medwireNews: Metabolic biomarkers that are differentially expressed in treated and untreated retinoblastoma (Rb) tumors have been linked to histopathology high-risk factors (HRFs) and may have prognostic significance, research indicates.
“Findings from this study highlight the importance of metabolic marker profiling in the management of retinoblastoma,” write the authors in the British Journal of Ophthalmology.
Seema Kashyap, from the All India Institute of Medical Sciences in New Delhi, and colleagues analyzed the expression of glucose transporter (GLUT)-1, pyruvate dehydrogenase kinase (PDK)-1, and peroxisome proliferator-activated receptor gamma coactivator (PGC)1α in enucleated Rb samples from 81 children that were collected between December 2020 and December 2022.
Each marker is linked to cellular adaptation within the tumor microenvironment under hypoxic conditions, and each is directly or indirectly regulated by hypoxia-inducible factor (HIF)-1α.
The study participants, aged 2 months to 8 years, were divided into two groups: 53 children (aged 56.6% boys) underwent primary enucleation (primary group), while 28 (78.6% boys) received chemotherapy or radiotherapy prior to surgery (chemoreduced group). Follow-up was between 6 and 42 months, during which nine patients died of disease-related causes – eight in the primary group and one in the chemoreduced group.
All three metabolic markers were more highly expressed in the primary group than the chemoreduced group.
At the protein level, immunoexpression of GLUT-1, PDK-1, and PGC1α in the tumor cells of the primary group was seen in 77.4%, 60.4%, and 56.6% of patients, respectively. This compared with a corresponding 60.7%, 50.0%, and 35.7% of those in the chemoreduced group. Western blot findings supported these patterns.
Expression of the markers was also associated with HRFs. Specifically, in the primary group, all three metabolic markers were significantly associated with HIF-1α expression; GLUT-1 and PDK-1 were significantly associated with optic nerve head and retrolaminar invasion; GLUT-1 was significantly associated with anterior chamber invasion; PGC1α with optic nerve retrolaminar invasion; and PDK-1 with pathological staging.
In the chemoreduced group, significant associations with HRFs were only seen for PDK-1 expression, namely pathological staging, and optic nerve head and retrolaminar invasion.
Reverse transcriptase-polymerase chain reaction of primary tumor tissue showed gene expression upregulation relative to healthy tissue of 2.1-fold for GLUT-1, 2.3-fold for PDK-1, and 1.5-fold for PGC1α. By contrast, chemoreduced tumors demonstrated downregulation of GLUT-1 (1.8-fold), PDK-1 (1.4-fold), and PGC1α (1.2-fold) relative to healthy tissue.
The researchers note that “[i]dentifying pathways that get activated under hypoxia is crucial for developing new drug targets.” They found that 51% of tumors in the primary group and 46% of those in the chemoreduced group were classified as hypoxic due to high immunoexpression of HIF-1α status. And the majority (75%) of hypoxic tumors in the primary group had high expression of GLUT-1, PDK-1, and PGC1α, compared with a respective 61%, 41%, and 38% of those in the chemoreduced group.
Survival analyses revealed that only immunoexpression of the PDK-1 protein was significantly associated with poorer overall survival (OS). Kaplan–Meier analysis showed a 75.9% OS for patients expressing high levels of PDK-1, compared with rates of 86.3% for those expressing high levels of GLUT-1 and 82.6% for those expressing high levels of PGC1α.
The authors acknowledge that the study included a predominance of poorly differentiated tumors (81.1–89.3%). Nonetheless, they conclude that “this is the first of its kind study predicting a relevant role of the metabolic markers in primary and chemoreduced Rb with prognostic significance.”
They suggest that metabolic profiling may aid future risk stratification and “opens avenues for further exploration of metabolic markers as potential therapeutic targets in Rb, particularly in addressing chemoresistant tumours.”
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