Program Official

Principal Investigator

Chetan
Bettegowda
Awardee Organization

Johns Hopkins University
United States

Fiscal Year
2024
Activity Code
R37
Early Stage Investigator Grants (ESI)
Not Applicable
Project End Date

Interrogating malignant gliomas using released tumor DNA in cerebrospinal fluid

There are no biomarkers that are currently used in the management of high-grade gliomas. Therefore, patients are often required to undergo invasive biopsies or surgical resection to differentiate disease progression from treatment related changes, quantify disease burden and track the molecular evolution of these difficult to treat cancers. In work performed to date, we have been able to demonstrate that CSF is a rich reservoir for tumor derived DNA. We are now expanding upon that work to develop a multi-analyte assay that will incorporate copy number changes, sub-chromosomal changes and somatic mutations. We anticipate that by looking at multiple analytes we will be able to improve sensitivity of the assay while also being able to have a more wholistic understanding of the cancer genotype. The specificity of this multi-analyte assay will be tested using CSF from individuals without cancer. In the short term, we anticipate that this approach will allow us to generate personalized biomarkers capable of tracking brain cancers and providing insights into the tumor genotype, thereby allowing clinicians to make more informed decisions in real-time. In the long term, we anticipate that we can gain a broader understanding of the CSF DNA composition in non-neoplastic states, such as multiple sclerosis, neurosarcoidosis or infection. This could have broad ranging impact on our ability to diagnose and monitor other disorders impacting the brain.

Publications

  • Chen D, Nauen DW, Park HC, Li D, Yuan W, Li A, Guan H, Kut C, Chaichana KL, Bettegowda C, Quiñones-Hinojosa A, Li X. Label-free imaging of human brain tissue at subcellular resolution for potential rapid intra-operative assessment of glioma surgery. Theranostics. 2021 May 24;11(15):7222-7234. doi: 10.7150/thno.59244. eCollection 2021. PMID: 34158846
  • Schreck KC, Strowd RE, Nabors LB, Ellingson BM, Chang M, Tan SK, Abdullaev Z, Turakulov R, Aldape K, Danda N, Desideri S, Fisher J, Iacoboni M, Surakus T, Rudek MA, Bettegowda C, Grossman SA, Ye X. Response Rate and Molecular Correlates to Encorafenib and Binimetinib in BRAF-V600E Mutant High-Grade Glioma. Clinical cancer research : an official journal of the American Association for Cancer Research. 2024 May 15;30(10):2048-2056. PMID: 38446982
  • Douville C, Moinova HR, Thota PN, Shaheen NJ, Iyer PG, Canto MI, Wang JS, Dumot JA, Faulx A, Kinzler KW, Papadopoulos N, Vogelstein B, Markowitz SD, Bettegowda C, Willis JE, Chak A. Massively Parallel Sequencing of Esophageal Brushings Enables an Aneuploidy-Based Classification of Patients With Barrett's Esophagus. Gastroenterology. 2021 May;160(6):2043-2054.e2. Epub 2021 Jan 22. PMID: 33493502
  • Wang Y, Douville C, Cohen JD, Mattox A, Curtis S, Silliman N, Popoli M, Ptak J, Dobbyn L, Nehme N, Dudley JC, Summers M, Zhang M, Ho-Pham LT, Tran BNH, Tran TS, Nguyen TV, Bettegowda C, Papadopoulos N, Kinzler KW, Vogelstein B. Detection of rare mutations, copy number alterations, and methylation in the same template DNA molecules. Proceedings of the National Academy of Sciences of the United States of America. 2023 Apr 11;120(15):e2220704120. Epub 2023 Apr 4. PMID: 37014860
  • Douglass J, Hsiue EH, Mog BJ, Hwang MS, DiNapoli SR, Pearlman AH, Miller MS, Wright KM, Azurmendi PA, Wang Q, Paul S, Schaefer A, Skora AD, Molin MD, Konig MF, Liu Q, Watson E, Li Y, Murphy MB, Pardoll DM, Bettegowda C, Papadopoulos N, Gabelli SB, Kinzler KW, Vogelstein B, Zhou S. Bispecific antibodies targeting mutant RAS neoantigens. Science immunology. 2021 Mar 1;6. (57). PMID: 33649101
  • Douville C, Cohen JD, Ptak J, Popoli M, Schaefer J, Silliman N, Dobbyn L, Schoen RE, Tie J, Gibbs P, Goggins M, Wolfgang CL, Wang TL, Shih IM, Karchin R, Lennon AM, Hruban RH, Tomasetti C, Bettegowda C, Kinzler KW, Papadopoulos N, Vogelstein B. Assessing aneuploidy with repetitive element sequencing. Proceedings of the National Academy of Sciences of the United States of America. 2020 Mar 3;117(9):4858-4863. Epub 2020 Feb 19. PMID: 32075918
  • Azad TD, Jin MC, Bernhardt LJ, Bettegowda C. Liquid biopsy for pediatric diffuse midline glioma: a review of circulating tumor DNA and cerebrospinal fluid tumor DNA. Neurosurgical focus. 2020 Jan 1;48(1):E9. PMID: 31896079
  • Hsiue EH, Wright KM, Douglass J, Hwang MS, Mog BJ, Pearlman AH, Paul S, DiNapoli SR, Konig MF, Wang Q, Schaefer A, Miller MS, Skora AD, Azurmendi PA, Murphy MB, Liu Q, Watson E, Li Y, Pardoll DM, Bettegowda C, Papadopoulos N, Kinzler KW, Vogelstein B, Gabelli SB, Zhou S. Targeting a neoantigen derived from a common TP53 mutation. Science (New York, N.Y.). 2021 Mar 5;371. (6533). Epub 2021 Mar 1. PMID: 33649166
  • Pearlman AH, Hwang MS, Konig MF, Hsiue EH, Douglass J, DiNapoli SR, Mog BJ, Bettegowda C, Pardoll DM, Gabelli SB, Papadopoulos N, Kinzler KW, Vogelstein B, Zhou S. Targeting public neoantigens for cancer immunotherapy. Nature cancer. 2021 May;2(5):487-497. Epub 2021 May 17. PMID: 34676374
  • Konig MF, Powell M, Staedtke V, Bai RY, Thomas DL, Fischer N, Huq S, Khalafallah AM, Koenecke A, Xiong R, Mensh B, Papadopoulos N, Kinzler KW, Vogelstein B, Vogelstein JT, Athey S, Zhou S, Bettegowda C. Preventing cytokine storm syndrome in COVID-19 using α-1 adrenergic receptor antagonists. The Journal of clinical investigation. 2020 Jul 1;130(7):3345-3347. PMID: 32352407
  • Hwang MS, Mog BJ, Douglass J, Pearlman AH, Hsiue EH, Paul S, DiNapoli SR, Konig MF, Pardoll DM, Gabelli SB, Bettegowda C, Papadopoulos N, Vogelstein B, Zhou S, Kinzler KW. Targeting loss of heterozygosity for cancer-specific immunotherapy. Proceedings of the National Academy of Sciences of the United States of America. 2021 Mar 23;118. (12). PMID: 33731480
  • Zhang M, Iyer RR, Azad TD, Wang Q, Garzon-Muvdi T, Wang J, Liu A, Burger P, Eberhart C, Rodriguez FJ, Sciubba DM, Wolinsky JP, Gokaslan Z, Groves ML, Jallo GI, Bettegowda C. Genomic Landscape of Intramedullary Spinal Cord Gliomas. Scientific reports. 2019 Dec 10;9(1):18722. PMID: 31822682
  • Lee B, Mahmud I, Pokhrel R, Murad R, Yuan M, Stapleton S, Bettegowda C, Jallo G, Eberhart CG, Garrett T, Perera RJ. Medulloblastoma cerebrospinal fluid reveals metabolites and lipids indicative of hypoxia and cancer-specific RNAs. Acta neuropathologica communications. 2022 Feb 24;10(1):25. PMID: 35209946
  • Wright KM, DiNapoli SR, Miller MS, Aitana Azurmendi P, Zhao X, Yu Z, Chakrabarti M, Shi W, Douglass J, Hwang MS, Hsiue EH, Mog BJ, Pearlman AH, Paul S, Konig MF, Pardoll DM, Bettegowda C, Papadopoulos N, Kinzler KW, Vogelstein B, Zhou S, Gabelli SB. Hydrophobic interactions dominate the recognition of a KRAS G12V neoantigen. Nature communications. 2023 Aug 21;14(1):5063. PMID: 37604828
  • Hsu PJ, Yan K, Shi H, Izumchenko E, Agrawal N. Molecular biology of oral cavity squamous cell carcinoma. Oral oncology. 2020 Mar;102:104552. Epub 2020 Jan 7. PMID: 31918173
  • Douville C, Curtis S, Summers M, Azad TD, Rincon-Torroella J, Wang Y, Mattox A, Avigdor B, Dudley J, Materi J, Raj D, Nair S, Bhanja D, Tuohy K, Dobbyn L, Popoli M, Ptak J, Nehme N, Silliman N, Blair C, Judge K, Gallia GL, Groves M, Jackson CM, Jackson EM, Laterra J, Lim M, Mukherjee D, Weingart J, Naidoo J, Koschmann C, Smith N, Schreck KC, Pardo CA, Glantz M, Holdhoff M, Kinzler KW, Papadopoulos N, Vogelstein B, Bettegowda C. Seq-ing the SINEs of central nervous system tumors in cerebrospinal fluid. Cell reports. Medicine. 2023 Aug 15;4(8):101148. Epub 2023 Aug 7. PMID: 37552989
  • Nichakawade TD, Ge J, Mog BJ, Lee BS, Pearlman AH, Hwang MS, DiNapoli SR, Wyhs N, Marcou N, Glavaris S, Konig MF, Gabelli SB, Watson E, Sterling C, Wagner-Johnston N, Rozati S, Swinnen L, Fuchs E, Pardoll DM, Gabrielson K, Papadopoulos N, Bettegowda C, Kinzler KW, Zhou S, Sur S, Vogelstein B, Paul S. TRBC1-targeting antibody-drug conjugates for the treatment of T cell cancers. Nature. 2024 Apr;628(8007):416-423. Epub 2024 Mar 27. PMID: 38538786
  • Lee B, Katsushima K, Pokhrel R, Yuan M, Stapleton S, Jallo G, Wechsler-Reya RJ, Eberhart CG, Ray A, Perera RJ. The long non-coding RNA SPRIGHTLY and its binding partner PTBP1 regulate exon 5 skipping of SMYD3 transcripts in group 4 medulloblastomas. Neuro-oncology advances. 2022 Aug 2;4(1):vdac120. doi: 10.1093/noajnl/vdac120. eCollection 2022 Jan-Dec. PMID: 36267874
  • Paul S, Pearlman AH, Douglass J, Mog BJ, Hsiue EH, Hwang MS, DiNapoli SR, Konig MF, Brown PA, Wright KM, Sur S, Gabelli SB, Li Y, Ghiaur G, Pardoll DM, Papadopoulos N, Bettegowda C, Kinzler KW, Zhou S, Vogelstein B. TCR β chain-directed bispecific antibodies for the treatment of T cell cancers. Science translational medicine. 2021 Mar 10;13. (584). Epub 2021 Mar 1. PMID: 33649188
  • Paul S, Konig MF, Pardoll DM, Bettegowda C, Papadopoulos N, Wright KM, Gabelli SB, Ho M, van Elsas A, Zhou S. Cancer therapy with antibodies. Nature reviews. Cancer. 2024 Jun;24(6):399-426. Epub 2024 May 13. PMID: 38740967
  • Cohen JD, Douville C, Dudley JC, Mog BJ, Popoli M, Ptak J, Dobbyn L, Silliman N, Schaefer J, Tie J, Gibbs P, Tomasetti C, Papadopoulos N, Kinzler KW, Vogelstein B. Detection of low-frequency DNA variants by targeted sequencing of the Watson and Crick strands. Nature biotechnology. 2021 Oct;39(10):1220-1227. Epub 2021 May 3. PMID: 33941929
  • Mattox AK, Yan H, Bettegowda C. The potential of cerebrospinal fluid-based liquid biopsy approaches in CNS tumors. Neuro-oncology. 2019 Dec 17;21(12):1509-1518. PMID: 31595305
  • Sundby RT, Rhodes SD, Komlodi-Pasztor E, Sarnoff H, Grasso V, Upadhyaya M, Kim A, Evans DG, Blakeley JO, Hanemann CO, Bettegowda C. Recommendations for the collection and annotation of biosamples for analysis of biomarkers in neurofibromatosis and schwannomatosis clinical trials. Clinical trials (London, England). 2024 Feb;21(1):40-50. Epub 2023 Oct 31. PMID: 37904489
  • Shanmugam A, Hariharan AK, Hasina R, Nair JR, Katragadda S, Irusappan S, Ravichandran A, Veeramachaneni V, Bettadapura R, Bhati M, Ramaswamy V, Rao VUS, Bagadia RK, Manjunath A, Manjunath NML, Solomon MC, Maji S, Bahadur U, Bettegowda C, Papadopoulos N, Lingen MW, Hariharan R, Gupta V, Agrawal N, Izumchenko E. Ultrasensitive detection of tumor-specific mutations in saliva of patients with oral cavity squamous cell carcinoma. Cancer. 2021 May 15;127(10):1576-1589. Epub 2020 Dec 21. PMID: 33405231
  • Lennon AM, Buchanan AH, Kinde I, Warren A, Honushefsky A, Cohain AT, Ledbetter DH, Sanfilippo F, Sheridan K, Rosica D, Adonizio CS, Hwang HJ, Lahouel K, Cohen JD, Douville C, Patel AA, Hagmann LN, Rolston DD, Malani N, Zhou S, Bettegowda C, Diehl DL, Urban B, Still CD, Kann L, Woods JI, Salvati ZM, Vadakara J, Leeming R, Bhattacharya P, Walter C, Parker A, Lengauer C, Klein A, Tomasetti C, Fishman EK, Hruban RH, Kinzler KW, Vogelstein B, Papadopoulos N. Feasibility of blood testing combined with PET-CT to screen for cancer and guide intervention. Science (New York, N.Y.). 2020 Jul 3;369. (6499). Epub 2020 Apr 28. PMID: 32345712
  • Naidoo J, Schreck KC, Fu W, Hu C, Carvajal-Gonzalez A, Connolly RM, Santa-Maria CA, Lipson EJ, Holdhoff M, Forde PM, Douville C, Riemer J, Barnes A, Redmond KJ, Kleinberg L, Page B, Aygun N, Kinzler KW, Papadopoulos N, Bettegowda C, Venkatesan A, Brahmer JR, Grossman SA. Pembrolizumab for patients with leptomeningeal metastasis from solid tumors: efficacy, safety, and cerebrospinal fluid biomarkers. Journal for immunotherapy of cancer. 2021 Aug;9. (8). PMID: 34380662
  • Mattox AK, Douville C, Silliman N, Ptak J, Dobbyn L, Schaefer J, Popoli M, Blair C, Judge K, Pollard K, Pratilas C, Blakeley J, Rodriguez F, Papadopoulos N, Belzberg A, Bettegowda C. Detection of malignant peripheral nerve sheath tumors in patients with neurofibromatosis using aneuploidy and mutation identification in plasma. eLife. 2022 Mar 4;11. PMID: 35244537
  • Douville C, Lahouel K, Kuo A, Grant H, Avigdor BE, Curtis SD, Summers M, Cohen JD, Wang Y, Mattox A, Dudley J, Dobbyn L, Popoli M, Ptak J, Nehme N, Silliman N, Blair C, Romans K, Thoburn C, Gizzi J, Schoen RE, Tie J, Gibbs P, Ho-Pham LT, Tran BNH, Tran TS, Nguyen TV, Goggins M, Wolfgang CL, Wang TL, Shih IM, Lennon AM, Hruban RH, Bettegowda C, Kinzler KW, Papadopoulos N, Vogelstein B, Tomasetti C. Machine learning to detect the SINEs of cancer. Science translational medicine. 2024 Jan 24;16(731):eadi3883. Epub 2024 Jan 24. PMID: 38266106
  • Downs BM, Ding W, Cope LM, Umbricht CB, Li W, He H, Ke X, Holdhoff M, Bettegowda C, Tao W, Sukumar S. Methylated markers accurately distinguish primary central nervous system lymphomas (PCNSL) from other CNS tumors. Clinical epigenetics. 2021 May 5;13(1):104. PMID: 33952317
  • Hwang MS, Miller MS, Thirawatananond P, Douglass J, Wright KM, Hsiue EH, Mog BJ, Aytenfisu TY, Murphy MB, Aitana Azurmendi P, Skora AD, Pearlman AH, Paul S, DiNapoli SR, Konig MF, Bettegowda C, Pardoll DM, Papadopoulos N, Kinzler KW, Vogelstein B, Zhou S, Gabelli SB. Structural engineering of chimeric antigen receptors targeting HLA-restricted neoantigens. Nature communications. 2021 Sep 6;12(1):5271. PMID: 34489470
  • Bettegowda C, Upadhayaya M, Evans DG, Kim A, Mathios D, Hanemann CO, REiNS International Collaboration. Genotype-Phenotype Correlations in Neurofibromatosis and Their Potential Clinical Use. Neurology. 2021 Aug 17;97(7 Suppl 1):S91-S98. Epub 2021 Jul 6. PMID: 34230207