Study reveals activity of navtemadlin in glioblastoma, points to possible treatment improvements
- Date:
- February 19, 2025
- Source:
- Dana-Farber Cancer Institute
- Summary:
- Clinical research suggests that combining a novel agent called navtemadlin with DNA-damaging chemotherapy for the treatment of glioblastoma, a form of brain cancer, could increase efficacy. Navtemadlin is an MDM2 inhibitor that can help to kill cancer cells by boosting the activity of p53, a protein that controls cell growth and induces cell death in response to DNA damage. In lab experiments, the researchers found that navtemadlin was one of the best drugs at killing glioblastoma cells with intact, non-mutant p53.
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Clinical research by Dana-Farber scientists suggests that combining a novel agent called navtemadlin with DNA-damaging chemotherapy for the treatment of glioblastoma, a form of brain cancer, could increase efficacy. Navtemadlin is an MDM2 inhibitor that can help to kill cancer cells by boosting the activity of p53, a protein that controls cell growth and induces cell death in response to DNA damage. In lab experiments, the researchers found that navtemadlin was one of the best drugs at killing glioblastoma cells with intact, non-mutant p53.
In this clinical trial, patients received navtemadlin, followed by surgery to remove tumor tissue, enabling the researchers to see how well the drug penetrated the tumor and understand its effects on cancer cells. They found that navtemadlin reached effective concentrations in the tumor and activated the p53 pathway, but the tumors eventually relapsed. The team then used tissue samples from three relapses and other patients to create patient-derived tumor models. They tested a range of navtemadlin dosing and combinations on these tumor models and found that combining navtemadlin with other DNA-damaging chemotherapy, such as temozolomide, could increase the rates at which cancer cells die.
Glioblastoma is the most aggressive and most common malignant brain cancer in adults. It is currently treated with surgery, followed by radiation and chemotherapy. Prognosis is poor even with treatment. A challenge in conducting clinical trials in brain cancer is that it can be difficult to detect the cellular effects of new agents, as investigators are often limited to using imaging data and patient symptoms. This trial of navtemadlin sampled tumors on treatment, enabling the investigators to understand its effects in detail and conduct additional studies to optimize treatment strategies. This study suggests that a combination therapy strategy has the potential to increases the efficacy of navtemadlin and stave off resistance.
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Materials provided by Dana-Farber Cancer Institute. Note: Content may be edited for style and length.
Journal Reference:
- Veronica Rendo, Eudocia Q. Lee, Connor Bossi, Nicholas Khuu, Michelle A. Rudek, Sangita Pal, Narmen Azazmeh, Rumana Rashid, Jia-Ren Lin, Margaret Cusick, Abigail R. N. Reynolds, Auriole C. R. Fassinou, Georges Ayoub, Seth Malinowski, Emily Lapinskas, William Pisano, John Jeang, Sylwia A. Stopka, Michael S. Regan, Johan Spetz, Arati Desai, Frank Lieberman, Kamalakannan Palanichamy, Joy D. Fisher, Kristine Pelton, Raymond Y. Huang, Kristopher A. Sarosiek, Louis B. Nabors, Matthias Holdhoff, Neeraja Danda, Roy Strowd, Serena Desideri, Tobias Walbert, Xiaobu Ye, Arnab Chakravarti, Peter K. Sorger, Sandro Santagata, Nathalie Y. R. Agar, Stuart A. Grossman, Brian M. Alexander, Patrick Y. Wen, Keith L. Ligon, Rameen Beroukhim. A window-of-opportunity trial reveals mechanisms of response and resistance to navtemadlin in patients with recurrent glioblastoma. Science Translational Medicine, 2025; 17 (786) DOI: 10.1126/scitranslmed.adn6274
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