New approach to treating ependymoma with leukemia drug

Rakesh Jain PhD, Director of the E.L. Steele Laboratories for Tumor Biology at Massachusetts General Hospital and A. Werk Cook Professor of Radiation Oncology at Harvard Medical School, is senior author of a new study in PNAS, Targeting EPHB2/ABL1 Restores Anti-Tumor Immunity in Preclinical Models of Ependymoma.

How would you summarize your study for a lay audience?

Ependymoma (EPN) is a common form of brain cancer in children, with few available therapies that have limited efficacy.

Despite the advances in understanding the biology of EPN, managing patients with different stages of

EPN remains challenging. Surgical resection and radiation therapy are the standard treatments for EPN. However, not all EPNs can be safely resected, especially those that develop intracranially, and irradiation may cause long-term toxicities.

Thus, new and more effective treatments for EPN are urgently needed.

In this study, our research team used a mouse model of EPN in immunocompetent mice, where we discovered that dasatinib, an approved drug for leukemia, potently inhibited the growth of a molecular subgroup EPN and works in part by activating the anti-tumor immune responses.

Our findings support the clinical evaluation of dasatinib in patients suffering from EPN of this molecular subgroup.

What was your approach?

My postdoctoral fellows, Jun Ren, PhD, Zohreh Amoozgar, PhD, and Taylor Uccello, PhD, used subtype-specific EPHB2-driven and ZFTA–RELA fusion-driven EPN tumor models that recapitulate human ST-EPN-ZFTA molecular subgroup to identify druggable targets and tested their hypotheses using mice with an intact immune system.

We identified those targets by matching transcriptomic signatures with the target spectrum of FDA-approved drugs to facilitate the translation of these treatments to the clinic.

Our multidisciplinary research team of scientists, engineers, and clinicians also used various laboratory techniques, including state-of-the-art in vivo imaging and multiplexed flow cytometry, immunostaining, and ELISA.

What did you find?

We discovered that the multi-kinase inhibitor dasatinib, an approved drug for leukemia, potently inhibited the growth of ST-ZFTA molecular subgroup EPN driven by EPHB2 and ZFTA–RELA fusion-driven both in vitro and in vivo, mainly through blocking EPHB2 and ABL1.

We found an increased frequency of pro-tumor immune cells – known as M2-like tumor-associated macrophages (TAMs), which proportionally increased with tumor size during tumor progression. Treatment with dasatinib reprogrammed the EPN immune microenvironment by polarizing the TAMs toward an anti-tumor phenotype and increased the activation of effector CD8 T lymphocytes that kill cancer cells.

Furthermore, dasatinib treatment induced complete regression of established EPNs in 78% of the animals.

Depletion of CD8 T cells compromised the durability of EPN responses and reduced overall survival.

These data indicate that dasatinib is an effective therapy for EPHB2-driven molecular subgroup of EPN and works in part by activating the anti-tumor immune responses.

Our findings support the clinical evaluation of dasatinib in patients suffering from EPN of this molecular subgroup.