bluuebunny/crossref_metadata_2025 huggingface dataset:
CTNI-71. RELA FUSION-POSITIVE EPENDYMOMA, DIFFUSE MIDLINE GLIOMA AND GRADE 4 IDH MUTANT ASTROCYTOMA TREATED WITH VAL-083 UNDER EXPANDED ACCESS: CASE REPORTS
Authors: Kamiya-Matsuoka Carlos , Weathers Shaio-Pei , Knight Stephanie , Hanna Teresa , Langlands John , Brown Dennis , Puduvalli Vinay
Published: November 2024

RELA fusion-positive ependymoma is associated with supratentorial location, higher WHO grade and poor prognosis. Diffuse Midline Glioma (DMG) is a relatively rare CNS tumor, originating in the midline location of the brain. Surgical intervention is restricted to biopsy and radiation. Grade-4 astrocytoma, is highly aggressive with rapid progression. Standard treatment includes surgery and radiation therapy, with limited systemic options other than clinical trials for recurrent disease. VAL-083 is a DNA-targeting agent which rapidly induces inter-strand DNA cross-links at O6- and N7-guanine inducing double-strand breaks causing cell death and acts independent of MGMT DNA repair in high-grade gliomas. We report on 4 patients who had recent disease progression and unmethylated MGMT promoter status treated with VAL-083 under an expanded access program: Case #1: a 47-yo male diagnosed with IDHwt, RELA fusion-positive ependymoma. Case #2: an 18-yo male diagnosed with IDHwt, MAP2K1 and RELA fusion-positive ependymoma. Case #3: a 25-yo male diagnosed with IDHmut Grade 4 astrocytoma, with ATRX, INPP4A, RET and TP53 mutations. Case #4: a 21 yo male diagnosed with IDHwt DMG of the brain stem. All patients had multiple recurrences, received radiation and multiple systemic treatment regimens. They received VAL-083 (30 mg/m2 for 3 days every 21 days) under an expanded access program. Patients with ependymoma received 6 and 5 cycles of VAL-083, (case 1 and 2, respectively), while the patients with IDHmut Gr 4. astrocytoma and DMG received 5 and 18 cycles of VAL-083, respectively. No adverse events were reported and no dose reductions were required. These cases highlight that VAL-83 may be a treatment option for recurrent RELA fusion-positive ependymoma, Gr4. IDHmut astrocytoma, and DMG refractory to other treatment regimens. Additional outcomes related to these cases will be presented at the meeting. Clinicaltrials.gov Identifier: NCT03138629. The treatment plans for the EA patients were approved by MD Anderson Cancer Center IRB
CTNI-74. SONODYNAMIC THERAPY (SDT) USING INTRAVENOUS 5-AMINOLEVULINIC ACID WITH NON-ABLATIVE FOCUSED ULTRASOUND FOR THE TREATMENT OF DIFFUSE INTRINSIC PONTINE GLIOMAS IN PEDIATRICS: INITIAL SAFETY AND OUTCOMES THE MULTICENTER SDT-201 TRIAL
Authors: Kilburn Lindsay , Keating Robert , Patel Nirali , Fonseca Adriana , Donoho Dan , Oluigbo Chima , Myseros John , Narsinh Kazim , Mueller Sabine , Ho Winson , Khatib Ziad , Niazi Toba , Clanton Ryan , Henry Lenora , Potter Wyatt , Marcus Stuart , Benaim Ely , Packer Roger , Syed Hasan
Published: November 2024

Diffuse intrinsic pontine glioma (DIPG) is the leading cause of mortality amongst pediatric neuro-oncologic diseases. Sonodynamic therapy with non-ablative MR-guided focused ultrasound (MRgFUS) is being investigated in multiple clinical trials. We describe safety outcomes and initial efficacy of SDT with 5-ALA for the treatment of pediatric patients with DIPG. Twelve patients with DIPG were treated from August 2022-April 2024 as part of a dose-escalation protocol with SDT in a multicenter Phase 1/2 clinical trial (NCT05123534). MRgFUS was combined with the prodrug SONALA-001 (5-ALA iv) to activate its metabolite, protoporphyrin IX, and thereby induce apoptosis within tumor cells. Treatment is delivered every 4 weeks for up to 12 treatments. Patient ages ranged from 3-23 years and 60% were male. Twelve patients underwent a total of 45 SDT treatments (range 2-9). When enrolled, median tumor volume was 1,337 cm3 (range, 310-2078 cm3) and duration since diagnosis was 5 months. SONALA-001 doses tested were 5 mg/kg and 10 mg/kg. Delivered ultrasonic acoustic energy ranged from 190-444 joules/cm3. After 6 months of median follow-up (range 2-18), 2 partial responses occurred, and 9 of 12 patients had stable or improved baseline symptoms (Lansky Status), including improved mobility and diplopia. One adverse clinical event included a small non-operative epidural hematoma secondary to a stereotactic frame pin. There have been no grade 3 or worse treatment-related adverse events or dose-limiting toxicities. Ten patients are alive a median of 11 months after diagnosis; 2 have deceased; 4 have discontinued treatment. Maximum percent tumor volume changes throughout treatment ranged from a -68% reduction to over 100% enlargement. Preliminary analysis of twelve pediatric patients treated with SDT for DIPG demonstrates acceptable safety outcomes and promising clinical results. Additional patient enrollment and longer follow-up times are required to determine efficacy.
CTNI-75. TRIALS IN PROGRESS: REGISTRY OF SAFETY & EFFICACY IN ADULTS WITH PRIMARY & METASTATIC INTRACRANIAL TUMORS TREATED WITH START (GAMMATILES (CS-131 SOURCE BRACHY-THERAPY)): NCT04427384
Authors: Dunbar Erin , Lee Stuart , Peach Matthew Sean , Wanbo John , Smith Chris , Hansfit Simon , Mertitz Keith , Berkowitz Aviva , Sloan Lindsey , Ferreira Clara , Neil Elizabeth , Kotecha Rupesh , Nowlan Adam , McCracken David , Patel Toral , Wardak Zabi , Richardson Angela , Shah Mitesh , Chowdhary Sajeel , DiNapoli Vincent , Floyd John , Nagib Mahmoud , Wasilewski Andrea , Patel Akash , Rao Ganash , Pham Houng , Ryan Roby , Shen Colette , Robin Adam , Lee Ian , Leng Lewis , Hoang Kim , Olson Jeff , Choutka Ondrej , Mercado Catherine , Chamoun Rouboz , Camarata Paul , Smith William , Babu Harish , Piccioni David , Sevak Parag , Zhu James , Haydon Devon , Aizenberg Michelle , Hoeprich Mark , Williams Brian , Dickinson Lawrence , Baskin David , Farach Andrew , rodriguez alaniz
Published: November 2024

INTRO

This is the first observational registry study of R+STaRT, delivered by Cs-131 sources in permanently implanted resorbable collagen tile carriers, for patients with intracranial tumors.

METHODS

Since October 2020, 37 sites to-date have enrolled 359 patients with primary & metastatic intracranial tumors into the R+STaRT registry to assess the safety & efficacy of the addition of Gamma Tile to medically needed resection. Local control, overall survival, QOL, neurocognition, functional decline, and surgical and radiation associated AE’s are collected at 1, 3, 6, 9,12, 18 and 24 months, then every 6 months through 5 years.

RESULTS

Demographics include 359 patients, avg. age 57 y.o.. 162 malignant gliomas, 125 metastatic tumors, 38 meningiomas, and 34 rare other tumors. 197 Males (163 White, 23 Black, 5 Asian, and other races) and 157 Females (White 121, 28 Black, 0 Asian, and 8 other races). No unexpected outcomes reported in the hands of experienced providers have occurred, although close clinical-radiographic follow-up, to ensure early detection of possible treatment-effects, is paramount. Steroid-use, and above endpoints, continue to be collected.

CONCLUSIONS

In this observational registry of Gamma Tiles (Cs-131 source brachy-therapy) added to medically needed resections for patients with primary and metastatic intracranial tumors continues. Data will be used to benchmark clinical outcomes of R+STaRT therapy and allow for comparisons to existing standard-of-care treatments. The outcome measures captured will allow for evaluation of the potential risks and benefits of this treatment approach for patients in a real-world setting.
CTNI-77. PHASE 1 DOSE FINDING STUDY EVALUATING THE SAFETY, TOLERABILITY, AND EFFICACY OF IOPOFOSINE I 131 IN CHILDREN, ADOLESCENTS, AND YOUNG ADULTS WITH INOPERABLE RELAPSED OR REFRACTORY HIGH-GRADE GLIOMAS: A TRIAL-IN-PROGRESS
Authors: Sait Sameer Farouk , Morgenstern Daniel A , Pandit-Taskar Neeta , Das Anirban , Pudel Miriam , Fisher Callie , Zanzonico Pat , Haque Sofia , Longcor Jarrod , Shustov Andrei , Glade-Bender Julia
Published: November 2024

Iopofosine I 131, a radioconjugate therapy targeting tumor lipid rafts, is being assessed in CLOVER-2 [NCT05610891]–an ongoing dose-finding study evaluating iopofosine in children, adolescents, and young adults with relapsed, refractory, recurrent high-grade gliomas (HGGs) and ependymoma. Major inclusion criteria include patients aged 10-25 years, previously confirmed HGGs or ependymoma, ≥1 measurable intracranial lesion (≥10 mm in longest diameter), and performance status ≥60. Patients are assigned 1:1 to 2 treatment arms which will be assessed in parallel. Arm 1 has 2 cycles, each composed of 2 doses of 20 mCi/m2 given 14 days apart (± 1 day). Cycle 2 is given 8 weeks (± 4 days) post-initial infusion. Arm 2 patients receive 3 cycles of 10 mCi/m2 per dose. Patients in either arm are eligible for 1 additional cycle at the physician’s discretion. If after the first 10 patients, Arm 1 is not tolerated, dosing is reduced to 15 mCi/m2 per infusion. If after the first 10 patients in Arm 2 are deemed to be ineffective and Arm 1 is deemed to be tolerated, dosing is increased to 15 mCi/m2 per infusion. Final visits occur 57 days following the last cycle initiation, with quarterly follow-ups in year 1 and annually in years 2 and 3. Primary endpoints include safety, tolerability, and progression-free survival (PFS). Secondary endpoints are dosimetry, recommended phase 2 dosing determination, overall survival, antitumor and therapeutic activity, and duration of response and clinical benefit. Safety analysis uses the Wilson score method and nonparametric Wilcoxon signed-rank test. Efficacy analyses use the Response Assessment in Pediatric Neuro-Oncology criteria and the Kaplan-Meier method to detect a median PFS of 5 months compared to a historical control of 2 months. For 90% power by a 1-sided, 1-sample log-rank test: ≥10 evaluable patients must be enrolled (≤90) across ≤15 sites.
CTNI-79. ASSESSING SYSTEMIC AND LOCAL LEVELS OF LIDOCAINE DURING SURGERY FOR GLIOBLASTOMA
Authors: Riestenberg Robert , Goodarzi Amir , Goodrich Dylan , Chen Shuai , Chen Yichu , Schloemerkemper Nina , Lechpammer Mirna , Bloch Orin , Shahlaie Kiarash
Published: November 2024

The objective of this study is to assess the pharmacokinetics of lidocaine penetration into tumor tissue during glioblastoma surgery. In-vitro studies of glioblastoma have demonstrated co-culture with lidocaine inhibits glioblastoma proliferation via inhibition of TRPM7 channels. TRPM7 is a transmembrane ion channel that modulates proliferation and migration in several human cancers. Scalp block with lidocaine during glioblastoma surgery has been associated with improved survival in human studies. Twelve patients were enrolled in this study. The study group received an intravenous bolus dose of 1.5 mg/kg IBW of lidocaine at induction of anesthesia followed by 2 mg/kg IBW/hr infusion of lidocaine. Craniotomy was performed in the standard fashion. A total of 3 fresh tumor specimens were collected hourly from each patient after confirmation of glioblastoma diagnosis by frozen section. Plasma samples were simultaneously collected for analysis. Lidocaine concentration was measured using mass spectroscopy. The maximum concentration of lidocaine (Cmax), time from bolus to maximum concentration (Tmax), and area under curve from 0-3 hours (AUC) were calculated for each patient. Patients were followed for survival and adverse events. The median tumor specimen Cmax, Tmax, and AUC values were 333 ng/dL (range 226-555), 179 min (range 126-211), and 20665 ng*min/dL (range 8003-55,426), respectively. Peak lidocaine concentration was reached in 6 of 12 cases. Median Cmax and Tmax for plasma samples were 1195 ng/dL (range 951-1475) and 191 min (range 156-211), respectively. Median overall survival was 308 days (range 74-413). Two grade 3 adverse events occurred which were deemed to be unlikely to be related to the study intervention. In conclusion, lidocaine infiltrates tumor tissue when administered intravenously during glioblastoma surgery. Concentrations do not reach levels previously demonstrated to inhibit tumor growth in in vitro studies (roughly 2*108 ng/dL lidocaine). Alternative mechanisms may explain previously observed improved outcomes with lidocaine administration in human studies.
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

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

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 >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

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

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

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

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

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

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

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

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.
DDDR-11. INHIBITING OXIDATIVE PHOSPHORYLATION AND HYPOXIA WITH ATOVAQUONE – A STRATEGY TO RADIOSENSITIZE DIFFUSE MIDLINE GLIOMA
Authors: Mudassar Faiqa , Ing Prunella , Nguyen Sandy , Chang Cecilia , Cook Kristina M , Warnken Zachary N , O’Neill Geraldine , Shen Han , Hau Eric
Published: November 2024

Diffuse midline glioma (DMG) is a uniformly fatal paediatric brainstem tumour with median survival of less than 1 year. Radiotherapy has been the only effective treatment for decades, but most DMGs recur within several months due to radioresistance. The hypoxic tumour microenvironment is a main feature of solid tumours including gliomas and a major contributor to radioresistance. Therefore, alleviating tumour hypoxia to enhance the effectiveness of radiotherapy is a potential therapeutic strategy to improve the survival outcomes of DMG patients. We found evidence suggesting increased mitochondrial oxidative phosphorylation (OXPHOS) in DMG. Hence, we aimed to target OXPHOS by decreasing the oxygen consumption rate (OCR) of DMG cells, which in turn will alleviate hypoxia by sparing more oxygen and subsequently improve the radiosensitivity of DMG cells. We performed a high-throughput screening to identify potent OCR inhibitors from a library of 1963 FDA-approved drugs. The most promising OCR inhibitor identified was atovaquone, a drug used for treatment of pneumocystis pneumonia and malaria. We found that atovaquone inhibited mitochondrial metabolism of DMG cells by specifically targeting the mitochondrial complex III. Increased mitochondrial reactive oxygen species after exposure to atovaquone suggested that it increases oxidative stress. The treatment alleviated hypoxia and decreased the expression of hypoxia-inducible factor-1a in 3-dimensional DMG neurospheres and improved the radiosensitivity in several DMG cultures. To overcome the poor bioavailability of commercially available atovaquone that results in low therapeutically effective brain concentrations, we tested its efficacy against the amorphous solid dispersion (ASD) atovaquone formulation which appears to enhance atovaquone levels in the brain. We found that both the formulations inhibited OCR and hypoxia at similar doses and enhanced DMG radiosensitivity. The combination of ASD atovaquone and radiation significantly improved survival in orthotopic DMG mouse model. Collectively, this data provides evidence of atovaquone as a potential radiosensitizer for DMG.
DDDR-21. MPT0G521 AS A DUAL INHIBITOR OF LSD1 AND HDAC: A POTENTIAL THERAPEUTIC AGENT AGAINST PARENTAL AND TEMOZOLOMIDE-RESISTANT GLIOBLASTOMA MULTIFORME
Authors: Lo Wei-Lun , Chuang Jian-Yin , Wu Ming-Shao
Published: November 2024

INTRODUCTION

Glioblastoma multiforme (GBM) is an aggressive brain tumor with limited treatment options and poor prognosis. Resistance to temozolomide (TMZ), the standard chemotherapy for GBM, further complicates treatment. This study investigates the effects of MPT0G521, a dual inhibitor of LSD1 and HDAC, on both parental and TMZ-resistant GBM cells to determine its potential as a therapeutic agent.

MATERIALS AND METHODS

TMZ and MPT0G521 were introduced in our study. Human GBM cell lines A172 and patient-derived primary GBM cells Pt#3, along with their TMZ-resistant counterparts, were cultured under specified conditions. Assays conducted include cell proliferation (MTT), colony formation, cell cycle analysis via flow cytometry, and western blot analysis for protein expression. Statistical significance was evaluated using ANOVA.

RESULTS

MPT0G521 exhibited significant anti-proliferative activity and toxicity against both parental and TMZ-resistant GBM cells in a dose- and time-dependent manner. Treatment with MPT0G521 led to reduced cell viability and colony formation. Cell cycle analysis revealed G2M phase arrest and increased subG1 phase, indicating cell cycle disruption and apoptosis. Western blot analysis showed upregulation of histone H3 methylation and acetylation, confirming the dual inhibitory action of MPT0G521 on LSD1 and HDAC. Additionally, MPT0G521 modulated markers of cell cycle and apoptosis, including increased levels of cleaved caspase-3 and PARP.

CONCLUSION

MPT0G521 demonstrates potential as an effective therapeutic agent against GBM by inhibiting cell proliferation, inducing cell cycle arrest, and promoting apoptosis in both parental and TMZ-resistant cells. These findings support further investigation of MPT0G521 as a promising treatment for GBM, particularly in cases resistant to standard chemotherapy.
DDDR-25. IBUDILAST AND ANTI-PD-L1 COMBINATION TREATMENT SIGNIFICANTLY IMPROVES SURVIVAL IN A SEX-DEPENDENT MANNER IN A MURINE MODEL OF GLIOBLASTOMA
Authors: Jarmula Jakub , Lee Juyeun , Kurlich Andrew , Matsuda Kazuko , Bayik Defne , Lathia Justin
Published: November 2024

INTRODUCTION

Glioblastoma (GBM) is the most common primary malignant brain tumor, and there remains a significant need for new treatments. Previous trials studying immune checkpoint inhibitors (ICI) as single agents have been negative. Ibudilast is a brain penetrant inhibitor of the macrophage migration inhibitory factor (MIF)-CD74 interaction that sensitizes GBM to temozolomide in vitro and alters myeloid-derived suppressor cells in vitro and in vivo. The purpose of this study was to investigate whether ibudilast increases ICI efficacy in a murine model of GBM.

METHODS

6-week-old male and female C57BL/6 mice were implanted with SB28 cells intracranially. One week after implantation, each group was randomized to receive intraperitoneal treatment with either: ibudilast (50 mg/kg), anti-PD-L1 (1mg/kg), combination, or vehicle control. Mice were euthanized at neurological endpoint. Survival was modeled with Cox proportional hazards regression.

RESULTS

Among females, there was a significant difference in survival among treatment groups (p=0.0002). Specifically, combination treatment led to significantly longer survival compared to ibudilast (p=0.004) and control (p=0.03), but not anti-PD-L1 (p=0.12). Among males, there was no significant difference in survival among groups (p=0.40). Males had significantly shorter median survival compared to females (overall: 18 versus 22 days, combination treatment: 20 days versus 32 days, anti-PD-L1: 14 versus 22 days, ibudilast: 17 versus 17 days, control: 18 versus 22 days, p=0.02).

CONCLUSIONS

Ibudilast with anti-PD-L1 is a promising combination treatment against GBM. Future research is needed to identify the mechanisms underlying this treatment regimen and its sex-dependent effect. These results may inform the development of a combination new clinical trial, as ibudilast is currently being evaluated in the newly-diagnosed and recurrent GBM setting with temozolomide.
DDDR-27. BMP SIGNALING MODULATES APOPTOTIC AND NON-APOPTOTIC CELL DEATH IN GLIOBLASTOMA
Authors: Lee Weaverly Colleen , Salinas Jennifer , Nathanson David , Dixon Scott
Published: November 2024

Recurrence occurs in approximately 90% of glioblastoma (GBM) patients, in part due to the tumors becoming resistant to cell death in response to existing therapies. These therapies often trigger apoptosis; however, apoptosis is only one of several different forms of cell death. We hypothesize that activating non-canonical death mechanisms could provide a back door to killing treatment-resistant GBM cells. To test this hypothesis, we first developed a new imaging-based high-throughput method to directly quantify cell death in 3D models. Using this method, we find patient-derived GBM spheroids to be resistant to the induction of cell death in response to various standard-of-care and experimental therapeutic compounds. To further investigate mechanisms underlying this resistance, we screened a panel of extracellular protein ligands for the modulation of cell death response. We find that bone morphogenic protein (BMP) signaling increases resistance to several apoptosis-inducing compounds, including temozolomide and tyrosine kinase inhibitors. Intriguingly, BMP signaling simultaneously enhanced sensitivity to a novel non-apoptotic cell death pathway triggered by the small molecule CIL56. Efforts are ongoing to further understand how BMP signaling governs apoptotic and non-apoptotic cell death mechanisms. Nevertheless, our results suggest a novel approach to treating GBM, centered upon the modulation of BMP signaling combined with the use of agents that induce non-apoptotic cell death.
DDDR-30. ENHANCED CHEMO AND RADIO-SENSITIZATION OF GLIOMAS BY HSP90 INHIBITION WITH JIN-001, A NOVEL BLOOD-BRAIN BARRIER PENETRANT HSP90 INHIBITOR
Authors: Xu Jihong , Sugur Harsha S , Sharma Pratibha , Huo Longfei , Dasgupta Pushan , Chen Xiaohua , Seah Ethan , Sampath Deepa , Puduvalli Vinay K
Published: November 2024

BACKGROUND

HSP90, an abundant molecular chaperone, plays a pivotal role as a key regulator in the growth and survival of malignant cells and has been a therapeutic target in various cancers. We have previously reported a strong role for HSP90 inhibitors to disable DNA damage repair mechanisms and induce cell death. Here, we determined the effects of JIN-001 mediated HSP90 inhibition on alkylator and radiation induced DNA damage. Method: Using a panel of patient-derived glioma stem cells (GSCs) we determined the synergy scores for cell viability of JIN-001 (0.1µM to 0.5µM) in combination with radiation (RT) and Temozolomide (TMZ). We also examined cell cycle dynamics and cell death of the combination using flow cytometry (PI and PI/Annexin method) and cell viability assays. Additionally, organotypic human glioma slice cultures treated with JIN-001 and chemoradiation were analyzed for changes in gene and protein expression as well as cell viability in situ. Ongoing in-vivo studies are being conducted to further elucidate drug combination efficacy in mouse models.

RESULTS

JIN-001 sensitized the cells to chemoradiation leading to cell cycle arrest and cell death which was higher in the combination compared to single agent. Significant changes in expression of downstream molecules of homologous recombination pathway was noted (ATM, pATM, CHK1, pCHK1, ATR, pATR) in the cell lines and confirmed in human glioma slice culture. Based on the synergy score from four cell lines, an effective dose for combination of JIN-001+RT+TMZ was identified; Results of ongoing ex-vivo human glioma gene expression changes and in-vivo mouse studies will be presented.

CONCLUSION

Through a comprehensive analysis, we demonstrated that HSP90 inhibitor JIN-001 sensitizes glioma cells to radio-chemotherapy including in human glioma tissue. Our study underscores the potential of combining JIN-001 with standard therapies in glioma treatment in future clinical trials for patients with glioblastoma.
DDDR-41. A GENOME-WIDE CRISPR/CAS9 SCREEN IN GLIOBLASTOMA STEM CELLS UNVEILS SYNTHETIC LETHAL INTERACTIONS AND RESISTANCE MECHANISMS OF JIN001, A BLOOD-BRAIN BARRIER-PENETRANT HSP90 INHIBITOR
Authors: Chen Xiaohua , Anvar Nazanin Esmaeili , Colic Medina , Xu Jihong , Liang Jiyong , Sharma Pratibha , Huo Longfei , Sugur Harsha S , Hart Traver , Puduvalli Vinay K
Published: November 2024

Glioblastomas (GBMs) are aggressive brain tumors characterized by extensive genetic heterogeneity and therapeutic resistance. Heat shock protein 90 (Hsp90) is a molecular chaperone that stabilizes and facilitates the proper folding of numerous proteins, including oncogenic drivers and is overexpressed in cancers. Hsp90 inhibitors can disrupt multiple oncogenic signaling pathways by degrading various client proteins essential for tumor growth and survival, making them attractive therapeutic candidates for GBMs. We have previously reported on the efficacy of Hsp90 inhibitors against gliomas. However, cancer cells develop resistance to Hsp90 inhibitors by upregulating compensatory chaperones (e.g., Hsp70), mutating client proteins, or activating alternative survival pathways, reducing the long-term efficacy of these agents. Combination approaches overcoming such resistance mechanisms are needed. JIN001, a novel Hsp90 inhibitor, demonstrates superior blood-brain barrier (BBB) penetration, and high potential for clinical translation. we performed a genome-wide CRISPR/Cas9 knockout screen using the Toronto Knockout Library v3 (TKOv3) with screen selection pressure from JIN001 in GBM stem cells (GSC272) to identify synthetic lethal interactions and resistance mechanisms associated with JIN001 treatment. Experiments were performed in triplicate with two time points, T22 and T37. Quality control analysis of the NGS data indicated excellent quality and consistency between different replicates. DrugZ analysis revealed a set of sensitive and resistant genes, informing potential combination therapies and further elucidating JIN001’s mechanism of action. Validation studies for the top synthetic lethal targets are underway to confirm the identified interactions and will be presented. This CRISPR-Cas9 screen offers valuable insights into JIN001’s therapeutic potential, reveals new combination strategies to overcome resistance to Hsp90 inhibitors and for use of these agents in other cancers, and paves the way for the development of more effective GBM combination treatment strategies.