Principal Investigator

Awardee Organization

Beckman Research Institute/City Of Hope
United States

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

Noncoding RNA Biomarkers for Noninvasive and Early Detection of Pancreatic Cancer

Pancreatic cancer is the fourth leading cause of adult cancer deaths in the U.S., and will become the second leading cause of cancer-related deaths by 2030. The lack of reliable and cost-effective assays impedes wide-spread pancreatic cancer diagnostics. Clearly, early diagnostic procedures will improve the prognosis of patients with pancreatic ductal adenocarcinoma (PDAC), but will require novel methods of development. MicroRNAs (miRNAs) are small noncoding RNAs that are implicated in the tumorigenesis of every human cancer, including PDAC. Importantly, miRNAs are robust and resistant to degradation in tissues and body fluids, making them ideal candidates as non-invasive biomarkers. The recent discovery of cancers that actively excrete specific miRNAs in small vesicles, called “exosomes”, has brought additional enthusiasm to the cancer biomarker arena. Previous attempts to define blood-based miRNA biomarkers that can discriminate between non-invasive, early-stage and late-stage PDAC were insufficiently sensitive or specific because of improperly designed cohorts and the narrow dynamic ranges of technologies used. Furthermore, candidate markers were non-comprehensively selected, studies lacked important controls, and the cohorts were insufficiently powered or validated, or did not represent the average risk population. These factors stifled the discovery of miRNA biomarkers that could identify asymptomatic patients before metastatic disease had developed, or distinguish early stage, radiographically occult PDAC from noninvasive pancreatic precancerous neoplasms (PNs). In this proposal, innovative strategies including Next Generation Sequencing (NGS)-based miRNA-Seq will be applied to the genome-wide and systematic discovery of comprehensive and highly specific blood-based miRNAs by analyzing tissues and matching plasma that discern different stages of invasive PDAC and PN. A novel and powerful new approach is being proposed to identify biomarkers with the highest sensitivity and specificity, which will be validated in a prospective, large, well-characterized samples through the following Specific Aims. Aim #1: Discover candidate cell-free and exosomal-miRNA biomarkers using small RNA-Seq in matched tissue and plasma from patients with PDAC, PNs, pancreatitis and normal pancreas. Aim #2: Develop a cell-free and exosomal-miRNA biomarker panel that distinguishes patients with PDAC from those with PNs or pancreatitis. Aim #3: Clinically validate the optimized panel of non-invasive miRNA biomarkers (identified in Aim #2) in prospective cohorts of patients with PDAC and PNs. This project is innovative as it will use NGS-based miRNA-Sequencing for discovery of cell-free and exosomal miRNA biomarkers in matched tissue and plasma samples, and validate these in multiple, well-characterized cohorts of patients with PNs and PDAC vs. controls. If successful, this proposal will profoundly transform earlydetection of pancreatic cancer using a non-invasive, robust and inexpensive clinical assay.


  • Kandimalla R, Tomihara H, Banwait JK, Yamamura K, Singh G, Baba H, Goel A. A 15-Gene Immune, Stromal, and Proliferation Gene Signature that Significantly Associates with Poor Survival in Patients with Pancreatic Ductal Adenocarcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research. 2020 Jul 15;26(14):3641-3648. Epub 2020 Mar 31. PMID: 32234757
  • Zhao Z, Fan J, Hsu YS, Lyon CJ, Ning B, Hu TY. Extracellular vesicles as cancer liquid biopsies: from discovery, validation, to clinical application. Lab on a chip. 2019 Mar 27;19(7):1114-1140. PMID: 30882822
  • Zheng W, LaCourse SM, Song B, Singh DK, Khanna M, Olivo J, Stern J, Escudero JN, Vergara C, Zhang F, Li S, Wang S, Cranmer LM, Huang Z, Bojanowski CM, Bao D, Njuguna I, Xiao Y, Wamalwa DC, Nguyen DT, Yang L, Maleche-Obimbo E, Nguyen N, Zhang L, Phan H, Fan J, Ning B, Li C, Lyon CJ, Graviss EA, John-Stewart G, Mitchell CD, Ramsay AJ, Kaushal D, Liang R, Pérez-Then E, Hu TY. Diagnosis of paediatric tuberculosis by optically detecting two virulence factors on extracellular vesicles in blood samples. Nature biomedical engineering. 2022 Aug;6(8):979-991. Epub 2022 Aug 19. PMID: 35986185
  • Ruiz-Bañobre J, Rodriguez-Casanova A, Costa-Fraga N, Bao-Caamano A, Alvarez-Castro A, Carreras-Presas M, Brozos-Vazquez E, Vidal-Insua Y, Vazquez-Rivera F, Candamio-Folgar S, Mosquera-Presedo M, Lago-Lestón RM, Muinelo-Romay L, Vázquez-Bueno JÁ, Sanz-Pamplona R, Moreno V, Goel A, Castillo L, Martin AC, Arroyo R, Esteller M, Crujeiras AB, López-López R, Díaz-Lagares A. Noninvasive early detection of colorectal cancer by hypermethylation of the LINC00473 promoter in plasma cell-free DNA. Clinical epigenetics. 2022 Jul 9;14(1):86. PMID: 35810318
  • Sharma GG, Okada Y, Von Hoff D, Goel A. Non-coding RNA biomarkers in pancreatic ductal adenocarcinoma. Seminars in cancer biology. 2021 Oct;75:153-168. Epub 2020 Oct 10. PMID: 33049362
  • Weng W, Li H, Goel A. Piwi-interacting RNAs (piRNAs) and cancer: Emerging biological concepts and potential clinical implications. Biochimica et biophysica acta. Reviews on cancer. 2019 Jan;1871(1):160-169. Epub 2018 Dec 30. PMID: 30599187
  • Kandimalla R, Shimura T, Mallik S, Sonohara F, Tsai S, Evans DB, Kim SC, Baba H, Kodera Y, Von Hoff D, Chen X, Goel A. Identification of Serum miRNA Signature and Establishment of a Nomogram for Risk Stratification in Patients With Pancreatic Ductal Adenocarcinoma. Annals of surgery. 2022 Jan 1;275(1):e229-e237. PMID: 32398486
  • Wan M, Wang Y, Zhan L, Fan J, Hu TY. MALDI-TOF mass spectrometry-based quantification of C-peptide in diabetes patients. European journal of mass spectrometry (Chichester, England). 2020 Feb;26(1):55-62. Epub 2019 Jul 18. PMID: 31319703
  • Liu Y, Fan J, Xu T, Ahmadinejad N, Hess K, Lin SH, Zhang J, Liu X, Liu L, Ning B, Liao Z, Hu TY. Extracellular vesicle tetraspanin-8 level predicts distant metastasis in non-small cell lung cancer after concurrent chemoradiation. Science advances. 2020 Mar 11;6(11):eaaz6162. doi: 10.1126/sciadv.aaz6162. eCollection 2020 Mar. PMID: 32195353
  • Fan J, Wei Q, Koay EJ, Liu Y, Ning B, Bernard PW, Zhang N, Han H, Katz MH, Zhao Z, Hu Y. Chemoresistance Transmission via Exosome-Mediated EphA2 Transfer in Pancreatic Cancer. Theranostics. 2018 Nov 13;8(21):5986-5994. doi: 10.7150/thno.26650. eCollection 2018. PMID: 30613276
  • Lennon KM, Wakefield DL, Maddox AL, Brehove MS, Willner AN, Garcia-Mansfield K, Meechoovet B, Reiman R, Hutchins E, Miller MM, Goel A, Pirrotte P, Van Keuren-Jensen K, Jovanovic-Talisman T. Single molecule characterization of individual extracellular vesicles from pancreatic cancer. Journal of extracellular vesicles. 2019 Nov 4;8(1):1685634. doi: 10.1080/20013078.2019.1685634. eCollection 2019. PMID: 31741725
  • Amrollahi P, Rodrigues M, Lyon CJ, Goel A, Han H, Hu TY. Ultra-Sensitive Automated Profiling of EpCAM Expression on Tumor-Derived Extracellular Vesicles. Frontiers in genetics. 2019 Dec 17;10:1273. doi: 10.3389/fgene.2019.01273. eCollection 2019. PMID: 31921310
  • Lane JS, Hoff DV, Cridebring D, Goel A. Extracellular Vesicles in Diagnosis and Treatment of Pancreatic Cancer: Current State and Future Perspectives. Cancers. 2020 Jun 10;12. (6). PMID: 32532129
  • Okada Y, Nishiwada S, Yamamura K, Sho M, Baba H, Takayama T, Goel A. Identification of laminin γ2 as a prognostic and predictive biomarker for determining response to gemcitabine-based therapy in pancreatic ductal adenocarcinoma. European journal of cancer (Oxford, England : 1990). 2021 Mar;146:125-134. Epub 2021 Feb 16. PMID: 33607476
  • Wan M, Ning B, Spiegel S, Lyon CJ, Hu TY. Tumor-derived exosomes (TDEs): How to avoid the sting in the tail. Medicinal research reviews. 2020 Jan;40(1):385-412. Epub 2019 Jul 18. PMID: 31318078
  • Kandimalla R, Xu J, Link A, Matsuyama T, Yamamura K, Parker MI, Uetake H, Balaguer F, Borazanci E, Tsai S, Evans D, Meltzer SJ, Baba H, Brand R, Von Hoff D, Li W, Goel A. EpiPanGI Dx: A Cell-free DNA Methylation Fingerprint for the Early Detection of Gastrointestinal Cancers. Clinical cancer research : an official journal of the American Association for Cancer Research. 2021 Nov 15;27(22):6135-6144. Epub 2021 Aug 31. PMID: 34465601
  • Wan M, Amrollahi P, Sun D, Lyon C, Hu TY. Using Nanoplasmon-Enhanced Scattering and Low-Magnification Microscope Imaging to Quantify Tumor-Derived Exosomes. Journal of visualized experiments : JoVE. 2019 May 24;(147). PMID: 31180357
  • Rahmanuddin S, Korn R, Cridebring D, Borazanci E, Brase J, Boswell W, Jamil A, Cai W, Sabir A, Motarjem P, Koay E, Mitra A, Goel A, Ho J, Chung V, Von Hoff DD. Role of 3D Volumetric and Perfusion Imaging for Detecting Early Changes in Pancreatic Adenocarcinoma. Frontiers in oncology. 2021 Sep 8;11:678617. doi: 10.3389/fonc.2021.678617. eCollection 2021. PMID: 34568010
  • Tapial S, Olmedillas-López S, Rueda D, Arriba M, García JL, Vivas A, Pérez J, Pena-Couso L, Olivera R, Rodríguez Y, García-Arranz M, García-Olmo D, González-Sarmiento R, Urioste M, Goel A, Perea J. Cimp-Positive Status is More Representative in Multiple Colorectal Cancers than in Unique Primary Colorectal Cancers. Scientific reports. 2019 Jul 19;9(1):10516. PMID: 31324877
  • Markus H, Zhao J, Contente-Cuomo T, Stephens MD, Raupach E, Odenheimer-Bergman A, Connor S, McDonald BR, Moore B, Hutchins E, McGilvrey M, de la Maza MC, Van Keuren-Jensen K, Pirrotte P, Goel A, Becerra C, Von Hoff DD, Celinski SA, Hingorani P, Murtaza M. Analysis of recurrently protected genomic regions in cell-free DNA found in urine. Science translational medicine. 2021 Feb 17;13. (581). PMID: 33597261
  • Nakamura K, Zhu Z, Roy S, Jun E, Han H, Munoz RM, Nishiwada S, Sharma G, Cridebring D, Zenhausern F, Kim S, Roe DJ, Darabi S, Han IW, Evans DB, Yamada S, Demeure MJ, Becerra C, Celinski SA, Borazanci E, Tsai S, Kodera Y, Park JO, Bolton JS, Wang X, Kim SC, Von Hoff D, Goel A. An Exosome-based Transcriptomic Signature for Noninvasive, Early Detection of Patients With Pancreatic Ductal Adenocarcinoma: A Multicenter Cohort Study. Gastroenterology. 2022 Nov;163(5):1252-1266.e2. Epub 2022 Jul 16. PMID: 35850192
  • Nishiwada S, Cui Y, Sho M, Jun E, Akahori T, Nakamura K, Sonohara F, Yamada S, Fujii T, Han IW, Tsai S, Kodera Y, Park JO, Von Hoff D, Kim SC, Li W, Goel A. Transcriptomic Profiling Identifies an Exosomal microRNA Signature for Predicting Recurrence Following Surgery in Patients With Pancreatic Ductal Adenocarcinoma. Annals of surgery. 2022 Dec 1;276(6):e876-e885. Epub 2021 Jun 16. PMID: 34132691
  • Okada Y, Takahashi N, Takayama T, Goel A. LAMC2 promotes cancer progression and gemcitabine resistance through modulation of EMT and ATP-binding cassette transporters in pancreatic ductal adenocarcinoma. Carcinogenesis. 2021 Apr 30;42(4):546-556. PMID: 33624791
  • Nishiwada S, Sho M, Banwait JK, Yamamura K, Akahori T, Nakamura K, Baba H, Goel A. A MicroRNA Signature Identifies Pancreatic Ductal Adenocarcinoma Patients at Risk for Lymph Node Metastases. Gastroenterology. 2020 Aug;159(2):562-574. Epub 2020 May 4. PMID: 32376411
  • Ruiz-Bañobre J, Goel A. DNA Mismatch Repair Deficiency and Immune Checkpoint Inhibitors in Gastrointestinal Cancers. Gastroenterology. 2019 Mar;156(4):890-903. Epub 2018 Dec 19. PMID: 30578781
  • Wan YCE, Leung TCS, Ding D, Sun X, Liu J, Zhu L, Kang TZE, Yang D, Zhang Y, Zhang J, Qian C, Huen MSY, Li Q, Chow MZY, Zheng Z, Han J, Goel A, Wang X, Ishibashi T, Chan KM. Cancer-associated histone mutation H2BG53D disrupts DNA-histone octamer interaction and promotes oncogenic phenotypes. Signal transduction and targeted therapy. 2020 Mar 6;5(1):27. PMID: 32296031
  • Shimura T, Toden S, Kandimalla R, Toiyama Y, Okugawa Y, Kanda M, Baba H, Kodera Y, Kusunoki M, Goel A. Genomewide Expression Profiling Identifies a Novel miRNA-based Signature for the Detection of Peritoneal Metastasis in Patients With Gastric Cancer. Annals of surgery. 2021 Nov 1;274(5):e425-e434. PMID: 31663973
  • Okugawa Y, Toiyama Y, Shigeyasu K, Yamamoto A, Shigemori T, Yin C, Ichikawa T, Yasuda H, Fujikawa H, Yoshiyama S, Hiro J, Ohi M, Araki T, Kusunoki M, Goel A. Enhanced AZIN1 RNA editing and overexpression of its regulatory enzyme ADAR1 are important prognostic biomarkers in gastric cancer. Journal of translational medicine. 2018 Dec 18;16(1):366. PMID: 30563560
  • Rodrigues M, Richards N, Ning B, Lyon CJ, Hu TY. Rapid Lipid-Based Approach for Normalization of Quantum-Dot-Detected Biomarker Expression on Extracellular Vesicles in Complex Biological Samples. Nano letters. 2019 Nov 13;19(11):7623-7631. Epub 2019 Jul 25. PMID: 31317745
  • Zaid M, Elganainy D, Dogra P, Dai A, Widmann L, Fernandes P, Wang Z, Pelaez MJ, Ramirez JR, Singhi AD, Dasyam AK, Brand RE, Park WG, Rahmanuddin S, Rosenthal MH, Wolpin BM, Khalaf N, Goel A, Von Hoff DD, Tamm EP, Maitra A, Cristini V, Koay EJ. Imaging-Based Subtypes of Pancreatic Ductal Adenocarcinoma Exhibit Differential Growth and Metabolic Patterns in the Pre-Diagnostic Period: Implications for Early Detection. Frontiers in oncology. 2020 Dec 2;10:596931. doi: 10.3389/fonc.2020.596931. eCollection 2020. PMID: 33344245
  • Zhang F, Lyon CJ, Walls RJ, Ning B, Fan J, Hu TY. Cathepsin B Dependent Cleavage Product of Serum Amyloid A1 Identifies Patients with Chemotherapy-Related Cardiotoxicity. ACS pharmacology & translational science. 2019 Aug 12;2(5):333-341. doi: 10.1021/acsptsci.9b00035. eCollection 2019 Oct 11. PMID: 32259067
  • Hu Q, Su H, Li J, Lyon C, Tang W, Wan M, Hu TY. Clinical applications of exosome membrane proteins. Precision clinical medicine. 2020 Mar;3(1):54-66. Epub 2020 Feb 24. PMID: 32257533
  • Moloudizargari M, Asghari MH, Goel A. The therapeutic triad of extracellular vesicles: As drug targets, as drugs, and as drug carriers. Biochemical pharmacology. 2021 Oct;192:114714. Epub 2021 Jul 30. PMID: 34332957
  • Maity S, Mayer MG, Shu Q, Linh H, Bao D, Blair RV, He Y, Lyon CJ, Hu TY, Fischer T, Fan J. Cerebrospinal Fluid Protein Markers Indicate Neuro-Damage in SARS-CoV-2-Infected Nonhuman Primates. Molecular & cellular proteomics : MCP. 2023 Apr;22(4):100523. Epub 2023 Mar 3. PMID: 36870567
  • Nishiwada S, Sho M, Cui Y, Yamamura K, Akahori T, Nakagawa K, Nagai M, Nakamura K, Takagi T, Ikeda N, Li W, Baba H, Goel A. A gene expression signature for predicting response to neoadjuvant chemoradiotherapy in pancreatic ductal adenocarcinoma. International journal of cancer. 2021 Feb 1;148(3):769-779. Epub 2020 Sep 12. PMID: 32895958
  • Nishiwada S, Shimura T, Yamamura K, Nakagawa K, Nagai M, Nakamura K, Terai T, Yamada S, Fujii T, Kodera Y, Sho M, Goel A. Clinical significance and functional role of adhesion G-protein-coupled receptors in human pancreatic ductal adenocarcinoma. British journal of cancer. 2023 Jan;128(2):321-330. Epub 2022 Nov 17. PMID: 36396823
  • Ruiz-Bañobre J, Goel A. Liquid Biopsy Assessment of Molecular Residual Disease in Localized Colorectal Cancer: Is It Ready for Prime Time? JAMA oncology. 2023 Apr 20. Epub 2023 Apr 20. PMID: 37079293