Principal Investigator

Nickolas
Papadopoulos
Awardee Organization

Johns Hopkins University
United States

Fiscal Year
2023
Activity Code
U01
Early Stage Investigator Grants (ESI)
Not Eligible
Project End Date

Multi-analyte Approach for Earlier Detection of Cancers in Non Plasma Biofluids

Early detection of cancer provides one of the most effective ways to reduce cancer related morbidity and mortality. However, most malignancies including brain and head and neck cancers do not have effective minimally invasive strategies for early detection. Unfortunately, early detection is hindered by several factors, including the lack of suitable tests and cost. One of the chief challenges in developing non-invasive tests is the identification of the appropriate biofluid and specific markers. While blood-based testing has shown promise, many cancers are not easily detected in the circulation. Over the past two decades, DNA released from cancer cells has emerged as a specific biomarker of cancer. We have previously developed sensitive methods for the simultaneous detection of multiple DNA based analytes from a small quantity of starting material in a variety of biospecimens. We have extensive preliminary results that biofluids, such as cerebrospinal fluid (CSF) and saliva, associated with certain cancers are significantly enriched in released tumor DNA (rtDNA) compared to blood. In addition, our group has an ongoing relationship with an industrial partner to translate our promising technology into the clinical realm. This proposal will build on those strengths to develop assays for the sensitive and specific detection of brain and head and neck cancer in CSF and saliva, respectively. A non-plasma based “liquid biopsy” approach for the earlier detection of cancers difficult to detect in the blood would represent a significant medical advance.

Publications

  • Mishra V, Singh A, Chen X, Rosenberg AJ, Pearson AT, Zhavoronkov A, Savage PA, Lingen MW, Agrawal N, Izumchenko E. Application of liquid biopsy as multi-functional biomarkers in head and neck cancer. British journal of cancer. 2022 Feb;126(3):361-370. Epub 2021 Dec 7. PMID: 34876674
  • 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
  • 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
  • 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
  • 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
  • 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
  • Ghantous Y, Omar M, Broner EC, Agrawal N, Pearson AT, Rosenberg AJ, Mishra V, Singh A, El-Naaj IA, Savage PA, Sidransky D, Marchionni L, Izumchenko E. A robust and interpretable gene signature for predicting the lymph node status of primary T1/T2 oral cavity squamous cell carcinoma. International journal of cancer. 2022 Feb 1;150(3):450-460. Epub 2021 Oct 14. PMID: 34569064
  • 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
  • Cohen JD, Diergaarde B, Papadopoulos N, Kinzler KW, Schoen RE. Tumor DNA as a Cancer Biomarker through the Lens of Colorectal Neoplasia. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2020 Dec;29(12):2441-2453. Epub 2020 Oct 8. PMID: 33033144
  • 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
  • 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
  • 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