Publications by authors named "Jann Sarkaria"

Glioblastoma tumors are the most common and aggressive adult central nervous system malignancy. Nearly all patients experience disease progression, which significantly contributes to disease mortality. Recently, it has been suggested that recurrent tumors may be characterized by a ferroptosis-prone phenotype with a significant decrease in glutathione peroxidase 4 (GPx4) expression.

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Article Synopsis
  • Acquired resistance to temozolomide (TMZ) in glioblastoma patients, particularly those with DNA mismatch repair deficiencies, limits treatment effectiveness, prompting research into the new drug KL-50, which targets cancer cells in an MMR-independent manner.
  • In studies, KL-50 significantly improved the median survival of mice with both naive and post-TMZ glioblastoma xenografts, showcasing its potential as a superior treatment option.
  • Results indicate KL-50 may be particularly effective in MGMT and MMR-deficient tumors, offering hope for better management of recurrent glioblastoma after initial TMZ therapy.
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Background: Glioblastoma is the most aggressive malignant brain tumor with poor survival due to its invasive nature driven by cell migration, with unclear linkage to transcriptomic information. The aim of this study was to develop a physics-based framework connecting to transcriptomics to predict patient-specific glioblastoma cell migration.

Methods And Results: We applied a physics-based motor-clutch model, a cell migration simulator (CMS), to parameterize the migration of glioblastoma cells and define physical biomarkers on a patient-by-patient basis.

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ATM inhibitors are being developed as radiosensitizers to improve the antitumor effects of radiotherapy, but ATM inhibition can also radiosensitize normal tissues. Therefore, understanding the elevated risk for normal tissue toxicities is critical for radiosensitizer development. This study focused on modeling the relationship between acute mucosal toxicity, radiation dose, fractionation schedule, and radiosensitizer exposure.

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Article Synopsis
  • Glioblastoma patients typically have a poor prognosis even after standard treatments, prompting research into new combinations of therapy.
  • The study evaluated the effectiveness of veliparib combined with temozolomide for glioblastoma patients with MGMT promoter hypermethylation, hoping to enhance treatment outcomes.
  • Results showed a slight improvement in median overall survival for the veliparib group compared to the placebo, but the difference wasn't significant enough to meet efficacy goals, though the combination treatment was generally well tolerated.
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Glioblastoma (GBM) remains one of the most therapy-resistant malignancies with frequent local failures despite aggressive surgery, chemotherapy, and ionizing radiation (IR). Small molecule inhibitors of DNA-dependent protein kinase (DNA-PKi's) are potent radiosensitizers currently in clinical trials. Determining which patients may benefit from radiosensitization with DNA-PKi's is critical to avoid unnecessary increased risk of normal tissue toxicity.

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An accurate assessment of p53's functional status is critical for cancer genomic medicine. However, there is a significant challenge in identifying tumors with non-mutational p53 inactivations that are not detectable through DNA sequencing. These undetected cases are often misclassified as p53-normal, leading to inaccurate prognosis and downstream association analyses.

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Article Synopsis
  • Glioblastoma (GBM) is a severe brain cancer characterized by infiltrative tumor cells that evade treatment due to a protective blood-brain barrier, resulting in poor patient outcomes despite aggressive therapies like radiation and chemotherapy.* -
  • The study investigates a new drug called elimusertib, an ATR kinase inhibitor, which aims to enhance the effectiveness of DNA-damaging treatments such as temozolomide; however, it showed strong lab results but did not improve outcomes in live mice models.* -
  • Findings reveal that elimusertib is quickly removed from the bloodstream and struggles to penetrate the brain effectively, largely due to barriers like P-glycoprotein at the blood-brain barrier, suggesting challenges for
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Unlabelled: Intrinsic resistance to targeted therapeutics in PTEN-deficient glioblastoma (GBM) is mediated by redundant signaling networks that sustain critical metabolic functions. Here, we demonstrate that coordinated inhibition of the ribosomal protein S6 kinase 1 (S6K1) and the receptor tyrosine kinase AXL using LY-2584702 and BMS-777607 can overcome network redundancy to reduce GBM tumor growth. This combination of S6K1 and AXL inhibition suppressed glucose flux to pyrimidine biosynthesis.

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Determining the balance between DNA double strand break repair (DSBR) pathways is essential for understanding treatment response in cancer. We report a method for simultaneously measuring non-homologous end joining (NHEJ), homologous recombination (HR), and microhomology-mediated end joining (MMEJ). Using this method, we show that patient-derived glioblastoma (GBM) samples with acquired temozolomide (TMZ) resistance display elevated HR and MMEJ activity, suggesting that these pathways contribute to treatment resistance.

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ATP-binding cassette (ABC) transporters facilitate the movement of diverse molecules across cellular membranes, including those within the CNS. While most extensively studied in microvascular endothelial cells forming the blood-brain barrier (BBB), other CNS cell types also express these transporters. Importantly, disruptions in the CNS microenvironment during disease can alter transporter expression and function.

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Triple negative breast cancer (TNBC) accounts for 15-20% of all breast cancers and mainly affects pre-menopausal and minority women. Because of the lack of ER, PR or HER2 expression in TNBC, there are limited options for tailored therapies. While TNBCs respond initially to standard of care chemotherapy, tumor recurrence commonly occurs within 1 to 3 years post-chemotherapy and is associated with early organ metastasis and a high incidence of mortality.

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Radiation therapy, a standard treatment option for many cancer patients, induces DNA double-strand breaks (DSBs), leading to cell death. Ataxia telangiectasia mutated (ATM) kinase is a key regulator of DSB repair, and ATM inhibitors are being explored as radiosensitizers for various tumors, including primary and metastatic brain tumors. Efficacy of radiosensitizers for brain tumors may be influenced by a lack of effective drug delivery across the blood-brain barrier.

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Unlabelled: While serial sampling of glioma tissue is rarely performed prior to recurrence, cerebrospinal fluid (CSF) is an underutilized longitudinal source of candidate glioma biomarkers for understanding therapeutic impacts. However, the impact of key variables to consider in longitudinal CSF samples, including anatomical location and post-surgical changes, remains unknown. To that end, pre- versus post-resection intracranial CSF samples were obtained at early (1-16 days; n=20) or delayed (86-153 days; n=11) timepoints for patients with glioma.

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DNA damage response (DDR) mechanisms are critical to maintenance of overall genomic stability, and their dysfunction can contribute to oncogenesis. Significant advances in our understanding of DDR pathways have raised the possibility of developing therapies that exploit these processes. In this expert-driven consensus review, we examine mechanisms of response to DNA damage, progress in development of DDR inhibitors in IDH-wild-type glioblastoma and IDH-mutant gliomas, and other important considerations such as biomarker development, preclinical models, combination therapies, mechanisms of resistance and clinical trial design considerations.

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Article Synopsis
  • Antibody-drug conjugates (ADCs) are effective targeted therapies for solid cancers, and this study focuses on the efficacy of EGFR-targeted ADCs for treating EGFR-amplified glioblastoma (GBM).
  • The study compares two ADCs, Losatuxizumab vedotin (ABBV-221) and Depatuxizumab mafodotin (Depatux-M), for their effectiveness and toxicity using patient-derived models and nontumor-bearing mice through a delivery method called convection-enhanced delivery (CED).
  • Results showed that CED significantly increased survival rates in GBM models, but ABBV-221 caused more neuronal toxicity compared to Depatux-M, raising concerns about the stability
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Inactivating mutations of genes encoding the cohesin complex are common in a wide range of human cancers. STAG2 is the most commonly mutated subunit. Here we report the impact of stable correction of endogenous, naturally occurring STAG2 mutations on gene expression, 3D genome organization, chromatin loops, and Polycomb signaling in glioblastoma multiforme (GBM).

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ATM is a key mediator of radiation response, and pharmacological inhibition of ATM is a rational strategy to radiosensitize tumors. AZD1390 is a brain-penetrant ATM inhibitor and a potent radiosensitizer. This study evaluated the spectrum of radiosensitizing effects and the impact of mutation status in a panel of wild-type (WT) glioblastoma (GBM) patient-derived xenografts (PDXs).

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Objective: To establish a neurologic disorder-driven biospecimen repository to bridge the operating room with the basic science laboratory and to generate a feedback cycle of increased institutional and national collaborations, federal funding, and human clinical trials.

Methods: Patients were prospectively enrolled from April 2017 to July 2022. Tissue, blood, cerebrospinal fluid, bone marrow aspirate, and adipose tissue were collected whenever surgically safe.

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Unlabelled: Despite extensive advances in cancer research, glioblastoma (GBM) still remains a very locally invasive and thus challenging tumor to treat, with a poor median survival. Tumor cells remodel their microenvironment and utilize extracellular matrix to promote invasion and therapeutic resistance. We aim here to determine how GBM cells exploit hyaluronan (HA) to maintain proliferation using ligand-receptor dependent and ligand-receptor independent signaling.

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Radioresistance of melanoma brain metastases limits the clinical utility of conventionally fractionated brain radiation in this disease, and strategies to improve radiation response could have significant clinical impact. The catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) is critical for repair of radiation-induced DNA damage, and inhibitors of this kinase can have potent effects on radiation sensitivity. In this study, the radiosensitizing effects of the DNA-PKcs inhibitor peposertib were evaluated in patient-derived xenografts of melanoma brain metastases (M12, M15, M27).

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Glioblastoma (GBM), a highly lethal and aggressive central nervous system malignancy, presents a critical need for targeted therapeutic approaches to improve patient outcomes in conjunction with standard-of-care (SOC) treatment. Molecular subtyping based on genetic profiles and metabolic characteristics has advanced our understanding of GBM to better predict its evolution, mechanisms, and treatment regimens. Pharmacological ascorbate (P-AscH) has emerged as a promising supplementary cancer therapy, leveraging its pro-oxidant properties to selectively kill malignant cells when combined with SOC.

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Purpose: We evaluated the properties and activity of AZD9574, a blood-brain barrier (BBB) penetrant selective inhibitor of PARP1, and assessed its efficacy and safety alone and in combination with temozolomide (TMZ) in preclinical models.

Experimental Design: AZD9574 was interrogated in vitro for selectivity, PARylation inhibition, PARP-DNA trapping, the ability to cross the BBB, and the potential to inhibit cancer cell proliferation. In vivo efficacy was determined using subcutaneous as well as intracranial mouse xenograft models.

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Unlabelled: How cell metabolism regulates DNA repair is incompletely understood. Here, we define a GTP-mediated signaling cascade that links metabolism to DNA repair and has significant therapeutic implications. GTP, but not other nucleotides, regulates the activity of Rac1, a guanine nucleotide-binding protein, which promotes the dephosphorylation of serine 323 on Abl-interactor 1 (Abi-1) by protein phosphatase 5 (PP5).

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