Citations

Abstract Oncogenic translocations involving the MET gene have been reported in several cancer types, but detailed clinicogenomic characterization of these cancers is not well defined. In addition, prospective clinical trials evaluating the antitumor activity of MET inhibitors in MET rearrangement–positive cancers are limited. In this study, in a pan-cancer analysis of >46,000 solid tumors with comprehensive genomic profiling, we identified oncogenic MET rearrangements in ∼0.04% of cancers. Preliminary analysis from a phase II clinical trial of the type I MET tyrosine kinase inhibitor (TKI) vebreltinib in MET fusion–positive solid tumors demonstrated an objective response rate of 50% and disease control rate of 79%, with antitumor activity seen in diverse cancer types, including lung adenocarcinoma and intrahepatic cholangiocarcinoma, among others. Similar to MET exon 14–altered lung cancer, secondary mutations in the kinase domain can confer resistance to MET TKIs in MET fusion–positive cancers. Overall, these data categorize MET rearrangements as actionable targets in solid tumors. Significance: MET rearrangement–positive cancers are not well-characterized, and optimal treatment strategies are yet to be defined. Through comprehensive genomic analysis, preclinical modeling, and preliminary results of a phase II clinical trial, we demonstrate that MET fusions are a unique molecular subtype of cancers targetable with vebreltinib, a TKI in development.

Abstract Cellular senescence restrains the expansion of neoplastic cells through several layers of regulation, including epigenetic decoration of chromatin structure and functional modulation of bioactive components. Here we report that expression of the histone H3-specific demethylase KDM4 is upregulated in human stromal cells upon cellular senescence. In clinical oncology, upregulated KDM4 and diminished H3K9/H3K36 methylation are correlated with adverse survival of cancer patients post-chemotherapy. Global chromatin accessibility mapping via ATAC-seq and expression profiling through RNA-seq reveal extensive reorganization of chromosomes and spatiotemporal reprogramming of the transcriptomic landscape, events responsible for development of the senescence-associated secretory phenotype (SASP). Selectively targeting KDM4 dampens the SASP of senescent stromal cells and enhances the apoptotic index of cancer cells in the treatment-damaged tumor microenvironment (TME), together prolonging overall survival of experimental animals. Our study supports the dynamic change of H3K9/H3K36 methylation marks during cellular senescence, identifies an unusually permissive chromatin state, unmasks KDM4 as a key modulator of the SASP, and presents a novel therapeutic avenue to manipulate cellular senescence and curtail age-related pathologies.

Abstract MYCN is a major driver for the childhood cancer, neuroblastoma, however, there are no inhibitors of this target. Enhanced MYCN protein stability is a key component of MYCN oncogenesis and is maintained by multiple feedforward expression loops involving MYCN transactivation target genes. Here, we reveal the oncogenic role of a novel MYCN target and binding protein, proliferation-associated 2AG4 (PA2G4). Chromatin immunoprecipitation studies demonstrated that MYCN occupies the PA2G4 gene promoter, stimulating transcription. Direct binding of PA2G4 to MYCN protein blocked proteolysis of MYCN and enhanced colony formation in a MYCN-dependent manner. Using molecular modeling, surface plasmon resonance, and mutagenesis studies, we mapped the MYCN–PA2G4 interaction site to a 14 amino acid MYCN sequence and a surface crevice of PA2G4. Competitive chemical inhibition of the MYCN–PA2G4 protein–protein interface had potent inhibitory effects on neuroblastoma tumorigenesis in vivo. Treated tumors showed reduced levels of both MYCN and PA2G4. Our findings demonstrate a critical role for PA2G4 as a cofactor in MYCN-driven neuroblastoma and highlight competitive inhibition of the PA2G4-MYCN protein binding as a novel therapeutic strategy in the disease. Significance: Competitive chemical inhibition of the PA2G4–MYCN protein interface provides a basis for drug design of small molecules targeting MYC and MYCN-binding partners in malignancies driven by MYC family oncoproteins.

Abstract The amplified MYCN gene serves as an oncogenic driver in approximately 20% of high-risk pediatric neuroblastomas. Here we show that MYC itself is a potent transforming gene in a separate subset of high-risk neuroblastoma cases (~10%), based on (i) its upregulation by focal enhancer amplification or genomic rearrangements leading to enhancer hijacking, and (ii) its ability to transform neuroblastoma precursor cells in a transgenic animal model. The aberrant regulatory elements associated with oncogenic MYC activation include focally amplified distal enhancers or translocation of highly active enhancers from other genes to within topologically associating domains containing the MYC gene locus. The clinical outcome for patients with high levels of MYC expression is virtually identical to that of patients with amplification of the MYCN gene, a known high-risk feature of this disease. Together, these findings establish MYC as a bona fide oncogene in a clinically significant group of high-risk childhood neuroblastomas. Citation Format: Mark W. Zimmerman, Yu Liu, Shuning He, Adam D. Durbin, Brian J. Abraham, John Easton, Ying Shao, Beisi Xu, Shizhen Zhu, Xiaoling Zhang, Nina Weichert-Leahey, Richard A. Young, Jinghui Zhang, A. Thomas Look. MYC activation through enhancer hijacking or focal enhancer amplification drives a subset of high-risk pediatric neuroblastoma [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr IA19.

Abstract The amplified MYCN gene serves as an oncogenic driver in approximately 20% of high-risk pediatric neuroblastomas. Here we show that c-MYC itself is a potent transforming gene in a separate subset of high-risk neuroblastoma cases (~10%), based on (i) its upregulation by focal enhancer amplification or genomic rearrangements leading to enhancer hijacking, and (ii) its ability to transform neuroblastoma precursor cells in a transgenic animal model. The aberrant regulatory elements associated with oncogenic c-MYC activation include focally amplified distal enhancers or translocation of highly active enhancers from other genes to within topologically associating domains containing the c-MYC gene locus. The clinical outcome for patients with high levels of c-MYC expression is virtually identical to that of patients with amplification of the MYCN gene, a known high-risk feature of this disease. Together, these findings establish c-MYC as a bona fide oncogene in a clinically significant group of high risk childhood neuroblastomas. Citation Format: Mark W. Zimmerman, Yu Liu, Shuning He, Adam D. Durbin, Brian J. Abraham, John Easton, Ying Shao, Xu Beisi, Shizhen Zhu, Xiaoling Zhang, Zhaodong Li, Nina Weichert-Leahey, Richard A. Young, Jinghui Zhang, A. Thomas Look. c-MYC drives a subset of high-risk pediatric neuroblastoma and is activated through mechanisms including enhancer hijacking and focal enhancer amplification [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4135.

Abstract The amplified MYCN gene serves as an oncogenic driver in approximately 20% of high-risk pediatric neuroblastomas. Here, we show that the family member MYC is a potent transforming gene in a separate subset of high-risk neuroblastoma cases (∼10%), based on (i) its upregulation by focal enhancer amplification or genomic rearrangements leading to enhancer hijacking, and (ii) its ability to transform neuroblastoma precursor cells in a transgenic animal model. The aberrant regulatory elements associated with oncogenic MYC activation include focally amplified distal enhancers and translocation of highly active enhancers from other genes to within topologically associating domains containing the MYC gene locus. The clinical outcome for patients with high levels of MYC expression is virtually identical to that of patients with amplification of the MYCN gene, a known high-risk feature of this disease. Together, these findings establish MYC as a bona fide oncogene in a clinically significant group of high-risk childhood neuroblastomas. Significance: Amplification of the MYCN oncogene is a recognized hallmark of high-risk pediatric neuroblastoma. Here, we demonstrate that MYC is also activated as a potent oncogene in a distinct subset of neuroblastoma cases through either focal amplification of distal enhancers or enhancer hijacking mediated by chromosomal translocation. Cancer Discov; 8(3); 320–35. ©2017 AACR. This article is highlighted in the In This Issue feature, p. 253

Abstract Introduction Genetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood. Methods We conducted a transethnic genome‐wide association study (GWAS) for late‐onset AD in Stage 1 sample including whites of European Ancestry, African‐Americans, Japanese, and Israeli‐Arabs assembled by the Alzheimer's Disease Genetics Consortium. Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer's Project GWAS dataset. Results Genome‐wide significant (GWS) associations in single‐nucleotide polymorphism (SNP)–based tests ( P < 5 × 10 −8 ) were identified for SNPs in PFDN1/HBEGF , USP6NL/ECHDC3 , and BZRAP1‐AS1 and for the interaction of the (apolipoprotein E) APOE ε4 allele with NFIC SNP. We also obtained GWS evidence ( P < 2.7 × 10 −6 ) for gene‐based association in the total sample with a novel locus, TPBG ( P = 1.8 × 10 −6 ). Discussion Our findings highlight the value of transethnic studies for identifying novel AD susceptibility loci.

Abstract Neuroblastoma, an embryonic tumor of peripheral sympathetic nervous system (PSNS), accounts for 10% of all childhood cancer deaths. We recently developed a robust zebrafish model of neuroblastoma and demonstrated that activated ALK synergizes with MYCN by inhibiting a developmentally-timed apoptotic response that is otherwise induced by MYCN. Genomic studies show that PTPN11 (encoding SHP2) is the second most frequently mutated genes in high-risk neuroblastoma. We have now used our zebrafish model to ask whether mutationally activated SHP2 functions as an oncogene in neuroblastoma. We developed a transgenic line in which ptpn11E69K is overexpressed in the PSNS under control of the dopamine-beta-hydroxylase promoter. Interestingly, ptpn11E69K synergized with MYCN to accelerate the onset of neuroblastoma in the interrenal gland (IRG), the zebrafish analogue of the adrenal medulla. Tumors began to appear at 15 weeks in transgenic fish overexpressing MYCN alone, whereas latency was shortened to 7 weeks and the penetrance was increased more than four-fold in transgenic fish coexpressing MYCN and ptpn11E69K. Coexpression of ptpn11E69K and MYCN also induced ganglioneuroma in the sympathetic ganglia, an outcome that has not been observed in transgenic fish overexpressing MYCN and activated ALK. In addition, coexpression of ptpn11E69K and MYCN induced adrenal neuroblastic hyperplasia in the IRG of all the transgenic fish at 5 weeks of age, a phenotype that has only been observed in about 50% of transgenic fish overexpressing activated ALK and MYCN or MYCN alone. Thus, these results suggest that activated SHP2 can collaborate with MYCN in neuroblastoma tumorigenesis via mechanisms different from those of activated ALK. Thus, zebrafish appears to provide a robust model system for functional genomic analysis and for the investigation of the mechanisms and pathways underlying genetic alterations identified in integrative genomic studies. Citation Format: Xiaoling Zhang, Guang Yang, A.Thomas Look, Benjamin G. Neel, Shizhen (Jane) Zhu. Activated SHP2 collaborates with MYCN in neuroblastoma tumorigenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 80. doi:10.1158/1538-7445.AM2014-80