Brain cancer is one of the most aggressive and life-threatening diseases, with glioblastoma (GBM) being the most common and deadliest type. Patients often experience debilitating symptoms, including headaches, seizures, memory loss, and personality changes, all of which drastically reduce quality of life. Despite progress in surgery, radiotherapy, and chemotherapy, survival rates remain poor, highlighting the urgent need for more effective and targeted treatment strategies.
To address this gap, a team of researchers led by Professor Ajaikumar B. Kunnumakkara from the Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, India, and Assistant Professor Alan Prem Kumar from the Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, conducted a comprehensive review of a promising but underutilized class of molecular targets: nuclear receptors (NRs). Their findings were published in the Chinese Medical Journal , offering a detailed analysis of how these ligand-activated transcription factors influence brain cancer progression and therapy resistance.
"NRs regulate diverse cellular processes, and their altered signaling in brain cancer presents both challenges and opportunities for targeted therapy," says Prof. Kunnumakkara, These receptors act as on-off switches for genes that control metabolism, immune response, and cell survival. Dysregulation of NRs contributes to cancer hallmarks such as uncontrolled cell growth, invasion, metastasis, and resistance to treatment. The review also outlines how NRs interact with critical signaling pathways—such as PI3K/Akt, NF-κB, EGFR, and Wnt/β-catenin—that drive tumor aggressiveness.
The study systematically evaluates the role of multiple nuclear receptors in brain cancers. These include androgen receptors (ARs), estrogen receptors (ERs), glucocorticoid receptors (GRs), liver X receptors (LXRs), peroxisome proliferator-activated receptors (PPARs), and orphan receptors such as TLX. The authors detail how modulating these receptors with selective agonists or antagonists may offer new avenues for therapy.
Among these, ARs stand out for promoting tumor survival and resistance to treatment. Blocking ARs using drugs like enzalutamide has shown promise in reducing tumor growth and sensitizing GBM cells to radiation. ERs, particularly the ERβ subtype, have dual roles—either promoting or inhibiting tumor growth depending on the context. Drugs like tamoxifen, a selective estrogen receptor modulator, have been found to suppress GBM proliferation and improve responses to standard treatments such as temozolomide.
Although GRs are often used clinically to manage brain swelling, they may also promote tumor survival. In such cases, blocking GR activity with agents like mifepristone could provide therapeutic benefit. Activation of LXRs has shown tumor-shrinking effects in animal models, while PPARγ agonists may reduce tumor growth and enhance cancer cell death through metabolic reprogramming and anti-inflammatory effects.
Particularly noteworthy is the role of orphan receptors such as TLX and the NR4A family. These receptors are often overexpressed in gliomas and help maintain cancer stem cells, which are thought to contribute to recurrence and treatment resistance. "Orphan nuclear receptors like TLX represent especially promising targets because of their central role in glioma stemness and immune evasion," says Prof. Kumar.
In addition to their therapeutic potential, nuclear receptors could also serve as biomarkers to guide precision medicine approaches. Since NR expression varies significantly across patients and tumor types, profiling these receptors could help identify which patients are most likely to benefit from NR-targeted therapies. The review also highlights the potential of combining NR-modulating drugs with existing treatments—such as chemotherapy, radiotherapy, and immunotherapy—to achieve synergistic effects.
Despite their promise, several challenges remain. One of the major hurdles in brain cancer treatment is the blood–brain barrier, which limits drug delivery to the tumor site. The authors emphasize the importance of developing delivery systems that can effectively transport NR-targeted agents into the brain. Furthermore, large-scale preclinical studies and carefully designed clinical trials are needed to assess the safety and effectiveness of these strategies.
"Nuclear receptors represent an underexplored yet promising class of targets with significant potential for transforming the prevention and treatment of brain cancers," concludes Prof. Kunnumakkara.
This review provides a timely roadmap for future research and drug development focused on nuclear receptors in brain cancer. By targeting the molecular switches that drive tumor survival and growth, researchers may unlock new possibilities for combating one of the world's most lethal malignancies.
