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Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays
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Inhibition of the Phosphatidylinositol-3 Kinase Pathway Using Bimiralisib in Loss-of-Function NOTCH1-Mutant Head and
Faye M Johnson1,2, Filip Janku3, Mohamed A Gouda4
1Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
The Oncologist
|September 20, 2022
Summary
Bimiralisib showed promising results in patients with NOTCH1-mutant head and neck squamous cell carcinoma (HNSCC), with detectable mutations in circulating tumor DNA (ctDNA). Further trials are needed to confirm these findings in a larger cohort.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- PI3K/mTOR inhibition induces apoptosis in NOTCH1-mutant head and neck squamous cell carcinoma (HNSCC).
- Bimiralisib is a PI3K/mTOR inhibitor investigated for HNSCC treatment.
Purpose of the Study:
- To evaluate the efficacy of bimiralisib in patients with recurrent/metastatic NOTCH1-mutant HNSCC.
- To assess the detectability of NOTCH1 mutations in circulating tumor DNA (ctDNA).
- To quantify activated NOTCH1 protein levels via cleaved NOTCH1 (cl-NOTCH) immunohistochemistry.
Main Methods:
- Eight patients with advanced NOTCH1-mutant HNSCC received bimiralisib.
- Circulating tumor DNA (ctDNA) was analyzed for NOTCH1 mutations.
- Immunohistochemistry was used to assess cleaved NOTCH1 (cl-NOTCH) protein expression.
Main Results:
- Six of eight patients were evaluable for response, with an objective response rate of 17%.
- Median progression-free survival was 5 months, and median overall survival was 7 months.
- NOTCH1 mutations were detected in 83.3% of ctDNA samples; tumor cl-NOTCH1 staining was negative.
Conclusions:
- Bimiralisib demonstrated outcomes superior to historical standards of care in this small cohort.
- The detection of NOTCH1 mutations in ctDNA supports its utility in future clinical studies.
- Further validation in larger trials is warranted to confirm these preliminary findings.
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