Identification of new brain entities and therapies
- Li M Lee KF, Lu Y, Clarke I… Huang A. Frequent amplification of a chr19q13.41 microRNA polycistron in aggressive primitive neuroectodermal brain tumors. Cancer Cell. 2009;16(6):533-46. Comments in Nature/SciBx. SRI IF 25.28
- Spence T*, Sin-Chan P*, Picard D…..Huang A. CNS-PNETs with C19MC amplification and/or LIN28 expression comprise a distinct histogenetic diagnostic and therapeutic entity. Acta neuropathologica. 2014; 128(2):291-303 SRI IF 9.77
CNS-PNETs are rare highly lethal cancers for which (until our work) there were no specific diagnostic tools and for which existing therapies are largely empiric and ineffective. We performed the first molecular study of CNS-PNETs and reported that CNS-PNETs were molecularly heterogenous. Our first study led to the discovery a novel oncogenic miRNA cluster, which identifies a distinct aggressive sub-type of CNS-PNETs (Li et al., Cancer Cell 2009). In this paper, we further defined the biological and histological spectrum of this disease and demonstrated unexcpectedly that embryonal brain tumours with various histologic presentation that are presently considered distinct diseases at different intracranial anatomical sites, are in fact a common molecular disease. We demonstrated that tumours that expressed high levels of a pluripotency factor but without C19MC amplification also shared molecular profiles. This resulted in the development of LIN28 immunostains as a second diagnostic tool for this spectrum of tumour and indicated for the first time, an important role for this potent oncogene in embryonal brain tumour development.
- Spence T, Perotti C, Sin-Chan P, Picard D, Wu W, Singh A, Anderson C, Blough MD, Cairncross JG, Lafay-Cousin L, Strother D, Hawkins C, Narendran A, Huang A*, Chan JA*. A novel C19MC amplified cell line links Lin28/let-7 to mTOR signaling in embryonal tumor with multilayered rosettes. Neuro-oncology. 2014;16(1):62-71. *Co-SRI and co-corresponding senior authors IF 5.3
Based on our prior studies, which showed that C19MC and LIN28B identified a distinct group of CNS-PNETs, we investigated the therapeutic significance of this association in this paper. In collaboration with Dr Jennifer Chan at the University of Calgary, we characterized the only existing cell line derived from this tumour type (commonly refered to as ETANTR/EMTR) and conducted a drug screen for potential new therapies. Our study showed importantly that the potent LIN28 oncogene regulated PI3K signaling, and sensitized these tumour cells to inhibitors of P13K and mTOR signaling. Our study represents the first therapeutic study of this tumour type, and provided rationale to consider P13K and inhibitors for this disease, as well as additional new drugs to consider in trial development.
- Kleinman CL, Gerges N, Papillon-Cavanagh S, Sin-Chan P, Pramatarova A, Quang DA, Adoue V, Busche S, Caron M, Djambazian H, Bemmo A, Fontebasso AM, Spence T, Schwartzentruber J, Albrecht S, Hauser P, Garami M, Klekner A, Bognar L, Montes JL, Staffa A, Montpetit A, Berube P, Zakrzewska M, Zakrzewski K, Liberski PP, Dong Z, Siegel PM, Duchaine T, Perotti C, Fleming A, Faury D, Remke M, Gallo M, Dirks P, Taylor MD, Sladek R, Pastinen T, Chan JA, Huang A*, Majewski J*, Jabado N*. Fusion of TTYH1 with the C19MC microRNA cluster drives expression of a brain-specific DNMT3B isoform in the embryonal brain tumor ETMR. Nature genetics. 2014;46(1):39-44. *Co-SRI and co-corresponding senior authors IF 29.65
As part of our ongoing efforts to define the biology and molecular pathogenesis of the ETANTR/EMTR spectrum of CNS-PNETs, we collaborated with Dr Nada Jabado at McGill University to conduct RNA sequencing studies on these rare tumours. Significantly these studies identified novel fusion of the C19MC locus with TTHY1, a developmental regulated channel gene, resulting in high level expression of C19MC miRNAs in a very specific developmental window. We demonstrated using functional studies that C19MC targeted a tumour suppressor RBL2, which in turns regulate expression of an embryonic stage specific isoform of DNMT3B, a DNA methyl transferase. These findings suggested for the first time that ETANTR/EMTR resulted from deregulated epigenetic programming and provided rationale for use of DNMT inhibitors in therapy (Sin-Chan P and Huang A, Expert Opinions on Therapeutic Targets, 2014). The biological and clinical significance of our publication was highlighted in an accompanying editorial in Nature Genetics (Kleinman et al., Nature Genetics 2014).
- Picard D, Miller S, Hawkins CE, Bouffet E, Rogers HA, Chan TS, ..and Huang A. Markers of survival and metastatic potential in childhood CNS primitive neuro-ectodermal brain tumours: an integrative genomic analysis. Lancet Oncology. 2012 Aug, 13(8):834-48. SRI IF:24.72
To further define the molecular spectrum of CNS-PNETs, in this study we embarked on a large-scale collaborative study to profile the transcriptomes of a large cohort of CNS-PNETs. This study allowed us to further identify two additional sub-classes of CNS-PNETs. Our study showed that expression of OLIG2 a marker of glial differentiation distinguished CNS-PNETs with distinct clinic-pathologic features and propensity for metastases. In addition, our study identified novel pathways that may be targeted for these new CNS-PNET subtypes. In ongoing studies, we have defined additiona sub-types of CNS-PNETs thus underscoring the complexity of CNS-PNET diagnoses. Our studies have now spurred global efforts to establish robust diagnostic markers for sub-types of CNS-PNETs that can inform development of therapeutic trials. The significance of our findings was highlighted in two editorials – Lancet Oncology, and Translational Pediatrics.
Molecular sub-typing and novel therapies for ATRTs
- Lafay-Cousin L, Fay-McClymont T, Johnston D… Huang A et al. Neurocognitive evaluation of long term survivors of atypical teratoid rhabdoid tumors (ATRT): The Canadian registry experience. Pediatric blood & cancer. 2015;62(7):1265-9.
- Lafay-Cousin L, Hawkins C, Carret AS… Huang A. Central nervous system atypical teratoid rhabdoid tumors: the Canadian Pediatric Brain Tumor Consortium experience. EurJ Cancer. 2012; 48(3): 353-9. SRI IF 5.536
- Torchia J, Picard D, ….Chan TSY, Chan P, Huang A. Molecular subgroups of atypical teratoid rhabdoid tumours in children: an integrated genomic and clinicopathological analysis. The Lancet Oncology. 2015;16(5):569-82. SRI IF: 24.72
- Torchia J, Golbourn,…Huang A. Integrated (epi)-genomic analyses of ATRT identifies sub-types specific therapeutic targets. Cancer Cell. 2016. Accepted
Rhabdoid Brain Tumours/ATRTs are highly lethal tumours of infancy, which share a common genetic alteration of SMARCB1. Although methods for diagnoses of ATRTs have been long established, mechanisms underlying the heterogenous clinical spectrum of this disease remain unexplained. We showed in previous work (Lafay-Cousin…Huang A; 2012, EJC) that in fact a proportion of children with ATRTs have chemosensitive tumours. These observations provided a rationale for global transcriptional profiling of ATRTs in order to define molecular sub-types of disease that may require distinct stratified treatment with radiation. In this study we performed an integrated analyses on 120 ATRTs, and demonstrated that indeed ATRTs can be divided into 2 molecular sub-types with different lineage and signalling features. Importantly, we were able to identify that one sub-type of ATRT correlated with chemo sensitivity and radiation-free survival. In this paper, we developed and proposed an integrated model of molecular and clinical stratification, which will enable the segregation of ATRTs into 3 distinct clinical risk groups, which have vastly different treatment response and survival with current existing therapeutic strategies, and underscore the need for new biological approaches to different sub-types of this disease. The significance of our findings was highlighted in an accompanying editorial in Lancet Oncology (Torchia et al., Lancet Oncol. 2015). Indeed in a recent study submitted for publication (Torchia et al., Cancer Cell, 2016, In Revision) we have identified specific therapeutic agents for each of the disease sub-types. These findings have spurred collaborations for development of disease models, mechanistic investigations of disease, as well as for initiation of sub-type specific clinical trials.