2. Academic Validation
  3. A window-of-opportunity trial reveals mechanisms of response and resistance to navtemadlin in patients with recurrent glioblastoma

A window-of-opportunity trial reveals mechanisms of response and resistance to navtemadlin in patients with recurrent glioblastoma

  • Sci Transl Med. 2025 Feb 19;17(786):eadn6274. doi: 10.1126/scitranslmed.adn6274.
Veronica Rendo 1 2 3 4 5,  Eudocia Q Lee 1 3 6,  Connor Bossi 7,  Nicholas Khuu 1 2 4,  Michelle A Rudek 8,  Sangita Pal 1 2 3 4,  Narmen Azazmeh 1 2 3 4,  Rumana Rashid 9 10,  Jia-Ren Lin 11,  Margaret Cusick 7,  Abigail R N Reynolds 1 2 4,  Auriole C R Fassinou 1 2 4,  Georges Ayoub 7,  Seth Malinowski 7,  Emily Lapinskas 7,  William Pisano 7,  John Jeang 1 2 4,  Sylwia A Stopka 12,  Michael S Regan 13,  Johan Spetz 14,  Arati Desai 15,  Frank Lieberman 16,  Kamalakannan Palanichamy 17,  Joy D Fisher 8,  Kristine Pelton 7,  Raymond Y Huang 12,  Kristopher A Sarosiek 1 18,  Louis B Nabors 19,  Matthias Holdhoff 8,  Neeraja Danda 20,  Roy Strowd 17,  Serena Desideri 8,  Tobias Walbert 21,  Xiaobu Ye 8,  Arnab Chakravarti 22,  Peter K Sorger 11,  Sandro Santagata 9 11,  Nathalie Y R Agar 2 12 13,  Stuart A Grossman 8,  Brian M Alexander 23,  Patrick Y Wen 1 3 6,  Keith L Ligon 3 4 7 9 24,  Rameen Beroukhim 1 2 3 4
Affiliations

Affiliations

  • 1 Department of Medical Oncology and Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 2 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 3 Harvard Medical School, Boston, MA 02115, USA.
  • 4 Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • 5 Department of Immunology, Genetics and Pathology, Uppsala University, SE-751 05 Uppsala, Sweden.
  • 6 Department of Neurology, Brigham and Women's Hospital, Boston, MA 02115, USA.
  • 7 Department of Pathology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 8 Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
  • 9 Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
  • 10 Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, PA 15206-3701, USA.
  • 11 Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
  • 12 Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • 13 Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • 14 Department of Medical Radiation Sciences, Sahlgrenska Cancer Center, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden.
  • 15 Division of Hematology and Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 16 Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
  • 17 Department of Neurology, Wake Forest University, Winston-Salem, NC 27157, USA.
  • 18 John B. Little Center for Radiation Sciences, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA.
  • 19 Department of Neurology, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
  • 20 Division of Hematology, Departments of Medicine and Oncology, Montefiore Medical Center, New York, NY 10467, USA.
  • 21 Department of Neurology and Neurosurgery Henry Ford Health, Department of Neurology, Wayne State University and Michigan State University, Detroit, MI 48201, USA.
  • 22 Department of Radiation Oncology, Ohio State University College of Medicine, Columbus, OH 43210-1228, USA.
  • 23 Department of Radiation Oncology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • 24 Department of Pathology, Boston Children's Hospital, Boston, MA 02115, USA.
PMID: 39970230 DOI: 10.1126/scitranslmed.adn6274
Abstract

Inhibitors of murine double minute homolog 2 (MDM2) represent a promising therapeutic approach for the treatment of TP53 wild-type glioblastomas (GBMs), reactivating p53 signaling to induce Cancer cell death. We conducted a surgical window-of-opportunity trial (NCT03107780) of the MDM2 Inhibitor navtemadlin (KRT-232) in 21 patients with TP53 wild-type recurrent GBM to determine achievable drug concentrations within tumor tissues and biological mechanisms of response and resistance. Participants received navtemadlin at 120 mg (n = 10) or 240 mg (n = 11) for 2 days before surgical resection and after surgery until progression or unacceptable toxicity. Both 120 and 240 mg daily dosing achieved a pharmacodynamic impact, but median progression-free survival was 3.1 months. DNA Sequencing of three recurrent tumors revealed an absence of TP53-inactivating mutations, indicating alternative mechanisms of resistance. To understand the mechanisms of response and resistance associated with navtemadlin, we conducted functional and spatial analyses of human tissue and patient-derived GBM neurosphere models. Navtemadlin induced partial tumor cell death as monotherapy, and combination with temozolomide enhanced Apoptosis in GBM neurospheres while sparing normal bone marrow cells in vitro. We also observed up-regulation of oligodendrocyte differentiation genes with navtemadlin treatment and enrichment of oligodendrocyte transcription factor 2 (OLIG2)-positive cells at relapse, suggesting an unexplored mechanism of navtemadlin tolerance in GBM. Overall, these results indicated that clinically achievable doses of navtemadlin exert pharmacodynamic effects on GBM and suggest that combined treatment with temozolomide may be a route to more durable survival benefits.

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