MSGID: 1:317/3 64153e61   
   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
    New combination of drugs works together to reduce lung tumors in mice   
      
      
     Date:   
         March 17, 2023   
     Source:   
         Salk Institute   
     Summary:   
         A new study has revealed FDA-approved trametinib and entinostat   
         (which is currently in clinical trials) can be given in tandem   
         to produce fewer and smaller tumors in mice with LKB1-mutated   
         non-small cell lung cancer.   
      
      
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   FULL STORY   
   ==========================================================================   
   Cancer treatments have long been moving toward personalization --   
   finding the right drugs that work for a patient's unique tumor, based   
   on specific genetic and molecular patterns. Many of these targeted   
   therapies are highly effective, but aren't available for all cancers,   
   including non-small cell lung cancers (NSCLCs) that have an LKB1 genetic   
   mutation. A new study led by Salk Institute Professor Reuben Shaw and   
   former postdoctoral fellow Lillian Eichner, now an assistant professor at   
   Northwestern University, revealed FDA-approved trametinib and entinostat   
   (which is currently in clinical trials) can be given in tandem to produce   
   fewer and smaller tumors in mice with LKB1-mutated NSCLC.   
      
      
   ==========================================================================   
   The findings were published in Science Advances on March 17, 2023.   
      
   "For non-small cell lung cancer cases with the LKB1 mutation, standard   
   chemotherapy and immunotherapy treatments are not effective," says Shaw,   
   senior and co-corresponding author of the study, and director of Salk's   
   Cancer Center.   
      
   "Our findings demonstrate there is a way to target these cases using   
   drugs that are FDA-approved or already in clinical trials, so this   
   work could easily be used for a clinical trial in humans."  Roughly 20   
   percent of all NSCLCs have the LKB1 genetic mutation, which means there   
   are no effective targeted therapies currently on the market for patients   
   with this cancer type. To create a therapy that could target the LKB1   
   mutation, the researchers turned to histone deacetylases (HDACs). HDACs   
   are proteins associated with tumor growth and cancer metastasis, with   
   characteristic overexpression in solid tumors. Several HDAC-inhibitor   
   drugs are already FDA- approved (safe for human use) for specific forms   
   of lymphoma, but data on their efficacy in solid tumors or whether tumors   
   bearing specific genetic alterations may exhibit heightened therapeutic   
   potential has been lacking.   
      
   Based on previous findings connecting the LKB1 gene to three other HDACs   
   that all rely on HDAC3, the team started by conducting a genetic analysis   
   of HDAC3 in mouse models of NSCLC, discovering an unexpectedly critical   
   role for HDAC3 in multiple models. After establishing that HDAC3 was   
   critical for the growth of the difficult-to-treat LKB1-mutant tumors,   
   the researchers next examined whether pharmacologically blocking HDAC3   
   could give a similarly potent effect.   
      
   The team was curious about testing two drugs, entinostat (an HDAC   
   inhibitor in clinical trials known to target HDAC1 and HDAC3) and   
   FDA-approved trametinib (an inhibitor for a different class of enzymes   
   related to cancer). Tumors often become quickly resistant to trametinib,   
   but co-treatment with a drug that inhibits a protein downstream of HDAC3   
   helps reduce this resistance. Because that protein relies on HDAC3, the   
   researchers believed that a drug that targets HDAC3 -- like entinostat --   
   would help manage trametinib resistance, too.   
      
   After treating mice with LKB1-mutated lung cancer with variable treatment   
   regimens for 42 days, the team found that mice given both entinostat   
   and trametinib had 79 percent less tumor volume and 63 percent fewer   
   tumors in their lungs than the untreated mice. Additionally, the team   
   confirmed that entinostat was a viable treatment option in cases where   
   a tumor was resistant to trametinib.   
      
   "We thought the whole HDAC enzyme class was directly linked to the   
   cause of LKB1 mutant lung cancer. But we didn't know the specific role   
   of HDAC3 in lung tumor growth," says first and co-corresponding author   
   Eichner. "We've now shown that HDAC3 is essential in lung cancer, and that   
   it is a druggable vulnerability in therapeutic resistance."  The findings   
   may lead to clinical trials to test the new regimen in humans, since   
   entinostat is already in clinical trials and trametinib is FDA-approved.   
      
   Importantly, Shaw sees this discovery as transformative for cancers   
   beyond NSCLC, with potential applications in lymphoma, melanoma, and   
   pancreatic cancer.   
      
   "Our lab has committed years to this project, taking small and meaningful   
   steps toward these findings," says Shaw, holder of the William R. Brody   
   Chair. "This is truly a success story for how basic discovery science   
   can lead to therapeutic solutions in the not-so-distant future."   
   "My independent laboratory is fortunate to be part of the Lurie Cancer   
   Center at the Feinberg School of Medicine at Northwestern University,   
   which is very supportive of translational research. We hope that this   
   environment will facilitate the initiation of a clinical trial based on   
   these findings," says Eichner.   
      
   Other authors include Stephanie D. Curtis, Sonja N. Brun, Joshua   
   T. Baumgart, Elijah Trefts, Debbie S. Ross, and Tammy J. Rymoff of Salk;   
   and Caroline K.   
      
   McGuire and Irena Gushterova of Northwestern University.   
      
   The work was supported by the National Institutes of Health (R35CA220538,   
   P01CA120964, K22CA251636, 5T32CA009370, 5F32CA206400, CCSG P30CA014195,   
   and CCSG P30CA23100), Leona M. and Harry B. Helmsley Charitable Trust   
   (#2012-PG- MED002), American Cancer Society (PF-15-037-01-DMC), and   
   Chapman Foundation.   
      
       * RELATED_TOPICS   
             o Health_&_Medicine   
                   # Lung_Cancer # Cancer # Brain_Tumor # Breast_Cancer   
                   # Lung_Disease # Colon_Cancer # Pancreatic_Cancer #   
                   Ovarian_Cancer   
       * RELATED_TERMS   
             o Lung_cancer o Esophageal_cancer o Deep_brain_stimulation o   
             Pharmaceutical_company o Stomach_cancer o Cancer o Emphysema   
             o Hypoallergenic   
      
   ==========================================================================   
   Story Source: Materials provided by Salk_Institute. Note: Content may   
   be edited for style and length.   
      
      
   ==========================================================================   
   Journal Reference:   
      1. Lillian J. Eichner, Stephanie D. Curtis, Sonja N. Brun, Caroline K.   
      
         McGuire, Irena Gushterova, Joshua T. Baumgart, Elijah Trefts,   
         Debbie S.   
      
         Ross, Tammy J. Rymoff, Reuben J. Shaw. HDAC3 is critical in   
         tumor development and therapeutic resistance in Kras -mutant   
         non-small cell lung cancer. Science Advances, 2023; 9 (11) DOI:   
         10.1126/sciadv.add3243   
   ==========================================================================   
      
   Link to news story:   
   https://www.sciencedaily.com/releases/2023/03/230317184940.htm   
      
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