MSGID: 1:317/3 6279eab2   
   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
    Researchers identify key factors impacting adaptive therapy    
    Spatial organization and competition between drug-resistant cells affect   
   treatment outcomes    
      
     Date:   
         May 9, 2022   
     Source:   
         H. Lee Moffitt Cancer Center & Research Institute   
     Summary:   
         Researchers have been investigating an alternative treatment   
         approach called adaptive therapy that focuses on maintaining disease   
         control instead of complete tumor cell elimination. Researchers   
         used mathematical modeling to reveal that the spatial organization   
         of a tumor is an important factor that governs how cells compete   
         with one another and the effectiveness of adaptive therapy.   
      
      
      
   FULL STORY   
   ==========================================================================   
   Most cancer treatments are based on using the maximum tolerated dose   
   of a drug to kill as many cancer cells as possible. While this approach   
   has led to patients achieving good responses to therapy, most patients   
   develop drug resistance and disease recurrence. Researchers in the Center   
   of Excellence for Evolutionary Therapy at Moffitt Cancer Center have been   
   investigating an alternative treatment approach called adaptive therapy   
   that focuses on maintaining disease control instead of complete tumor   
   cell elimination. In a new study published in Communications Medicine,   
   the researchers used mathematical modeling to reveal that the spatial   
   organization of a tumor is an important factor that governs how cells   
   compete with one another and the effectiveness of adaptive therapy.   
      
      
   ==========================================================================   
   The development of drug resistance is one of the primary concerns in the   
   oncology field. As each new targeted therapy is added to the arsenal of   
   potential therapeutics, scientists are already addressing how to tackle   
   inevitable drug resistance that occurs through a variety of different   
   mechanisms. Drug resistance is common when using a maximum tolerated dose   
   of a drug because this approach provides a growth advantage to existing   
   resistant cells as they become free from competition with sensitive cells.   
      
   Alternatively, the emerging concept of adaptive therapy is based on   
   ecological principles that predict that maintaining a population of   
   cancer cells that is sensitive to therapies will keep the development   
   of resistance in check through competition. Similar approaches are used   
   in other biological situations, such as insecticide use. It is now well   
   accepted that using a less aggressive spraying approach and maintaining   
   a "refuge" insecticide-free spot allows insecticide-sensitive insects   
   to breed with resistant populations, which limits the propagation of   
   resistant groups.   
      
   These ecological concepts are now being more fully investigated in cancer.   
      
   Promising results were observed from a recent early-stage clinical trial   
   of prostate cancer patients treated with adaptive therapy, and additional   
   larger clinical studies of adaptive therapy are underway in prostate   
   cancer and melanoma. While these investigations continue, scientists   
   need to improve their understanding of the cellular interactions that   
   impact adaptive therapy.   
      
   Previous studies have revealed that adaptive therapy depends on the   
   competitive interactions of sensitive and resistance cells within a   
   spatially constrained tumor; however, it is unknown how competition occurs   
   and how it is impacted by the spatial arrangement of cells within the   
   tumor. Rather than using typical cell or mouse models to study adaptive   
   therapy, the Moffitt research team is using mathematical modeling that can   
   better incorporate the numerous variables that impact adaptive therapy.   
      
   In their study, the researchers used a two-dimensional model of a tumor   
   composed of drug sensitive and resistant cells to directly quantify how   
   different cells compete for space.   
      
   "While competition is thought to be the driving mechanism behind adaptive   
   therapy, it is challenging to assert its role in real tumors. This is   
   because it is difficult to rule out confounding factors, such as treatment   
   induced changes in the tumor vasculature or the immune response,"   
   said Maximilian Strobl, Ph.D., a postdoctoral researcher at Moffitt and   
   first author of the study. "However, in our computational model we can   
   control and monitor the cells in a way not possible in the wet lab. We   
   seized this opportunity to explicitly measure how often a resistant cell   
   is blocked from division during adaptive therapy. The results of these   
   experiments were surprising."  Currently, it is believed that adaptive   
   therapy permits drug sensitive cells to keep resistant cells in check   
   through competition, but the Moffitt team discovered that competition   
   between resistant cells themselves and their distribution across a tumor   
   are important factors that also impact adaptive therapy. The researchers   
   showed that adaptive therapy will be most effective when resistant cells   
   are clustered in a single area and surrounded by sensitive cells. This   
   scenario will allow resistant cells to be kept in check by sensitive   
   cells and other resistant cells.   
      
   These results suggest that it will be important to understand how   
   resistant cells are spatially organized to determine the appropriate   
   adaptive therapy treatment schedule; however, determining cell   
   resistance patterns may require tissue biopsies that would be invasive   
   and impractical. As an alternative approach, the researchers used   
   response data from prostate cancer patients undergoing adaptive therapy   
   to demonstrate that it may be possible to use mathematical modeling   
   to determine spatial organization patterns. Patients who cycled through   
   therapy quickly had more diffuse tumors, while patients who cycled through   
   therapy more slowly tended to have more compact tumors that may be better   
   suited to adaptive therapy.   
      
   While additional studies are needed to more fully understand adaptive   
   therapy, these results provide new insights into factors that are critical   
   in determining its success.   
      
   "We have shown that the spatial organization of resistant populations   
   is an important and understudied factor in cancer treatment. This   
   strengthens the argument for patient-specific, adaptive therapy   
   protocols that explicitly consider not only a tumor's evolution but   
   also its ecology," said Sandy Anderson, Ph.D., director of the Center   
   of Excellence for Evolutionary Therapy and chair of the Department of   
   Integrated Mathematical Oncology.   
      
   This work was supported by the Engineering and Physical Sciences Research   
   Council and the Medical Research Council (EP/L016044/1), the National   
   Cancer Institute (U01CA232382 and U54CA193489) and the Moffitt Center   
   of Excellence for Evolutionary Therapy.   
      
      
   ==========================================================================   
   Story Source: Materials provided by   
   H._Lee_Moffitt_Cancer_Center_&_Research_Institute. Note: Content may be   
   edited for style and length.   
      
      
   ==========================================================================   
   Journal Reference:   
      1. Maximilian A. R. Strobl, Jill Gallaher, Jeffrey West, Mark   
      Robertson-   
         Tessi, Philip K. Maini, Alexander R. A. Anderson. Spatial structure   
         impacts adaptive therapy by shaping intra-tumoral competition.   
      
         Communications Medicine, 2022; 2 (1) DOI: 10.1038/s43856-022-00110-x   
   ==========================================================================   
      
   Link to news story:   
   https://www.sciencedaily.com/releases/2022/05/220509162805.htm   
      
   --- up 10 weeks, 10 hours, 50 minutes   
    * Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1:317/3)   
   SEEN-BY: 15/0 106/201 114/705 123/120 129/330 331 153/7715 218/700   
   SEEN-BY: 229/110 111 112 317 400 426 428 470 664 700 292/854 298/25   
   SEEN-BY: 305/3 317/3 320/219 396/45   
   PATH: 317/3 229/426