TRLS-13. MULTI-OMICS AND FUNCTIONAL PRECISION MEDICINE FOR NEWLY DIAGNOSED AND RECURRENT PEDIATRIC CENTRAL NERVOUS SYSTEM TUMORS

John R Crawford; Yan Yuen Lo; Meghana S Pagadala; Owen S Chapman; Sunita Sridhar; Edwin F Juarez; Theophilos Tzaridis; Lianne Q Chau; Jun Wang; Tanja Eisemann; Meher Beigi Masihi; Kendall R Chambers; Deobrat Dixit; Daphne Koubourli; Jon D Larson; Lucia Guidugli; Monia Hammer; Terence Wong; Zied Abdullaev; Martha Quezado; Timothy J Martins; Michael Reich; Timothy Sears; Charlotte Hobbs; Stephen F Kingsmore; Michael L Levy; David Gonda; Denise M Malicki; Matija Snuderl; Pamela S Becker; Pablo Tamayo; Jennifer D Elster; Kenneth Aldape; Hannah Carter; Megan R Paul; Jill P Mesirov; Lukas Chavez; Robert J Wechsler-Reya

doi:10.1093/neuonc/noae064.166

. 2024 Jun 18;26(Suppl 4):0. doi: 10.1093/neuonc/noae064.166

TRLS-13. MULTI-OMICS AND FUNCTIONAL PRECISION MEDICINE FOR NEWLY DIAGNOSED AND RECURRENT PEDIATRIC CENTRAL NERVOUS SYSTEM TUMORS

John R Crawford ^1,², Yan Yuen Lo ^3,⁴, Meghana S Pagadala ⁵, Owen S Chapman ⁶, Sunita Sridhar ^7,⁸, Edwin F Juarez ⁹, Theophilos Tzaridis ¹⁰, Lianne Q Chau ^11,¹², Jun Wang ¹³, Tanja Eisemann ¹⁴, Meher Beigi Masihi ^15,¹⁶, Kendall R Chambers ^17,¹⁸, Deobrat Dixit ^19,²⁰, Daphne Koubourli ^21,²², Jon D Larson ²³, Lucia Guidugli ²⁴, Monia Hammer ²⁵, Terence Wong ²⁶, Zied Abdullaev ²⁷, Martha Quezado ²⁸, Timothy J Martins ²⁹, Michael Reich ³⁰, Timothy Sears ³¹, Charlotte Hobbs ^32,³³, Stephen F Kingsmore ^34,³⁵, Michael L Levy ^36,³⁷, David Gonda ^38,³⁹, Denise M Malicki ^40,⁴¹, Matija Snuderl ⁴², Pamela S Becker ^43,⁴⁴, Pablo Tamayo ^45,⁴⁶, Jennifer D Elster ^47,⁴⁸, Kenneth Aldape ⁴⁹, Hannah Carter ^50,⁵¹, Megan R Paul ^52,⁵³, Jill P Mesirov ^54,⁵⁵, Lukas Chavez ^56,⁵⁷, Robert J Wechsler-Reya ^58,⁵⁹

¹ Children’s Hospital Orange County, Orange, CA, USA

² Rady Children’s Hospital, San Diego, CA, USA

³ Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA

⁴ Rady Children’s Institute for Genomic Medicine, San Diego, CA, USA

⁵ University of California San DIego, La Jolla, CA, USA

⁶ Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA

⁷ Rady Children’s Hospital, San Diego, CA, USA

⁸ University of California San Diego, La Jolla, CA, USA

⁹ Rady Children’s Institute for Genomic Medicine, San Diego, CA, USA

¹⁰ Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA

¹¹ Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA

¹² University of California San Diego, La Jolla, CA, USA

¹³ Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA

¹⁴ Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA

¹⁵ Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA

¹⁶ Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA

¹⁷ Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA

¹⁸ Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA

¹⁹ Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA

²⁰ Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA

²¹ Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA

²² Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA

²³ Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA

²⁴ Rady Children’s Institute for Genomic Medicine, San Diego, CA, USA

²⁵ Rady Children’s Institute for Genomic Medicine, San Diego, CA, USA

²⁶ Rady Children’s Institute for Genomic Medicine, San Diego, CA, USA

²⁷ Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

²⁸ Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

²⁹ Institute for Stem Cell and Regenerative Medicine and Quellos High Throughput Screening Core, University of Washington School of Medicine, Seattle, WA, USA

³⁰ Division of Genomics and Precision Medicine, Department of Medicine, University of California San Diego, La Jolla, CA, USA

³¹ Division of Genomics and Precision Medicine, Department of Medicine, University of California San Diego, La Jolla, CA, USA

³² Rady Children’s Institute for Genomic Medicine, San Diego, CA, USA

³³ Rady Children’s Hospital, San Diego, CA, USA

³⁴ Rady Children’s Institute for Genomic Medicine, San Diego, CA, USA

³⁵ Rady Children’s Hospital, San Diego, CA, USA

³⁶ Rady Children’s Hospital, San Diego, CA, USA

³⁷ University of California San Diego, La Jolla, CA, USA

³⁸ Rady Children’s Hospital, San Diego, CA, USA

³⁹ University of California San DIego, La Jolla, CA, USA

⁴⁰ Rady Children’s Hospital, San Diego, CA, USA

⁴¹ University of California San Diego, La Jolla, CA, USA

⁴² Division of Neuropathology, Department of Pathology, NYU Langone Medical Center, New York, NY, USA

⁴³ University of Washington, Seattle, WA, USA

⁴⁴ Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA, USA

⁴⁵ Division of Genomics and Precision Medicine, Department of Medicine, University of California San Diego, La Jolla, CA, USA

⁴⁶ Moores Cancer Center, University of California San Diego, La Jolla, CA, USA

⁴⁷ Rady Children’s Hospital, San Diego, CA, USA

⁴⁸ University of California San Diego, La Jolla, CA, USA

⁴⁹ Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

⁵⁰ Division of Genomics and Precision Medicine, Department of Medicine, University of California San Diego, La Jolla, CA, USA

⁵¹ Moores Cancer Center, University of California San Diego, La Jolla, CA, USA

⁵² Rady Children’s Hospital, San Diego, CA, USA

⁵³ University of California San Diego, La Jolla, CA, USA

⁵⁴ Division of Genomics and Precision Medicine, Department of Medicine, University of California San Diego, La Jolla, CA, USA

⁵⁵ Moores Cancer Center, University of California San Diego, La Jolla, CA, USA

⁵⁶ Rady Children’s Institute for Genomic Medicine, San Diego, CA, USA

⁵⁷ Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA

⁵⁸ Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA

⁵⁹ Department of Neurology and Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA

PMCID: PMC11183810

Abstract

BACKGROUND

Comprehensive molecular characterization of pediatric brain tumors has led to a more refined diagnosis. However, the feasibility of performing multi-omic and functional precision medicine approaches using ex-vivo drug screening in the clinical setting is unknown.

METHODS

Patients with newly diagnosed or recurrent central nervous system tumors were enrolled in a feasibility study of multi-omic analysis including whole genome trio germline sequencing, tumor whole exome/RNA sequencing, RNA-based DiSCoVER analysis, methylation profiling, immunogenic potential analysis, and ex-vivo drug screening utilizing a customized panel of 175 FDA approved/investigational drugs. Findings were presented at a multidisciplinary molecular neuro-oncology tumor board.

RESULTS

Eighteen patients (9 female; average age 9.4 years; 12 newly diagnosed, 6 with recurrent disease; 5 high grade gliomas, 4 ependymomas, 4 embryonal tumors, 3 low grade gliomas, 2 others) were enrolled between 2020-2022. Whole genome germline testing (N=18) was normal in half of patients (pathogenic germline mutations in 3 patients, variants of unknown significance in 6 patients). Ex-vivo drug screening results (N=14) varied among patients, however sub-micromolar efficacy was commonly observed for proteosome inhibitors, HDAC inhibitors, and topoisomerase II inhibitors. Average time from surgery to receipt of finalized results varied across platforms (drug screening 5.7 days, whole exome/RNA sequencing 14.8 days, whole genome germline 10.6 days, methylation 21 days). Fifteen patients had a modification in diagnosis and 4 patients had a change in tumor classification. Multi-omic and functional precision medicine results alone or in combination led to changes in management in 50% of patients (Tumor Molecular Sequencing 6/18, Ex-Vivo Drug Screening 4/14, RNA DiSCoVER Analysis 2/15, Methylation 1/14).

CONCLUSION

Our studies demonstrate the feasibility of timely ex-vivo drug screening and multi-omic analysis and show that these data may lead to changes in patient diagnosis/management. These findings are the basis of an ongoing trial for recurrent medulloblastoma (NCT05057702).

PERMALINK

TRLS-13. MULTI-OMICS AND FUNCTIONAL PRECISION MEDICINE FOR NEWLY DIAGNOSED AND RECURRENT PEDIATRIC CENTRAL NERVOUS SYSTEM TUMORS

John R Crawford

Yan Yuen Lo

Meghana S Pagadala

Owen S Chapman

Sunita Sridhar

Edwin F Juarez

Theophilos Tzaridis

Lianne Q Chau

Jun Wang

Tanja Eisemann

Meher Beigi Masihi

Kendall R Chambers

Deobrat Dixit

Daphne Koubourli

Jon D Larson

Lucia Guidugli

Monia Hammer

Terence Wong

Zied Abdullaev

Martha Quezado

Timothy J Martins

Michael Reich

Timothy Sears

Charlotte Hobbs

Stephen F Kingsmore

Michael L Levy

David Gonda

Denise M Malicki

Matija Snuderl

Pamela S Becker

Pablo Tamayo

Jennifer D Elster

Kenneth Aldape

Hannah Carter

Megan R Paul

Jill P Mesirov

Lukas Chavez

Robert J Wechsler-Reya

Abstract

BACKGROUND

METHODS

RESULTS

CONCLUSION

ACTIONS

PERMALINK

RESOURCES

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