Metabolic Reprogramming: A Promising Approach to Tackling Therapeutic Resistance in Glioblastoma

Targeting pyrimidine synthesis inhibits GSC self-renewal and tumorigenesis

Inhibiting two critical steps in the metabolism of glioblastoma stem cells (GSCs) attenuates GSC self-renewal and reduces tumorigenesis, finds a new study presented at the 2019 annual meeting of the American Society for Radiation Oncology (ASTRO).

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“Determining how to target glioma stem cells effectively has been a major challenge in treating glioblastoma [GBM],” says Kailin Yang, MD, PhD, a radiation oncology resident at Cleveland Clinic Cancer Center who presented the abstract under the supervision of Jeremy Rich, MD, MHS, of the University of California at San Diego. “Our previous studies suggested that pyrimidine synthesis is associated with clinical outcome in glioblastoma patients, and thus is a productive place to focus our energy.”

The current study demonstrates that simultaneous targeting of two vital enzymes in the pyrimidine synthetic pathway inhibits self-renewal and tumorigenesis of GSCs.

The first enzyme is rate-limiting carbamoyl-phosphate synthetase 2, aspartate transcarbamyolase, dihydroorotase (CAD). EGFR or PTEN driver mutations demonstrated distinct CAD phosphorylation patterns. The second, dihydroorotate dehydrogenase (DHODH), catalyzes the subsequent step in pyrimidine synthesis after CAD. Targeting both enzymes with clinically approved inhibitors produced sustained inhibition of the survival, self-renewal and in vivo tumor initiation of GSCs in patient-derived xenografts, when compared with single treatments.

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Gutting GBM resistance

GBM, the most lethal primary brain tumor, has long frustrated researchers and devastated patients with its ability to acquire resistance to standard treatments. Resistance is driven by GSCs, an especially aggressive type of cancer cell that can self-renew, spread and resist conventional treatments. GSCs reprogram glucose metabolism by commandeering glucose uptake to survive. GSCs rely on pyrimidine to continue replicating.

Cleveland Clinic is engaged in a full-court press to defeat GBM, with one of the largest programs of active glioblastoma clinical trials in the country. The Cleveland Clinic Center of Excellence in Brain Tumor Research and Therapeutic Development brings together bench research and clinical expertise to advance therapeutic options for patients. Cleveland Clinic Lerner Research Institute’s Center for Cancer Stem Cell Research, directed by abstract coauthor Shideng Bao, PhD, is focused on understanding the role of cancer stem cells in promoting tumor growth, malignant progression, therapeutic resistance and tumor recurrence in many types of cancer.

The current study combined the Center for Excellence’s expertise with that of Cleveland Clinic Cancer Center’s Department of Radiation Oncology to uncover a novel therapeutic approach to building precision treatment in GBM.

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Researchers used whole-genome enhancer analysis and metabolomic profiling to validate identified metabolic pathways in GSCs. Such metabolic aberration was necessary for GSC maintenance, and the combined targeting of pyrimidine synthesis and tumor-specific driver mutations using approved drugs improved the survival and inhibited tumor growth compared with single treatments in mouse models. Since GSCs mediate tumor recurrence through the intrinsic resistance to standard chemoradiation, such an approach may sensitize glioblastoma to radiation and chemotherapy.

An important step forward

While additional research is critical, these preclinical findings are highly promising. Since the therapies administered are already FDA-approved for use in humans for other diseases, clinical trials of this approach as a treatment option for glioblastoma may be considered in the future.

“The connection between driver mutations and metabolic reprogramming is critical in sensitizing glioblastoma stem cells to conventional therapies such as radiation and chemotherapy,” says Dr. Yang. “Now that we understand how this approach works, the next step is to bring our study results into clinical trial, particularly testing the combination of inhibitors in a mutation-specific manner.”