Isocitrate dehydrogenase 1–mutant (IDH1m) gliomas are recalcitrant tumors for which radiotherapy remains a standard treatment. A recent study identified ZMYND8 as a key mediator of radioresistance for IDH1m gliomas, and pharmacologic targeting of this pathway may heighten radiotherapy-induced tumor response, providing a prospect of improved clinical outcomes.

See related article by Carney et al., p. 1763

In this issue of Clinical Cancer Research, Carney and colleagues identified ZMYND8 as an important molecular mediator of radiation resistance in isocitrate dehydrogenase 1 (IDH1)-mutated (IDH1m) gliomas (1). These are recalcitrant tumors prone to recurrence following radiotherapy. These tumors ultimately progress despite aggressive multimodal treatment. In this study, pharmacologic targeting of ZMYND8 led to increased tumor cell susceptibility to radiotherapy. Therefore, this discovery has clear translational implications, which may allow for improved outcomes.

Beyond maximal safe resection, the standard-of-care approach for most gliomas continues to be a combination of radiotherapy and alkylating chemotherapy (2). This has not only been established in higher grade lesions but also been shown (thus far) as the best multimodal approach in lower grade gliomas. In the latter, randomized clinicals have shown clear improvements in outcomes with early addition of chemotherapy to radiotherapy. Prospective data testing the addition of radiotherapy in lower-grade (grade 2–3) gliomas have been more limited, and in clinical trials the omission of radiotherapy has also been associated with poorer outcomes, confirming that that multimodal radiotherapy-based therapy yields the best patient outcomes (3–5). Yet, controversy exists on whether radiotherapy is required upfront at time of diagnosis of a low-grade glioma, as the alternative of surgery and in some cases chemotherapy, might delay the need for radiotherapy, and achieve prolonged tumor control while avoiding the cognitive effects of radiotherapy.

The role of radiotherapy for malignant glioma was established over 40 years ago in a series of randomized controlled trials comparing alkylating agent chemotherapies such as BCNU (carmustine), MeCCNU (semustine), and bleomycin versus the addition of radiotherapy (6–8). In these studies, the use of radiotherapy encompassing tumor and peritumoral brain was associated with improved survival. Since then, a multiweek fractionated radiotherapy course has essentially become the backbone of all glioma therapy (2, 9). Clinical trial data have demonstrated that the benefit of radiotherapy is independent of a tumor's molecular features (such as MGMT promoter methylation which predicts a response to alkylating agents) and inferior tumor-control and survival outcomes occur when radiotherapy is withheld (10, 11). However, despite improvements in disease control and delaying disease progression when radiotherapy is used, infiltrative gliomas ultimately recur. This suggests that an initial radiotherapy benefit is lost in the course of the disease. As a result, multiple dose-escalation attempts have been carried out but unfortunately have repeatedly shown no benefit with higher doses as tested by clinical trials like RTOG 7401, RTOG 8302, RTOG 9006, RTOG 9305 (which utilized stereotactic radiosurgery to give higher dose) and more recently the NRG-BN001 trial (12–15). A collective conclusion derived from these studies is that omitting radiotherapy leads to inferior outcomes but intensifying it fails to improve outcomes, suggesting the possible existence of a threshold of radioresistance which may limit the benefit of this therapy.

Carney and colleagues delve into this important question for IDH1m gliomas, a group of brain tumors with distinct molecular and epigenetic characteristics. In particular, they focus on IDH1m astrocytoma, which in addition to IDH1 mutation, has canonical TP53 and ATRX mutations. In these tumors, the mutant IDH1 enzyme converts alpha-ketoglutarate to an excess of 2-hydroxyglutarate (2-HG), an oncometabolite which can induce DNA methylation in large yet specific regions of the genome. This epigenetic state has been shown to exhibit heightened DNA damage response (DDR) and significantly increased radioresistance. Dr. Castro and her group have previously shown that this radioresistant state can be reversed by inhibiting the mutant IDH1 enzyme (and thus the heightened 2-HG levels; ref. 16). Now, in the current study, they take an important next step to identify a key molecular downstream driver of radiotherapy resistance.

While radiation causes different types of tumor cell DNA damage (such as nucleotide damage and single-strand breaks), the principal drivers of biological benefit are double-strand breaks (DSB) which cause mitotic catastrophe and eventual tumor cell death (17, 18). Tumor cells that harbor or upregulate molecular mechanisms of DNA DSB repair can evade the effects (and thus the clinical benefit) of radiotherapy.

In this study, Carney and colleagues, perform a thorough molecular characterization of patient-derived IDH1m glioma models and pharmacologic IDH1m enzyme inhibition to demonstrate ZMYND8 as a driver of radiotherapy resistance in these tumors (1). Their data show, that in an IDH1m-mediated state of excess 2-HG, the ZMYND8 locus is marked with H3K4me3, and transcriptionally active. This is an important finding because ZMYND8 has been previously shown to be a principal driver of DDR (19). It is recruited early and helps bind the NURD (nucleosome remodeling and histone deacetylase) complex—which holds important regulatory roles in DDR and transcriptional control. Serving as a key DNA damage locator, ZMYND8 allows NURD-mediated homologous recombination repair, an important DSB DDR pathway and a barrier to radiotherapy-induced tumor cell death. Indeed, with suppression of ZMYND8, Carney and colleagues showed significantly improved radiosensitivity and reduced tumor cell survival.

For a recalcitrant brain tumor, these data point to a pathway of potential clinical translation. With testing of a mature pharmacologic IDH1m enzyme inhibitor, the authors demonstrate successful significant proof-of-principle reduction in ZMYND8 expression in three human-derived glioma cell lines. Furthermore, the recruitment and function of this key molecular mediator may be further shaped by important pharmacologic targets in BRD4, HDAC, and PARP, which interact with ZMYND8, and for which there are inhibitor agents being actively tested in clinical trials (Fig. 1).

Figure 1.

Proposed mechanism of ZMYND8-mediated radioresistance in IDHm gliomas. ZMYND8, which is upregulated in IDH1m gliomas, interacts with HDAC1/2 and PARP complexes at the site of DNA damage, dampening the effect of radiation. However, treatment with IDH1m-specific inhibitor AGI-5198 decreases the levels of ZMYND8 and hence repair of the damaged DNA. Similarly, knockdown/knockout of ZMYND8 or treatment with HDAC inhibitors (iHDAC) or PARP inhibitors (iPARP) can overcome the radioresistance in IDH1m gliomas. (Adapted from an image created with BioRender.com.)

Figure 1.

Proposed mechanism of ZMYND8-mediated radioresistance in IDHm gliomas. ZMYND8, which is upregulated in IDH1m gliomas, interacts with HDAC1/2 and PARP complexes at the site of DNA damage, dampening the effect of radiation. However, treatment with IDH1m-specific inhibitor AGI-5198 decreases the levels of ZMYND8 and hence repair of the damaged DNA. Similarly, knockdown/knockout of ZMYND8 or treatment with HDAC inhibitors (iHDAC) or PARP inhibitors (iPARP) can overcome the radioresistance in IDH1m gliomas. (Adapted from an image created with BioRender.com.)

Close modal

Optimal local radiotherapy has continued to improve over time, with incremental updates in image-guided highly-conformal treatment delivery and intensity-modulated inverse planning techniques. This has led to the current state of treatment—with high-dose gradients that can be three-dimensionally shaped in high resolution to the tumor and surrounding areas where microscopic disease is predominantly found (20). While such technologies will likely continue to be used as a backbone of glioma treatment, a future pathway to clinical improvement may very well be realized by seeking concomitant improvement in multimodal approaches that exploit therapeutic vulnerabilities; this could be accomplished via intelligently designed trials that query synergy between radiotherapy and other systemic agents. In their study, Carney and colleagues point to such a future pathway. ZMYND8 appears to be a key molecular mechanism of therapy resistance that, with pharmacologic targeting, may remove a barrier to heightened radiotherapy-induced tumor cell killing and improved clinical outcomes. As we saw with temozolomide, it might be important to pursue synergy between drugs and radiotherapy to improved clinical outcomes for gliomas once again (2).

No disclosures were reported.

This work is funded by the NIH/NCI 1R01CA245969-01A1 (A.M. Sonabend), NIH/NINDS 5R01NS110703 (A.M. Sonabend), NIH/NCI 1U19CA264338-01 (A.M. Sonabend), NIH/NCI P50CA221747 SPORE for Translational Approaches to Brain Cancer (A.M. Sonabend; P.I.: M.S. Lesniak), funding support from the Lou and Jean Malnati Brain Tumor Institute (A.M. Sonabend), as well as generous philanthropic support from the Moceri Family Foundation.

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