Trending With Impact: Interrelated Oncogenic Pathways in Osteosarcoma

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Osteosarcoma (OS) is a fairly uncommon type of bone cancer that primarily develops in the long bones found in the arms and legs. While most osteosarcomas occur in patients between the ages of 10 and 30 years old, half of all osteosarcomas develop in children. Osteosarcoma is a genetically diverse cancer that lacks a consistent targetable mutation—saddling patients and researchers with major challenges when it comes to treatment options.

“Despite their high mutation burden, OS has proven surprisingly recalcitrant to the numerous immunotherapies that have revolutionized the treatment of other mutation-high cancers.”

The lack of consistent therapeutic targets in osteosarcoma has driven researchers to investigate the role of oncogenic signaling pathways in this disease. In a trending research paper published in Oncotarget on March 9, 2022, researchers from The University of Texas’ MD Anderson Cancer Center and Rice University evaluated osteosarcoma and two cancer-related signaling pathways: IGF-1/mTOR and YAP/TAZ (the Hippo Pathway). Their paper was entitled, “Correlation of nuclear pIGF-1R/IGF-1R and YAP/TAZ in a tissue microarray with outcomes in osteosarcoma patients.”

The Study

Oncogenic signaling pathways are often deregulated in cancer, which means that these pathways can potentially be targeted and exploited for therapeutic purposes. The insulin/insulin-like growth factor (IGF) signaling pathway to mTOR (IGF-I/mTOR) is a well-known oncogenic pathway that is frequently deregulated in solid tumors. The YAP/TAZ (Hippo pathway) plays an important role in organ size control and tissue regeneration.

In this study, the researchers retrospectively evaluated the correlation between nuclear pIGF-IR/IGF-IR, YAP/TAZ expression and outcomes in patients with osteosarcoma. Effectors and pathways were investigated among 37 post-treatment human osteosarcoma tumor specimens. The specimens were analyzed using tissue microarray (TMA), confocal imaging, quantitative image analysis, nuclear staining, the Cox proportional hazards model, and Kaplan–Meier analysis. Researchers who evaluated images of de-identified patient samples were blind to patient demographics and outcomes until after analysis was complete.

The Results

Their results demonstrated that nuclear IGF-1R and YAP/TAZ are interrelated in human osteosarcoma. Their findings also showed that high nuclear-phosphorylated IGF-1R and low YAP nuclear-to-cytoplasmic (N:C) ratio are potentially negative prognostic indicators of overall survival in osteosarcoma patients.

“While sole targeting of the IGF/PI3K/mTOR cascade has had limited success in early phase osteosarcoma trials, our study suggests that nuclear pIGF-1R might serve as a prognostic biomarker to identify osteosarcoma patients that have an especially poor prognosis.”

Findings from this study may have revealed a clinically important relationship between these pathways in osteosarcoma. Osteosarcoma is currently treated with a combination of surgery, chemotherapy and radiation therapy. However, this study suggests that therapies targeting the IGF-I/mTOR and/or YAP/TAZ pathways may improve the diagnosis and treatment of patients with osteosarcoma.

Conclusion

The researchers were forthcoming about limitations in their study. They recognized that the sample size was relatively small and the study design only involved post-treatment specimens and retrospective analysis. However, the authors note that the likely crosstalk observed between the YAP/TAZ and IGF/PI3K/mTOR pathways is an important finding. They hypothesize that a dual-targeted pathway approach may have synergistic antineoplastic activity.

“Given the rarity of osteosarcoma, clinical validation of our results will almost certainly require the active participation of national and international high-volume cancer centers.”

Click here to read the full research paper published by Oncotarget.

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