Combined MYC and P53 Defects Emerge at Medulloblastoma Relapse and Define Rapidly Progressive, Therapeutically Targetable Disease

Hill, Rebecca; Kuijper, Sanne; Lindsey, John H.; Petrie, Kevin; Schwalbe, Ed C.; Barker, Karen; Boult, Jessica K.R.; Williamson, Daniel; Ahmad, Zahida; Hallsworth, Albert; Ryan, Sarra; Poon, Evon; Robinson, Simon P.; Ruddle, Ruth; Raynaud, Florence I.; Howell, Louise; Kwok, Colin; Joshi, Abhijit; Nicholson, Sarah Leigh; Crosier, Stephen; Ellison, David W.; Wharton, Stephen B.; Robson, Keith; Michalski, Antony; Hargrave, Darren; Jacques, Thomas S.; Pizer, Barry; Bailey, Simon; Swartling, Fredrik J.; Weiss, William A.; Chesler, Louis; Clifford, Steven C.

doi:10.1016/j.ccell.2014.11.002

Cited by 176 publications

(221 citation statements)

References 46 publications

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“…Furthermore, p53 loss of function gives rise to tumors that can acquire growth and survival mechanisms that are resistant to the reintroduction of functional p53. This is in stark contrast with a medulloblastoma GEM model driven by expression of MYCN and p53 deficiency, GTML/Trp53 KI/KI (GTML; Glt1-tTA/TRE-MYCN-Luc), where restoration of functional p53ER TAM by Tam led to increased survival and inhibition of tumor growth (5). Other transgenic models of p53 loss of function do, however, develop tumors that display partial resistance to the restoration of functional p53ER…”

Section: Discussionmentioning

confidence: 89%

p53 Loss in MYC-Driven Neuroblastoma Leads to Metabolic Adaptations Supporting Radioresistance

et al. 2016

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Neuroblastoma is the most common childhood extracranial solid tumor. In high-risk cases, many of which are characterized by amplification of MYCN, outcome remains poor. Mutations in the p53 (TP53) tumor suppressor are rare at diagnosis, but evidence suggests that p53 function is often impaired in relapsed, treatment-resistant disease. To address the role of p53 loss of function in the development and pathogenesis of high-risk neuroblastoma, we generated a MYCN-driven genetically engineered mouse model in which the tamoxifen-inducible p53ER TAM fusion protein was expressed from a knock-in allele (Th-MYCN/Trp53 KI ). We observed no significant differences in tumor-free survival between Th-MYCN mice heterozygous for Trp53 KI (n ¼ 188) and Th-MYCN mice with wild-type p53 (n ¼ 101). Conversely, the survival of Th-MYCN/Trp53 KI/KI mice lacking functional p53 (n ¼ 60) was greatly reduced. We found that Th-MYCN/Trp53 KI/KI tumors were resistant to ionizing radiation (IR), as expected. However, restoration of functional p53ER TAM reinstated sensitivity to IR in only 50% of Th-MYCN/ Trp53 KI/KI tumors, indicating the acquisition of additional resistance mechanisms. Gene expression and metabolic analyses indicated that the principal acquired mechanism of resistance to IR in the absence of functional p53 was metabolic adaptation in response to chronic oxidative stress. Tumors exhibited increased antioxidant metabolites and upregulation of glutathione S-transferase pathway genes, including Gstp1 and Gstz1, which are associated with poor outcome in human neuroblastoma. Accordingly, glutathione depletion by buthionine sulfoximine together with restoration of p53 activity resensitized tumors to IR. Our findings highlight the complex pathways operating in relapsed neuroblastomas and the need for combination therapies that target the diverse resistance mechanisms at play. Cancer Res; 76(10); 3025-35. Ó2016 AACR.

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Section: Discussionmentioning

confidence: 89%

p53 Loss in MYC-Driven Neuroblastoma Leads to Metabolic Adaptations Supporting Radioresistance

et al. 2016

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“…Examples of second-site SMOis include the antifungal agent itraconazole and the cyclopamine derivative IPI-926 (saridegib), both of which have shown promise in preclinical studies (65,66). Inhibitors of downstream components of the SHH pathway include arsenic trioxide, which can promote GLI2 degradation (65); bromodomain inhibitors, which not only reduce expression and transcriptional activity of the SHH target MYCN (67) but also impair the function of GLI1 and GLI2 (68); and Aurora kinase A inhibitors, some of which can impair cell cycle progression as well as destabilize MYCN (69)(70)(71). The observation of increased PI3K pathway activity in tumors that develop resistance to SMOis (63,64), along with reports of recurrent mutations affecting this pathway (12,42), has suggested that PI3K inhibition may be an important strategy for preventing or overcoming resistance of SHH-MB.…”

Section: Shh Subgroupmentioning

confidence: 99%

“…Combined MYC and TP53 defects have been found in patients with relapsed MB (70), and thus, these mouse models may represent valuable tools for studying recurrent tumors. Because TP53 aberrations have not been found in newly diagnosed G3-MBs, the search has begun for alternative "second hits" that can cooperate with Myc to drive tumorigenesis in mice.…”

Section: Groupmentioning

confidence: 99%

“…Targeted expression of human MYCN in glutamate transporter 1 (Glt1)-expressing cells generated tumors that were initially suggested to model G4-MB (96,97), but subsequent genomic analysis has suggested that these tumors may more closely resemble G3-MB (70). Because G4-MBs have few recurrent SNVs and indels and frequently harbor i17q or other chromosomal changes (12,91), it is likely that multiple genetic driver events are necessary for initiation of this disease.…”

Section: Groupmentioning

confidence: 99%

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Molecular mechanisms and therapeutic targets in pediatric brain tumors

et al. 2017

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Brain tumors are among the leading causes of cancer-related deaths in children. Although surgery, aggressive radiation, and chemotherapy have improved outcomes, many patients still die of their disease. Moreover, those who survive often suffer devastating long-term side effects from the therapies. A greater understanding of the molecular underpinnings of these diseases will drive the development of new therapeutic approaches. Advances in genomics and epigenomics have provided unprecedented insight into the molecular diversity of these diseases and, in several cases, have revealed key genes and signaling pathways that drive tumor growth. These not only serve as potential therapeutic targets but also have facilitated the creation of animal models that faithfully recapitulate the human disease for preclinical studies. In this Review, we discuss recent progress in understanding the molecular basis of the three most common malignant pediatric brain tumors-medulloblastoma, ependymoma, and high-grade glioma-and the implications for development of safer and more effective therapies.

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“…Current treatment strategies include a combination of surgery, radiotherapy, and chemotherapy, which have achieved 70%-80% 5-yr survival rates; however, recurrence is common and often proves fatal (Hill et al 2015). In addition, both the brain exposure to ionizing radiation and the systemic exposure to chemotherapy agents can induce severe side effects, leading to mental and physical disability of the affected children.…”

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confidence: 99%

TAp73 is a marker of glutamine addiction in medulloblastoma

et al. 2017

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Medulloblastoma is the most common solid primary brain tumor in children. Remarkable advancements in the understanding of the genetic and epigenetic basis of these tumors have informed their recent molecular classification. However, the genotype/phenotype correlation of the subgroups remains largely uncharacterized. In particular, the metabolic phenotype is of great interest because of its druggability, which could lead to the development of novel and more tailored therapies for a subset of medulloblastoma. p73 plays a critical role in a range of cellular metabolic processes. We show overexpression of p73 in a proportion of non-WNT medulloblastoma. In these tumors, p73 sustains cell growth and proliferation via regulation of glutamine metabolism. We validated our results in a xenograft model in which we observed an increase in survival time in mice on a glutamine restriction diet. Notably, glutamine starvation has a synergistic effect with cisplatin, a component of the current medulloblastoma chemotherapy. These findings raise the possibility that glutamine depletion can be used as an adjuvant treatment for p73-expressing medulloblastoma.

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Combined MYC and P53 Defects Emerge at Medulloblastoma Relapse and Define Rapidly Progressive, Therapeutically Targetable Disease

Cited by 176 publications

References 46 publications

p53 Loss in MYC-Driven Neuroblastoma Leads to Metabolic Adaptations Supporting Radioresistance

p53 Loss in MYC-Driven Neuroblastoma Leads to Metabolic Adaptations Supporting Radioresistance

Molecular mechanisms and therapeutic targets in pediatric brain tumors

TAp73 is a marker of glutamine addiction in medulloblastoma

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