Central nervous system tumors in adolescents and young adults: A Society for Neuro-Oncology consensus review on diagnosis, management, and future directions.

Adolescents and young adults (AYAs; ages 15-39 years) are a vulnerable population facing challenges in oncological care, including access to specialized care, transition of care, unique tumor biology, and poor representation in clinical trials. Brain tumors are the second most common tumor type in AYA, with malignant brain tumors being the most common cause of cancer-related death. The 2021 WHO Classification for central nervous system (CNS) Tumors highlights the importance of integrated molecular characterization with histologic diagnosis in several tumors relevant to the AYA population.

PARG inhibition induces nuclear aggregation of PARylated PARP1.

Poly (ADP-ribose) glycohydrolase (PARG) inhibitors are currently under clinical development for the treatment of DNA repair-deficient cancers; however, their precise mechanism of action is still unclear. Here, we report that PARG inhibition leads to excessive PARylated poly (ADP-ribose) polymerase 1 (PARP1) reducing the ability of PARP1 to properly localize to sites of DNA damage. Strikingly, the mis-localized PARP1 accumulates as aggregates throughout the nucleus.

NAPRT Silencing in FH-Deficient Renal Cell Carcinoma Confers Therapeutic Vulnerabilities via NAD+ Depletion.

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is caused by loss of function mutations in fumarate hydratase (FH) and results in an aggressive subtype of renal cell carcinoma with limited treatment options. Loss of FH leads to accumulation of fumarate, an oncometabolite that disrupts multiple cellular processes and drives tumor progression. High levels of fumarate inhibit alpha ketoglutarate-dependent dioxygenases, including the ten-eleven translocation (TET) enzymes, and can lead to global DNA hypermethylation.

Mechanism of Action of KL-50, a Candidate Imidazotetrazine for the Treatment of Drug-Resistant Brain Cancers.

Aberrant DNA repair is a hallmark of cancer, and many tumors display reduced DNA repair capacities that sensitize them to genotoxins. Here, we demonstrate that the differential DNA repair capacities of healthy and transformed tissue may be exploited to obtain highly selective chemotherapies. We show that the novel N3-(2-fluoroethyl)imidazotetrazine "KL-50" is a selective toxin toward tumors that lack the DNA repair protein O-methylguanine-DNA-methyltransferase (MGMT), which reverses the formation of O-alkylguanine lesions.

DNA damage response in brain tumors: A Society for Neuro-Oncology consensus review on mechanisms and translational efforts in neuro-oncology.

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.

Intrathecal delivery of nanoparticle PARP inhibitor to the cerebrospinal fluid for the treatment of metastatic medulloblastoma.

The morbidity associated with pediatric medulloblastoma, in particular in patients who develop leptomeningeal metastases, remains high in the absence of effective therapies. Administration of substances directly into the cerebrospinal fluid (CSF) is one approach to circumvent the blood-brain barrier and focus delivery of drugs to the site of tumor. However, high rates of CSF turnover prevent adequate drug accumulation and lead to rapid systemic clearance and toxicity.

Platinum Sensitivity in Mutated Intrahepatic Cholangiocarcinoma: Not All "BRCAness" Is Created Equal.

Preclinical data suggest that mutations result in defective homologous recombination repair (HRR). We hypothesized that patients with mt intrahepatic cholangiocarcinoma (IHCC) would benefit more from 1 L platinum chemotherapy than patients with wildtype (WT) tumors. We performed a multicenter retrospective study of 81 patients with unresectable IHCC treated with 1 L platinum with a primary endpoint of clinical benefit rate (CBR).

Quantitative DNA Repair Biomarkers and Immune Profiling for Temozolomide and Olaparib in Metastatic Colorectal Cancer.

Purpose: O-methylguanine DNA methyltransferase ()-silenced tumors reveal sensitivity to temozolomide (TMZ), which may be enhanced by PARP inhibitors. Approximately 40% of colorectal cancer has silencing and we aimed to measure antitumoral and immunomodulatory effects from TMZ and olaparib in colorectal cancer.

Experimental Design: Patients with advanced colorectal cancer were screened for promoter hypermethylation using methylation-specific PCR of archival tumor.

Multicenter Phase II Trial of the PARP Inhibitor Olaparib in Recurrent and -mutant Glioma.

Purpose: Isocitrate dehydrogenase () and mutations (mt) are frequent in glioma. Preclinical studies suggest mts confer "BRCAness" phenotype, a vulnerability that can be targeted through PARP inhibition. To test this hypothesis, we conducted a multicenter study of olaparib monotherapy in patients with mt gliomas.

Anti-seed PNAs targeting multiple oncomiRs for brain tumor therapy.

Glioblastoma (GBM) is one of the most lethal malignancies with poor survival and high recurrence rates. Here, we aimed to simultaneously target oncomiRs 10b and 21, reported to drive GBM progression and invasiveness. We designed short (8-mer) γ-modified peptide nucleic acids (sγPNAs), targeting the seed region of oncomiRs 10b and 21.

The Role of PARP Inhibitors in Patients with Primary Malignant Central Nervous System Tumors.

Primary malignant central nervous (CNS) tumors are a devastating group of diseases with urgent need for improved treatment options. Surgery, radiation, and cytotoxic chemotherapy remain the primary standard treatment modalities, with molecularly targeted therapies having proven efficacy in only small subsets of cases. Poly(ADP-ribose) polymerase (PARP) inhibitors, which have had immense success in the treatment of extracranial cancers with homologous recombination deficiency (HRD), are emerging as a potential targeted treatment for various CNS tumors.

Polymer nanocarriers for targeted local delivery of agents in treating brain tumors.

Glioblastoma (GBM), the deadliest brain cancer, presents a multitude of challenges to the development of new therapies. The standard of care has only changed marginally in the past 17 years, and few new chemotherapies have emerged to supplant or effectively combine with temozolomide. Concurrently, new technologies and techniques are being investigated to overcome the pharmacokinetic challenges associated with brain delivery, such as the blood brain barrier (BBB), tissue penetration, diffusion, and clearance in order to allow for potent agents to successful engage in tumor killing.

Targeting Krebs-cycle-deficient renal cell carcinoma with Poly ADP-ribose polymerase inhibitors and low-dose alkylating chemotherapy.

Loss-of-function mutations in genes encoding the Krebs cycle enzymes Fumarate Hydratase () and Succinate Dehydrogenase () induce accumulation of fumarate and succinate, respectively and predispose patients to hereditary cancer syndromes including the development of aggressive renal cell carcinoma (RCC). Fumarate and succinate competitively inhibit αKG-dependent dioxygenases, including Lysine-specific demethylase 4A/B (KDM4A/B), leading to suppression of the homologous recombination (HR) DNA repair pathway. In this study, we have developed new syngeneic - and -deficient murine models of RCC, which demonstrate the expected accumulation of fumarate and succinate, alterations in the transcriptomic and methylation profile, and an increase in unresolved DNA double-strand breaks (DSBs).

Development and validation of a liquid chromatography coupled with tandem mass spectrometry method for determining total and unbound pamiparib in human plasma and brain tumors.

Pamiparib (BGB-290) is an orally bioavailable, small molecule inhibitor of poly (ADP-ribose) polymerase 1 (PARP1) and PARP2. A reversed-phase LC with tandem mass spectrometry method was developed and fully validated for determining total and unbound pamiparib concentrations in human plasma and brain tumor tissue. Plasma and tissue homogenate samples were prepared by methanol protein precipitation.

Impact of radiotherapy delay following biopsy for patients with unresected glioblastoma.

Objective: Because of the aggressive nature of glioblastoma, patients with unresected disease are encouraged to begin radiotherapy within approximately 1 month after craniotomy. The aim of this study was to investigate the potential association between time interval from biopsy to radiotherapy with overall survival in patients with unresected glioblastoma.

Methods: Patients with unresected glioblastoma diagnosed between 2010 and 2014 who received adjuvant radiotherapy and concurrent chemotherapy were identified in the National Cancer Database.

Mechanism-based design of agents that selectively target drug-resistant glioma.

Approximately half of glioblastoma and more than two-thirds of grade II and III glioma tumors lack the DNA repair protein O-methylguanine methyl transferase (MGMT). MGMT-deficient tumors respond initially to the DNA methylation agent temozolomide (TMZ) but frequently acquire resistance through loss of the mismatch repair (MMR) pathway. We report the development of agents that overcome this resistance mechanism by inducing MMR-independent cell killing selectively in MGMT-silenced tumors.

Intrathecal delivery and its applications in leptomeningeal disease.

Intrathecal delivery (IT) of opiates into the cerebrospinal fluid (CSF) for anesthesia and pain relief has been used clinically for decades, but this relatively straightforward approach of bypassing the blood-brain barrier has been underutilized for other indications because of its lack of utility in delivering small lipid-soluble drugs. However, emerging evidence suggests that IT drug delivery be an efficacious strategy for the treatment of cancers in which there is leptomeningeal spread of disease. In this review, we discuss CSF flow dynamics and CSF clearance pathways in the context of intrathecal delivery.

Practice Patterns Related to Mitigation of Neurocognitive Decline in Patients Receiving Whole Brain Radiation Therapy.

Purpose: Whole brain radiation therapy (WBRT) is often used as an effective treatment for patients with brain metastasis, although it is also known to have deleterious cognitive effects. Multiple trials have identified strategies to help mitigate neurocognitive decline after WBRT, although there may be barriers to integrating these techniques into routine clinical practice. The aim of this study was to characterize national practice patterns related to neurocognitive preservation strategies used during WBRT.

TOP1-DNA Trapping by Exatecan and Combination Therapy with ATR Inhibitor.

Exatecan and deruxtecan are antineoplastic camptothecin derivatives in development as tumor-targeted-delivery warheads in various formulations including peptides, liposomes, polyethylene glycol nanoparticles, and antibody-drug conjugates. Here, we report the molecular pharmacology of exatecan compared with the clinically approved topoisomerase I (TOP1) inhibitors and preclinical models for validating biomarkers and the combination of exatecan with ataxia telangiectasia and Rad3-related kinase (ATR) inhibitors. Modeling exatecan binding at the interface of a TOP1 cleavage complex suggests two novel molecular interactions with the flanking DNA base and the TOP1 residue N352, in addition to the three known interactions of camptothecins with the TOP1 residues R364, D533, and N722.