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Published on: March 28, 2021
Personalized N-of-1 Combination Therapies for Advanced Gastrointestinal Stromal Tumors
Sangkyu Noh1,2,3, Ashwyn K Sharma1,2, Paul T Fanta2,4
1Division of Surgical Oncology, Department of Surgery, University of California San Diego, San Diego, CA.
Purpose:
Gastrointestinal stromal tumor (GIST) resistance to imatinib and other tyrosine kinase inhibitors poses an ongoing clinical challenge. We investigated molecularly matched combination therapies for treatment-refractory GIST, including drugs not previously combined in human studies.
Methods:
Patients of all ages with unresectable and/or metastatic GIST treated with combination therapies were included (February 13, 2015-December 31, 2022). These patients were discussed at molecular tumor board and enrolled in the prospective Investigation of Profile-Related Evidence Determining Individualized Cancer Therapy (I-PREDICT) study (ClinicalTrials.gov identifier: NCT02534675). Patient demographics, tumor next-generation sequencing (NGS), treatment responses, and survival outcomes were retrospectively analyzed.
Results:
Six (1.6%) patients met the inclusion criteria. The median age at diagnosis was 59.5 years with the majority (4/6) of patients being male. NGS revealed median of six deleterious genomic alterations per patient excluding variants of unknown significance. Five (5/6) patients had KIT-mutant GIST, and one patient had BRAFV600E-mutant GIST. Two thirds of tumors had CDKN2A/B loss. Patients received median of 1 (range, 1-3) customized combination therapy consisting of median of 2 (range, 2-3) drugs targeting median of 2 (range, 2-4) genomic alterations. One patient experienced a treatment-related grade ≥3 adverse event (hypertension). For all patients, the best response by RECIST v1.1 was stable disease (SD). Combination therapies led to SD ≥6 months (range, 6.2-11.3 months) in four (4/6) patients compared with none in the immediate previous single-agent targeted therapies (SD range, 1.5-5.4 months). Most (5/6) patients had at least 60% prolongation of their progression-free survival compared with their immediate previous single-agent targeted therapy.
Conclusion:
Our results demonstrate that a multitargeted, biomarker-matched combination approach can be safely administered to obtain disease control. Tailored combination therapies for advanced GIST with multiple genomic alterations warrant further investigation.
Insights
Combination therapies targeting multiple genomic alterations in advanced gastrointestinal stromal tumors (GIST) showed disease control. This biomarker-matched approach improved progression-free survival in treatment-refractory GIST patients.
Area of Science:
- Oncology
- Genomics
- Pharmacology
Background:
- Gastrointestinal stromal tumors (GIST) often develop resistance to single-agent tyrosine kinase inhibitors (TKIs).
- Treatment-refractory GIST presents a significant clinical challenge requiring novel therapeutic strategies.
- Identifying effective combination therapies is crucial for improving patient outcomes.
Purpose of the Study:
- To investigate the efficacy and safety of molecularly matched combination therapies for treatment-refractory GIST.
- To explore the use of novel drug combinations not previously studied in humans for GIST.
- To assess disease control and survival outcomes in patients receiving tailored combination treatments.
Main Methods:
- Retrospective analysis of patients with unresectable/metastatic GIST treated with combination therapies (2015-2022).
- Patients were enrolled in the I-PREDICT study (NCT02534675) after molecular tumor board discussion.
- Tumor next-generation sequencing (NGS) guided the selection of combination therapies targeting identified genomic alterations.
Main Results:
- Six patients received customized combination therapies targeting multiple genomic alterations.
- Four out of six patients achieved stable disease (SD) for ≥6 months, a significant improvement over previous single-agent therapies.
- Most patients (5/6) experienced at least a 60% prolongation in progression-free survival compared to prior treatments.
Conclusions:
- Multitargeted, biomarker-matched combination therapy can be safely administered to achieve disease control in advanced GIST.
- Tailored combination therapies demonstrate potential for managing GIST with multiple genomic alterations.
- Further investigation of these individualized combination approaches for advanced GIST is warranted.
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