Research Across 5 Sarcoma Stem Cell Subtypes Identifies EZH2 as a Potential Therapeutic Target

The first genetic and epigenetic analysis of cancer stem cells across high-grade complex karyotype sarcoma subtypes revealed that EZH2 may be a target to sensitize cells to anthracycline-based chemotherapy, according to R. Lor Randall, MD, FACS.¹

“One of the takeaways from this [study] is that there’s a correlation between these cancer stem cells abundance and the IC50 [value] of doxorubicin in 5 different cell lines. They all had similar signatures, and there is epigenetic targeting that is available commercially now that may be able to selectively affect these cancer stem cells and stop the cycle of disease progression, which is the theory behind stem cell biology in cancer,” Randall said in an interview with OncLive®.

The study, conducted by Randall and colleagues at the University of California Davis, used patient-derived samples from 5 sarcoma subtypes and identified that all subtypes displayed EZH2 activity and shared an epigenetic profile.¹ Investigators noted that beyond needed future preclinical evaluation, research in the clinic could examine tazemetostat (Tazverik), which is currently approved by the FDA for patients aged 16 years and older with metastatic or locally advanced epithelioid sarcoma not eligible for complete resection,² in combination with doxorubicin to reduce the rate of recurrent disease for patients with sarcoma.¹

In the interview, Randall detailed the study methods, key findings, and future research directions for EZH2 in the sarcoma field. Randall is the David Linn Endowed Chair for Orthopedic Surgery, the chair of the Department of Orthopedic Surgery, and a professor at UC Davis Comprehensive Cancer Center in Sacramento, California.

OncLive: What was the rationale for conducting this genetic and epigenetic analysis of cancer stem cells across high-grade complex karyotype sarcoma subtypes?

Randall: The [research] looking at genetic and epigenetic characterization of sarcoma stem cells in soft tissue sarcoma has come out of the laboratory of my [colleague] Janai R. Carr-Ascher, MD, PhD, and we’ve been collaborating with our orthopedic surgery chief resident. We are discovering that there may be epigenetic modifier targets that could be [targeted] effectively using commercially available agents already.

We appreciate that high-grade complex karyotype soft tissue sarcomas are a very heterogeneous mixed bag of tumors. They’re very aggressive [and] have a predilection for metastasis, but although they’re heterogenous, we share a common treatment strategy [of using] anthracycline-based chemotherapy, namely with doxorubicin, [as] first-line treatment. But in advanced cases, [this strategy] is still associated with poor outcomes when there’s disease progression on doxorubicin.

How was this research conducted?

In Dr Carr-Asher’s laboratory, we looked specifically at soft tissue sarcoma cancer stem cells and their doxorubicin-resistance. We identified a correlation between cancer stem cell abundance and the IC50 [values] for doxorubicin in resistant cell lines. We looked at the genetic signatures across these cancer stem cells, [which] were all from patient-derived tumor samples with 5 sarcoma subtypes [included]. We noticed one target, EZH2, that is part of the polycomb repressive complex 2 [PRC2]; PRC2 is an epigenetic pathway for methylation and gene expression in a cancer stem cell population.

This EZH2 activity shared an epigenetic profile across all 5 subtypes of soft tissue sarcomas. Tazemetostat is available and able to target EZH2, and we’re going to [examine] this further for those tumors that we predict are going to be resistant to doxorubicin, to potentially build this in as a therapy. We also may get to the point where we do a clinical trial.

How are sarcoma stem cell targets different from targets that are expressed on the surface of a cancer cell?

As somewhat of a skeptic for stem cell biology, because I’m not able to wrap my head fully around it, it has to do with what the immunohistochemistry profile of these stem cell populations are and how [clinicians] categorize them by membrane proteins. I’m certainly not a stem cell biologist, so I’m unsure what specific markers define a sarcoma cancer stem cell from any other type of cancer stem cell.

[Seeing EZH2 expressed across all 5 subtypes] is something that gives us hope that we might find a commonality in these tumors. We look at them under the microscope, [perform] karyotypic analysis, and they’re all very disparate, and yet, there is hope that they can all funnel into a common new monotherapy or [combination] therapy [approach] that will affect these different subtypes.

If the agent shows activity in doxorubicin-resistant disease models, do you anticipate it moving to clinical trials to be evaluated in combination with chemotherapy in patients with cancer?

Yes, that’s the excitement here and those will be some of the next steps. We have some preclinical mouse models that we will [use to perform] some preclinical trials before we go to a potential phase 1 study. I want to recognize my coauthors, as this is [work coming from] the brain trust of Dr Carr-Ascher and Edmond F. O'Donnell, MD, and my other coauthors. It’s exciting to see these findings and there will be ongoing work.

References

1. O’Donnell E, Muñoz M, Davis R, Randall RL, Tepper C, Carr-Ascher J. Genetic and epigenetic characterization of sarcoma stem cells across subtypes identifies EZH2 as a therapeutic target. bioRxiv. Preprinted on May 14, 2024. Accessed August 5, 2024. doi:10.1101/2024.05.14.594060.
2. FDA approves tazemetostat for advanced epithelioid sarcoma. FDA. Updated January 24, 2020. Accessed August 5, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tazemetostat-advanced-epithelioid-sarcoma