-7 h and 13a-13 h. In the light of MTT assay, phenyl triazole derivatives 7a-7 h exhibited moderate anti-proliferative activities against KM-12 cells with the IC50 values of 1.78-17.51 μM, while phenyl thiazole derivatives 13a-13 h showed the weaker efficacy. Further structure-guided optimizations by combining the phenyl triazole skeleton with 3,5‑difluorophenyl and 3-carbamoyl-4-piperazinylaniline moiety led to compounds 19a-19d and 20. Eventually, 19c bearing (2-(4-methylpiperazin-1-yl)phenyl)(morpholino)methanone moiety exhibited excellent anti-proliferative activity on TrkA-positive KM-12 cells with IC50 value of 0.17 μM. Meanwhile, compound 19c showed the inhibitory potency on TrkA with IC50 value of 1.6 nM, and displayed higher selectivity on TrkA over TrkB (IC50 = 12.3 nM) and TrkC (IC50 = 18.4 nM). The dedicated wound healing and colony formation assay indicated that the optimal compound 19c could suppress migration and significantly inhibit KM-12 cell colony formation in a dose-dependent manner. In addition, 19c could weakly induce apoptosis of KM-12 cell in immunofluorescent staining analysis. Taken together, the above results suggest 19c as a novel TrkA inhibitor worthy of further profiling.
Collapse
|
|
3
|
Synthetic Heterocyclic Derivatives as Kinase Inhibitors Tested for the Treatment of Neuroblastoma. Molecules 2021; 26:molecules26237069. [PMID: 34885651 PMCID: PMC8658969 DOI: 10.3390/molecules26237069] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 11/18/2021] [Accepted: 11/19/2021] [Indexed: 12/21/2022] Open
Abstract
In the last few years, small molecules endowed with different heterocyclic scaffolds have been developed as kinase inhibitors. Some of them are being tested at preclinical or clinical levels for the potential treatment of neuroblastoma (NB). This disease is the most common extracranial solid tumor in childhood and is responsible for 10% to 15% of pediatric cancer deaths. Despite the availability of some treatments, including the use of very toxic cytotoxic chemotherapeutic agents, high-risk (HR)-NB patients still have a poor prognosis and a survival rate below 50%. For these reasons, new pharmacological options are urgently needed. This review focuses on synthetic heterocyclic compounds published in the last five years, which showed at least some activity on this severe disease and act as kinase inhibitors. The specific mechanism of action, selectivity, and biological activity of these drug candidates are described, when established. Moreover, the most remarkable clinical trials are reported. Importantly, kinase inhibitors approved for other diseases have shown to be active and endowed with lower toxicity compared to conventional cytotoxic agents. The data collected in this article can be particularly useful for the researchers working in this area.
Collapse
|
|
4
|
Farina AR, Cappabianca LA, Zelli V, Sebastiano M, Mackay AR. Mechanisms involved in selecting and maintaining neuroblastoma cancer stem cell populations, and perspectives for therapeutic targeting. World J Stem Cells 2021; 13:685-736. [PMID: 34367474 PMCID: PMC8316860 DOI: 10.4252/wjsc.v13.i7.685] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/09/2021] [Accepted: 04/14/2021] [Indexed: 02/06/2023] Open
Abstract
Pediatric neuroblastomas (NBs) are heterogeneous, aggressive, therapy-resistant embryonal tumours that originate from cells of neural crest (NC) origin and in particular neuroblasts committed to the sympathoadrenal progenitor cell lineage. Therapeutic resistance, post-therapeutic relapse and subsequent metastatic NB progression are driven primarily by cancer stem cell (CSC)-like subpopulations, which through their self-renewing capacity, intermittent and slow cell cycles, drug-resistant and reversibly adaptive plastic phenotypes, represent the most important obstacle to improving therapeutic outcomes in unfavourable NBs. In this review, dedicated to NB CSCs and the prospects for their therapeutic eradication, we initiate with brief descriptions of the unique transient vertebrate embryonic NC structure and salient molecular protagonists involved NC induction, specification, epithelial to mesenchymal transition and migratory behaviour, in order to familiarise the reader with the embryonic cellular and molecular origins and background to NB. We follow this by introducing NB and the potential NC-derived stem/progenitor cell origins of NBs, before providing a comprehensive review of the salient molecules, signalling pathways, mechanisms, tumour microenvironmental and therapeutic conditions involved in promoting, selecting and maintaining NB CSC subpopulations, and that underpin their therapy-resistant, self-renewing metastatic behaviour. Finally, we review potential therapeutic strategies and future prospects for targeting and eradication of these bastions of NB therapeutic resistance, post-therapeutic relapse and metastatic progression.
Collapse
Affiliation(s)
- Antonietta Rosella Farina
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Lucia Annamaria Cappabianca
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Veronica Zelli
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Michela Sebastiano
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Andrew Reay Mackay
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy.
| |
Collapse
|
|
5
|
Zafar A, Wang W, Liu G, Wang X, Xian W, McKeon F, Foster J, Zhou J, Zhang R. Molecular targeting therapies for neuroblastoma: Progress and challenges. Med Res Rev 2020; 41:961-1021. [PMID: 33155698 PMCID: PMC7906923 DOI: 10.1002/med.21750] [Citation(s) in RCA: 213] [Impact Index Per Article: 42.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 09/25/2020] [Accepted: 10/28/2020] [Indexed: 01/09/2023]
Abstract
There is an urgent need to identify novel therapies for childhood cancers. Neuroblastoma is the most common pediatric solid tumor, and accounts for ~15% of childhood cancer‐related mortality. Neuroblastomas exhibit genetic, morphological and clinical heterogeneity, which limits the efficacy of existing treatment modalities. Gaining detailed knowledge of the molecular signatures and genetic variations involved in the pathogenesis of neuroblastoma is necessary to develop safer and more effective treatments for this devastating disease. Recent studies with advanced high‐throughput “omics” techniques have revealed numerous genetic/genomic alterations and dysfunctional pathways that drive the onset, growth, progression, and resistance of neuroblastoma to therapy. A variety of molecular signatures are being evaluated to better understand the disease, with many of them being used as targets to develop new treatments for neuroblastoma patients. In this review, we have summarized the contemporary understanding of the molecular pathways and genetic aberrations, such as those in MYCN, BIRC5, PHOX2B, and LIN28B, involved in the pathogenesis of neuroblastoma, and provide a comprehensive overview of the molecular targeted therapies under preclinical and clinical investigations, particularly those targeting ALK signaling, MDM2, PI3K/Akt/mTOR and RAS‐MAPK pathways, as well as epigenetic regulators. We also give insights on the use of combination therapies involving novel agents that target various pathways. Further, we discuss the future directions that would help identify novel targets and therapeutics and improve the currently available therapies, enhancing the treatment outcomes and survival of patients with neuroblastoma.
Collapse
Affiliation(s)
- Atif Zafar
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas, USA
| | - Wei Wang
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas, USA.,Drug Discovery Institute, University of Houston, Houston, Texas, USA
| | - Gang Liu
- Department of Pharmacology and Toxicology, Chemical Biology Program, University of Texas Medical Branch, Galveston, Texas, USA
| | - Xinjie Wang
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas, USA
| | - Wa Xian
- Department of Biology and Biochemistry, Stem Cell Center, University of Houston, Houston, Texas, USA
| | - Frank McKeon
- Department of Biology and Biochemistry, Stem Cell Center, University of Houston, Houston, Texas, USA
| | - Jennifer Foster
- Department of Pediatrics, Texas Children's Hospital, Section of Hematology-Oncology Baylor College of Medicine, Houston, Texas, USA
| | - Jia Zhou
- Department of Pharmacology and Toxicology, Chemical Biology Program, University of Texas Medical Branch, Galveston, Texas, USA
| | - Ruiwen Zhang
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas, USA.,Drug Discovery Institute, University of Houston, Houston, Texas, USA
| |
Collapse
|
|
6
|
Serafim Junior V, Fernandes GMDM, Oliveira-Cucolo JGD, Pavarino EC, Goloni-Bertollo EM. Role of Tropomyosin-related kinase B receptor and brain-derived neurotrophic factor in cancer. Cytokine 2020; 136:155270. [PMID: 32911446 DOI: 10.1016/j.cyto.2020.155270] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Accepted: 08/27/2020] [Indexed: 02/07/2023]
Abstract
The tropomyosin-related kinase B (TrkB) receptor is a member of the neurotrophic tyrosine kinase receptors family and, together with the brain-derived neurotrophic factor (BDNF), plays an important role in the development of breast cancer, lung cancer, neuroblastoma, colorectal cancer, leukemia, cervical cancer, gallbladder cancer, gastric cancer, kidney cancer, Ewing's sarcoma, esophageal cancer, and head and neck cancer. Overexpression of these two factors has been associated with increased processes involved in carcinogenesis, such as invasion, migration, epithelial-mesenchymal transition (EMT), angiogenesis, metastasis, cell proliferation, resistance to apoptosis, resistance to cell death due to loss of adhesion (anoikis), activation of cell proliferation pathways, regulation of tumor suppressor genes, and drug resistance, and is related to advanced clinical stage. Inhibition of the TrkB/BDNF axis using drugs in phase 1 studies, approved drugs, and small interfering RNA (siRNA) are promising strategies for the treatment of various malignant tumors in addition to increasing the sensitivity of cells resistant to chemotherapy, improving the effectiveness of drugs without increasing toxicity. Another factor related to poor cancer prognosis is the presence of cancer stem cells, having effects similar to the high expression of the TrkB/BDNF axis, on cancer. This review aimed to show the role of the TrkB/BDNF axis in several types of cancer, its possible use as a prognostic biomarker, the effects of inhibiting this axis, and its role in the cancer stem cells.
Collapse
Affiliation(s)
- Vilson Serafim Junior
- Genetics and Molecular Biology Research Unit (UPGEM), São José do Rio Preto Medical School (FAMERP), São José do Rio Preto, São Paulo, Brazil
| | - Glaucia Maria de Mendonça Fernandes
- Genetics and Molecular Biology Research Unit (UPGEM), São José do Rio Preto Medical School (FAMERP), São José do Rio Preto, São Paulo, Brazil
| | - Juliana Garcia de Oliveira-Cucolo
- Genetics and Molecular Biology Research Unit (UPGEM), São José do Rio Preto Medical School (FAMERP), São José do Rio Preto, São Paulo, Brazil
| | - Erika Cristina Pavarino
- Genetics and Molecular Biology Research Unit (UPGEM), São José do Rio Preto Medical School (FAMERP), São José do Rio Preto, São Paulo, Brazil
| | - Eny Maria Goloni-Bertollo
- Genetics and Molecular Biology Research Unit (UPGEM), São José do Rio Preto Medical School (FAMERP), São José do Rio Preto, São Paulo, Brazil.
| |
Collapse
|
|
7
|
Shulman DS, DuBois SG. The Evolving Diagnostic and Treatment Landscape of NTRK-Fusion-Driven Pediatric Cancers. Paediatr Drugs 2020; 22:189-197. [PMID: 31965543 DOI: 10.1007/s40272-020-00380-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
The neurotrophin receptor tyrosine kinase (NTRK1-3) genes have been identified as key fusion partners in a range of pediatric cancers. In childhood cancers, ETV6-NTRK3 fusions are found in the majority of infantile fibrosarcomas and congenital mesoblastic nephromas. NTRK fusions are also found in mammary analog secretory carcinomas (MASC), secretory breast carcinomas, and with modest frequency in high-grade gliomas in very young children. While there are a range of multi-receptor tyrosine kinase inhibitors that show efficacy against TRK kinases, there are now multiple highly selective TRK inhibitors in clinical evaluation. Entrectinib and larotrectinib have been evaluated in early-phase clinical trials for children and demonstrated high response rates with good durability of response. Both agents are now approved in the United States in an age and histology agnostic manner for children (age > 12 years for entrectinib; all ages for larotrectinib) for the treatment of solid tumors harboring NTRK fusions without an option for complete surgical resection, with relapsed disease, or without a viable alternative systemic option. More recently, two second-generation TRK inhibitors, selitrectinib and repotrectinib, have been developed and are currently being evaluated in pediatric early phase trials. The Children's Oncology Group has also launched a phase II trial of larotrectinib as a neoadjuvant agent for patients with newly diagnosed infantile fibrosarcoma. While the clinical use of these agents has developed rapidly, many questions remain in terms of duration of therapy, treatment of CNS disease, and long-term toxicities. Further development of this class of agents will continue to require multi-center trials for these rare tumors. Tumor sequencing and potentially sequencing of circulating tumor DNA will improve our understanding of patterns of resistance and the most effective treatment strategies for these patients.
Collapse
Affiliation(s)
- David S Shulman
- Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, 450 Brookline Avenue, Boston, MA, 02215, USA
| | - Steven G DuBois
- Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, 450 Brookline Avenue, Boston, MA, 02215, USA.
| |
Collapse
|
|
8
|
MacFarland SP, Naraparaju K, Iyer R, Guan P, Kolla V, Hu Y, Tan K, Brodeur GM. Mechanisms of Entrectinib Resistance in a Neuroblastoma Xenograft Model. Mol Cancer Ther 2019; 19:920-926. [PMID: 31871269 DOI: 10.1158/1535-7163.mct-18-1044] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2018] [Revised: 06/03/2019] [Accepted: 12/12/2019] [Indexed: 11/16/2022]
Abstract
TrkB with its ligand, brain-derived neurotrophic factor (BDNF), are overexpressed in the majority of high-risk neuroblastomas (NB). Entrectinib is a novel pan-TRK, ALK, and ROS1 inhibitor that has shown excellent preclinical efficacy in NB xenograft models, and recently it has entered phase 1 trials in pediatric relapsed/refractory solid tumors. We examined entrectinib-resistant NB cell lines to identify mechanisms of resistance. Entrectinib-resistant cell lines were established from five NB xenografts initially sensitive to entrectinib therapy. Clonal cell lines were established in increasing concentrations of entrectinib and had >10X increase in IC50 Cell lines underwent genomic and proteomic analysis using whole-exome sequencing, RNA-Seq, and proteomic expression profiling with confirmatory RT-PCR and Western blot analysis. There was no evidence of NTRK2 (TrkB) gene mutation in any resistant cell lines. Inhibition of TrkB was maintained in all cell lines at increasing concentrations of entrectinib (target independent). PTEN pathway downregulation and ERK/MAPK pathway upregulation were demonstrated in all resistant cell lines. One of these clones also had increased IGF1R signaling, and two additional clones had increased P75 expression, which likely increased TrkB sensitivity to ligand. In conclusion, NB lines overexpressing TrkB developed resistance to entrectinib by multiple mechanisms, including activation of ERK/MAPK and downregulation of PTEN signaling. Individual cell lines also had IGF1R activation and increased P75 expression, allowing preservation of downstream TrkB signaling in the presence of entrectinib. An understanding of changes in patterns of expression can be used to inform multimodal therapy planning in using entrectinib in phase II/III trial planning.
Collapse
Affiliation(s)
- Suzanne P MacFarland
- Division of Oncology, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
| | - Koumudi Naraparaju
- Division of Oncology, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
| | - Radhika Iyer
- Division of Oncology, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
| | - Peng Guan
- Division of Oncology, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
| | - Venkatadri Kolla
- Division of Oncology, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
| | - Yuxuan Hu
- Division of Oncology, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
| | - Kai Tan
- Division of Oncology, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
| | - Garrett M Brodeur
- Division of Oncology, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania. .,Department of Pediatrics, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| |
Collapse
|
|
9
|
Nunes-Xavier CE, Aurtenetxe O, Zaldumbide L, López-Almaraz R, Erramuzpe A, Cortés JM, López JI, Pulido R. Protein tyrosine phosphatase PTPN1 modulates cell growth and associates with poor outcome in human neuroblastoma. Diagn Pathol 2019; 14:134. [PMID: 31837707 PMCID: PMC6911276 DOI: 10.1186/s13000-019-0919-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Accepted: 12/06/2019] [Indexed: 02/08/2023] Open
Abstract
Background Protein tyrosine phosphatases (PTPs) regulate neuronal differentiation and survival, but their expression patterns and functions in human neuroblastoma (NB) are scarcely known. Here, we have investigated the function and expression of the non-receptor PTPN1 on human NB cell lines and human NB tumor samples. Material/methods NB tumor samples from 44 patients were analysed by immunohistochemistry using specific antibodies against PTPN1, PTPRH, PTPRZ1, and PTEN. PTPN1 knock-down, cell proliferation and tyrosine phosphorylation analyses, and RT-qPCR mRNA expression was assessed on SH-SY5Y, SMS-KCNR, and IMR-32 human NB cell lines. Results Knock-down of PTPN1 in SH-SY5Y NB cells resulted in increased tyrosine phosphorylation and cell proliferation. Retinoic acid-mediated differentiation of NB cell lines did not affect PTPN1 mRNA expression, as compared with other PTPs. Importantly, PTPN1 displayed high expression on NB tumors in association with metastasis and poor prognosis. Conclusions Our results identify PTPN1 as a candidate regulator of NB cell growth and a potential NB prognostic biomarker.
Collapse
Affiliation(s)
- Caroline E Nunes-Xavier
- Biomarkers in Cancer Unit, Biocruces Bizkaia Health Research Institute, Barakaldo, Bizkaia, Spain. .,Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, P.O. Box 4950 Nydalen, N-0424, Oslo, Norway.
| | - Olaia Aurtenetxe
- Biomarkers in Cancer Unit, Biocruces Bizkaia Health Research Institute, Barakaldo, Bizkaia, Spain
| | - Laura Zaldumbide
- Department of Pathology, Cruces University Hospital, University of the Basque Country (UPV/EHU), Barakaldo, Bizkaia, Spain
| | - Ricardo López-Almaraz
- Pediatric Oncology and Hematology, Cruces University Hospital, Barakaldo, Bizkaia, Spain
| | - Asier Erramuzpe
- Quantitative Biomedicine Unit, Biocruces Bizkaia Health Research Institute, Barakaldo, Bizkaia, Spain
| | - Jesús M Cortés
- Quantitative Biomedicine Unit, Biocruces Bizkaia Health Research Institute, Barakaldo, Bizkaia, Spain.,IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
| | - José I López
- Biomarkers in Cancer Unit, Biocruces Bizkaia Health Research Institute, Barakaldo, Bizkaia, Spain.,Department of Pathology, Cruces University Hospital, University of the Basque Country (UPV/EHU), Barakaldo, Bizkaia, Spain
| | - Rafael Pulido
- Biomarkers in Cancer Unit, Biocruces Bizkaia Health Research Institute, Barakaldo, Bizkaia, Spain. .,IKERBASQUE, Basque Foundation for Science, Bilbao, Spain. .,Biocruces Bizkaia Health Research Institute, Hospital Universitario de Cruces, Plaza Cruces s/n, 48903, Barakaldo, Spain.
| |
Collapse
|
|
10
|
Thomaz A, Pinheiro KDV, Souza BK, Gregianin L, Brunetto AL, Brunetto AT, de Farias CB, Jaeger MDC, Ramaswamy V, Nör C, Taylor MD, Roesler R. Antitumor Activities and Cellular Changes Induced by TrkB Inhibition in Medulloblastoma. Front Pharmacol 2019; 10:698. [PMID: 31297057 PMCID: PMC6606946 DOI: 10.3389/fphar.2019.00698] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Accepted: 05/29/2019] [Indexed: 12/12/2022] Open
Abstract
Neurotrophins are critically involved in regulating normal neural development and plasticity. Brain-derived neurotrophic factor (BDNF), a neurotrophin that acts by binding to the tropomyosin receptor kinase B (TrkB) receptor, has also been implicated in the progression of several types of cancer. However, its role in medulloblastoma (MB), the most common type of malignant brain tumor afflicting children, remains unclear. Here we show that selective TrkB inhibition with the small molecule compound ANA-12 impaired proliferation and viability of human UW228 and D283 MB cells, and slowed the growth of MB tumors xenografted into nude mice. These effects were accompanied by increased apoptosis, reduced extracellular-regulated kinase (ERK) activity, increased expression of signal transducer and activator of transcription 3 (STAT3), and differential modulation of p21 expression dependent on the cell line. In addition, MB cells treated with ANA-12 showed morphological alterations consistent with differentiation, increased levels of the neural differentiation marker β-III Tubulin (TUBB3), and reduced expression of the stemness marker Nestin. These findings are consistent with the possibility that selective TrkB inhibition can display consistent anticancer effects in MB, possibly by modulating intracellular signaling and gene expression related to tumor progression, apoptosis, and differentiation.
Collapse
Affiliation(s)
- Amanda Thomaz
- Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, Brazil.,Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
| | - Kelly de Vargas Pinheiro
- Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, Brazil.,Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
| | - Bárbara Kunzler Souza
- Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, Brazil.,Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
| | - Lauro Gregianin
- Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, Brazil.,Department of Pediatrics, School of Medicine, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.,Pediatric Oncology Service, Clinical Hospital, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
| | - Algemir L Brunetto
- Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, Brazil.,Children's Cancer Institute, Porto Alegre, Brazil
| | - André T Brunetto
- Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, Brazil.,Children's Cancer Institute, Porto Alegre, Brazil
| | - Caroline Brunetto de Farias
- Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, Brazil.,Children's Cancer Institute, Porto Alegre, Brazil
| | - Mariane da Cunha Jaeger
- Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, Brazil.,Children's Cancer Institute, Porto Alegre, Brazil
| | - Vijay Ramaswamy
- The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.,Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada
| | - Carolina Nör
- The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.,Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada
| | - Michael D Taylor
- The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.,Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada.,Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.,Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.,Division of Neurosurgery, The Hospital for Sick Children, Toronto, ON, Canada
| | - Rafael Roesler
- Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, Brazil.,Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
| |
Collapse
|
|
11
|
Targeting tropomyosin receptor kinase for cancer therapy. Eur J Med Chem 2019; 175:129-148. [PMID: 31077998 DOI: 10.1016/j.ejmech.2019.04.053] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Revised: 04/17/2019] [Accepted: 04/18/2019] [Indexed: 02/08/2023]
Abstract
NTRKs and their expression product tropomyosin receptor kinases (Trks) are widely distributed in mammals. While neural growth factor (NGF)-induced normal Trk activation plays a key role in nerve growth, NTRK alternations occurring in tumor cells were highly correlated to tumor progression and invasion. Recent clinical data from several pan-Trk inhibitors have demonstrated potential and broad applications in various cancers. This intrigues us to summarize the development of inhibitors targeting Trks with different mechanisms of action and their applications in cancer therapy. We believe that this perspective would be of great help in investigating novel anticancer drugs with better therapeutic index.
Collapse
|
|
12
|
Pastor ER, Mousa SA. Current management of neuroblastoma and future direction. Crit Rev Oncol Hematol 2019; 138:38-43. [PMID: 31092383 DOI: 10.1016/j.critrevonc.2019.03.013] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Revised: 03/11/2019] [Accepted: 03/20/2019] [Indexed: 01/08/2023] Open
Abstract
Neuroblastoma is the most common solid extracranial tumor in pediatrics and can regress spontaneously or grow and metastasize with resistance to multiple therapeutic approaches. The prognosis and approach to treatment depends on the tumor presentation and whether it expresses certain drivers such as MYCN, ALK, and TrkB. Expression or mutation of these genes and kinases correlates with high-risk and poor prognosis. Multiple therapeutic approaches are being used to target MYCN, ALK, and TrkB, as well as GD2, a surface antigen present on the surface of neuroblastoma tumor cells. This review discusses the nature of these targets and several current therapies for neuroblastoma. A focus is placed on recent therapeutic developments including targeted delivery of chemotherapy, novel radiation therapy, and immunotherapy.
Collapse
Affiliation(s)
- Elizabeth R Pastor
- The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY, USA
| | - Shaker A Mousa
- The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY, USA.
| |
Collapse
|
|
13
|
Pacenta HL, Macy ME. Entrectinib and other ALK/TRK inhibitors for the treatment of neuroblastoma. DRUG DESIGN DEVELOPMENT AND THERAPY 2018; 12:3549-3561. [PMID: 30425456 PMCID: PMC6204873 DOI: 10.2147/dddt.s147384] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
RTK plays important roles in many cellular signaling processes involved in cancer growth and development. ALK, TRKA, TRKB, TRKC, and ROS1 are RTKs involved in several canonical pathways related to oncogenesis. These proteins can be genetically altered in malignancies, leading to receptor activation and constitutive signaling through their respective downstream pathways. Neuroblastoma (NB) is the most common extracranial solid tumor in childhood, and despite intensive therapy, there is a high mortality rate in cases with a high-risk disease. Alterations of ALK and differential expression of TRK proteins are reported in a proportion of NB. Several inhibitors of ALK or TRKA/B/C have been evaluated both preclinically and clinically in the treatment of NB. These agents have had variable success and are not routinely used in the treatment of NB. Entrectinib (RXDX-101) is a pan-ALK, TRKA, TRKB, TRKC, and ROS1 inhibitor with activity against tumors with ALK, NTRK1, NTRK2, NTRK3, and ROS1 alterations in Phase I clinical trials in adults. Entrectinib’s activity against both ALK and TRK proteins suggests a possible role in NB treatment, and it is currently under investigation in both pediatric and adult oncology patients.
Collapse
Affiliation(s)
- Holly L Pacenta
- Department of Pediatrics, University of Colorado Anschutz Medical Campus and Children's Hospital Colorado, Aurora, CO, USA,
| | - Margaret E Macy
- Department of Pediatrics, University of Colorado Anschutz Medical Campus and Children's Hospital Colorado, Aurora, CO, USA,
| |
Collapse
|
|
14
|
Molecularly Targeted Therapy for Neuroblastoma. CHILDREN-BASEL 2018; 5:children5100142. [PMID: 30326621 PMCID: PMC6210520 DOI: 10.3390/children5100142] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/04/2018] [Revised: 09/26/2018] [Accepted: 09/27/2018] [Indexed: 12/13/2022]
Abstract
Neuroblastoma is the most common extra-cranial solid tumor encountered in childhood and accounts for 15% of pediatric cancer-related deaths. Although there has been significant improvement in the outcomes for patients with high-risk disease, the therapy needed to achieve a cure is quite toxic and for those that do experience a disease recurrence, the prognosis is very dismal. Given this, there is a tremendous need for novel therapies for children with high-risk neuroblastoma and the molecular discoveries over recent years provide hope for developing new, less toxic, and potentially more efficacious treatments. Here I discuss many of the molecular aberrations identified thus far in neuroblastoma, as well as the agents in development to target these changes. The progress made in both the preclinical arena and in early phase drug development provide much promise for the future of precision medicine in neuroblastoma.
Collapse
|
|
15
|
Abstract
Neuroblastomas are characterized by heterogeneous clinical behavior, from spontaneous regression or differentiation into a benign ganglioneuroma, to relentless progression despite aggressive, multimodality therapy. Indeed, neuroblastoma is unique among human cancers in terms of its propensity to undergo spontaneous regression. The strongest evidence for this comes from the mass screening studies conducted in Japan, North America and Europe and it is most evident in infants with stage 4S disease. This propensity is associated with a pattern of genomic change characterized by whole chromosome gains rather than segmental chromosome changes but the mechanism(s) underlying spontaneous regression are currently a matter of speculation. There is evidence to support several possible mechanisms of spontaneous regression in neuroblastomas: (1) neurotrophin deprivation, (2) loss of telomerase activity, (3) humoral or cellular immunity and (4) alterations in epigenetic regulation and possibly other mechanisms. It is likely that a better understanding of the mechanisms of spontaneous regression will help to identify targeted therapeutic approaches for these tumors. The most easily targeted mechanism is the delayed activation of developmentally programmed cell death regulated by the tropomyosin receptor kinase A (TrkA) pathway. Pan-Trk inhibitors are currently in clinical trials and so Trk inhibition might be used as the first line of therapy in infants with biologically favorable tumors that require treatment. Alternative approaches consist of breaking immune tolerance to tumor antigens but approaches to telomere shortening or epigenetic regulation are not easily druggable. The different mechanisms of spontaneous neuroblastoma regression are reviewed here, along with possible therapeutic approaches.
Collapse
Affiliation(s)
- Garrett M Brodeur
- Division of Oncology, Department of Pediatrics, the Children's Hospital of Philadelphia, University of Pennsylvania/Perelman School of Medicine, Philadelphia, PA, 19104, USA.
- Oncology Research, The Children's Hospital of Philadelphia, CTRB Rm. 3018, 3501 Civic Center Blvd., Philadelphia, PA, 19104-4302, USA.
| |
Collapse
|
|
16
|
Johnsen JI, Dyberg C, Fransson S, Wickström M. Molecular mechanisms and therapeutic targets in neuroblastoma. Pharmacol Res 2018; 131:164-176. [PMID: 29466695 DOI: 10.1016/j.phrs.2018.02.023] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Revised: 02/13/2018] [Accepted: 02/14/2018] [Indexed: 12/20/2022]
Abstract
Neuroblastoma is the most common extracranical tumor of childhood and the most deadly tumor of infancy. It is characterized by early age onset and high frequencies of metastatic disease but also the capacity to spontaneously regress. Despite intensive therapy, the survival for patients with high-risk neuroblastoma and those with recurrent or relapsed disease is low. Hence, there is an urgent need to develop new therapies for these patient groups. The molecular pathogenesis based on high-throughput omics technologies of neuroblastoma is beginning to be resolved which have given the opportunity to develop personalized therapies for high-risk patients. Here we discuss the potential of developing targeted therapies against aberrantly expressed molecules detected in sub-populations of neuroblastoma patients and how these selected targets can be drugged in order to overcome treatment resistance, improve survival and quality of life for these patients and also the possibilities to transfer preclinical research into clinical testing.
Collapse
Affiliation(s)
- John Inge Johnsen
- Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital Solna, 171 77 Stockholm, Sweden.
| | - Cecilia Dyberg
- Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital Solna, 171 77 Stockholm, Sweden
| | - Susanne Fransson
- Department of Pathology and Genetics, Sahlgrenska Academy at the University of Gothenburg, 405 30 Gothenburg, Sweden
| | - Malin Wickström
- Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital Solna, 171 77 Stockholm, Sweden
| |
Collapse
|
|
17
|
Abstract
Neuroblastoma (NB) is the most common solid childhood tumor outside the brain and causes 15% of childhood cancer-related mortality. The main drivers of NB formation are neural crest cell-derived sympathoadrenal cells that undergo abnormal genetic arrangements. Moreover, NB is a complex disease that has high heterogeneity and is therefore difficult to target for successful therapy. Thus, a better understanding of NB development helps to improve treatment and increase the survival rate. One of the major causes of sporadic NB is known to be MYCN amplification and mutations in ALK (anaplastic lymphoma kinase) are responsible for familial NB. Many other genetic abnormalities can be found; however, they are not considered as driver mutations, rather they support tumor aggressiveness. Tumor cell elimination via cell death is widely accepted as a successful technique. Therefore, in this review, we provide a thorough overview of how different modes of cell death and treatment strategies, such as immunotherapy or spontaneous regression, are or can be applied for NB elimination. In addition, several currently used and innovative approaches and their suitability for clinical testing and usage will be discussed. Moreover, significant attention will be given to combined therapies that show more effective results with fewer side effects than drugs targeting only one specific protein or pathway.
Collapse
|
|
18
|
Trk inhibition reduces cell proliferation and potentiates the effects of chemotherapeutic agents in Ewing sarcoma. Oncotarget 2017; 7:34860-80. [PMID: 27145455 PMCID: PMC5085195 DOI: 10.18632/oncotarget.8992] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2015] [Accepted: 04/10/2016] [Indexed: 02/06/2023] Open
Abstract
Ewing sarcoma (ES) is a highly aggressive pediatric cancer that may arise from neuronal precursors. Neurotrophins stimulate neuronal devlopment and plasticity. Here, we found that neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), as well as their receptors (TrkA and TrkB, respectively) are expressed in ES tumors. Treatment with TrkA (GW-441756) or TrkB (Ana-12) selective inhibitors decreased ES cell proliferation, and the effect was increased when the two inhibitors were combined. ES cells treated with a pan-Trk inhibitor, K252a, showed changes in morphology, reduced levels of β-III tubulin, and decreased mRNA expression of NGF, BDNF, TrkA and TrkB. Furthermore, combining K252a with subeffective doses of cytotoxic chemotherapeutic drugs resulted in a decrease in ES cell proliferation and colony formation, even in chemoresistant cells. These results indicate that Trk inhibition may be an emerging approach for the treatment of ES.
Collapse
|
|
19
|
Abstract
In the last few years, exciting properties have emerged regarding the activation, signaling, mechanisms of action, and therapeutic targeting of the two types of neurotrophin receptors: the p75NTR with its intracellular and extracellular peptides, the Trks, their precursors and their complexes. This review summarizes these new developments, with particular focus on neurodegenerative diseases. Based on the evolving knowledge, innovative concepts have been formulated regarding the pathogenesis of these diseases, especially the Alzheimer's and two other, the Parkinson's and Huntington's diseases. The medical progresses include original procedures of diagnosis, started from studies in mice and now investigated for human application, based on innovative classes of receptor agonists and blockers. In parallel, comprehensive studies have been and are being carried out for the development of drugs. The relevance of these studies is based on the limitations of the therapies employed until recently, especially for the treatment of Alzheimer's patients. Starting from well known drugs, previously employed for non-neurodegenerative diseases, the ongoing progress has lead to the development of small molecules that cross rapidly the blood-brain barrier. Among these molecules the most promising are specific blockers of the p75NTR receptor. Additional drugs, that activate Trk receptors, were shown effective against synaptic loss and memory deficits. In the near future such approaches, coordinated with treatments with monoclonal antibodies and with developments in the microRNA field, are expected to improve the therapy of neurodegenerative diseases, and may be relevant also for other human disease conditions.
Collapse
Affiliation(s)
- Jacopo Meldolesi
- Department of Neuroscience, Vita-Salute San Raffaele University and Scientific Institute San Raffaele, via Olgettina 58, 20132 Milan, Italy.
| |
Collapse
|
|
20
|
Odate S, Veschi V, Yan S, Lam N, Woessner R, Thiele CJ. Inhibition of STAT3 with the Generation 2.5 Antisense Oligonucleotide, AZD9150, Decreases Neuroblastoma Tumorigenicity and Increases Chemosensitivity. Clin Cancer Res 2017; 23:1771-1784. [PMID: 27797972 PMCID: PMC5381521 DOI: 10.1158/1078-0432.ccr-16-1317] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2016] [Revised: 09/30/2016] [Accepted: 10/04/2016] [Indexed: 12/29/2022]
Abstract
Purpose: Neuroblastoma is a pediatric tumor of peripheral sympathoadrenal neuroblasts. The long-term event-free survival of children with high-risk neuroblastoma is still poor despite the improvements with current multimodality treatment protocols. Activated JAK/STAT3 pathway plays an important role in many human cancers, suggesting that targeting STAT3 is a promising strategy for treating high-risk neuroblastoma.Experimental Design: To evaluate the biologic consequences of specific targeting of STAT3 in neuroblastoma, we assessed the effect of tetracycline (Tet)-inducible STAT3 shRNA and the generation 2.5 antisense oligonucleotide AZD9150 which targets STAT3 in three representative neuroblastoma cell line models (AS, NGP, and IMR32).Results: Our data indicated that Tet-inducible STAT3 shRNA and AZD9150 inhibited endogenous STAT3 and STAT3 target genes. Tet-inducible STAT3 shRNA and AZD9150 decreased cell growth and tumorigenicity. In vivo, STAT3 inhibition by Tet-inducible STAT3 shRNA or AZD9150 alone had little effect on growth of established tumors. However, when treated xenograft tumor cells were reimplanted into mice, there was a significant decrease in secondary tumors in the mice receiving AZD9150-treated tumor cells compared with the mice receiving ntASO-treated tumor cells. This indicates that inhibition of STAT3 decreases the tumor-initiating potential of neuroblastoma cells. Furthermore, inhibition of STAT3 significantly increased neuroblastoma cell sensitivity to cisplatin and decreased tumor growth and increased the survival of tumor-bearing mice in vivoConclusions: Our study supports the development of strategies targeting STAT3 inhibition in combination with conventional chemotherapy for patients with high-risk neuroblastoma. Clin Cancer Res; 23(7); 1771-84. ©2016 AACR.
Collapse
Affiliation(s)
- Seiichi Odate
- Cell & Molecular Biology Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Veronica Veschi
- Cell & Molecular Biology Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Shuang Yan
- Cell & Molecular Biology Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Norris Lam
- Cell & Molecular Biology Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Richard Woessner
- Cancer Bioscience Drug Discovery, AstraZeneca Pharmaceuticals, Waltham, Massachusetts
| | - Carol J Thiele
- Cell & Molecular Biology Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
| |
Collapse
|
|
21
|
Esposito MR, Aveic S, Seydel A, Tonini GP. Neuroblastoma treatment in the post-genomic era. J Biomed Sci 2017; 24:14. [PMID: 28178969 PMCID: PMC5299732 DOI: 10.1186/s12929-017-0319-y] [Citation(s) in RCA: 83] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2016] [Accepted: 01/31/2017] [Indexed: 02/07/2023] Open
Abstract
Neuroblastoma is an embryonic malignancy of early childhood originating from neural crest cells and showing heterogeneous biological, morphological, genetic and clinical characteristics. The correct stratification of neuroblastoma patients within risk groups (low, intermediate, high and ultra-high) is critical for the adequate treatment of the patients. High-throughput technologies in the Omics disciplines are leading to significant insights into the molecular pathogenesis of neuroblastoma. Nonetheless, further study of Omics data is necessary to better characterise neuroblastoma tumour biology. In the present review, we report an update of compounds that are used in preclinical tests and/or in Phase I-II trials for neuroblastoma. Furthermore, we recapitulate a number of compounds targeting proteins associated to neuroblastoma: MYCN (direct and indirect inhibitors) and downstream targets, Trk, ALK and its downstream signalling pathways. In particular, for the latter, given the frequency of ALK gene deregulation in neuroblastoma patients, we discuss on second-generation ALK inhibitors in preclinical or clinical phases developed for the treatment of neuroblastoma patients resistant to crizotinib. We summarise how Omics drive clinical trials for neuroblastoma treatment and how much the research of biological targets is useful for personalised medicine. Finally, we give an overview of the most recent druggable targets selected by Omics investigation and discuss how the Omics results can provide us additional advantages for overcoming tumour drug resistance.
Collapse
Affiliation(s)
- Maria Rosaria Esposito
- Paediatric Research Institute, Fondazione Città della Speranza, Neuroblastoma Laboratory, Corso Stati Uniti, 4, Padua, 35127, Italy.
| | - Sanja Aveic
- Paediatric Research Institute, Fondazione Città della Speranza, Neuroblastoma Laboratory, Corso Stati Uniti, 4, Padua, 35127, Italy
| | - Anke Seydel
- Department of Biology, University of Padua, Padua, Italy
| | - Gian Paolo Tonini
- Paediatric Research Institute, Fondazione Città della Speranza, Neuroblastoma Laboratory, Corso Stati Uniti, 4, Padua, 35127, Italy
| |
Collapse
|
|
22
|
Abstract
In the last few years, exciting reports have emerged regarding the role of the two types of neurotrophin receptors, p75NTR and Trks, not only in neurons, where they were discovered, but also in non-neural cells and, especially, in numerous cancers, including breast, lung, colon-rectum, pancreas, prostate, glioblastoma, neuroblastoma, myeloma, and lymphoid tumors. Traditionally, p75NTR, activated by all neurotrophins and their precursors, is an inhibitor. In various cancers, however, activated p75NTR induces variable effects, from inhibition to stimulation of cell proliferation, dependent on their direct or coordinate/indirect mechanism(s) of action. TrkA, TrkB, and TrkC, activated by distinct neurotrophins, are high affinity stimulatory receptors. In cancers, activation of Trks, especially of TrkB, are stimulators of cell proliferation, aggressiveness, and metastases. In rare cancers, these processes are due not to receptor activation but to fusion or mutation of the encoding genes. A considerable panel of anti-Trk drugs, developed recently, has been investigated both in vitro and in living mice for their effects on cancer cells. Many such drugs protect from cancers by preventing cell proliferation and inducing apoptosis. At present, these drugs are under control by trials, to promote introduction in human therapy. Moreover, anti-Trk drugs have been employed also in combination with classical chemotherapeutic drugs. So far, studies in mice have been positive. The chemotherapeutic/anti-receptor combinations exhibited in fact increased potency and down-regulation of resistance, with no increase of side effects.
Collapse
|
|
23
|
Hua Z, Gu X, Dong Y, Tan F, Liu Z, Thiele CJ, Li Z. PI3K and MAPK pathways mediate the BDNF/TrkB-increased metastasis in neuroblastoma. Tumour Biol 2016; 37:16227–16236. [PMID: 27752996 PMCID: PMC5250655 DOI: 10.1007/s13277-016-5433-z] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Accepted: 09/23/2016] [Indexed: 12/13/2022] Open
Abstract
Brain-derived neurotrophic factor (BDNF) and its tyrosine kinase receptor TrkB have been reported to be associated with poor prognosis in neuroblastoma (NB) patients. Our previous studies indicated that BDNF activation of TrkB induces chemo-resistance through activation of phosphoinositide-3-kinase (PI3K)/Akt pathway. In this study, we investigated the role of BDNF/TrkB on metastasis in NB. A tetracycline-regulated TrkB-expressing NB cell line (TB3) was used. Scratch wound healing assay, Boyden chamber migration, and invasion assays were performed to study the migration and invasion of TB3 cells. A tumor xenograft model using SCID-Beige mice was utilized to detect the metastasis of NB tumors in vivo. Inhibitors of PI3K, MAPK, Akt, and mTOR were used. Western blotting was performed to study the expressions of P-Akt, P-Erk, and P-mTOR. Our results showed that in TrkB-expressing NB cells, BDNF treatment significantly increased gap closing (P < 0.01) in scratch wound healing assay, also significantly enhanced the numbers of migrating cells (P < 0.01) and invading cells (P < 0.01) in the Boyden chamber migration and invasion assays. In vivo, NB distant metastases were significantly increased in mice with TrkB-expressing xenograft tumors compared to those with non-TrkB-expressing tumors (P < 0.05). Pre-treatment with any of the inhibitors for PI3K (LY294002), MAPK (PD98059), Akt (perifosine), or mTOR (rapamycin) blocked the BDNF/TrkB-induced increases of cell migration and invasion in TB3 cells, and also blocked the BDNF/TrkB-induced expressions of P-Akt, P-Erk, and P-mTOR. These data indicated that BDNF/TrkB increased metastasis in NB via PI3K/Akt/mTOR and MAPK pathways, and BDNF/TrkB and the downstream targets may be potential targets for the treatment of NB metastasis.
Collapse
Affiliation(s)
- Zhongyan Hua
- Medical Research Center, Shengjing Hospital of China Medical University, #36 Sanhao Street, Heping District, Shenyang, 110004, China
| | - Xiao Gu
- Medical Research Center, Shengjing Hospital of China Medical University, #36 Sanhao Street, Heping District, Shenyang, 110004, China
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yudi Dong
- Medical Research Center, Shengjing Hospital of China Medical University, #36 Sanhao Street, Heping District, Shenyang, 110004, China
| | - Fei Tan
- Department of Neurology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Zhihui Liu
- Cellular and Molecular Biology Section, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Carol J Thiele
- Cellular and Molecular Biology Section, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Zhijie Li
- Medical Research Center, Shengjing Hospital of China Medical University, #36 Sanhao Street, Heping District, Shenyang, 110004, China.
| |
Collapse
|
|
24
|
Iyer R, Wehrmann L, Golden RL, Naraparaju K, Croucher JL, MacFarland SP, Guan P, Kolla V, Wei G, Cam N, Li G, Hornby Z, Brodeur GM. Entrectinib is a potent inhibitor of Trk-driven neuroblastomas in a xenograft mouse model. Cancer Lett 2016; 372:179-86. [PMID: 26797418 DOI: 10.1016/j.canlet.2016.01.018] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2015] [Revised: 01/08/2016] [Accepted: 01/11/2016] [Indexed: 02/07/2023]
Abstract
Neuroblastoma (NB) is one of the most common and deadly childhood solid tumors. These tumors are characterized by clinical heterogeneity, from spontaneous regression to relentless progression, and the Trk family of neurotrophin receptors plays an important role in this heterogeneous behavior. We wanted to determine if entrectinib (RXDX-101, Ignyta, Inc.), an oral Pan-Trk, Alk and Ros1 inhibitor, was effective in our NB model. In vitro effects of entrectinib, either as a single agent or in combination with the chemotherapeutic agents Irinotecan (Irino) and Temozolomide (TMZ), were studied on an SH-SY5Y cell line stably transfected with TrkB. In vivo growth inhibition activity was studied in NB xenografts, again as a single agent or in combination with Irino-TMZ. Entrectinib significantly inhibited the growth of TrkB-expressing NB cells in vitro, and it significantly enhanced the growth inhibition of Irino-TMZ when used in combination. Single agent therapy resulted in significant tumor growth inhibition in animals treated with entrectinib compared to control animals [p < 0.0001 for event-free survival (EFS)]. Addition of entrectinib to Irino-TMZ also significantly improved the EFS of animals compared to vehicle or Irino-TMZ treated animals [p < 0.0001 for combination vs. control, p = 0.0012 for combination vs. Irino-TMZ]. We show that entrectinib inhibits growth of TrkB expressing NB cells in vitro and in vivo, and that it enhances the efficacy of conventional chemotherapy in in vivo models. Our data suggest that entrectinib is a potent Trk inhibitor and should be tested in clinical trials for NBs and other Trk-expressing tumors.
Collapse
Affiliation(s)
- Radhika Iyer
- Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Lea Wehrmann
- Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Rebecca L Golden
- Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Koumudi Naraparaju
- Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Jamie L Croucher
- Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Suzanne P MacFarland
- Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Peng Guan
- Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Venkatadri Kolla
- Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Ge Wei
- The Department of Pediatrics, The University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Nicholas Cam
- The Department of Pediatrics, The University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Gang Li
- The Department of Pediatrics, The University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Zachary Hornby
- The Department of Pediatrics, The University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Garrett M Brodeur
- Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Ignyta Inc., San Diego, CA 92121, USA.
| |
Collapse
|
|
25
|
Bernard-Gauthier V, Schirrmacher R. Evaluation of WO2015042088 A1 - a novel urea-based scaffold for TrkA inhibition. Expert Opin Ther Pat 2015; 26:291-5. [DOI: 10.1517/13543776.2016.1118062] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
|
|
26
|
Choi HS, Rucker PV, Wang Z, Fan Y, Albaugh P, Chopiuk G, Gessier F, Sun F, Adrian F, Liu G, Hood T, Li N, Jia Y, Che J, McCormack S, Li A, Li J, Steffy A, Culazzo A, Tompkins C, Phung V, Kreusch A, Lu M, Hu B, Chaudhary A, Prashad M, Tuntland T, Liu B, Harris J, Seidel HM, Loren J, Molteni V. (R)-2-Phenylpyrrolidine Substituted Imidazopyridazines: A New Class of Potent and Selective Pan-TRK Inhibitors. ACS Med Chem Lett 2015; 6:562-7. [PMID: 26005534 DOI: 10.1021/acsmedchemlett.5b00050] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2015] [Accepted: 03/16/2015] [Indexed: 02/07/2023] Open
Abstract
Deregulated kinase activities of tropomyosin receptor kinase (TRK) family members have been shown to be associated with tumorigenesis and poor prognosis in a variety of cancer types. In particular, several chromosomal rearrangements involving TRKA have been reported in colorectal, papillary thyroid, glioblastoma, melanoma, and lung tissue that are believed to be the key oncogenic driver in these tumors. By screening the Novartis compound collection, a novel imidazopyridazine TRK inhibitor was identified that served as a launching point for drug optimization. Structure guided drug design led to the identification of (R)-2-phenylpyrrolidine substituted imidazopyridazines as a series of potent, selective, orally bioavailable pan-TRK inhibitors achieving tumor regression in rats bearing KM12 xenografts. From this work the (R)-2-phenylpyrrolidine has emerged as an ideal moiety to incorporate in bicyclic TRK inhibitors by virtue of its shape complementarity to the hydrophobic pocket of TRKs.
Collapse
Affiliation(s)
- Ha-Soon Choi
- Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States
| | - Paul V. Rucker
- Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States
| | - Zhicheng Wang
- Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States
| | - Yi Fan
- Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States
| | - Pamela Albaugh
- Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States
| | - Greg Chopiuk
- Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States
| | - Francois Gessier
- Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States
| | - Fangxian Sun
- Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States
| | - Francisco Adrian
- Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States
| | - Guoxun Liu
- Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States
| | - Tami Hood
- Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States
| | - Nanxin Li
- Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States
| | - Yong Jia
- Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States
| | - Jianwei Che
- Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States
| | - Susan McCormack
- Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States
| | - Allen Li
- Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States
| | - Jie Li
- Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States
| | - Auzon Steffy
- Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States
| | - AnneMarie Culazzo
- Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States
| | - Celine Tompkins
- Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States
| | - Van Phung
- Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States
| | - Andreas Kreusch
- Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States
| | - Min Lu
- Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States
| | - Bin Hu
- Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States
| | - Apurva Chaudhary
- Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States
| | - Mahavir Prashad
- Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States
| | - Tove Tuntland
- Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States
| | - Bo Liu
- Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States
| | - Jennifer Harris
- Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States
| | - H. Martin Seidel
- Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States
| | - Jon Loren
- Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States
| | - Valentina Molteni
- Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States
| |
Collapse
|
|
27
|
Bernard-Gauthier V, Bailey JJ, Aliaga A, Kostikov A, Rosa-Neto P, Wuest M, Brodeur GM, Bedell BJ, Wuest F, Schirrmacher R. Development of subnanomolar radiofluorinated (2-pyrrolidin-1-yl)imidazo[1,2-b]pyridazine pan-Trk inhibitors as candidate PET imaging probes. MEDCHEMCOMM 2015. [DOI: 10.1039/c5md00388a] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Dysregulation of tropomyosin receptor kinases (TrkA/B/C) expression and signalling is recognized as a hallmark of numerous neurodegenerative diseases including Parkinson's, Huntington's and Alzheimer's disease.
Collapse
Affiliation(s)
| | | | - Arturo Aliaga
- Translational Neuroimaging Laboratory
- McGill Centre for Studies in Aging
- Douglas Mental Health University Institute
- Montreal
- Canada
| | - Alexey Kostikov
- McConnell Brain Imaging Centre
- Montreal Neurological Institute
- McGill University
- Montreal
- Canada
| | - Pedro Rosa-Neto
- Translational Neuroimaging Laboratory
- McGill Centre for Studies in Aging
- Douglas Mental Health University Institute
- Montreal
- Canada
| | - Melinda Wuest
- Department of Oncology
- University of Alberta
- Edmonton
- Canada
| | | | - Barry J. Bedell
- Biospective Inc
- Montreal
- Canada
- Research Institute of the McGill University Health Centre
- Montreal
| | - Frank Wuest
- Department of Oncology
- University of Alberta
- Edmonton
- Canada
| | | |
Collapse
|