Cell-cycle checkpoint inhibitors as a novel anti-cancer strategy in Glioblastoma multiforme

• Applicant: Dr. Frank Dubois
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Hematology, Oncology ; Pathology
• Term: from 2019 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 424790222

• Final Report Year: 2021

Final Report Abstract

High grade gliomas, including Glioblastoma, are the most common cause of brain cancer related death in adults and children. Despite improvements achieved in neurosurgery, drug design and molecular understanding, few patients survive beyond 5 years. To advance toward effective therapies we need a better understanding of the mechanisms driving these tumors. We aimed to show how specific combination of genetic variants in the DNA damage response and cell cycle checkpoints could shape the susceptibly of glioma cells to pharmacologic cell cycle checkpoint inhibitors. Our preliminary data revealed that an understanding of the consequences of different genetic disruptions of these pathways was essential to interpret the different drug responses in our experiments. We focused our efforts on characterizing the consequences of different degrees of disruption of the DNA damage response and cell cycle checkpoints in human tumors. Structural Variants (SVs) are the most directly observable consequence of failures of the DNA damage response and cell cycle checkpoints based on short read sequencing. Therefore, we analyzed the structural variants (SVs) in whole-genome sequences of 179 pediatric high-grade gliomas (pHGGs), including a de-novo sequenced cohort of treatment naïve samples. This constitutes the largest WGS unique cohort assembled in adult or pediatric glioma. The most recurrent SVs targeted MYC isoforms and receptor tyrosine kinases, including a novel SV amplifying a MYC enhancer in the lncRNA CCDC26 in 12% of diffuse midline gliomas (DMGs). This revealed a more central role for MYC in these cancers than previously known. Applying de novo SV signature discovery, we identified five signatures including three (SVsig1-3) involving primarily simple SVs, and two (SVsig4-5) involving complex, clustered SVs. These SV signatures associated with genetic variants that differed from what was observed for SV signatures in other cancers, suggesting different links to underlying biology. Gliomas with simple SV signatures were TP53 wild-type but were enriched with alterations in TP53 pathway members PPM1D and MDM4. Complex signatures were associated with direct aberrations in TP53, CDKN2A, and RB1 early in tumor evolution, and with extrachromosomal amplicons that likely occurred later. All pHGGs exhibited at least one simple SV signature but complex SV signatures were primarily restricted to subsets of H3.3K27M DMGs and hemispheric pHGGs. Importantly, DMGs with the complex SV signatures SVsig4-5 were associated with shorter overall survival independent of histone type and TP53 status. These data inform the role and impact of SVs in gliomagenesis and mechanisms that shape them.

Publications

• “Neuronal differentiation and cell-cycle programs mediate response to BET- bromodomain inhibition in MYC-driven medulloblastoma.” Nature communications
  Bandopadhayay P, Piccioni F, O'Rourke R, Ho P, Gonzalez EM, Buchan G, Qian K, Gionet G, Girard E, Coxon M, Rees MG, Brenan L, Dubois F, Shapira O, Greenwald NF, …, Vazquez F, Hahn WC, Tsherniak A, Bradner JE, Yaffe MB, Milde T, Pfister SM, Qi J, Schenone M, Carr SA, Ligon KL, Kieran MW, Santagata S, Olson JM, Gokhale PC, Jaffe JD, Root DE, Stegmaier K, Johannessen CM, Beroukhim R
  
• “Histone H3.3G34-Mutant Interneuron Progenitors Co-opt PDGFRA for Gliomagenesis”. In: Cell
  Chen CCL, Deshmukh S, Jessa S, Hadjadj D, Lisi V, Andrade AF, Faury D, Jawhar W, Dali R, Suzuki H, Pathania M, A D, Dubois F, Woodward E, Hébert S, Coutelier M, Karamchandani J, Albrecht S, Brandner S, De Jay N, Gayden T, Bajic A, Harutyunyan AS, Marchione DM, Mikael LG, Juretic N, Zeinieh M, Russo C, Maestro N, Bassenden AV, Hauser P, Virga J, Bognar L, Klekner A, Zapotocky M, Vicha A, Krskova L, Vanova K, Zamecnik J, Sumerauer D, Ekert PG, Ziegler DS, Ellezam B, Filbin MG, Blanchette M, Hansford JR, Khuong-Quang DA, Berghuis AM, Weil AG, Garcia BA, Garzia L, Mack SC, Beroukhim R, Ligon KL, Taylor MD, Bandopadhayay P, Kramm C, Pfister SM, Korshunov A, Sturm D, Jones DTW, Salomoni P, Kleinman CL, Jabado N
  
• “Mechanisms and therapeutic implications of hypermutation in gliomas.” Nature
  Touat M, Li YY, Boynton AN, Spurr LF, Iorgulescu JB, Bohrson CL, Cortes-Ciriano I, Birzu C, Geduldig JE, Pelton K, Lim-Fat MJ, Pal S, Ferrer-Luna R, Ramkissoon SH, Dubois F, Bellamy C, Currimjee N, …, Chi SN, Haas-Kogan D, Batchelor TT, Frampton GM, Alexander BM, Huang RY, Ligon AH, Coulet F, Delattre JY, Hoang-Xuan K, Meredith DM, Santagata S, Duval A, Sanson M, Cherniack AD, Wen PY, Reardon DA, Marabelle A, Park PJ, Idbaih A, Beroukhim R, Bandopadhayay P, Bielle F, Ligon KL
  
• “MR Imaging Correlates for Molecular and Mutational Analyses in Children with Diffuse Intrinsic Pontine Glioma.” AJNR. American journal of neuroradiology
  Jaimes C, Vajapeyam S, Brown D, Kao PC, Ma C, Greenspan L, Gupta N, Goumnerova L, Bandopahayay P, Dubois F, Greenwald NF, Zack T, Shapira O, Beroukhim R, Ligon KL, Chi S, Kieran MW, Wright KD, Poussaint TY