MSGID: 1:317/3 6274a4d3   
   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
    Patient-derived micro-organospheres enable cutting-edge precision   
   oncology    
      
     Date:   
         May 5, 2022   
     Source:   
         Terasaki Institute for Biomedical Innovation   
     Summary:   
         Scientists develop micro-organospheric models to predict therapeutic   
         response accurately and rapidly, enabling cutting-edge precision   
         oncology.   
      
      
      
   FULL STORY   
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   A patient's tumor cell response to therapy is affected by many factors,   
   including genetic alterations, tumor microenvironment, and intratumoral   
   heterogeneity. This can make it extremely difficult to determine optimum   
   treatment regimens, amidst the ever-increasing number of drug candidates   
   and cancer therapies that have recently been developed. Added to these   
   challenges is the limited timeframe in which treatment decisions must   
   be made after diagnosis -- frequently on the order of two weeks or less.   
      
      
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   Shortcomings of existing oncogenic models make them unsuitable for   
   clinical use. Patient-derived tumor cell lines change when sub-cultured,   
   rendering them inaccurate as tumor models, and models made from   
   xenografts -- patient tumor cells injected into immuno-deficient mice   
   -- retain their characteristics but are time-consuming and costly to   
   produce. Patient-derived organoids, miniaturized 3D versions of tumor   
   tissues, lose the patient tumor microenvironment during sub-culturing,   
   and production of these organoids in a timely enough manner for clinical   
   decision making remains unattainable.   
      
   These challenges have been addressed in a multi-organizational   
   collaborative effort, which included scientists from the Terasaki   
   Institute for Biomedical Innovation (TIBI) and Duke University, led by   
   TIBI's chief scientific officer and professor, Dr. Xiling Shen.   
      
   As outlined in their recent publication in Cell Stem Cell,the   
   team developed a droplet-based microfluidic technology to produce   
   micro-organospheres (MOS) from cancer patient biopsies within an   
   hour. Patient tumor, immune, and connective tissue cells quickly form   
   miniature tumors that retain the original microenvironment within   
   thousands of these MOS, which can be used for testing many drug   
   conditions. Tests on MOS of various cancerous origins demonstrated   
   the retention of the cells' genetic profiles, as well as gene and   
   immunosuppressive marker expression of the original tumor tissues.   
      
   Initial tests using MOS from a small cohort of metastatic colorectal   
   cancer patients were screened against a panel of therapeutic drug   
   candidates. When the drug sensitivity results were compared against actual   
   clinical treatment outcomes, there was almost perfect correlation. What's   
   more, the MOS could be generated from small numbers of cells, as typically   
   collected from biopsies, and the whole MOS generation and drug screening   
   process took less than two weeks.   
      
   In a series of subsequent and elegant experiments, the researchers   
   developed assays to test the MOS response to immune therapies. They were   
   successfully able to demonstrate that bispecific antibodies mobilize   
   resident immune cells in the original microenvironment to attack tumor   
   cells, an unprecedented achievement in immunotherapeutic screening. In   
   another series of experiments, the scientists tested their MOS against   
   the effects of combination immune therapies and were able to demonstrate   
   both predicted responses and optimization of multiple treatment regimens.   
      
   They were also able to observe effective penetration into the MOS   
   by activated T-cells and subsequent killing of the MOS tumor cells;   
   such T-cell infiltration was achievable due to the small size and large   
   surface-to-volume ratio of the MOS droplets that mimic natural diffusion   
   limits within tissues, and could not be obtained using conventional   
   models.   
      
   The findings of the research team have tremendous implications for   
   the clinic.   
      
   With all the difficulties presented in developing cancer treatment models,   
   their work fulfills many needs. Their methods to produce an accurate   
   tumor model from limited biopsy tissue in a timely and less costly manner   
   opens the door to a variety of testing avenues for drug and immune   
   therapies. The automation of MOS production ensures reproducibility,   
   which is a requirement by the FDA.   
      
   "The technology developed here is a groundbreaking advancement   
   in physiological modeling for solid tumor diseases and personalized   
   medicine," said Ali Khademhosseini, Ph.D., TIBI's Director and CEO. "It is   
   sure to have a highly significant impact in the clinic."  Authors are:   
   Shengli Ding, Carolyn Hsu, Zhaohui Wang, Naveen R. Natesh, Rosemary   
   Millen, Marcos Negrete, Nicholas Giroux, Grecia O. Rivera, Anders Dohlman,   
   Shree Bose, Tomer Rotstein, Kassandra Spiller, Athena Yeung, Zhiguo Sun,   
   Chongming Jiang, Rui Xi, Benjamin Wilkin, Peggy M. Randon, Ian Williamson,   
   Daniel A. Nelson, Daniel Delubac, Sehwa Oh, Gabrielle Rupprecht, James   
   Isaacs, Jingquan Jia, Chao Chen, John Paul Shen, Scott Kopetz, Shannon   
   McCall, Amber Smith, Nikolche Gjorevski, Antje-Christine Walz, Scott   
   Antonia, Estelle Marrer- Berger, Hans Clevers, David Hsu, Xiling Shen.   
      
   This work was supported by funding from the National Institutes of Health   
   (U01 CA217514, U01 CA214300) and the Duke Woo Center for Big Data and   
   Precision Health.   
      
      
   ==========================================================================   
   Story Source: Materials provided by   
   Terasaki_Institute_for_Biomedical_Innovation. Note: Content may be edited   
   for style and length.   
      
      
   ==========================================================================   
   Journal Reference:   
      1. Shengli Ding, Carolyn Hsu, Zhaohui Wang, Naveen R. Natesh, Rosemary   
         Millen, Marcos Negrete, Nicholas Giroux, Grecia O. Rivera,   
         Anders Dohlman, Shree Bose, Tomer Rotstein, Kassandra Spiller,   
         Athena Yeung, Zhiguo Sun, Chongming Jiang, Rui Xi, Benjamin Wilkin,   
         Peggy M. Randon, Ian Williamson, Daniel A. Nelson, Daniel Delubac,   
         Sehwa Oh, Gabrielle Rupprecht, James Isaacs, Jingquan Jia, Chao   
         Chen, John Paul Shen, Scott Kopetz, Shannon McCall, Amber Smith,   
         Nikolche Gjorevski, Antje-Christine Walz, Scott Antonia, Estelle   
         Marrer-Berger, Hans Clevers, David Hsu, Xiling Shen. Patient-derived   
         micro-organospheres enable clinical precision oncology. Cell Stem   
         Cell, 2022; DOI: 10.1016/j.stem.2022.04.006   
   ==========================================================================   
      
   Link to news story:   
   https://www.sciencedaily.com/releases/2022/05/220505154455.htm   
      
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