Program Official
Principal Investigator
Nickolas
Papadopoulos
Awardee Organization
Johns Hopkins University
United States
Fiscal Year
2022
Activity Code
U01
Early Stage Investigator Grants (ESI)
Not Applicable
Project End Date
NIH RePORTER
For more information, see NIH RePORTER Project 5U01CA230691-05
Earlier Detection of Cancers using Non-Plasma Based Liquid Biopsies
Early detection of cancer provides one of the most effective ways to reduce cancer related morbidity and mortality. Unfortunately, early detection of cancers is hindered by several factors, including the lack of suitable tests and cost. Personalized medicine and technological advances are changing the approach to cancer diagnosis. Blood based liquid biopsy has provided an opportunity for the development of early detection tests. However, most malignancies do not have effective minimally invasive strategies for early detection and certain pre-neoplastic or neoplastic conditions are not readily detectable using blood based assays. One of the chief challenges in developing minimally-invasive tests is the identification of the appropriate biofluid and cancer specific biomarkers. Over the past two decades, DNA released from cancer cells has emerged as a specific clinical biomarker of cancer. We have previously developed sensitive methods for detection of this released tumor DNA (rtDNA) and demonstrated its potential applications in variety of clinical samples. We have extensive preliminary results that biofluids associated with certain cancers are significantly enriched in rtDNA when compared to blood. Our group has developed sensitive methods to detect and quantify rtDNA in numerous biofluids. In addition, our group has an ongoing relationship with an industrial partner, PapGene Inc that has already participated in the clinical development of liquid biopsy applications. This project will build on those strengths to develop tests for the detection of brain, head and neck, and colon cancers in cerebrospinal fluid, saliva, and stool, respectively. A non-plasma based liquid biopsy approach for the earlier detection of cancers or premalignant lesions 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
- 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
- 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
- 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
- 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