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Targeting glutamine metabolism improves sarcoma response to radiation therapy in vivo
Rutulkumar Patel1, Daniel E Cooper2, Kushal T Kadakia2
1Department of Radiation Oncology, Baylor College of Medicine, 7200 Cambridge St, Houston, TX, 77030, USA.
Abstract:
Diverse tumor metabolic phenotypes are influenced by the environment and genetic lesions. Whether these phenotypes extend to rhabdomyosarcoma (RMS) and how they might be leveraged to design new therapeutic approaches remains an open question. Thus, we utilized a Pax7Cre-ER-T2/+; NrasLSL-G12D/+; p53fl/fl (P7NP) murine model of sarcoma with mutations that most frequently occur in human embryonal RMS. To study metabolism, we infuse 13C-labeled glucose or glutamine into mice with sarcomas and show that sarcomas consume more glucose and glutamine than healthy muscle tissue. However, we reveal a marked shift from glucose consumption to glutamine metabolism after radiation therapy (RT). In addition, we show that inhibiting glutamine, either through genetic deletion of glutaminase (Gls1) or through pharmacological inhibition of glutaminase, leads to significant radiosensitization in vivo. This causes a significant increase in overall survival for mice with Gls1-deficient compared to Gls1-proficient sarcomas. Finally, Gls1-deficient sarcomas post-RT elevate levels of proteins involved in natural killer cell and interferon alpha/gamma responses, suggesting a possible role of innate immunity in the radiosensitization of Gls1-deficient sarcomas. Thus, our results indicate that glutamine contributes to radiation response in a mouse model of RMS.
Insights
In rhabdomyosarcoma (RMS), inhibiting glutamine metabolism enhances radiation therapy effectiveness. This metabolic shift improves survival and involves innate immunity responses in a preclinical model.
Area of Science:
- Oncology
- Cancer Metabolism
- Molecular Biology
Background:
- Tumor metabolic phenotypes are influenced by genetic and environmental factors.
- Rhabdomyosarcoma (RMS) metabolic phenotypes and therapeutic potential remain under investigation.
- A specific murine sarcoma model (P7NP) with common human embryonal RMS mutations was used.
Purpose of the Study:
- To investigate metabolic phenotypes in a preclinical RMS model.
- To determine if targeting glutamine metabolism can enhance radiation therapy (RT) response.
- To explore the role of innate immunity in radiosensitization.
Main Methods:
- Utilized a Pax7Cre-ER-T2/+; NrasLSL-G12D/+; p53fl/fl (P7NP) murine sarcoma model.
- Administered 13C-labeled glucose or glutamine to assess tumor metabolism.
- Investigated the effects of glutaminase (Gls1) inhibition (genetic and pharmacological) on RT response and survival.
Main Results:
- Sarcomas consumed more glucose and glutamine than healthy muscle tissue.
- Radiation therapy induced a metabolic shift from glucose to glutamine utilization.
- Inhibiting glutaminase (Gls1) significantly radiosensitized sarcomas and increased overall survival.
- Gls1-deficient sarcomas post-RT showed elevated innate immune response markers (NK cells, IFN-α/γ).
Conclusions:
- Glutamine metabolism plays a crucial role in the response to radiation therapy in RMS.
- Targeting glutamine metabolism represents a potential therapeutic strategy to enhance RT efficacy in RMS.
- Innate immune responses may contribute to the radiosensitizing effects of Gls1 inhibition in RMS.
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