New drug combination works together to reduce lung tumors in mice – Zoo House News

New drug combination works together to reduce lung tumors in mice – Zoo House News

  • Science
  • March 18, 2023
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Cancer treatments have long been moving toward personalization — finding the right drugs to work for a patient’s unique tumor based on specific genetic and molecular patterns. Many of these targeted therapies are highly effective but are not 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 researcher Lillian Eichner, now an assistant professor at Northwestern University, found that the FDA-approved trametinib and entinostat (currently in clinical trials) are given together able to produce fewer and fewer tumors in mice with LKB1-mutant NSCLC.

The results were published in Science Advances on March 17, 2023.

“In cases of non-small cell lung cancer with the LKB1 mutation, standard chemotherapy and immunotherapy are not effective,” said Shaw, senior and co-corresponding author of the study and director of Salk’s Cancer Center. “Our results show that there is an opportunity to address these cases with drugs that are FDA approved or already in clinical trials, such that this work could easily be applied to a human clinical trial.”

About 20 percent of all NSCLCs have the LKB1 gene mutation, meaning there are currently no effective targeted therapies on the market for patients with this cancer. To develop a therapy that could target the LKB1 mutation, 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 humans) for certain forms of lymphoma, but data are lacking on their efficacy in solid tumors or whether tumors with specific genetic alterations might have increased therapeutic potential.

Based on previous findings linking the LKB1 gene to three other HDACs that all depend on HDAC3, the team first performed a genetic analysis of HDAC3 in mouse models of NSCLC and discovered an unexpectedly crucial role for HDAC3 in several models. Having established that HDAC3 is critical for the growth of the difficult-to-treat LKB1-mutated tumors, the researchers next investigated whether pharmacological blocking of HDAC3 could produce a similarly potent effect.

The team was curious to test two drugs, entinostat (an HDAC inhibitor in clinical trials known to target HDAC1 and HDAC3) and the FDA-approved trametinib (an inhibitor of another class of cancer-related enzymes). . Tumors often quickly become resistant to trametinib, but concomitant treatment with a drug that blocks a protein downstream of HDAC3 helps reduce this resistance. Because this protein relies on HDAC3, the researchers believed that a drug that targets HDAC3 – like entinostat – would also help manage trametinib resistance.

After treating mice with LKB1-mutated lung cancer with different 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 . In addition, the team confirmed that entinostat is a viable treatment option in cases where a tumor is resistant to trametinib.

“We thought that the entire HDAC class of enzymes 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-author Eichner. “We have now shown that HDAC3 is essential in lung cancer and that it represents a drug vulnerability to therapeutic resistance.”

The results could 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 laboratory has dedicated years to this project and has taken small and significant strides toward these results,” said Shaw, holder of the William R. Brody Chair. “This is truly a success story of how fundamental discovery science may lead to therapeutic solutions in the not too distant future.”

“My independent lab 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 results,” says Eicher.

Additional authors include Stephanie D. Curtis, Sonja N. Brun, Joshua T. Baumgart, Elijah Trefts, Debbie S. Ross, and Tammy J. Rymoff von 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 the Chapman Foundation.

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