bluuebunny/crossref_metadata_2025_split huggingface dataset:
CTNI-81. PROPOSAL FOR A PHASE IB PILOT CLINICAL TRIAL TO STUDY SAFETY AND IMPROVING ANTI-NEOPLASTIC ADVERSE EFFECTS BY ADDITION OF NATURAL MARINE PRODUCT FUCOIDAN TO THE STANDARD THERAPY FOR PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA (GBM)
Authors: Kong Xiao-Tang , Miyazaki Yoshiyuki , Ma Chunxiao , Abbott Geoffrey Winston , Bota Daniela A , Yuen Carlen A 
Published: November 2024

Abstract

INTRODUCTION
GBM is the most aggressive primary brain tumor. Despite standard of care (SOC) with the Stupp protocol and tumor treating fields (TTFs), survival remains poor. In addition, SOC treatment is associated with 96% any adverse effects (AE) and 25% severe AEs (Chinot et al, NEJM 2014), which affects quality of life (QOL) and can lead to early treatment termination. Therefore, novel therapies are needed and minimization of chemoradiation-related AEs is crucial. Marine natural product, fucoidan, may have an important role in oncological management as tumor-directed therapy and as a protectant against chemoradiation-related AEs. Fucoidan is a seaweed-derived sulfated polysaccharide. Mounting evidence garnered from randomized clinical trials for colon, head and neck, and lung cancer patients suggests that fucoidan can improve certain AEs associated with chemoradiation. Furthermore, data gleaned from multiple studies have shown that fucoidan is tolerable with a good safety profile.

HYPOTHESIS
Fucoidan is safe in combination with chemoradiation and chemotherapy and improves treatment related AE profile. Fucoidan may improve survival outcome in GBM patients by augmenting cytotoxic effects, inhibiting angiogenesis, and improving the tolerability of SOC therapy.

METHOD
12 newly diagnosed GBM patients will be enrolled. A Fucoidan-based product will be administered orally at the established dose for cancer patients daily with concurrent chemoradiation therapy and adjuvant chemotherapy over 6 months. Patients will be evaluated weekly to monthly for AEs and QOL scoring; laboratory and brain MRI monitoring will be performed per SOC guidelines. NK cell activity, proinflammatory cytokines, including interleukin (IL)-1β, will be measured.

POTENTIAL OUTCOME
This pilot study may establish a foundation for future larger randomized clinical trials to treat brain cancer more effectively by adding nature products.
CTNI-83. PROPOSAL FOR A PILOT PHASE 1B CLINICAL TRIAL WITH ADDITION OF NATURAL MARINE PRODUCT FUCOIDAN TO ANTI-NEOPLASTIC THERAPY FOR PATIENTS WITH RECURRENT GLIOBLASTOMA (RGBM) TO IMPROVE FATIGUE AND OTHER HEALTH-RELATED QUALITY OF LIFE (HRQOL) SYMPTOMS
Authors: Kong Xiao-Tang , Yuen Carlen A , Choi Yoon Jae , Miyazaki Yoshiyuki , Bota Daniela A , Abbott Geoffrey Winston 
Published: November 2024

Abstract

BACKGROUND
Recurrent Glioblastoma (rGBM) has poor outcome with limited treatment options. rGBM causes significant fatigue and other health-related quality of life (HRQOL) symptoms secondary to tumor progression and anti-neoplastic therapies. More than 80% of brain tumor patients were found to experience fatigue during anti-neoplastic therapy and the incidence of cancer related fatigue may reach 89-94% among patients with rGBM. Therefore, improvement of fatigue and HRQOL in rGBM patients are crucial. Marine natural product, fucoidan, available as health supplement in the US, was found to play important roles in oncological management as supportive therapy against cancer and chemoradiation-related adverse effects and as a potential anti-neoplastic therapy. Fucoidan is a seaweed-derived sulfated polysaccharide. Data resulted from randomized clinical trials for colon, head and neck, and lung cancer patients suggest that fucoidan can improve cancer and chemotherapy or chemoradiation therapy related negative symptoms. In addition, Tachikawa et al. reported &gt;50% tumor regression and increased natural killer (NK) cell activity in sarcoma-transplanted mice treated with Fucoidan. In Vitro anticancer investigation found that Fucoidan fractions clearly suppressed the growth of GBM U-251MG cancer cells. Multiple studies have also shown that fucoidan is tolerable with a good safety profile.

METHOD
18 rGBM patients will be enrolled. Fucoidan based product will be administered orally at established dose for cancer patients daily with anti-neoplastic therapy over 6 months. Patients will be evaluated monthly for AEs and HRQOL score; laboratory and brain MRI monitoring will be performed per SOC guidelines. NK cell activity will be measured.

POTENTIAL OUTCOME
Fucoidan is safe and has good tolerability in combination with anti-neoplastic therapy for rGBM and improves fatigue and other HRQOL symptoms by ameliorating tumor progression and treatment related negative impact. Fucoidan may also improve survival in rGBM patients by improving the tolerability of anti-tumor therapy, augmenting cytotoxic effects, and inhibiting angiogenesis.
DNAR-07. ATR INHIBITORS IN COMBINATION WITH RADIATION AND TEMOZOLOMIDE INCREASE CELL DEATH OF PATIENT-DERIVED GLIOBLASTOMA CELLS
Authors: Lozinski Mathew , Bowden Nikola , Fay Michael , Graves Moira , Day Bryan , Stringer Brett , Tooney Paul 
Published: November 2024

Abstract
Glioblastoma is treated with surgery to remove as much as the tumour as possible then radiation therapy (RT) and temozolomide (TMZ) to cause extensive DNA damage in any remaining tumour cells, triggering cell death by apoptosis. However, glioblastoma cells respond by upregulating the DNA damage response (DDR) triggering DNA repair that contributes to treatment resistance. Progression then generally occurs rapidly leaving patients with a poor prognosis and survival. We previously showed that gartisertib, an inhibitor of ATM- and Rad3-Related protein (ATR), a serine/threonine kinase that triggers DNA repair, sensitises glioblastoma cells to TMZ and RT. We extend this investigation to brain-penetrant ATR inhibitors elimusertib (BAY1895344) and ceralasertib (AZD6738). Patient-derived glioblastoma cell lines were treated with a dose response of ATRi (elimusertib and ceralasertib) combined with a clinically relevant dose of TMZ (35uM) and/or RT (2Gy). A human astrocyte cell line was also treated with a dose response of single agent elimusertib and ceralasertib. Cells were incubated for 7 days and assessed for cell viability through an MTT assay or cell-cell Incucyte analysis. Both elimusertib and ceralasertib as single agents reduced glioblastoma cell growth, with elimusertib being more potent compared to ceralasertib. Elimusertib had greater potency in causing cell death of the glioblastoma cell lines than a human astrocyte cell line. However, there was less difference between glioblastoma and astrocyte cell death when treated with ceralasetib. When combined with RT and/or TMZ, elimusertib once again was more potent in reducing glioblastoma cell growth compared to ceralasertib. We have expanded our in vitro data showing that various ATR inhibitors (elimusertib, ceralasertib and previously gartisertib) are able to reduce the growth of glioblastoma cells in combination with RT and TMZ treatment. This provides further support for initiating a clinical trial of ATR inhibition in combination with standard treatment for patients with glioblastoma.
DNAR-10. PHASE I CLINICAL TRIAL OF PEPOSERTIB PLUS RADIOTHERAPY IN ADULTS WITH NEWLY-DIAGNOSED MGMT-UNMETHYLATED GLIOBLASTOMA
Authors: Majd Nazanin , Liu John , Yeboa Nana , Wang Shuqi , Weathers Shiao-Pei , Yuan Ying , Gachimova Evguenia , Wathoo Chetna , Kamiya-Matsuoka Carlos , O’Brien Barbara , Aaroe Ashley , Patel Chirag , Patel Anuj , Dagher Samir , Wintermark Max , Ferguson Sherise , Puduvalli Vinay , Raleigh David , de Groot John 
Published: November 2024

Abstract

BACKGROUND
DNA-dependent protein kinase (DNA-PK) is an attractive target in GBM because it promotes unwanted DNA repair and renders cancer cells less vulnerable to DNA damaging agents, such as radiotherapy (RT). Peposertib, a small molecule inhibitor of DNA-PK, has demonstrated pre-clinical efficacy in sensitizing GBM to RT, resulting in tumor regression.

METHODS
21 patients with newly-diagnosed MGMT-unmethylated GBM received peposertib plus 6-weeks of RT to determine the maximum-tolerated dose (MTD) based on the Bayesian Optimal Interval design. The dose-limiting toxicity (DLT) period was 10-weeks. Patients received at least 6-cycles of adjuvant temozolomide (NCT04555577). Single-nuclei RNA-sequencing (snRNA-Seq) and spatial transcriptomics (Visium, 10x Genomics) were performed on matched pair primary-recurrent tumors and controls, incorporating tumor cell state and cell type definitions by automated cluster classification and differential expression of marker genes.

RESULTS
The MTD of peposertib in combination with RT was 300mg per RT fraction day. One DLT (G3 radiation necrosis @300mg) was observed. After a median follow-up of 15.4 months (interquartile-range 8.9-18.5), mPFS was 10.8 months (95%CI 8.33-NR) and mOS was 22.9 months (95%CI 16-NR). 6/21 (29%) patients have undergone re-resection to date. snRNA-Seq on 102,709 cells from 12 primary and 3 recurrent tumors revealed that pre-treatment tumor cell states were progenitor-like, while treatment with peposertib plus RT was associated with differentiated and inflammatory malignant cell states, along with macrophage infiltration. Spatial transcriptomics of 8 matched primary-recurrent tumors (20,793 transcriptomes) confirmed malignant cell differentiation and enrichment of pro-inflammatory macrophages after inhibition of DNA-PK. 5 patients will be enrolled into a window-of-opportunity expansion cohort to evaluate intratumoral drug concentration.

CONCLUSION
The combination of peposertib and intracranial RT was safe. Survival data for this MGMT-unmethylated GBM population was promising. Single nuclei and spatial transcriptomic analyses revealed enrichment of pro-inflammatory macrophages in the tumor microenvironmentafter DNA-PK inhibition. The study was supported by EMD-Serono (CrossRef Funder ID: 10.13039/100004755).
DNAR-13. LONG TERM FOLLOW-UP OF A LYNCH SYNDROME-ASSOCIATED GLIOBLASTOMA RESISTANT TO STANDARD-OF-CARE CHEMORADIATION
Authors: Hazal Ser Merve , Baykal Duru , White Jessica D , Breen William G , Parney Ian F , Walbert Tobias , Forsyth Peter , Etame Arnold , Macaulay Robert , Pina Yolanda , Sener Uğur 
Published: November 2024

Abstract

BACKGROUND
Lynch syndrome is caused by pathogenic germline variants in the DNA mismatch repair (MMR) genes, predisposing individuals to malignancies, including glioblastoma (GBM). MMR-deficient tumors are resistant to monofunctional alkylators such as temozolomide but not to bifunctional alkylators such as the nitrosourea lomustine. Anti-programmed cell death protein 1 (PD1) immune checkpoint inhibitor (ICI) pembrolizumab represents another treatment option, which is approved by the United States Food and Drug Administration (FDA) for the treatment of mismatch repair deficient cancers.

METHODS
We present a patient with multifocal GBM and Lynch syndrome who experienced rapid progression following standard-of-care chemoradiation, followed by durable responses to lomustine and then to pembrolizumab.

RESULTS
A 58-year-old man with Lynch syndrome (MSH2 mutation) and prior history of colon cancer presented with seizures. Magnetic resonance imaging (MRI) brain identified right frontal and left parietal masses. Right frontal tumor was resected; pathology was consistent with GBM, IDH wildtype, MGMT-unmethylated. Both lesions were treated with radiation therapy (60 Gy, 30 fractions) with concurrent and adjuvant temozolomide. After two cycles of adjuvant temozolomide, his left parietal tumor progressed and was subtotally resected, followed by four cycles of lomustine (stopped due to myelotoxicity). He remained progression-free for 15 months. Surveillance MRI identified new enhancement involving the left frontal lobe, left periventricular white matter, and right internal auditory canal, concerning for leptomeningeal dissemination. MRI spine identified no additional lesions. Cerebrospinal fluid cytology was negative for tumor cells on two occasions. Patient was treated with pembrolizumab. He remains on treatment with stable disease four months after ICI initiation and 31 months after GBM diagnosis.

CONCLUSIONS
Patients with MMR-deficient GBM resist standard chemoradiation. Alternatives such as nitrosourea or ICI therapy may achieve durable responses. While data is insufficient to administer these agents as upfront therapy in this specific setting, both should be considered as options for recurrent disease.
DDEL-05. IMPRESSIVE RESPONSE TO IDH-INHIBITOR THERAPY IN IDH-MUTANT, H3K27M INTACT BRAINSTEM GLIOMAS
Authors: Shah Trusha , Taylor Lynne , Venur Vyshak 
Published: November 2024

Abstract
IDH-mutated brainstem gliomas in adults are a rare entity, with only a handful of cases reported in the literature. Diagnosis and treatment of these gliomas remain challenging. There is significant morbidity associated with a surgical biopsy, thus biopsies are often deferred, and tumors of the brainstem are treated presumptively with radiation and temozolomide. However, in the presence of new targeted therapies, confirming pathology for these patients is becoming increasingly important. We present two cases of IDH-mutant grade 2 astrocytomas of the brainstem that revealed both clinical and radiographic responses to IDH-inhibitor therapy. Interestingly, both patients had the same non-canonical IDH mutation, IDH-R132C, towards which ivosedinib is known to have activity. One patient had tumor progression following radiation therapy and 8 cycles of temozolomide and had subsequently exhibited a dramatic radiographic improvement, including resolution of enhancing disease following initiation of ivosidenib therapy. Clinically, this patient improved from a KPS 50 to KPS 100 after 2.5 years of ivosedinib. The other patient also had an impressive clinical improvement after only 3 months of ivosedinib treatment, with radiographic stability, improvement in balance, and resolution of his previous refractory nausea. These case reports suggest that consideration should be given to brainstem biopsy in adults specifically to evaluate for the presence of a targetable IDH mutation.
DDEL-06. CONVECTION-ENHANCED DELIVERY OF SEVEN DIFFERENT MOLECULES SHOW LARGE DIFFERENCES IN CONVECTIVE PROPERTIES BETWEEN MOLECULES. INFORMED DECISION MAKING FOR OPTIMIZED CATHETER PLACEMENT AND SUBSEQUENT INFUSION STRATEGIES
Authors: Halle Bo , Woolley Max , Johnson Dave , Williams Julia , Kidd Charlotte , Andersen Mikkel Schou , Poulsen Frantz Rom , Gammelsrød Vigga Sand , Nielsen Aaraby Yoheswaran , Amirrashedi Mahsa , Willem Straathof Natan Johannes , Ravn Katharina , Tang Qing , Pedersen Christian Glarbo , Jensen Andrea Tue Ingemann , Thisgaard Helge 
Published: November 2024

Abstract

INTRODUCTION
Glioblastoma (GBM) trials based on convection-enhanced drug delivery (CED) bypassing the blood-brain barrier have failed to prove efficient until now. Many factors influence CED. In this study we evaluated CED of seven different molecules using dynamic PET/MRI during infusion. This enabled in-depth evaluation of drug distribution and concentration gradients providing a more precise understanding of the Vd/Vi ratio and the extent of efficacy level across the Vd zone. Novel surgical catheter placement software algorithms, results in more informed-decision-making for catheter positioning and subsequent infusion planning strategies.

METHODS
Pigs were implanted with neuroinfuse™ drug delivery systems enabling intermittent drug infusions. Gadolinium, [124I]-UdR, [55Co]Co-DOTA-hEGF, [55Co]Co-DOTA-SP4, [18F]PSMA-1007 and three differently sized [64Cu]-labelled nanocarriers were evaluated in both pigs with and without a brain resection cavity. Gadolinium distribution was followed by MRI. PET imaging was used for the rest. To inform clinical trial design, strategic catheter placement and volumes to be infused, planning was investigated on several historical GBM cases.

RESULTS
Vd/Vi ratios ranged between 1.00 – 3.77. where large-sized liposomes performed best. Catheters stayed patent during weeks of repeated infusions. In the resected animals no leakage of drugs into the brain resection cavity was observed. Effective 3D modelling of novel catheter infusion planning aids provided visualized representations of tailor-made infusion plumes, capable of being suitably positioned to optimize surgical planning of catheters and transcutaneous reaccess port.

CONCLUSION
Large differences in convective properties between different molecules were observed. Large-sized liposomes as drug-carrier system showed superior performance to all other molecules. Vd/Vi ratios for promising drugs should be determined before initiating future clinical CED trials. Infusion concentration gradients to facilitate more precise Vd/Vi ratios provided important performance metrics for visualised infusion planning aids of a novel chronic drug delivery system, illustrating informed decision making for optimised catheter placement and subsequent infusion strategies is clinically translatable for GBM indications.
DDDR-07. FUNCTIONAL GENOMICSIN VIVO USING CRISPR/CAS9 IDENTIFIES POTENTIAL METABOLIC VULNERABILITIES WITHIN MELANOMA BRAIN METASTASIS
Authors: Ma Yanxia , Nguyen Nhat , He Wei , Singh Sanjay , Fu Rongjie , Zhang Liang , Holmen Sheri , Jones Phil , Davies Michael , Xu Han , Ene Chibawanye 
Published: November 2024

Abstract

BACKGROUND
Inhibition of the oxidative phosphorylation (OxPhos) pathway in mice suppressed the growth of melanoma brain metastasis but not extracranial or primary skin melanoma. This indicates that melanoma brain metastasis may have targetable metabolic vulnerabilities. Human clinical trials, however showed toxicities following OxPhos pathway inhibition. This suggests that more selective metabolic targets are needed to minimize off target effects.

METHODS
We designed a focused CRISPR guide RNA (gRNA) lentiviral knockout library targeting 106 metabolism genes significantly enriched in human melanoma brain metastasis (n=88) relative to extracranial (n=50) or primary skin melanoma (n=52). We infected mouse B16F10 melanoma cell lines with the CRISPR library and implanted 1X106 cells subcutaneously or intracerebrally into male (n=3) and female (n=3) C57/Bl6 mice. DNA from cell lines and tumor samples were sent for next generation sequencing. Candidate metabolism genes that may drive growth of melanoma lesion within the brain were identified based on loss of gRNA copies in brain relative to skin.

RESULTS
The CRISPR/Cas9 in vivo screen identified metabolic genes whose knockout resulted in loss of gRNA clones within established B16F10 melanoma brain lesions relative to skin lesions. These putative metabolism targets included specific components in the oxidative phosphorylation pathway, choline metabolism, and ubiquitin cascade activation.

CONCLUSION
Using a focused CRISPR/Cas9 in vivo screen, we uncovered potential metabolic targets within established mouse melanoma brain lesions. vWe are currently performing the in vivo screen in melanoma mouse models with spontaneous brain metastasis. Top 3 hits across all models will be validated individually prior to a compound screen for inhibitors.
DDDR-08. PIM1 INHIBITION: A NOVEL THERAPEUTIC APPROACH FOR IDH-MUTANT GLIOMAS
Authors: Li Qi , Kim Olga , Sergi Zach , Lu Peng , Gujral Taranjit S , Wu Jing 
Published: November 2024

Abstract

BACKGROUND
PIM1, a constitutively active serine/threonine kinase has emerged as a relevant target in cancer treatment. Previously, we discovered that IDH-mutant glioma exhibited high kinase activity of PIM1, suggesting an increased sensitivity to PIM1 inhibition. Here we sought to investigate PIM1 inhibition as a therapeutic approach for IDH-mutant gliomas.

METHODS
Patient-derived IDH-mutant and wildtype glioma cell lines were used to evaluate the impact of PIM1inhibition on cell viability, proliferation, and colony formation. mRNA and protein expression of PIM1 were determined by qRT-PCR, Western-blot, and immunohistochemistry. m6A dot-blot assay was conducted to detect m6A RNA levels in glioma cells. m6A modification status and its location in PIM1 transcript were evaluated by m6A RNA immunoprecipitation array. RNA-binding protein immunoprecipitation was performed using anti-YTHDF1 antibody to identify PIM1 RNA-YTHDF1 protein interactions.

RESULTS
An upregulation of PIM1 protein is demonstrated in IDH-mutant patient tumor tissues and cells. A pan-PIM inhibitor, AZD1208 significantly suppressed cell viability, cell proliferation, and colony formation in IDH-mutant cells but had a lesser effect in IDH-wildtype cells. Interestingly, a lower mRNA expression of PIM1 is observed, while the protein level is significantly elevated in IDH-mutant cells compared to wildtype cells, suggesting post-transcriptional and translational regulation of PIM1 associated with IDH mutation. Mechanistically, 2-hydroxyglutarate, unique to IDH-mutant gliomas, competitively inhibits α-KG-dependent RNA demethylase FTO. We demonstrated suppressed FTO activity and an increased m6A RNA level in IDH-mutant glioma cells. An enrichment of m6A modification at motif “GG (m6A) CU” located in the 3’UTR is found in the PIM1 transcript. Furthermore, we demonstrated that the m6A modification site is recognized by the m6A reader YTHDF1 to promote protein translation, leading to an elevated PIM1 protein expression.

CONCLUSION
m6A RNA modification contributes to an enhanced PIM1 activity and thereby a selective sensitivity to PIM1 inhibition in IDH-mutant gliomas.
DDDR-10. MYELOID CELLS COORDINATELY INDUCE GLIOMA CELL-INTRINSIC AND -EXTRINSIC PATHWAYS FOR CHEMORESISTANCE VIA GP130 SIGNALING
Authors: Cheng Jiying , Li Min , Motta Edyta , Barci Deivi , Song Wangyang , Zhou Ding , Li Gen , Zhu Sihan , Yang Anru , Vaillant Brian , Imhof Axel , Forné Ignasi , Spiegel-Kreinecker Sabine , Zhang Nu , Katayama Hiroshi , Bhat Krishna , Flüh Charlotte , Kälin Roland , Glass Rainer 
Published: November 2024

Abstract
The DNA damage response (DDR) and the blood tumor barrier (BTB) restrict chemotherapeutic success for primary brain tumors like glioblastoma (GBM). Coherently, GBM almost invariably relapse with fatal outcome. We here show that interaction of GBM and myeloid cells simultaneously induces chemoresistance on the genetic and the vascular level by activating GP130 receptor signaling, which can be addressed therapeutically. We performed transcriptomic and immunohistochemical screens with human brain material, pharmacological experiments with a humanized organotypic GBM model, proteomics and cell-based assays and observed that nanomolar concentrations of the signaling peptide Humanin promoted TMZ resistance through DDR activation. GBM mouse models recapitulating intratumoral Humanin-release showed accelerated BTB formation. Genetic analysis of pericyte to endothelial cell signaling in transgenic mice revealed increased GP130 activation in Humanin releasing tumors as compared to controls. GP130 blockade attenuated both DDR activity and BTB formation resulting in improved preclinical chemotherapeutic efficacy. Altogether, we describe an overarching mechanism for TMZ resistance and outline a translatable strategy with predictive markers to improve chemotherapy for GBM.