FOXR2 (Forkhead Box R2)

A first-in-class neutralizing antibody targeting SCUBE3, which was developed using a sophisticated antibody discovery platform and engineered with specific mutations in the heavy chain for enhanced specificity and efficacy, demonstrated profound therapeutic potential across various cancer types in preclinical models, including breast and ovarian cancer patient-derived xenografts. This discovery marks an advancement toward developing a targeted therapy for cancers characterized by hyperactive SCUBE3-associated signaling pathways.

Epigenetically defined PB subtypes are characterized by distinct genetic events. Frequent gains of the oncogene OTX2 indicate a role in the pathogenesis of PB independent of its subtype.

They share an aggressive imaging appearance with frequent disseminated disease and guarded prognosis; however, patient age, tumor location, and imaging characteristics such as enhancement pattern and peritumoral edema can help with differential diagnosis. In this article, we have reviewed medulloblastoma, atypical teratoid rhabdoid tumor, embryonal tumor with multilayered rosettes as well as newly recognized CNS neuroblastoma, FOXR2-activated and CNS tumor with BCOR internal tandem duplication.

P2, N=133, Completed, National Cancer Institute (NCI) | Active, not recruiting --> Completed | Trial completion date: Jul 2026 --> Jun 2025

Consistent with this, mutation of these residues inhibited cellular transformation. This is the first report of an ITD spanning the transmembrane domain of an RTK, characterizing an additional mechanism by which RTKs are activated in cancer.

CNS tumors with FOXR2 overexpression manifest significant histological, molecular, imaging, and clinical diversity. While HGGs and PBs with FOXR2 overexpression demonstrated inferior prognosis, CNS NBs showed favorable outcomes. Integrating histologic and molecular diagnostic approaches is imperative for accurate prognostication and optimal therapeutic decision-making.

Despite extensive research on FOXR2 dysregulation, its practical applications remain underexplored. This review delves into the mechanisms underlying FOXR2 dysregulation during oncogenesis and its implications for cancer diagnosis, prognosis, and treatment.

This approach serves as a blueprint for investigating other rare pediatric brain tumors, potentially accelerating progress toward the development of mouse models and identification of effective therapies. See related article by Jessa et al., p. 231.

P2, N=108, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting | N=180 --> 108 | Trial completion date: Apr 2027 --> Jul 2026 | Trial primary completion date: Apr 2026 --> Jul 2025

The majority of OFMTs harbor PHF1 gene rearrangements, with EP400 being the most common fusion partner. Herein, we present a patient with malignant metastatic OFMT, with the very rare PHF1::FOXR2 fusion, and discuss the potential clinical implications of this genetic alteration.

These data indicate that NB-FOXR2 originate from LHX6+/DLX+ interneuron lineages, a lineage-of-origin distinct from that of other FOXR2-driven brain tumors, highlight the susceptibility of ventral telencephalon-derived interneurons to FOXR2-driven oncogenesis, and suggest that FOXR2-induced activation of glial programs may explain the mixed neuronal and oligodendroglial features in these tumors. More broadly, this work underscores systematic profiling of brain development as an efficient approach to orient oncogenic targeting for in vivo modeling, critical for the study of rare tumors and development of therapeutics.

The MEK inhibitor trametinib suppressed the proliferation of FOXR2-expressing MGE progenitors more than nonexpressing cells. Our study collectively demonstrates that MGE progenitors are the cell of origin of CNS NB-FOXR2 and that FOXR2 activates the MEK/ERK signaling pathway, providing a potential therapeutic target.