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High-grade gliomas (HGGs) are aggressive brain tumors with limited treatment options and poor survival outcomes. Variants including isocitrate dehydrogenase (IDH)-wildtype, IDH-mutant, and histone 3 lysine to methionine substitution (H3K27M)-mutant subtypes demonstrate considerable tumor heterogeneity at the genetic, cellular, and microenvironmental levels. This presents a major barrier to the development of reliable models that recapitulate tumor heterogeneity, allowing for the development of effective therapies. Glioma tumor organoids (GTOs) have emerged as a promising model, offering a balance between biological relevance and practical scalability for precision medicine. In this study, we present a refined methodology for generating three-dimensional, multiregional, patient-derived GTOs across a spectrum of glioma subtypes (including primary and recurrent tumors) while preserving the transcriptomic and phenotypic heterogeneity of their source tumors. We demonstrate the feasibility of a high-throughput drug-screening platform to nominate multi-drug regimens, finding marked variability in drug response, not only between patients and tumor types, but also across regions within the tumor. These findings underscore the critical impact of spatial heterogeneity on therapeutic sensitivity and suggest that multiregional sampling is critical for adequate glioma model development and drug discovery. Finally, regional differential drug responses suggest that multi-agent drug therapy may provide better comprehensive oncologic control and highlight the potential of multiregional GTOs as a clinically actionable tool for personalized treatment strategies in HGG.

AbstractOsteosarcoma is the most common primary malignant bone tumor and predominantly affects adolescents and young adults. It is the third most common cause of cancer-related deaths among 9 to 24 year olds. Despite aggressive chemotherapeutic and surgical therapies, the survival rate is only 25% for patients with detectable lung metastases at diagnosis and only 70% in patients who present without detectable lung metastases. The poor prognosis is due to growth of metastases irrespective of whether they are initially large enough to detect clinically. It is therefore necessary to develop new methods to target the growth of lung micrometastases. An NCI panel of FDA-approved oncology drugs was therefore screened using three highly metastatic human osteosarcoma cell lines. To more closely approximate in vivo micrometastases, the screen used a three-dimensional multicellular in vitro osteosarcoma spheroid (sarcosphere) model. Among 13 hits from the initial screen, we identified the histone deacetylase inhibitor (HDI) romidepsin as the most promising inhibitor in secondary screens comparing effects on sarcospheres with clinically achievable levels and to effects on non-transformed cells. Romidepsin potency was evident with and without standard-of-care chemotherapeutics (MAP: methotrexate, adriamycin, and cisplatin) at romidepsin concentrations that are clinically achievable and did not affect non-transformed cells. Romidepsin also substantially outperformed the other three FDA-approved HDIs and eight HDIs in clinical trials. The effects of romidepsin were a transient cell cycle block at G2/M and cell death. Importantly, sarcospheres derived from ∼30% of human and 50% of canine patient samples responded to romidepsin at clinically tolerable concentrations (ED50s <70 nmol/L).Significance:Our unbiased sarcosphere-based drug screen identified romidepsin as a promising candidate to repurpose for human and canine patients with metastatic osteosarcoma. This screening strategy allowed us to identify romidepsin-sensitive and -resistant patients. Sarcosphere-based screening may therefore be useful to identify patients most likely to respond clinically to romidepsin or other drugs.

AbstractAntibodies targeting folate receptor 1 (FOLR1) induce autophagic cell death in addition to antibody-dependent cytotoxicity, but the biological relevance of anti-FOLR1 antibody–induced autophagy for clinical applications remains unclear. In this study, we investigated the role of autophagic cell death triggered by IMGN853 (mirvetuximab soravtansine), an FOLR1-targeted antibody–drug conjugate, and explored potential combinations of IMGN853 with chemotherapeutic drugs used for ovarian cancer treatment. We discovered that FOLR1 was predominantly expressed in epithelial ovarian cancer cells, with similar expression levels observed in both primary ovarian tumors and metastatic omental tumors from patients with high-grade serous ovarian cancer (HGSC). Treatment with IMGN853 improved survival in mice bearing patient-derived xenografts of HGSC, enhanced autophagic flux, and induced cell death in HGSC cells. Additionally, it increased expression of the autophagy-related marker LC3B-II and cell death as marked by cleaved caspase-3, in a manner dependent on beclin-1, in HGSC models. Notably, combinations of IMGN853 with topotecan or the anti–VEGF-A antibody (B20) significantly reduced tumor growth compared with IMGN853 alone, whereas no significant effect was observed with olaparib. Our findings indicate that IMGN853 induces autophagic cell death, which contributes to its tumor-inhibiting effects. The identification of these effective combination therapies and the mechanisms behind FOLR1-mediated autophagic cell death could facilitate further clinical development of IMGN853.Significance:FOLR1 is heterogeneously overexpressed in epithelial ovarian cancer. We examined the combined effects of the anti-FOLR1 antibody–drug conjugate (IMGN853) with other drugs, including topotecan, anti–VEGF-A antibody, and olaparib. These findings could contribute to the continued development of IMGN853 in the treatment of ovarian cancer.