EXTH-69. FUNCTIONAL GENOMICS UNCOVER GENETIC DEPENDENCIES IN ATRTS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi179-vi179
Author(s):  
Daniel Merk ◽  
Sophie Hirsch ◽  
Foteini Tsiami ◽  
Bianca Walter ◽  
Lara Haeusser ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Small Molecule ◽  
Human Cancer ◽  
Human Cancer Cell Lines ◽  
Drug Assays ◽  
Atypical Teratoid ◽  
Embryonal Brain ◽  
Atypical Teratoid Rhabdoid Tumors ◽  
Rhabdoid Tumors ◽  
Context Specific

Abstract Brain tumors are the leading cause of cancer-related deaths in children. Embryonal brain tumors including medulloblastoma and atypical teratoid rhabdoid tumors (ATRTs) account for 15% of all primary brain and CNS tumors under the age of 14 years, with ATRTs being most prevalent in infants. Despite intensive research efforts, survival estimates for ATRT patients stay relatively low as compared to other tumor entities with a median survival of around 17 months. We here describe genome-wide CRISPR/Cas9 knockout screens in combination with small-molecule drug assays to identify targetable vulnerabilities in ATRTs. Based on functional genomic screening revealing ATRT context-specific genetic vulnerabilities (n = 671 genes), we successfully generated a small-molecule library that shows preferential activity in ATRT cells as compared to a broad selection of other human cancer cell lines. Of note, none of these drugs differentially affect ATRT cells from distinct molecular subgroups, suggesting that top candidate inhibitors might serve as pan-ATRT therapeutic avenues. CDK4/6 inhibitors, among the most potent drugs in our library, are capable of inhibiting tumor growth due to mutual exclusive dependency of ATRTs on either CDK4 or CDK6. Our approach might serve as a blueprint for fostering the identification of functionally-instructed therapeutic strategies in other incurable diseases beyond ATRT, whose genomic profiles also lack actionable alterations so far.

scholarly journals Genome-wide CRISPR and small-molecule screens uncover targetable dependencies in ATRT

2020 ◽  
Author(s):  
Daniel J. Merk ◽  
Sophie Hirsch ◽  
Foteini Tsiami ◽  
Bianca Walter ◽  
Lara A. Haeusser ◽  
...  
Keyword(s):  
Small Molecule ◽  
Pediatric Brain Tumors ◽  
Genetic Alterations ◽  
Therapeutic Strategies ◽  
Genome Wide ◽  
Atypical Teratoid ◽  
Atypical Teratoid Rhabdoid Tumors ◽  
Rhabdoid Tumors ◽  
Context Specific ◽  
Pediatric Brain

SummaryAtypical teratoid rhabdoid tumors (ATRT) are incurable high-grade pediatric brain tumors. Concepts for molecular-driven therapies in ATRTs lag behind, mainly due to the absence of actionable genetic alterations. We performed genome-wide CRISPR/Cas9 knockout screens in six human ATRT cell lines and identified a total of 671 context-specific essential genes. Based on these genetic dependencies, we constructed a library of small-molecule inhibitors that we found to preferentially inhibit growth of ATRT cells. CDK4/6 inhibitors, among the most potent drugs in our library, are capable of inhibiting tumor growth due to mutual exclusive dependency of ATRTs on CDK4 or CDK6. These distinct dependencies drive heterogeneity in response to CDK4/6 inhibitors in ATRTs. Our approach might serve as a blueprint for fostering the identification of functionally-instructed therapeutic strategies in other incurable diseases beyond ATRT, whose genomic profiles also lack actionable alterations so far.

Marrow-ablative chemotherapy followed by tandem autologous hematopoietic cell transplantation (AuHCT) in pediatric patients with malignant brain tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2049-2049
Author(s):  
Jhon Guerra ◽  
Girish Dhall ◽  
Araz Marachelian ◽  
Esmeralda Castillo ◽  
Jemily Malvar ◽  
...  
Keyword(s):  
Los Angeles ◽  
Brain Tumors ◽  
Hematopoietic Cell Transplantation ◽  
Germ Cell Tumors ◽  
Newly Diagnosed ◽  
Post Transplant ◽  
Malignant Brain Tumors ◽  
Atypical Teratoid ◽  
Atypical Teratoid Rhabdoid Tumors ◽  
Rhabdoid Tumors

2049 Background: In an effort to both improve cure rates and quality of survival in young children with malignant brain tumors, irradiation-avoiding or at least minimizing marrow-ablative chemotherapy with AuHCT has been incorporated in both up-front as well as recurrent therapies. To decrease the toxicity of single cycle marrow-ablative chemotherapy regimens, and possibly enhance cure through overall dose intensification, use of fractionated multiple (tandem) cycles of marrow-ablative chemotherapy with AuHCT has been explored. Methods: In this retrospective analysis, we investigated the outcome of children with malignant brain tumors treated with marrow-ablative chemotherapy and tandem AuHCT at Children’s Hospital Los Angeles between June 1999 and July 2012. Results: Forty-four children (24 males) with a median age of 7.1 years (range 0.6- 19.0 years) with malignant brain tumors were studied. Twenty-one had medulloblastomas/primitive neuro-ectodermal tumors, 8 atypical teratoid/rhabdoid tumors, 5 high-grade gliomas, 4 malignant germ cell tumors, 3 ependymomas and 3 choroid plexus carcinomas. Twenty-nine patients receive 3 and 15 received 2 tandem transplants, respectively. Twenty-seven patients were newly-diagnosed and 17 recurrent disease. Thirty-one patients received irradiation at some time. The 5-year post-transplant progression-free (PFS) and overall survivals (OS) for all patients were 46.3±8.2% and 51.7±8.5% respectively. The PFS and OS for newly-diagnosed patients were 68.9 ± 9.9% and 73.5±9.3% respectively, compared with those transplanted at relapse 11.8±9.8 (p <0.001) and 15.1±12.3% (p = 0.0231) respectively. The 5-year post-transplant PFS and OS in unirradiated patients was 74.0±13.0% and 74.0±13.0% versus33.2±9.8% and 40.2+/-10.6% in irradiated patients (p = 0.11 and p = 0.239 respectively). One patient (2.3%) died of transplant-related toxicity. Conclusions: Marrow-ablative chemotherapy with tandem AuHCT is feasible and safe in children with malignant brain tumors with encouraging irradiation-free survival in newly-diagnosed children.

scholarly journals ATRT-32. GENOME-WIDE CRISPR AND SMALL-MOLECULE SCREENS UNCOVER TARGETABLE DEPENDENCIES IN AT/RTs

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii282-iii282
Author(s):  
Daniel Merk ◽  
Sophie Hirsch ◽  
Bianca Walter ◽  
Lara Häusser ◽  
Nicole Persky ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Small Molecule ◽  
Molecular Mechanisms ◽  
Young Patients ◽  
Chemical Library ◽  
Genome Wide ◽  
Starting Point ◽  
Drug Assays ◽  
Tumor Entity ◽  
Rhabdoid Tumors

Abstract Brain tumors are the leading cause of cancer-related deaths in children and adolescents. Embryonal brain tumors are a group of high-grade neoplasms which primarily affect young patients, and atypical teratoid rhabdoid tumors (AT/RTs) are the second most common type of tumor within this group. In spite of intensive research efforts and the knowledge of molecular mechanisms driving subgroup-specific heterogeneity within ATRTs, survival estimates stay relatively low as compared to other tumor entities with a median survival of around 17 months. More efficacious and durable therapies are urgently needed to improve the situation of patients. We here used a combination of genome-wide CRISPR dependency screens and small-molecule drug assays to identify genetic vulnerabilities and novel therapeutic targets for this tumor entity. Here, we successfully generated a chemical library that shows preferential activity in AT/RT cell lines, thereby validating our CRISPR approach to identify tumor-specific vulnerabilities. Of note, none of the identified dependencies seemed to be subgroup-specific, suggesting that targets identified here can be used as pan-AT/RT therapeutic avenues. Among others, these include inhibition of EGF signaling and CDK4/6. Our data provide a comprehensive map of dependencies for AT/RTs which will serve as a starting point in the development of targeted therapies for this tumor entity.

scholarly journals P11.23 Oncolytic adenovirus Delta-24-RGD exerts a potent anti-tumor effect in preclinical models of atypical teratoid/rhabdoid tumors

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii47-iii47
Author(s):  
M Garcia Moure ◽  
M González Huarriz ◽  
L Marrodán ◽  
A Patiño-García ◽  
M M Alonso
Keyword(s):  
Overall Survival ◽  
Brain Tumors ◽  
Phase I ◽  
Cell Lines ◽  
Pediatric Brain Tumors ◽  
Preclinical Models ◽  
Atypical Teratoid ◽  
Atypical Teratoid Rhabdoid Tumors ◽  
Rhabdoid Tumors ◽  
Pediatric Brain

Abstract BACKGROUND Atypical teratoid/rhabdoid tumors (AT/RTs) are rare pediatric brain tumors affecting mainly infants and young children. However, AT/RTs encompass almost 10% of death caused by pediatric brain tumors, and the 2-year overall survival for these children remains below 20%. For this reason, AT/RT ranks among the deadliest pediatric brain tumors. Therefore, it is clear we need to find out new therapeutic options for these children. Delta-24-RGD is an oncolytic adenovirus that has already demonstrated its efficacy as in Phase I/II clinical trials in adult patients affected by high grade gliomas with no evidence of severe side effects. Of interest for pediatric brain tumors, the safety of Delta-24-RGD is has also been demonstrated in an ongoing Phase I clinical trial for the treatment of DIPGs (NCT03178032). For these reasons, we propose to evaluate the anti-tumor effect of Delta-24-RGD in preclinical models of ATRT. MATERIAL AND METHODS Our studies have been carried out in three stablished AT/RT cell lines (BT-12, CHLA-06 and CHLA-266). In vitro, AT/RT cultures were infected with Delta-24-RGD-GFP to confirm the infectivity of the virus by flow cytometry. Replication of Delta-24-RGD was ensured by titrating the PFUs generated in AT/RT infected cultures. In regard to cytolytic effect, viability assays (MTS) were conducted in AT/RT cultures infected at increasing MOIs of Delta-24-RGD. In vivo, AT/RT cell lines were engrafted in Rag-2 mice in supratentorial and infratentorial locations, and the animals were treated with Delta-24-RGD at 107 or 108 PFU/animal (intra-tumor administration), or PBS. The therapeutic benefit of Delta-24-RGD was evaluated comparing the overall survival obtained for treated and untreated animals using the Log-rank test. We have also generated models of disseminated disease through intraventricular injection of the tumor cells, thus mimicking the lesions found in patients. AT/RT cell lines were transduced with a luc-expressing lentivirus to facilitate the follow up of these tumors. Mice bearing disseminated AT/RT were treated with Delta-24-RGD at 107 or 108 PFU/animal, or PBS (control). The therapeutic effect was monitored by bioluminescence and by comparison of the survival curves (Log-rank). RESULTS The virus was able to infect and replicate in tumor three different cell culture models of AT/RT, inducing a potent cytotoxic effect that resulting in IC50 values below 1 PFU/cell. Administration of the virus in mice bearing localized AT/RT (supratentorial and infratentorial) extended significantly the survival the animals, leading to up to 20% of long-term survivors. In disseminated AT/RT models, light emission reveals reduction of tumor growth in virus treated animals, resulting in an increased overall survival. CONCLUSION In conclusion, these results demonstrate that Delta-24-RGD could be a feasible therapeutic choice for patients affected by AT/RT.

Expression of the HOX genes and HOTAIR in atypical teratoid rhabdoid tumors and other pediatric brain tumors

2014 ◽  
Vol 207 (9) ◽  
pp. 425-428 ◽  
Author(s):  
Madhavi Chakravadhanula ◽  
Victor V. Ozols ◽  
Chris N. Hampton ◽  
Li Zhou ◽  
Daniel Catchpoole ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Hox Genes ◽  
Pediatric Brain Tumors ◽  
Atypical Teratoid ◽  
Atypical Teratoid Rhabdoid Tumors ◽  
Rhabdoid Tumors ◽  
Pediatric Brain

scholarly journals ATRT-05. RESULTS OF MULTICENTER TRIAL CONCERNING THE TREATMENT OF CHILDREN WITH ATYPICAL TERATOID/RHABDOID TUMORS (ATRT) OF THE CENTRAL NERVOUS SYSTEM

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii276-iii276
Author(s):  
Olga Zheludkova ◽  
Lyudmila Olkhova ◽  
Yuri Kushel’ ◽  
Armen Melikyan ◽  
Marina Ryzhova ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Progression Free Survival ◽  
Multicenter Trial ◽  
Intrathecal Methotrexate ◽  
Subtotal Resection ◽  
Tumor Biopsy ◽  
Atypical Teratoid ◽  
The Central Nervous System ◽  
Atypical Teratoid Rhabdoid Tumors ◽  
Rhabdoid Tumors

Abstract We analyzed 105 patients under 18 years. The median age was 21 months. There were 54 boys and 51 girls. The supratentorial tumors were in 53 patients, infratentorial in 48, and in spinal cord in 4. 60 had stage M0,29-М+and 16-Mx. All the patients got surgical treatment:total tumor removal in 34,subtotal in 37,partial in 30,and biopsy in 4;75 patients got chemoradiotherapy to ATRT-2006;6-CWS;13-EU-RHAB;5-HIT-SKK;individual schemes in 6. RESULTS: 47 are alive,1 was LFU, and 57 died. PFS was 32%±0.05; the five-year OS 40%±0.05. The median survival-30 months, the median progression-free survival-12 months, and the median of follow-up-23 months. PFS was significantly better in patients more than 12 months compared to patients younger than 12 months:40 and 12%;p=0.00161.After total resection PFS was higher compared to subtotal resection, partial resection, and tumor biopsy:48,38,0,and 0%(p=0.025). After chemoradiotherapy, PFS was higher compared to patients without radiotherapy: 49and 0%(р=0.0000000).PFS for stage M0 was higher compared to stage M+and stage Mx:41,15,and 27%,respectively(р=0.00032).PFS was better for the tumors in the spinal cord and infratentorial location compared to the supratentorial location:67,37,and 25%(p=0.0876).The survival rate was higher among the patients who got treatment according to the ATRT-2006 protocol compared to EU-RHAB, individual regimens, CWS, and HIT-SKK:39,19,17,17,and 0% respectively;p=0.00159.The survival was higher among the patients who got intraventricular/intrathecal Methotrexate,Cytarabine, Prednisolone than among the patients who got only Methotrexate or none at all:40,0,and 5%, respectively; p=0.00015. CONCLUSIONS: Survival was significantly better in patients more than 12month, without metastases, with total removal tumor, chemotheradiotherapy by ATRT-2006 protocol with i/t, i/v Methotrexate/Cytarabine/Prednisolone.

scholarly journals Histomorphology Evolution of Recurrent Atypical Teratoid/Rhabdoid Tumors

2015 ◽  
Vol 144 (suppl 2) ◽  
pp. A023-A023
Author(s):  
Esther Yoon ◽  
Taliya Farooq ◽  
Lawrence Sann ◽  
Eric Vail ◽  
George Kleinman
Keyword(s):  
Atypical Teratoid ◽  
Atypical Teratoid Rhabdoid Tumors ◽  
Rhabdoid Tumors
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