Abstract
SUMMARYOsteosarcoma is the most common pediatric and adult primary malignant bone cancer. Curative regimens target the folate pathway, downstream of serine metabolism, with high-dose methotrexate. Here, the rate-limiting enzyme in the biosynthesis of serine from glucose, 3-phosphoglycerate dehydrogenase (PHGDH), is examined, and an inverse correlation between PHGDH expression and relapse-free and overall survival in osteosarcoma patients is found. PHGDH inhibition in osteosarcoma cell lines attenuated cellular proliferation without causing cell death, prompting a robust metabolic analysis to characterize pro-survival compensation. Using metabolomic and lipidomic profiling, cellular response to PHGDH inhibition is identified as accumulation of unsaturated lipids, branched chain amino acids, and methionine cycle intermediates, leading to activation of pro-survival mammalian target of rapamycin complex 1 (mTORC1) signaling. Increased mTORC1 activation sensitizes cells to mTORC1 pathway inhibition, resulting in significant, synergistic cell death in vitro and in vivo. Identifying a therapeutic combination for PHGDH-high cancers offers preclinical justification for a dual metabolism-based combination therapy for osteosarcoma.
Highlights
Osteosarcoma is the most common primary malignant bone tumor in both children and adults, accounting for approximately 4% of all childhood cancers and 56% of pediatric malignant bone tumors (Geller and Gorlick, 2010)
This study demonstrates that high levels of phosphoglycerate dehydrogenase (PHGDH) correlated with poor overall relapse-free and poor overall survival outcomes in patients with osteosarcoma
Folate cycle inhibition results in cytostasis in vitro To test the effect of methotrexate, the osteosarcoma cell line NOS1 was cultured in the presence of increasing doses of methotrexate for up to 96 h, and cellular proliferation rate was measured using the IncuCyte ZOOM live cell analysis system (Figure 1A)
Summary
Osteosarcoma is the most common primary malignant bone tumor in both children and adults, accounting for approximately 4% of all childhood cancers and 56% of pediatric malignant bone tumors (Geller and Gorlick, 2010). High-dose methotrexate has been a key component of standard-of-care treatment for osteosarcoma since the 1970s, based on small cohort clinical trials that measured levels of tumor necrosis at the time of surgery (Grem et al, 1988; Rosen et al, 1974, 1979) These trials showed that most patients demonstrated little viable tumor tissue with methotrexate treatment, it was noted that high levels of toxicity were associated with this treatment (Li et al, 2019; Perez et al, 1978; Rosen et al, 1974, 1979). Identifying lesstoxic therapies for osteosarcoma is a goal of the field (Shaikh et al, 2016)
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