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Cerebrospinal Fluid Penetration and Combination Therapy of Entrectinib for Disseminated ROS1/NTRK-Fusion Positive
Lisa Mayr1,2,3, Armin S Guntner4, Sibylle Madlener1,3
1Department of Pediatrics and Adolescent Medicine and Comprehensive Center for Pediatrics, Medical University of Vienna, 1090 Vienna, Austria.
Abstract:
Targeting oncogenic fusion-genes in pediatric high-grade gliomas (pHGG) with entrectinib has emerged as a highly promising therapeutic approach. Despite ongoing clinical studies, to date, no reports on the treatment of cerebrospinal fluid (CSF) disseminated fusion-positive pHGG exist. Moreover, clinically important information of combination with other treatment modalities such as intrathecal therapy, radiotherapy and other targeted agents is missing. We report on our clinical experience of entrectinib therapy in two CSF disseminated ROS1/NTRK-fusion-positive pHGG cases. Combination of entrectinib with radiotherapy or intrathecal chemotherapy appears to be safe and has the potential to act synergistically with entrectinib treatment. In addition, we demonstrate CSF penetrance of entrectinib for the first time in patient samples suggesting target engagement even upon CSF dissemination. Moreover, in vitro analyses of two novel cell models derived from one case with NTRK-fusion revealed that combination therapy with either a MEK (trametinib) or a CDK4/6 (abemaciclib) inhibitor synergistically enhances entrectinib anticancer effects. In summary, our comprehensive study, including clinical experience, CSF penetrance and in vitro data on entrectinib therapy of NTRK/ROS1-fusion-positive pHGG, provides essential clinical and preclinical insights into the multimodal treatment of these highly aggressive tumors. Our data suggest that combined inhibition of NTRK/ROS1 and other therapeutic vulnerabilities enhances the antitumor effect, which should be followed-up in further preclinical and clinical studies.
Insights
Entrectinib shows promise for pediatric high-grade gliomas (pHGG) with ROS1/NTRK fusions, even with cerebrospinal fluid (CSF) spread. Combination therapies, including intrathecal treatments and targeted agents, appear safe and potentially synergistic, with demonstrated CSF penetrance.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Pediatric high-grade gliomas (pHGG) with oncogenic fusion genes are challenging to treat.
- Current treatments for cerebrospinal fluid (CSF) disseminated fusion-positive pHGG are limited.
- Information on combining entrectinib with other therapies for pHGG is scarce.
Purpose of the Study:
- To report clinical experience with entrectinib in CSF-disseminated fusion-positive pHGG.
- To investigate the safety and efficacy of combination therapies.
- To demonstrate entrectinib's CSF penetrance and target engagement in vivo.
- To explore synergistic effects of combination therapies in vitro.
Main Methods:
- Clinical case series of two patients with CSF-disseminated ROS1/NTRK-fusion-positive pHGG treated with entrectinib.
- Analysis of entrectinib levels in CSF samples.
- In vitro studies using novel cell models with NTRK-fusion.
- Combination therapy experiments with MEK and CDK4/6 inhibitors.
Main Results:
- Entrectinib treatment in combination with radiotherapy or intrathecal chemotherapy was safe and showed potential synergy.
- Entrectinib demonstrated CSF penetrance, indicating target engagement in disseminated disease.
- In vitro studies revealed synergistic anticancer effects when combining entrectinib with trametinib (MEK inhibitor) or abemaciclib (CDK4/6 inhibitor).
Conclusions:
- Entrectinib is a promising agent for ROS1/NTRK-fusion-positive pHGG, including CSF-disseminated cases.
- Combination therapies (radiotherapy, intrathecal chemotherapy, other targeted agents) are safe and potentially synergistic.
- Further preclinical and clinical studies are warranted to explore combined inhibition strategies for enhanced antitumor effects.
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