A window-of-opportunity trial reveals mechanisms of response and resistance to navtemadlin in patients with recurrent glioblastoma
Recommended Citation
Rendo V, Lee EQ, Bossi C, Khuu N, Rudek MA, Pal S, Azazmeh N, Rashid R, Lin JR, Cusick M, Reynolds ARN, Fassinou ACR, Ayoub G, Malinowski S, Lapinskas E, Pisano W, Jeang J, Stopka SA, Regan MS, Spetz J, Desai A, Lieberman F, Palanichamy K, Fisher JD, Pelton K, Huang RY, Sarosiek KA, Nabors LB, Holdhoff M, Danda N, Strowd R, Desideri S, Walbert T, Ye X, Chakravarti A, Sorger PK, Santagata S, Agar NYR, Grossman SA, Alexander BM, Wen PY, Ligon KL, and Beroukhim R. A window-of-opportunity trial reveals mechanisms of response and resistance to navtemadlin in patients with recurrent glioblastoma. Sci Transl Med 2025; 17(786):eadn6274.
Document Type
Article
Publication Date
2-19-2025
Publication Title
Sci Transl Med
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.
Medical Subject Headings
Adult; Aged; Female; Humans; Male; Middle Aged; Brain Neoplasms; Cell Line, Tumor; Drug Resistance, Neoplasm; Glioblastoma; Neoplasm Recurrence, Local; Proto-Oncogene Proteins c-mdm2; Tumor Suppressor Protein p53
PubMed ID
39970230
Volume
17
Issue
786
First Page
6274
Last Page
6274
