Abstract
Purpose: We recently reported on clinical trials for patients with recurrent glioblastoma where low-intensity pulsed ultrasound and microbubbles (LIPU/MB) improved paclitaxel or carboplatin delivery into the brain. Here, we report variable local tumor control with paclitaxel at the maximal/target dose in our phase I trial (NCT04528680). To address this, we investigated the combination of paclitaxel with carboplatin in preclinical glioma models. Experimental Design: We performed MRI-based analysis to evaluate disease control in patients from our trial. We studied the cytotoxicity of paclitaxel and carboplatin against 11 human glioma lines as monotherapy and in combination at concentrations derived from human intraoperative studies. Synergy was assessed with the Loewe model and the survival benefit evaluated in two xenografts. We examined the effects on cell cycle progression, DNA damage, and apoptosis. Results: Patients treated with paclitaxel and LIPU/MB exhibited variable local tumor control, which correlated with overall survival. We observed limited cross-resistance to paclitaxel and carboplatin in glioma lines, with almost a third of them being exclusively susceptible to one drug. This combination led to susceptibility of 81% of lines and synergy in 55% of them. The combination proved more efficacious in two intracranial xenografts when administered with LIPU/MB, leading to complementary effects on cell cycle arrest. Conclusions: Combining paclitaxel and carboplatin in gliomas may be more efficacious than monotherapy, as in other cancers, due to synergy and independent susceptibility to each drug. These results form the basis for an ongoing phase II trial (NCT04528680) where we investigate this combination with LIPU/MB.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1619-1629 |
| Number of pages | 11 |
| Journal | Clinical Cancer Research |
| Volume | 30 |
| Issue number | 8 |
| DOIs | |
| State | Published - Apr 15 2024 |
Funding
This work was funded by 1R01CA245969-01A1 (A.M. Sonabend and R. Stupp), P50CA221747 SPORE for Translational Approaches to Brain Cancer (A.M. Sonabend and R. Stupp), funding support from the Lou and Jean Malnati Brain Tumor Institute (A.M. Sonabend), and philanthropic support from the Moceri Family Foundation and the Panattoni family. Imaging work was performed at the Northwestern University Center for Advanced Microscopy generously supported by NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center. Histology services were provided by the North-western University Research Histology and Phenotyping Laboratory which is supported by NCI P30-CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center. Flow cytometry was performed at Northwestern University Robert H Lurie Comprehensive Cancer Center Flow Cytometry Core Facility supported by Cancer Center Support Grant (NCI CA060553). G.Bouchoux reports a patent for US2023149743 issued, a patent for WO2023126430 issued, a patent for US2022110607 issued, a patent for US2020138580 issued, and a patent for US2020139159 issued; in addition, G. Bouchoux is a paid employee of Carthera. K.B. Burdett reports grants from NCI during the conduct of the study; in addition, K.B. Burdett has a patent for Disc-ID-23-05-10-002 issued to INVO North-western University. H. Zhang reports grants from NIH during the conduct of the study. M. Canney reports other support from Carthera during the conduct of the study; in addition, M. Canney has a patent for US8977361B2 issued to Carthera and a patent for US11738214B2 issued to Carthera. R. Stupp reports grants, personal fees, and nonfinancial support from Carthera and other support from Bristol Myers Squibb (BMS) during the conduct of the study. A.M. Sonabend reports grants, personal fees, and non-financial support from Carthera; personal fees from EnClear Therapies; and non-financial support from BMS during the conduct of the study. In addition, A.M. Sonabend has a patent filed by Northwestern University issued. No disclosures were reported by the other authors.
ASJC Scopus subject areas
- General Medicine
