Dena Panovska

All Publications

• BRAF/MEK inhibition induces cell state transitions boosting immune checkpoint sensitivity in BRAFV600E-mutant glioma. Cell reports. Medicine Xing, Y. L., Panovska, D., Park, J. W., Grossauer, S., Koeck, K., Bui, B., Nasajpour, E., Nirschl, J. J., Feng, Z. P., Cheung, P., Habib, P., Wei, R., Wang, J., Thomason, W., Monje, M., Xiu, J., Beck, A., Weber, K. J., Harter, P. N., Lim, M., Mahaney, K. B., Prolo, L. M., Grant, G. A., Ji, X., Walsh, K. M., Mulcahy Levy, J. M., Hambardzumyan, D., Petritsch, C. K. 2025: 102183

  Abstract

  Resistance to v-raf murine sarcoma viral oncogene homolog B1 (BRAF) plus mitogen-activated protein kinase kinase (MEK) inhibition (BRAFi+MEKi) in BRAFV600E-mutant gliomas drives rebound, progression, and high mortality, yet it remains poorly understood. This study addresses the urgent need to develop treatments for BRAFi+MEKi-resistant glioma using preclinical mouse models and patient-derived materials. BRAFi+MEKi reveals glioma plasticity by heightening cell state transitions along glial differentiation trajectories, giving rise to astrocyte- and immunomodulatory oligodendrocyte (OL)-like states. PD-L1 upregulation in OL-like cells links cell state transitions to immune evasion, possibly orchestrated by Galectin-3. BRAFi+MEKi induces interferon response signatures, tumor infiltration, and suppression of T cells. Combining BRAFi+MEKi with immune checkpoint inhibition enhances survival in a T cell-dependent manner, reinvigorates T cells, and outperforms individual or sequential therapies in mice. Elevated PD-L1 expression in BRAF-mutant versus BRAF-wild-type glioblastoma supports the rationale for PD-1 inhibition in patients. These findings underscore the potential of targeting glioma plasticity and highlight combination strategies to overcome therapy resistance in BRAFV600E-mutant high-grade glioma.

  View details for DOI 10.1016/j.xcrm.2025.102183

  View details for PubMedID 40505659

• CONCURRENT IMMUNE CHECKPOINT BLOCKADE ENHANCES THE SURVIVAL BENEFIT OF CLINICALLY RELEVANT MAPK PATHWAY INHIBITORS IN A T CELL-DEPENDENT MANNER Xing, Y., Park, J., Grossauer, S., Panovska, D., Bui, B., Morales, D., Nirschl, J., Feng, Z., Anderson, W., Levy, J., Schreck, K., Prolo, L., Hambardzymyan, D., Petritsch, C. OXFORD UNIV PRESS INC. 2024

  View details for DOI 10.1093/neuonc/noae165.0181

  View details for Web of Science ID 001362558000008

• Successes and challenges in modeling heterogeneous BRAFV600Emutated central nervous system neoplasms. Frontiers in oncology Xing, Y. L., Panovska, D., Petritsch, C. K. 2023; 13: 1223199

  Abstract

  Central nervous system (CNS) neoplasms are difficult to treat due to their sensitive location. Over the past two decades, the availability of patient tumor materials facilitated large scale genomic and epigenomic profiling studies, which have resulted in detailed insights into the molecular underpinnings of CNS tumorigenesis. Based on results from these studies, CNS tumors have high molecular and cellular intra-tumoral and inter-tumoral heterogeneity. CNS cancer models have yet to reflect the broad diversity of CNS tumors and patients and the lack of such faithful cancer models represents a major bottleneck to urgently needed innovations in CNS cancer treatment. Pediatric cancer model development is lagging behind adult tumor model development, which is why we focus this review on CNS tumors mutated for BRAFV600E which are more prevalent in the pediatric patient population. BRAFV600E-mutated CNS tumors exhibit high inter-tumoral heterogeneity, encompassing clinically and histopathological diverse tumor types. Moreover, BRAFV600E is the second most common alteration in pediatric low-grade CNS tumors, and low-grade tumors are notoriously difficult to recapitulate in vitro and in vivo. Although the mutation predominates in low-grade CNS tumors, when combined with other mutations, most commonly CDKN2A deletion, BRAFV600E-mutated CNS tumors are prone to develop high-grade features, and therefore BRAFV600E-mutated CNS are a paradigm for tumor progression. Here, we describe existing in vitro and in vivo models of BRAFV600E-mutated CNS tumors, including patient-derived cell lines, patient-derived xenografts, syngeneic models, and genetically engineered mouse models, along with their advantages and shortcomings. We discuss which research gaps each model might be best suited to answer, and identify those areas in model development that need to be strengthened further. We highlight areas of potential research focus that will lead to the heightened predictive capacity of preclinical studies, allow for appropriate validation, and ultimately improve the success of "bench to bedside" translational research.

  View details for DOI 10.3389/fonc.2023.1223199

  View details for PubMedID 37920169