Principal Investigator

Awardee Organization

Johns Hopkins University
United States

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

Development of in vitro diagnostic multivariate index assay using liquid-based cervical cytology specimen and/or serum/plasma biomarkers for the detection of early stage or low-volume ovarian cancer

We have assembled a multidisciplinary team including biomarker researchers, cancer biologist, pathologist, gynecologic oncologist, proteomic technologists, and experts in biostatistics, epidemiology, and bioinformatics to establish a Biomarker Developmental Laboratory for the NCI's Early Detection Research Network with the objective to develop an in vitro diagnostic multivariate index assay (IVDMIA) to detect ovarian cancer at low tumor volume. The intended use of such a test is to further enrich ovarian cancer prevalence in high-risk populations to allow for cost-effective additional workup tests. The rationale is based on 1) prognosis of ovarian cancer patients, in addition to stage/grade at diagnosis, is affected by the initial size of the metastatic disease and the size of residual disease after cytoreductive surgery; and 2) newly developed cancer-specific biomarkers detecting mutant DNAs in liquid-based cervical cytology specimens and circulating tumor DNA (ctDNA) in plasma have demonstrated a remarkable specificity. We hypothesize that combining such biomarkers with additional sensitive and disease burden-associated biomarkers in an IVDMIA will allow us to detect ovarian cancer at low volume which currently represents an unmet clinical need.


  • Song J, Ma S, Sokoll LJ, Eguez RV, Höti N, Zhang H, Mohr P, Dua R, Patil D, May KD, Williams S, Arnold R, Sanda MG, Chan DW, Zhang Z. A panel of selected serum protein biomarkers for the detection of aggressive prostate cancer. Theranostics. 2021 Apr 15;11(13):6214-6224. doi: 10.7150/thno.55676. eCollection 2021. PMID: 33995654
  • Liberto JM, Chen SY, Shih IM, Wang TH, Wang TL, Pisanic TR 2nd. Current and Emerging Methods for Ovarian Cancer Screening and Diagnostics: A Comprehensive Review. Cancers. 2022 Jun 11;14. (12). PMID: 35740550
  • Cordova R, Kiekens K, Burrell S, Drake W, Kmeid Z, Rice P, Rocha A, Diaz S, Yamada S, Yozwiak M, Nelson OL, Rodriguez GC, Heusinkveld J, Shih IM, Alberts DS, Barton JK. Sub-millimeter endoscope demonstrates feasibility of in vivo reflectance imaging, fluorescence imaging, and cell collection in the fallopian tubes. Journal of biomedical optics. 2021 Jul;26. (7). PMID: 34216135
  • Asaka S, Davis C, Lin SF, Wang TL, Heaphy CM, Shih IM. Analysis of Telomere Lengths in p53 Signatures and Incidental Serous Tubal Intraepithelial Carcinomas Without Concurrent Ovarian Cancer. The American journal of surgical pathology. 2019 Aug;43(8):1083-1091. PMID: 31107721
  • Xing D, Suryo Rahmanto Y, Zeppernick F, Hannibal CG, Kjaer SK, Vang R, Shih IM, Wang TL. Mutation of NRAS is a rare genetic event in ovarian low-grade serous carcinoma. Human pathology. 2017 Oct;68:87-91. Epub 2017 Sep 2. PMID: 28873354
  • Pisanic TR 2nd, Cope LM, Lin SF, Yen TT, Athamanolap P, Asaka R, Nakayama K, Fader AN, Wang TH, Shih IM, Wang TL. Methylomic Analysis of Ovarian Cancers Identifies Tumor-Specific Alterations Readily Detectable in Early Precursor Lesions. Clinical cancer research : an official journal of the American Association for Cancer Research. 2018 Dec 15;24(24):6536-6547. Epub 2018 Aug 14. PMID: 30108103
  • Anglesio MS, Papadopoulos N, Ayhan A, Nazeran TM, Noë M, Horlings HM, Lum A, Jones S, Senz J, Seckin T, Ho J, Wu RC, Lac V, Ogawa H, Tessier-Cloutier B, Alhassan R, Wang A, Wang Y, Cohen JD, Wong F, Hasanovic A, Orr N, Zhang M, Popoli M, McMahon W, Wood LD, Mattox A, Allaire C, Segars J, Williams C, Tomasetti C, Boyd N, Kinzler KW, Gilks CB, Diaz L, Wang TL, Vogelstein B, Yong PJ, Huntsman DG, Shih IM. Cancer-Associated Mutations in Endometriosis without Cancer. The New England journal of medicine. 2017 May 11;376(19):1835-1848. PMID: 28489996
  • Cohen JD, Li L, Wang Y, Thoburn C, Afsari B, Danilova L, Douville C, Javed AA, Wong F, Mattox A, Hruban RH, Wolfgang CL, Goggins MG, Dal Molin M, Wang TL, Roden R, Klein AP, Ptak J, Dobbyn L, Schaefer J, Silliman N, Popoli M, Vogelstein JT, Browne JD, Schoen RE, Brand RE, Tie J, Gibbs P, Wong HL, Mansfield AS, Jen J, Hanash SM, Falconi M, Allen PJ, Zhou S, Bettegowda C, Diaz LA Jr, Tomasetti C, Kinzler KW, Vogelstein B, Lennon AM, Papadopoulos N. Detection and localization of surgically resectable cancers with a multi-analyte blood test. Science (New York, N.Y.). 2018 Feb 23;359(6378):926-930. Epub 2018 Jan 18. PMID: 29348365
  • 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
  • Song G, Wang G, Luo X, Cheng Y, Song Q, Wan J, Moore C, Song H, Jin P, Qian J, Zhu H. An all-to-all approach to the identification of sequence-specific readers for epigenetic DNA modifications on cytosine. Nature communications. 2021 Feb 4;12(1):795. PMID: 33542217
  • Song J, Sokoll LJ, Chan DW, Zhang Z. Validation of Serum Biomarkers That Complement CA19-9 in Detecting Early Pancreatic Cancer Using Electrochemiluminescent-Based Multiplex Immunoassays. Biomedicines. 2021 Dec 14;9. (12). PMID: 34944713
  • Song G, Chen L, Zhang B, Song Q, Yu Y, Moore C, Wang TL, Shih IM, Zhang H, Chan DW, Zhang Z, Zhu H. Proteome-wide Tyrosine Phosphorylation Analysis Reveals Dysregulated Signaling Pathways in Ovarian Tumors. Molecular & cellular proteomics : MCP. 2019 Mar;18(3):448-460. Epub 2018 Dec 6. PMID: 30523211
  • 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
  • Song J, Merbs SL, Sokoll LJ, Chan DW, Zhang Z. A multiplex immunoassay of serum biomarkers for the detection of uveal melanoma. Clinical proteomics. 2019 Mar 5;16:10. doi: 10.1186/s12014-019-9230-8. eCollection 2019. PMID: 30867659
  • Uzoma I, Hu J, Cox E, Xia S, Zhou J, Rho HS, Guzzo C, Paul C, Ajala O, Goodwin CR, Jeong J, Moore C, Zhang H, Meluh P, Blackshaw S, Matunis M, Qian J, Zhu H. Global Identification of Small Ubiquitin-related Modifier (SUMO) Substrates Reveals Crosstalk between SUMOylation and Phosphorylation Promotes Cell Migration. Molecular & cellular proteomics : MCP. 2018 May;17(5):871-888. Epub 2018 Feb 8. PMID: 29438996
  • Chen LY, Huang RL, Chan MW, Yan PS, Huang TS, Wu RC, Suryo Rahmanto Y, Su PH, Weng YC, Chou JL, Chao TK, Wang YC, Shih IM, Lai HC. TET1 reprograms the epithelial ovarian cancer epigenome and reveals casein kinase 2α as a therapeutic target. The Journal of pathology. 2019 Jul;248(3):363-376. Epub 2019 Apr 23. PMID: 30883733
  • Labidi-Galy SI, Papp E, Hallberg D, Niknafs N, Adleff V, Noe M, Bhattacharya R, Novak M, Jones S, Phallen J, Hruban CA, Hirsch MS, Lin DI, Schwartz L, Maire CL, Tille JC, Bowden M, Ayhan A, Wood LD, Scharpf RB, Kurman R, Wang TL, Shih IM, Karchin R, Drapkin R, Velculescu VE. High grade serous ovarian carcinomas originate in the fallopian tube. Nature communications. 2017 Oct 23;8(1):1093. PMID: 29061967
  • Yu Y, Suryo Rahmanto Y, Lee MH, Wu PH, Phillip JM, Huang CH, Vitolo MI, Gaillard S, Martin SS, Wirtz D, Shih IM, Wang TL. Inhibition of ovarian tumor cell invasiveness by targeting SYK in the tyrosine kinase signaling pathway. Oncogene. 2018 Jul;37(28):3778-3789. Epub 2018 Apr 11. PMID: 29643476
  • Song J, Zhang Z, Chan DW. Detection of Uveal Melanoma by Multiplex Immunoassays of Serum Biomarkers. Methods in molecular biology (Clifton, N.J.). 2021;2265:447-459. PMID: 33704733
  • Galvez D, Hong Z, Rocha AD, Heusinkveld JM, Ye P, Liang R, Barton JK. Characterizing close-focus lenses for microendoscopy. Journal of optical microsystems. 2023 Jan;3. (1). Epub 2023 Jan 4. PMID: 38084130
  • Song J, Sokoll LJ, Pasay JJ, Rubin AL, Li H, Bach DM, Chan DW, Zhang Z. Identification of Serum Biomarker Panels for the Early Detection of Pancreatic Cancer. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2019 Jan;28(1):174-182. Epub 2018 Oct 17. PMID: 30333219
  • Shih IM, Wang Y, Wang TL. The Origin of Ovarian Cancer Species and Precancerous Landscape. The American journal of pathology. 2021 Jan;191(1):26-39. Epub 2020 Oct 1. PMID: 33011111
  • Wang Y, Huang P, Wang BG, Murdock T, Cope L, Hsu FC, Wang TL, Shih IM. Spatial Transcriptomic Analysis of Ovarian Cancer Precursors Reveals Reactivation of IGFBP2 during Pathogenesis. Cancer research. 2022 Dec 16;82(24):4528-4541. PMID: 36206311
  • 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
  • Wu RC, Wang P, Lin SF, Zhang M, Song Q, Chu T, Wang BG, Kurman RJ, Vang R, Kinzler K, Tomasetti C, Jiao Y, Shih IM, Wang TL. Genomic landscape and evolutionary trajectories of ovarian cancer precursor lesions. The Journal of pathology. 2019 May;248(1):41-50. Epub 2019 Feb 15. PMID: 30560554
  • Pisanic TR 2nd, Asaka S, Lin SF, Yen TT, Sun H, Bahadirli-Talbott A, Wang TH, Burns KH, Wang TL, Shih IM. Long Interspersed Nuclear Element 1 Retrotransposons Become Deregulated during the Development of Ovarian Cancer Precursor Lesions. The American journal of pathology. 2019 Mar;189(3):513-520. Epub 2018 Dec 13. PMID: 30553834
  • Whelan S, Ophir E, Kotturi MF, Levy O, Ganguly S, Leung L, Vaknin I, Kumar S, Dassa L, Hansen K, Bernados D, Murter B, Soni A, Taube JM, Fader AN, Wang TL, Shih IM, White M, Pardoll DM, Liang SC. PVRIG and PVRL2 Are Induced in Cancer and Inhibit CD8+ T-cell Function. Cancer immunology research. 2019 Feb;7(2):257-268. Epub 2019 Jan 18. PMID: 30659054
  • Gu J, Wang C, Shih IeM, Wang TL, Wang Y, Clarke R, Xuan J. GIST: a Gibbs sampler to identify intracellular signal transduction pathways. Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference. 2011;2011:2434-7. PMID: 22254833
  • Pisanic TR 2nd, Wang Y, Sun H, Considine M, Li L, Wang TH, Wang TL, Shih IM. Methylomic Landscapes of Ovarian Cancer Precursor Lesions. Clinical cancer research : an official journal of the American Association for Cancer Research. 2020 Dec 1;26(23):6310-6320. Epub 2020 Aug 17. PMID: 32817081
  • Song J, Sokoll LJ, Zhang Z, Chan DW. VCAM-1 complements CA-125 in detecting recurrent ovarian cancer. Clinical proteomics. 2023 Jun 25;20(1):25. PMID: 37357306
  • Wang Y, Li L, Douville C, Cohen JD, Yen TT, Kinde I, Sundfelt K, Kjær SK, Hruban RH, Shih IM, Wang TL, Kurman RJ, Springer S, Ptak J, Popoli M, Schaefer J, Silliman N, Dobbyn L, Tanner EJ, Angarita A, Lycke M, Jochumsen K, Afsari B, Danilova L, Levine DA, Jardon K, Zeng X, Arseneau J, Fu L, Diaz LA Jr, Karchin R, Tomasetti C, Kinzler KW, Vogelstein B, Fader AN, Gilbert L, Papadopoulos N. Evaluation of liquid from the Papanicolaou test and other liquid biopsies for the detection of endometrial and ovarian cancers. Science translational medicine. 2018 Mar 21;10. (433). PMID: 29563323