A new study from researchers at The University of Texas MD Anderson Cancer Centre has uncovered how one of the most common genetic alterations in glioma rewires the cancer cell genome to fuel tumour progression, suggesting a potential new therapeutic strategy for patients with ATRX-mutant gliomas.

The findings show that mutations in the ATRX gene fundamentally reprogram the epigenome and change the three-dimensional structure of chromatin, creating new interactions that activate developmental programmes which tumours exploit to grow and spread.

Targeting one of the genes downstream of ATRX in preclinical models – particularly in the HOXA family – slowed cancer progression.

The study, published in Nucleic Acids Research, was co-led by Jason Huse, M.D., Ph.D., professor of Anatomic Pathology, and Kunal Rai, Ph.D., professor of Genomic Medicine, with major contributions from Prit Benny Malgulwar, Ph.D., instructor of Translational Molecular Pathology, Anand Singh, Ph.D., senior research scientist in Genomic Medicine, and Ajay Saw, Ph.D., previous postdoctoral fellow in Genomic Medicine.

“ATRX mutations are a defining feature in many gliomas. Our findings show that losing ATRX doesn't just cause random damage but actually reprograms gene regulation architecture in ways that drive glioma formation and progression,” Huse said.

“The next generation of personalised medicine will depend on integrating these genetic, epigenetic and structural components in order to identify the right treatment for the right patient at the right time.”

What is the role of ATRX in brain cancer?

The ATRX protein helps organise and regulate DNA.

Mutations that inactivate ATRX disrupt DNA repair and allow cancer cells to multiply uncontrollably.

ATRX mutations are a defining feature in several cancers, including gliomas.

While researchers have known they are somehow involved in cancer development, it wasn’t clearly understood how they influence cell behaviour.

The researchers found that ATRX-deficient cells change the DNA folding patterns and create new interactions in chromatin – the tightly packed complex of DNA, RNA and proteins that form chromosomes.

Reorganising the structure of chromatin leads to the activation of new gene pathways that promote tumour progression.

These pathways include WNT5A, which is linked to cancer cell movement and neurogenesis; SLITRK6, which is linked to cell migration and malignant brain tumours; and multiple HOXA genes that control spatial and temporal patterns in early brain development.

How could this finding be used to slow progression in ATRX-mutant tumours?

The researchers showed that blocking WNT5A or SLITRK6 slowed cancer cell movement in vitro.

Additionally, targeting HOXA genes blocked tumour progression.

The researchers tested a peptide called HXR9 to disrupt HOXA-mediated signalling, which led to cancer cell death, slowed tumour growth and extended survival in vivo.

“This study underscores the need to examine the functional consequences of genetic mutations rather than solely focusing on the mutations themselves,” Rai said.

“These findings could also apply to ATRX mutations in other cancers and, on a larger level, epigenetic dysfunction reprogramming cellular differentiation state and plasticity.”

Further clinical research is needed, but these results suggest that targeting the HOXA pathway could be a promising strategy for treating ATRX-deficient brain tumours and other ATRX-mutant cancer types.

Current treatment options for many gliomas remain limited, and these new biomarkers and potential drug targets could help researchers and clinicians develop more precise therapies that can address ATRX deficiency.

Source: University of Texas M. D. Anderson Cancer Center