bims-malgli 2023-10-08 papers

Issue of 2023–10–08
five papers selected by
Oltea Sampetrean, Keio University

F1000Res. 2023 ;12 954

Ex-vivo drug screening of surgically resected glioma stem cells to replace murine avatars and provide personalise cancer therapy for glioblastoma patients.

Hannah Gagg, Sophie T Williams, Samantha Conroy, Katie N Myers, Connor McGarrity-Cottrell, Callum Jones, Thomas Helleday, Juha Rantala, Ola Rominiyi, Sarah J Danson, Spencer J Collis, Greg Wells.

With diminishing returns and high clinical failure rates from traditional preclinical and animal-based drug discovery strategies, more emphasis is being placed on alternative drug discovery platforms. Ex vivo approaches represent a departure from both more traditional preclinical animal-based models and clinical-based strategies and aim to address intra-tumoural and inter-patient variability at an earlier stage of drug discovery. Additionally, these approaches could also offer precise treatment stratification for patients within a week of tumour resection in order to direct tailored therapy. One tumour group that could significantly benefit from such ex vivo approaches are high-grade gliomas, which exhibit extensive heterogeneity, cellular plasticity and therapy-resistant glioma stem cell (GSC) niches. Historic use of murine-based preclinical models for these tumours has largely failed to generate new therapies, resulting in relatively stagnant and unacceptable survival rates of around 12-15 months post-diagnosis over the last 50 years. The near universal use of DNA damaging chemoradiotherapy after surgical resection within standard-of-care (SoC) therapy regimens provides an opportunity to improve current treatments if we can identify efficient drug combinations in preclinical models that better reflect the complex inter-/intra-tumour heterogeneity, GSC plasticity and inherent DNA damage resistance mechanisms. We have therefore developed and optimised a high-throughput ex vivo drug screening platform; GliExP, which maintains GSC populations using immediately dissociated fresh surgical tissue. As a proof-of-concept for GliExP, we have optimised SoC therapy responses and screened 30+ small molecule therapeutics and preclinical compounds against tumours from 18 different patients, including multi-region spatial heterogeneity sampling from several individual tumours. Our data therefore provides a strong basis to build upon GliExP to incorporate combination-based oncology therapeutics in tandem with SoC therapies as an important preclinical alternative to murine models (reduction and replacement) to triage experimental therapeutics for clinical translation and deliver rapid identification of effective treatment strategies for individual gliomas.

Keywords: GliExP; Glioblastoma; cancer therapeutics; ex vivo drug screening; functional precision medicine; glioma stem cells

DOI: https://doi.org/10.12688/f1000research.135809.1

Neurooncol Adv. 2023 Jan-Dec;5(1):5(1): vdad111

MRI-guided focused ultrasound blood-brain barrier opening increases drug delivery and efficacy in a diffuse midline glioma mouse model.

Payton Martinez, Genna Nault, Jenna Steiner, Michael F Wempe, Angela Pierce, Breauna Brunt, Mathew Slade, Jane J Song, Andrew Mongin, Kang-Ho Song, Nicholas Ellens, Natalie Serkova, Adam L Green, Mark Borden.

Background: Diffuse intrinsic pontine glioma (DIPG) is the most common and deadliest pediatric brainstem tumor and is difficult to treat with chemotherapy in part due to the blood-brain barrier (BBB). Focused ultrasound (FUS) and microbubbles (MBs) have been shown to cause BBB opening, allowing larger chemotherapeutics to enter the parenchyma. Panobinostat is an example of a promising in vitro agent in DIPG with poor clinical efficacy due to low BBB penetrance. In this study, we hypothesized that using FUS to disrupt the BBB allows higher concentrations of panobinostat to accumulate in the tumor, providing a therapeutic effect.
Methods: Mice were orthotopically injected with a patient-derived diffuse midline glioma (DMG) cell line, BT245. MRI was used to guide FUS/MB (1.5 MHz, 0.615 MPa peak negative pressure, 1 Hz pulse repetition frequency, 10-ms pulse length, 3 min treatment time)/(25 µL/kg, i.v.) targeting to the tumor location.
Results: In animals receiving panobinostat (10 mg/kg, i.p.) in combination with FUS/MB, a 3-fold increase in tumor panobinostat concentration was observed, without significant increase of the drug in the forebrain. In mice receiving 3 weekly treatments, the combination of panobinostat and FUS/MB led to a 71% reduction of tumor volumes (P = .01). Furthermore, we showed the first survival benefit from FUS/MB improved delivery increasing the mean survival from 21 to 31 days (P < .0001).
Conclusions: Our study demonstrates that FUS-mediated BBB disruption can increase the delivery of panobinostat to an orthotopic DMG tumor, providing a strong therapeutic effect and increased survival.

Keywords: blood–brain barrier opening; diffuse midline gliomas; drug delivery; focused ultrasound; microbubbles

DOI: https://doi.org/10.1093/noajnl/vdad111

JCI Insight. 2023 Oct 03. pii: e167049. [Epub ahead of print]

The Semaphorin 3A-Neuropilin-1 Pathway Promotes Clonogenic Growth of Glioblastoma via Activation of TGFβ Signaling.

Hye-Min Jeon, Yong Jae Shin, Jaehyun Lee, Nakho Chang, Dong-Hun Woo, Won Jun Lee, Dayna Nguyen, Wonyoung Kang, Hee Jin Cho, Heekyoung Yang, Jin-Ku Lee, Jason K Sa, Yeri Lee, Donggeon Kim, Benjamin W Purow, Yeup Yoon, Do-Hyun Nam, Jeongwu Lee.

Glioblastoma (GBM) is the most lethal brain cancer with a dismal prognosis. Stem-like GBM cells (GSCs) are a major driver of GBM propagation and recurrence, thus understanding the molecular mechanisms that promote GSCs may lead to effective therapeutic approaches. Through in vitro clonogenic growth-based assays, we determined mitogenic activities of the ligand molecules that are implicated in neural development. We have identified that Semaphorin 3A (Sema3A), originally known as an axon guidance molecule in the central nervous system, promotes clonogenic growth of GBM cells but not normal neural progenitor cells (NPCs). Mechanistically, Sema3A binds to its receptor Neuropilin-1 (NRP1) and facilitates an interaction between NRP1 and TGF receptor 1 (TGFR1), which in turn leads to activation of canonical TGF signaling in both GSCs and NPCs. TGF signaling enhances self-renewal and survival of GBM tumors through induction of key stem cell factors, but it evokes cytostatic responses in NPCs. Blockage of the Sema3A-NRP1 axis via shRNA-mediated knockdown of Sema3A or NRP1 impeded clonogenic growth and TGF pathway activity in GSCs and inhibited tumor growth in vivo. Taken together, these findings suggest that the Sema3A-NRP1-TGFR1 signaling axis is a critical regulator of GSC propagation and a potential therapeutic target for GBM.

Keywords: Brain cancer; Development; Growth factors; Oncogenes; Oncology

DOI: https://doi.org/10.1172/jci.insight.167049

Sci Transl Med. 2023 Oct 04. 15(716): eadh4181

Identifying predictors of glioma evolution from longitudinal sequencing.

Clonal evolution drives cancer progression and therapeutic resistance. Recent studies have revealed divergent longitudinal trajectories in gliomas, but early molecular features steering posttreatment cancer evolution remain unclear. Here, we collected sequencing and clinical data of initial-recurrent tumor pairs from 544 adult diffuse gliomas and performed multivariate analysis to identify early molecular predictors of tumor evolution in three diffuse glioma subtypes. We found that CDKN2A deletion at initial diagnosis preceded tumor necrosis and microvascular proliferation that occur at later stages of IDH-mutant glioma. Ki67 expression at diagnosis was positively correlated with acquiring hypermutation at recurrence in the IDH-wild-type glioma. In all glioma subtypes, MYC gain or MYC-target activation at diagnosis was associated with treatment-induced hypermutation at recurrence. To predict glioma evolution, we constructed CELLO2 (Cancer EvoLution for LOngitudinal data version 2), a machine learning model integrating features at diagnosis to forecast hypermutation and progression after treatment. CELLO2 successfully stratified patients into subgroups with distinct prognoses and identified a high-risk patient group featured by MYC gain with worse post-progression survival, from the low-grade IDH-mutant-noncodel subtype. We then performed chronic temozolomide-induction experiments in glioma cell lines and isogenic patient-derived gliomaspheres and demonstrated that MYC drives temozolomide resistance by promoting hypermutation. Mechanistically, we demonstrated that, by binding to open chromatin and transcriptionally active genomic regions, c-MYC increases the vulnerability of key mismatch repair genes to treatment-induced mutagenesis, thus triggering hypermutation. This study reveals early predictors of cancer evolution under therapy and provides a resource for precision oncology targeting cancer dynamics in diffuse gliomas.

DOI: https://doi.org/10.1126/scitranslmed.adh4181

Neuro Oncol. 2023 Oct 04. 25(Supplement_4): iv1-iv99

CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2016-2020.

Quinn T Ostrom, Mackenzie Price, Corey Neff, Gino Cioffi, Kristin A Waite, Carol Kruchko, Jill S Barnholtz-Sloan.

The Central Brain Tumor Registry of the United States (CBTRUS), in collaboration with the Centers for Disease Control and Prevention and the National Cancer Institute, is the largest population-based registry focused exclusively on primary brain and other central nervous system (CNS) tumors in the United States (US) and represents the entire US population. This report contains the most up-to-date population-based data on primary brain tumors available and supersedes all previous CBTRUS reports in terms of completeness and accuracy. All rates are age-adjusted using the 2000 US standard population and presented per 100,000 population. The average annual age-adjusted incidence rate (AAAIR) of all malignant and non-malignant brain and other CNS tumors was 24.83 per 100,000 population (malignant AAAIR=6.94 and non-malignant AAAIR=17.88). This overall rate was higher in females compared to males (27.85 versus 21.62 per 100,000) and non-Hispanic persons compared to Hispanic persons (25.24 versus 22.61 per 100,000). Gliomas accounted for 26.3% of all tumors. The most commonly occurring malignant brain and other CNS histopathology was glioblastoma (14.2% of all tumors and 50.9% of all malignant tumors), and the most common predominantly non-malignant histopathology was meningioma (40.8% of all tumors and 56.2% of all non-malignant tumors). Glioblastomas were more common in males, and meningiomas were more common in females. In children and adolescents (ages 0-19 years), the incidence rate of all primary brain and other CNS tumors was 6.13 per 100,000 population. There were 86,030 deaths attributed to malignant brain and other CNS tumors between 2016 and 2020. This represents an average annual mortality rate of 4.42 per 100,000 population and an average of 17,206 deaths per year. The five-year relative survival rate following diagnosis of a malignant brain and other CNS tumor was 35.7%, for a non-malignant brain and other CNS tumor the five-year relative survival rate was 91.8%.

DOI: https://doi.org/10.1093/neuonc/noad149