Principal Investigator

Andrew K.
Godwin
Awardee Organization

University Of Kansas Medical Center
United States

Fiscal Year
2023
Activity Code
R01
Early Stage Investigator Grants (ESI)
Not Applicable
Project End Date

Extracellular Vesicle Proteomic Fingerprinting of Ovarian Cancer for Early Detection with a Nanoengineered Microsystem

Ovarian cancer is a silent killer that strikes with few, if any, symptoms. By the time a woman knows she has it, the cancer is often advanced and the outlook grim. However, if epithelial ovarian cancer is caught early the prognosis for the patient is excellent. Developing non-invasive and highly specific blood-based tests for presymptomatic screening and early detection of ovarian cancer is therefore crucial. This is especially essential since obtaining a biopsy is difficult, costly, and sometimes not even an option. In addition, most blood biomarkers to date lack the necessary sensitivity and specificity for early detection of this silent killer. A fundamental challenge is the extremely low concentrations of circulating biomolecules released from the developing tumors at pre-clinical stages which can be 10,000-fold lower than their clinically detectable levels. Therefore, there is a pressing need to uncover novel biomarkers, apply new strategies, and develop robust technologies to propel the advancement of cancer diagnostics, especially in a disease such as ovarian cancer. We have focused our efforts on small extracellular vesicles (sEVs), primarily small and large exosomes derived from the endolysosomal pathway, which play important roles in cellular communication, immune response, and cancer progression via transfer of a selective repertoire of biomolecules. sEVs/exosome release is significantly increased in most neoplastic cells, including ovarian cancer and occurs continuously at all stages of tumor development. Tumorderived sEVs accumulate in human blood and malignant effusions. These vesicles carry enriched subsets of biomolecules mirroring the tumor cells of origin, such as signaling proteins, tumor antigens, and functional RNAs (mRNA and miRNAs), which offer a new strategy to surmount the challenge in reliable detection of intrinsically low-level serum markers during early malignant transformation. Thus, the constitutive release and enrichment of certain tumor markers within sEVs present distinctive opportunities for early cancer diagnosis. We hypothesize that circulating sEVs, much akin to circulating tumor cells but more robust due to their active release and incredible stability in bodily fluids, represent a greater source for the discovery of exo-biomarkers for early detection, potentially while still confined to the fallopian tube. In addition, sEVs can serve as a 'liquid biopsy’ to assess benefits and treatment responses in real time in cancer patients. Our innovative application merges EV biology with nano-material/microfluidic technology to develop an advanced microfluidic platform to capture and detect ovarian cancer-derived sEVs with high specificity and sensitivity from the circulation. This approach will integrate validated fallopian tube and ovarian cancer associated exo-protein biomarkers (SA1), which will be applied to a second-generation nano-engineered EV analysis chip (SA2). These studies will be followed by clinical validation using longitudinal samples collected from asymptomatic women who later develop epithelial ovarian cancer (SA3). Our ultimate goal is to develop a reliable blood-based assay that, when used in conjunction with current screening approaches will decrease the mortality from ovarian cancer.

Publications

  • He N, Thippabhotla S, Zhong C, Greenberg Z, Xu L, Pessetto Z, Godwin AK, Zeng Y, He M. Nano pom-poms prepared exosomes enable highly specific cancer biomarker detection. Communications biology. 2022 Jul 4;5(1):660. PMID: 35787656
  • Bantis LE, Tsimikas JV. On optimal biomarker cutoffs accounting for misclassification costs in diagnostic trilemmas with applications to pancreatic cancer. Statistics in medicine. 2022 Aug 15;41(18):3527-3546. Epub 2022 May 11. PMID: 35543227
  • Mahoney DE, Chalise P, Rahman F, Pierce JD. Influences of Gastrointestinal Microbiota Dysbiosis on Serum Proinflammatory Markers in Epithelial Ovarian Cancer Development and Progression. Cancers. 2022 Jun 20;14. (12). PMID: 35740687
  • Mahoney DE, Pierce JD. Ovarian Cancer Symptom Clusters: Use of the NIH Symptom Science Model for Precision in Symptom Recognition and Management. Clinical journal of oncology nursing. 2022 Sep 15;26(5):533-542. PMID: 36108208
  • Bantis LE, Young KJ, Tsimikas JV, Mosier BR, Gajewski B, Yeatts S, Martin RL, Barsan W, Silbergleit R, Rockswold G, Korley FK. Statistical assessment of the prognostic and the predictive value of biomarkers-A biomarker assessment framework with applications to traumatic brain injury biomarker studies. Research methods in medicine & health sciences. 2023 Jan;4(1):34-48. Epub 2022 Dec 13. PMID: 37009524
  • Yan H, Li Y, Cheng S, Zeng Y. Advances in Analytical Technologies for Extracellular Vesicles. Analytical chemistry. 2021 Mar 23;93(11):4739-4774. Epub 2021 Feb 26. PMID: 33635060
  • Zhang P, Wu X, Gardashova G, Yang Y, Zhang Y, Xu L, Zeng Y. Molecular and functional extracellular vesicle analysis using nanopatterned microchips monitors tumor progression and metastasis. Science translational medicine. 2020 Jun 10;12. (547). PMID: 32522804
  • Pierce JD, Shen Q, Mahoney DE, Rahman F, Krueger KJ, Diaz FJ, Clark L, Smith C, Vacek J, Hiebert JB. Effects of Ubiquinol and/or D-ribose in Patients With Heart Failure With Preserved Ejection Fraction. The American journal of cardiology. 2022 Aug 1;176:79-88. Epub 2022 May 27. PMID: 35644694
  • Cheng S, Li Y, Yan H, Wen Y, Zhou X, Friedman L, Zeng Y. Advances in microfluidic extracellular vesicle analysis for cancer diagnostics. Lab on a chip. 2021 Sep 7;21(17):3219-3243. Epub 2021 Aug 5. PMID: 34352059
  • Mosier BR, Bantis LE. Estimation and construction of confidence intervals for biomarker cutoff-points under the shortest Euclidean distance from the ROC surface to the perfection corner. Statistics in medicine. 2021 Sep 10;40(20):4522-4539. Epub 2021 Jun 3. PMID: 34080733
  • Yan H, Wen Y, Tian Z, Hart N, Han S, Hughes SJ, Zeng Y. A one-pot isothermal Cas12-based assay for the sensitive detection of microRNAs. Nature biomedical engineering. 2023 Apr 27. Epub 2023 Apr 27. PMID: 37106152
  • Zha D, Rayamajhi S, Sipes J, Russo A, Pathak HB, Li K, Sardiu ME, Bantis LE, Mitra A, Puri RV, Trinidad CV, Cain BP, Isenberg BC, Coppeta J, MacLaughlan S, Godwin AK, Burdette JE. Proteomic Profiling of Fallopian Tube-Derived Extracellular Vesicles Using a Microfluidic Tissue-on-Chip System. Bioengineering (Basel, Switzerland). 2023 Mar 27;10. (4). PMID: 37106610