Thomas K. Sears

Abstract 2496: In silico screening of therapeutics candidates targeting minimal residual disease in glioblastoma

Harrshavasan T. S. Congivaram, Shashwat Tripathi, Mateo Gomez, Katy McCortney et autres

Abstract Background: Glioblastoma recurrence is inevitable despite aggressive surgical resection of contrast enhancing (CE) tumor. Unlike the deep molecular characterization of CE glioblastoma, unresected infiltrating tumor, representing minimal residual disease (MRD) has not been well profiled. Increasingly, clinical trials are being conducted …

us (code pays fourni par la source)

Mismatch repair deficiency reshapes glioblastoma through immune suppression rather than hypermutation

Andrew Li, Thomas K. Sears, Craig M. Horbinski

Mismatch repair (MMR) deficiency is classically associated with microsatellite instability, a high tumor mutational burden (TMB), and sensitivity to immune checkpoint blockade in cancer. In this issue of the JCI, Puigdelloses Vallcorba et al. reported that this paradigm does not hold true …

STING activation induces cytotoxic and immune responses in meningiomas via inflammatory cell death pathways

Mark W. Youngblood, Shashwat Tripathi, Hinda Najem, Harrshavasan T. S. Congivaram et autres

Meningiomas are common tumors of the central nervous system that are typically treated with surgery or radiation, but lack established systemic therapies. Activation of the stimulator of interferon genes pathway with an agonist such as 8803 can trigger anti-tumor immune responses. Using …

us, ph, fr (code pays fourni par la source)

Dynamic release of extracellular particles after opening of the blood-brain barrier predicts glioblastoma susceptibility to paclitaxel

Mark W. Youngblood, Abha Kumari, Yoon‐Tae Kang, Andrew P. Gould et autres

Liquid biopsies hold promise to improve the diagnosis, assessment of response to therapy, and ultimately guide the management of cancer patients. However, implementation of this approach in brain tumors has proven challenging due to the limited passage of molecules across the blood-brain …

us (code pays fourni par la source)

EXTH-105. Comparative analysis of the MGMT-sensitive interstrand crosslinking agent KL50 based on IDH status in MMR-proficient and -deficient gliomas

Thomas K. Sears, Rahul Kishore Chaliparambil, Wenxia Wang, Alicia Steffens et autres

Abstract Developing resistance to temozolomide (TMZ) is one reason glioma patients experience disease recurrence. One mechanism of TMZ resistance is the inactivation of DNA mismatch repair (MMR)-encoding genes, especially MSH6. The MGMT-sensitive interstrand cross-linking (ICL) agent KL50 is emerging as a promising …

us, ph (code pays fourni par la source)

IMMU-07. Synergistic STING activation in meningioma neoplastic and immune populations triggers programmed necrosis and modulates the collagen-rich immunosuppressive microenvironment

Mark W. Youngblood, Shashwat Tripathi, Hinda Najem, Harrshavasan T. S. Congivaram et autres

Abstract Despite recent progress in elucidating the molecular events underlying meningioma aggressiveness, there remain no established adjuvant therapies for tumors that are intractable to surgery and radiation. Using integrated approaches of single-cell RNA/ATAC-seq, spatial multiprotein immunofluorescence, and bulk RNA-seq and methylation profiling, …

us, ph, fr (code pays fourni par la source)

IMMU-24. CHEK2 haploinsufficiency drives immune responsiveness in aggressive meningiomas

Heba Ali, Harrshavasan T. S. Congivaram, Ningjia Zhou, Li Chen et autres

Abstract Meningiomas account for more than 30% of all primary central nervous system (CNS) tumors. Although approximately 80% of meningiomas are benign (WHO Grade 1), the remaining 20%, which include Grade 2 and 3 tumors, exhibit poor progression-free survival and resistance to …

us (code pays fourni par la source)

Methylation-induced suppression of YAP/TAZ confers sensitivity to HDAC inhibitors in high-grade IDH mutant gliomas

Thomas K. Sears, Matthew McCord, Wenxia Wang, Alicia Steffens et autres

IDH1/2 mutations (IDHmut) increase methylation of DNA and histones in gliomas. IDHmut inhibitors are effective against low-grade IDHmut gliomas, but new strategies against high-grade IDHmut gliomas are needed. Although histone deacetylase inhibitors (HDACi) are ineffective against IDHwt glioblastoma (GBM), their potential in …

us (code pays fourni par la source)

F3 Expression Drives Sensitivity to the Antibody-Drug Conjugate Tisotumab Vedotin in Glioblastoma

Thomas K. Sears, Wenxia Wang, Michael R. Drumm, Dusten J. Unruh et autres

Background/Objectives: The gene F3, encoding Tissue Factor (TF), is expressed in many cancers and contributes to their malignancy. Among adult-type diffuse gliomas, IDH1/2 wild-type (IDHwt) glioblastomas (GBM) express more TF than IDH1/2 mutant (IDHmut) gliomas. Tisotumab vedotin (TisVed), an anti-TF antibody conjugated …

us (code pays fourni par la source)

F3 expression drives sensitivity to the antibody-drug conjugate tisotumab vedotin in glioblastoma

Thomas K. Sears, Wenxia Wang, Michael R. Drumm, Dusten J. Unruh et autres

us (code pays fourni par la source)

The novel DNA cross-linking agent KL-50 is active against patient-derived models of new and recurrent post-temozolomide mismatch repair-deficient glioblastoma

Matthew McCord, Thomas K. Sears, Wenxia Wang, Rahul Kishore Chaliparambil et autres

BACKGROUND: Acquired resistance to temozolomide (TMZ) chemotherapy due to DNA mismatch repair (MMR) enzyme deficiency is a barrier to improving outcomes for isocitrate dehydrogenase (IDH) wild-type glioblastoma (GBM) patients. KL-50 is a new imidazotetrazine-based therapeutic designed to induce DNA interstrand cross-links, and …

us (code pays fourni par la source)

EXTH-23. NEW DNA-CROSSLINKING CHEMOTHERAPY IS EFFECTIVE AGAINST POST-TEMOZOLOMIDE MISMATCH REPAIR-DEFICIENT PATIENT-DERIVED HYPERMUTANT GLIOMAS

Matthew McCord, Wenxia Wang, Shejuan An, Thomas K. Sears et autres

Abstract The DNA mismatch repair (MMR) pathway triggers glioblastoma (GBM) apoptosis when base mismatches induced by the alkylating agent temozolomide (TMZ) cannot be repaired. GBMs often develop hypermutation and resistance to TMZ through acquired inactivation of DNA MMR enzymes (MSH2, MSH6, MLH1, …

ph, us (code pays fourni par la source)