Research Focus:

• Mechanism-based novel combination approaches to cancer therapy
• Molecular and cellular mechanisms of cancer metastasis
• Molecular and cellular mechanisms of chemo-resistance
• The role of cell adhesion molecules in tumor progression and metastasis
• Novel therapeutic interventions to prevent metastatic progression
• Pancreatic cancer, ovarian cancer, cholangiocarcinoma, neuroblastoma
• Patient-derived xenograft (PDX) models of solid tumors

Our primary research goals are to understand molecular mechanisms of tumor progression and metastasis of solid tumors, to identify molecular interactions or pathways that regulate these processes, and to develop novel, effective mechanism-based therapeutic strategies that target these interactions and pathways. Our long-term goal is to use observations made in the laboratory with preclinical models as a basis for developing therapies for solid tumors.

My research interests include three major areas: to develop novel therapies for the treatment of cancer, to identify molecular interactions as targets to suppress metastatic progression, and to develop targeted therapies guided by genetic analysis and patient-derived xenograft models.

Developing novel therapies for the treatment of cancer: using preclinical models that reflect human cancers for therapeutic application: Our laboratory has established a series of patient-derived xenograft (PDX) models of pancreatic ductal adenocarcinoma (PDAC) and cholangiocarcinoma (CCA). We propose that these models represent a useful tool for identifying characteristics common to PDAC and CCA tumors, underlying mechanisms and for evaluating potential therapies such as novel BET bromodomain inhibitors.

Identifying molecular interactions as targets to suppress metastatic progression: Progressive metastatic disease is a major cause of mortality for patients diagnosed with multiple types of solid tumors. One of the long-term goals of our laboratory is to identify molecular interactions that regulate metastasis, as a basis for developing agents that inhibit this process. Cell adhesion molecules participate in diverse function in normal and tumor cells. We determined that expression of intercellular adhesion molecule-2 (ICAM-2) confers a non-metastatic phenotype in NB cells, and data generated with primary tumor cells are consistent with observations made using model systems. We envision that identification of proteins that comprise key regulators of the metastatic process will facilitate identification of protein interactions that support or suppress a metastatic phenotype in human cancer cells, and will serve as the basis for structural studies and targeted drug development in the future.

Developing targeted therapies guided by genetic analysis and patient-derived xenograft (PDX) models: To overcome the challenge of eradicating tumors with subpopulations of cells having unique genetic and molecular profiles, we propose to develop personalized treatments based on the genetic, phenotypic, and molecular characteristics of a given tumor. Genetic analyses will focus on detecting mutations that would predict constitutive activation of pathways or gain of function activities that support tumor cell growth and proliferation. Where possible, approaches to treatment will be based on circumventing the dysfunctional pathways, and the efficacy of each treatment will be examined using patient-derived xenograft models.

Garcia PL, Miller AL, Zeng L, van Waardenburg RCAM, Yang ES, Yoon KJ (2022). The BET inhibitor JQ1 potentiates the anticlonogenic effect of radiation in pancreatic cancer cells. Frontiers in Oncology, 12: 925718. PMID: 35795040.

Miller AL, Garcia PL, Fehling SC, Gamblin TL, Vance RB, Council LN, Chen D, Yang ES, van Waardenburg RCAM, Yoon KJ (2021). The BET inhibitor JQ1 augments the antitumor efficacy of gemcitabine in preclinical models of pancreatic cancer. Cancers 13(14): 3470. PMID: 34298684.

Marayati R, Brownes LV, Staffman LL, Williams AP, Quinn CH, Atigadda V, Aye JM, Stewart JE, Yoon KJ, Beierle EA (2021) 9-cis-UAB30, a novel retinoid agonist, decreases tumorigenicity and cancer cell stemness of human neuroblastoma patient-derived xenografts. Transl Oncol 14(1): 100893. PMID: 33010553.

Fehling SC, Miller AL, Garcia PL, Vance RB, Yoon KJ (2020) The combination of BET and PARP inhibitor is synergistic in models of cholangiocarcinoma. Cancer Lett 468: 48-58. PMID: 31605774. Miller AL, Garcia PL, Gamblin RB, Vance RB, Yoon KJ (2020) Development of gemcitabine-resistant patient-derived xenograft models of pancreatic ductal adenocarcinoma. Cancer Drug Resist 3: 572-585. PMID: 33073205.

Kreitzburg KM, Fehling SC, Landen CN, Gamblin TL, Vance RB, Arend RC, Katre AA, Oliver PG, van Waardenburg RCAM, Alvarez RD, Yoon KJ (2018) FTY720 enhances the anti-tumor activity of carboplatin and tamoxifen in a patient-derived xenograft model of ovarian cancer. Cancer Lett 436: 75-86. PMID: 30120964.

Miller AL, Fehling SC, Garcia PL, Gamblin TL, Council LN, van Waardenburg RCAM, Yang ES, Bradner JE, Yoon KJ (2019). The BET inhibitor JQ1 attenuates double-strand break repair and sensitizes models of pancreatic ductal adenocarcinoma to PARP inhibitors. EBioMedicine June;44: 419-430. PMID: 31126889.

Cramer SL, Miller AL, Pressey JG, Gamblin TL, Beierle EA, Kulbersh BD, Garcia PL, Council LN, Radhakrishnan R, Hendrix SV, Kelly DR, Watts RG, Yoon KJ (2018) Pediatric anaplastic embryonal rhabdomyosarcoma: Targeted therapy guided by genetic analysis and a patient-derived xenograft study. Front Oncol 7: 327. PMID: 29376028.

Garcia PL, Miller AL, Gamblin TL, Council LN, Christein JD, Arnoletti JP, Heslin MJ, Reddy S, Richardson JH, Cui X, van Waardenburg RCAM, Bradner JE, Yang ES, Yoon KJ (2018) JQ1 induces DNA damage and apoptosis, and inhibits tumor growth in a patient-derived xenograft model of cholangiocarcinoma. Mol Cancer Ther 17(1): 107-118. PMID: 29142067.

Miller AL, Garcia PL, Pressey JG, Beierle EA, Kelly DR, Crossman DK, Council LN, Daniel R, Watts RG, Cramer SL, Yoon KJ (2017) Whole exome sequencing identified sixty-five coding mutations in four neuroblastoma tumors. Sci Rep 7(1): 17787. PMID: 29259192.

Schultz MJ, Holdbrooks AT, Chakraborty Am Grizzle WE, Landen CN, Buchsbaum DJ, Conner MG, Arend RC, Yoon KJ, Klug CA, Bullard DC, Kesterson RA, Oliver PG, O’Connor AK, Yoder BK, Bellis SL (2016) The tumor-associated glycosyltransferase ST6Gal-1 regulates stem cell transcription factors and confers a cancer stem cell phenotype. Cancer Res 76(13): 3978-3988. PMID: 27216178.

Garcia PL, Miller AL, Kreitzburg KM, Gamblin TL, Christein JD, Heslin MJ, Arnoletti JP, Richardson JH, Chen D, Hanna CA, Cramer SL, Yang ES, Qi J, Bradner JE, Yoon KJ (2016) The BET bromodomain inhibitor JQ1 suppresses growth of pancreatic ductal adenocarcinoma in patient-derived xenograft models. Oncogene 35(7): 833-845. PMID: 25961927.

Feduska JM, Aller SG, Garcia PL, Cramer SL, van Waardenburg RCAM, Yoon KJ (2015) ICAM-2 confers a non-metastatic phenotype in neuroblastoma cells by interaction with α-actinin. Oncogene 34(12): 1553-1562. PMID: 24704826.

Garcia PL, Council LN, Christein JD, Arnoletti JP, Heslin MJ, Richardson JH, Gamblin TL, Bjornsti M-A, Yoon KJ (2013) Development and pathophysiological evaluation of tumorgraft models of pancreatic ductal adenocarcinoma. PLoS One, 8(10): e78183. PMID: 24194913.

Feduska JM, Garcia PL, Brennan SB, Bu S, Council LN, Yoon KJ (2013) N-glycosylation of ICAM-2 is required for ICAM-2-mediated complete suppression of metastatic potential of SK-N-AS neuroblastoma cells. BMC Cancer, 13:261. PMID: 23714211.