bluuebunny/crossref_metadata_2025 huggingface dataset:
CTNI-61. MYCOPHENOLATE MOFETIL INHIBITS GLIOBLASTOMA PURINE METABOLISM IN HUMANS: AN INTERIM RESULT OF PHASE 0/1 CLINICAL TRIAL TO OVERCOME TREATMENT RESISTANCE IN NEWLY DIAGNOSED AND RECURRENT GLIOBLASTOMA
Authors: Umemura Yoshie , Al-Holou Wajd , Elaimy Ameer , Scott Andrew J , Leung Denise , Clarke Nathan , Kim Michelle M , Ferris Sean , Thomas Jennifer , Heth Jason , Schipper Matthew , Suresh Krithika , Lawrence Theodore , Wahl Daniel
Published: November 2023

BACKGROUND

Mycophenolate mofetil (MMF), a purine synthesis inhibitor, improves radiation and temozolomide efficacy in preclinical glioblastoma models. This phase 0/1 trial (NCT04477200) is the first-in-human study to assess the tolerability of MMF with chemoradiation in glioblastoma, MPA accumulation, and purine synthesis inhibition in tumor.

METHODS

Adult patients meeting eligibility are given MMF 500-2000 PO BID using TITE-CRM dose assignment. Thirty recurrent glioblastoma patients receive MMF one-week prior to and concurrently with re-irradiation (40.5 Gy), with 28 days of dose-limiting toxicity (DLT) period. Thirty newly-diagnosed glioblastoma patients receive MMF one-week prior to and concurrently with chemoradiation and followed for 28 days for DLT1-period. During the adjuvant temozolomide (days 1-5/28-day cycle) period, MMF is given days 0-5 on a separate dose-escalation (DLT2 period = cycles 1-2). Tissues from phase-0 recurrent glioblastoma patients (N = 8) receiving MMF 500-2000mg BID one-week pre-operatively are analyzed using mass spectrometry.

RESULTS

Enhancing and non-enhancing tumor from phase 0 subjects yielded above 1 µM active drug metabolite, and the GTP/IMP ratio was decreased by 75% in enhancing tumor in MMF-treated patients compared to untreated controls (p = 0.009), indicating effective target engagement and inhibition of purine synthesis. No DLT has been observed with adjuvant cyclic temozolomide in phase 1 newly-diagnosed group (N = 26), nor in the recurrent-disease group (N = 18) with re-irradiation. In newly diagnosed arm, 3 subjects experienced DLT1 at 2000mg BID; grade-3 hemiparesis and cognitive disturbance, and grade-4 thrombocytopenia. Other main toxicities are mild nausea and fatigue. Interim median overall survival in recurrent phase 1 is 15.6 months, and not reached yet in newly diagnosed phase 1.

CONCLUSION

MMF combined with chemoradiation has been reasonably well tolerated in glioblastoma patients with preliminary promising evidence of intracranial target engagement of its active metabolite. This study will yield a recommended phase 2 dose and preliminary efficacy estimate for future randomized phase 2/3 trial.
CTNI-62. INTERIM DATA ON DUAL INHIBITION OF POST-RADIOGENIC ANGIO-VASCULOGENESIS BY OLAPTESED PEGOL (NOX-A12) AND BEVACIZUMAB IN GLIOBLASTOMA FROM THE FIRST EXPANSION ARM OF THE PHASE 1/2 GLORIA TRIAL
Authors: Giordano Frank , Layer Julian , Leonardelli Sonia , Friker Lea , Schaub Christina , Zeyen Thomas , Sperk Elena , Hambsch Peter , Oster Christoph , Grau Franziska , Paech Daniel , Müller Wolf , Pietsch Torsten , Schmeel L Christopher , Grauer Oliver , Renovanz Mirjam , Tabatabai Ghazaleh , Kebir Sied , Bisdas Sotirios , Güresir Erdem , Glas Martin , Seidel Clemens , Hölzel Michael , Herrlinger Ulrich
Published: November 2023

BACKGROUND

We recently reported favorable safety and preliminary efficacy signals for treatment with radiotherapy (RT), the CXCL12 neutralizing L-RNA aptamer olaptesed pegol (NOX-A12) and bevacizumab for glioblastoma (GBM) in the German multicenter phase 1/2 GLORIA trial (NCT04121455). Here, we report updated outcomes on dual inhibition of vasculogenesis (NOX-A12) and angiogenesis (bevacizumab).

METHODS

Six patients with incompletely resected, MGMT-unmethylated GBM, ECOG≤ 2 were enrolled, receiving standard RT (60 Gy in 30 fractions), continuous i.v. infusions of NOX-A12 (600 mg/week) and i.v. infusions of bevacizumab (10 mg/kg q2w). The primary endpoint was safety. Secondary endpoints included radiographic response according to modified RANO criteria (mRANO) as well as perfusion/diffusion imaging.

RESULTS

Combination treatment was well-tolerated and safe. Of all G≥2 AEs (n = 79), two G2 events (2.5%) were deemed related to NOX-A12 only. There were no dose-limiting toxicities and no treatment-related deaths. At a median follow-up of 14.6 months, one patient deceased due to distant leptomeningeal spread. Median overall survival (OS) has not yet been reached. With an overall response rate (ORR) of 83.3% under treatment, one patient achieved confirmed complete response (CR), four patients partial response (PR) and one patient stable disease (SD). The median best response under treatment was -68.9% (-53,8% to -100%) for target lesion sums and -100% (-99.9% to -100%) for non-target lesion (NTL) sums. In all three patients with NTLs at least one lesion disappeared. The median best change from baseline of the highly perfused-tumor fraction was -98.2% (-61.3% to -100%) and the median best change of the apparent diffusion coefficient was 24.9% (7.3% to 59.1%).

CONCLUSIONS

Interim data of the ongoing trial confirm the previously established safety profile of NOX-A12 for combinatory treatment with bevacizumab while demonstrating improved efficacy with deeper and longer-lasting responses and a higher ORR compared to treatment with RT and NOX-A12 only.
CTNI-65. INVESTIGATING SAFETY AND EFFICACY OF TTFIELDS PRIOR AND CONCOMITANT TO RADIOTHERAPY IN NEWLY DIAGNOSED GLIOBLASTOMA - FIRST RESULTS OF THE PRICOTTF PHASE I/II TRIAL
Authors: Kebir Sied , Lazaridis Lazaros , Schmidt Teresa , Oster Christoph , Feldheim Jonas , Pierscianek Daniela , Proescholdt Martin , Hau Peter , Grosu Anca-Ligia , Krex Dietmar , Sure Ulrich , Scheffler Björn , Kleinschnitz Christoph , Pöttgen Christoph , Stuschke Martin , Glas Martin
Published: November 2023

BACKGROUND

A synergistic inhibiting effect on glioblastoma cell proliferation was reported for the combination of TTFields and radiotherapy. Based on these preclinical findings, we performed the phase I/II PriCoTTF trial in adult nGBM patients to investigate the safety and efficacy of TTFields therapy initiated prior and concomitant to radiochemotherapy. Material and

METHODS

In this phase I/II trial, TTFields therapy was initiated following surgery and continued throughout radiochemotherapy and adjuvant chemotherapy for a total of approximately 9 months. TTFields rechallenge was allowed at recurrence. Radiotherapy was conducted with arrays applied on the patients’ scalp. Safety and tolerance are the study’s primary endpoint, determined by a selection of pre-specified treatment-limiting toxicities (TLTs).

RESULTS

A total of 33 patients have been enrolled. Patients' characteristics were mostly typical for glioblastoma, except for a rather low fraction of patients with gross total resection (GTR, 22.5%). The distribution of adverse events of ≥ common toxicity criteria (CTC) grade 3 was comparable to that of established glioblastoma trials. Notably, skin toxicity of ≥ CTC grade 3 was uncommon (n = 2, 6%). No patient developed TLTs. Median TTFields treatment duration was 8.4 months. Overall survival data was not mature enough (event rate 48%) to allow for a definite conclusion. Notably, on multivariable Cox regression, the number of days with TTFields adherence >23 hours was independently associated with overall survival (HR 0.96, 95% confidence interval 0.93 - 0.99, p = 0.008).

CONCLUSION

The PriCoTTF trial met its primary endpoint indicating that combined TTFields and radiotherapy is safe and well tolerated. High-grade skin toxicity was quite uncommon and the patients with high TTFields adherence seem to perform particularly well. An extended follow-up is required to provide first estimates regarding putative efficacy. At that point in time, the reduced overall TTFields duration and fraction of patients with GTR need to be factored in.
CTNI-73. ALLIANCE A071601: PHASE II TRIAL OF BRAF/MEK INHIBITION IN NEWLY DIAGNOSED PAPILLARY CRANIOPHARYNGIOMAS
Authors: Brastianos Priscilla , Twohy Erin , Geyer Susan , Gerstner Elizabeth , Kaufmann Timothy , Tabrizi Shervin , Kabat Brian , Thierauf Julia , Ruff Michael , Bota Daniela , Reardon David , Cohen Adam , de la Fuente Macarena , Lesser Glenn , Campian Jian , Agarwalla P K , Kumthekar Priya , Mann Bhupinder , Vora Shivangi , Knopp Michael , John Iafrate A , Curry William , Cahill Daniel , Shih Helen , Brown Paul , Santagata Sandro , Barker Frederick , Galanis Evanthia
Published: November 2023

BACKGROUND

Craniopharyngiomas, primary brain tumors of the pituitary-hypothalamic axis, can cause significant clinical sequelae. Treatment using surgery, radiation, or both often entails significant morbidity. In prior work, we demonstrated that ninety-five percent of papillary craniopharyngiomas (PCP) harbor BRAF V600E mutations (Brastianos et al. Nature Genetics 2014). In this multicenter National Cancer Institute cooperative group trial (Alliance A071601), we evaluated the safety and efficacy of BRAF/MEK inhibition in patients with PCP without prior irradiation.

METHODS

Eligible patients, with measurable disease and whose PCP screened positively for BRAF mutations, without prior radiation, received the BRAF/MEK inhibitor combination vemurafenib/cobimetinib in 28-day cycles. The primary endpoint of objective response rate at 4 months based on centrally determined volumetric data was evaluated in 16 patients on this single arm phase 2 trial.

RESULTS

Based on volumetric response criteria by central radiology review, 15 of 16 patients (94%; 95% CI: 70% to 100%) had a durable objective partial response to therapy. Thus, this study met primary endpoint for overall response rate. The median tumor reduction was 91% (range of 68% to 99%). Median follow-up was 22 months (95% CI: 19 to 30 months) and median number of treatment cycles was 8. Median progression-free survival and duration of response were not yet reached. Three patients progressed during follow-up after therapy was discontinued; none have died. The sole non-responder stopped treatment after eight days due to toxicity. Grade 3 toxicities at least possibly related to treatment occurred in 12 patients (rash in 6 patients). Grade 4 toxicities were observed in two patients: hyperglycemia (n=1) and increased creatine phosphokinase (n=1). Three patients discontinued treatment for adverse events.

CONCLUSIONS

Our study indicates that BRAF/MEK inhibitors are a safe and effective treatment for PCP without prior irradiation. Support: U10CA180821, U10CA180882; U24CA196171, U10CA180868 (NRG); Genentech; . ClinicalTrials.gov Identifier: NCT03224767.
CTNI-74. ON-TRK: A NON-INTERVENTIONAL STUDY OF LAROTRECTINIB IN PATIENTS WITH TROPOMYOSIN RECEPTOR KINASE (TRK) FUSION SOLID TUMORS
Authors: Tabatabai Ghazaleh , Trent Jonathan , Novello Silvia , Passiglia Francesco , Burcoveanu Domnita-Ileana , Norenberg Ricarda , Laetsch Theodore
Published: November 2023

Increasingly, health authorities and the medical community are investing resources into evaluating real-world data (RWD) on precision biomarker-based treatments. Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are oncogenic drivers in various cancers. Larotrectinib is a highly selective, central nervous system (CNS)-active TRK inhibitor approved for tumor-agnostic use in pediatric and adult patients with various cancers. ON-TRK (NCT04142437) is an ongoing non-interventional post-approval study that is critical in gaining RWD on the treatment of patients with TRK fusion cancer and will contribute to the broader understanding of personalized therapy. This open-label, global, multi-cohort, prospective study will enroll up to 300 pediatric and adult patients with TRK fusion cancer scheduled to receive larotrectinib, including ≥ 30 pediatric patients. Patients with cancer harboring NTRK gene fusions, detected locally, are eligible. Patients who have had prior TRK inhibitor therapy and patients with NTRK genomic alterations other than functional gene fusions are excluded. Decisions on the dose and duration of treatment are at the discretion of the treating physician. The primary endpoint is safety, including specific long-term parameters in pediatric patients. Secondary endpoints include: efficacy (objective response rate, disease control rate, time to response, duration of response, progression-free survival, and overall survival), dosing patterns and long-term effects of larotrectinib in pediatric patients. The effects of larotrectinib on growth and developmental milestones in pediatric patients will be reported, including change in height and weight from baseline, age at adrenarche for males and menarche for females, number and percentage of patients with abnormal Tanner stages, and abnormal neurological assessments. All variables will be analyzed using descriptive statistics. Pediatric and adult patients will be followed for ≥ 5 years and ≥ 2 years, respectively, unless lost to follow-up, withdrawal, or death. Enrollment is ongoing worldwide; 24 patients with primary CNS cancer have been enrolled to date.
CTNI-83. MATRIX REGIMEN FOR NEWLY DIAGNOSED PRIMARY CNS DIFFUSE B-CELL LYMPHOMA
Authors: Green Richard , Guzman-Marin Ruben , Miranda Candy
Published: November 2023

We report our experience treating 25 patients with newly diagnosed primary CNS diffuse B-cell lymphoma with the MATRix regimen as reported by Ferreri, et al in 2016. The median age was 66 y (range 30-85); 12 patients were men and 13 were women. Twenty-three had cerebral mass lesions, 1 had a paraspinal mass, and 1 leptomeningeal disease. Treatment consisted of 4 cycles of rituximab 375 mg/sq m (Days 1, 6); methotrexate 3.5 g/sq m (Day 2); cytarabine 2 g/sq m every 12 h (Days 3, 4); and thiotepa 30 mg/sq m (Day 5). Patients without disease progression received carmustine 400 mg/sq m and thiotepa 5 mg/kg followed by autologous bone marrow transplantation. Four patients were switched to MATRix after 6 cycles of methotrexate and rituximab and received only 2 initial cycles including cytarabine and thiotepa. Overall, 18 patients completed initial chemotherapy. Sixteen of these 18 went on to transplantation; one patient had had early disease progression, and in one no stem cells could be collected. Five patients (median 73 y; range 64-85 y) died early after 1-2 cycles. The causes of early death were neutropenic fever, septic thrombophlebitis, and cardiac arrest. One of the 16 patients who completed the entire regimen including transplantation died of fungal pneumonia and the other 15 experienced no serious acute toxicity. One patient had late disease progression and 2 developed symptomatic leukoencephalopathy. Seventeen of the 25 patients remain alive. Median TTP for the cohort is 605 days, and OS 738 days. These preliminary data suggest that the MATRix regimen in safe and highly effective in the newly diagnosed setting. However, the high incidence of early death in patients over 65 y shows that the regimen is too toxic for older individuals.
CTNI-84. PNOC022: A COMBINATION THERAPY TRIAL USING AN ADAPTIVE PLATFORM DESIGN FOR PATIENTS WITH DIFFUSE MIDLINE GLIOMAS (DMGS) AT INITIAL DIAGNOSIS, POST-RADIATION THERAPY AND AT TIME OF PROGRESSION
Authors: Kline Cassie , Franson Andrea , Banerjee Anu , Reddy Alyssa T , Raber Shannon , Hoffman Carly , Minturn Jane , van der Lugt Jasper , de Vos-Kerkhof E , van Vuurden Dannis , Gerber Nicolas , Stuecklin Ana Guerreiro , Kilburn Lindsay , Elster Jennifer , Whipple Nicholas , Cohen Kenneth , Oren Michal Yalon , Gardner Sharon , Cluster Andrew , Chi Susan , Landi Daniel , McCowage Geoffrey , Resnick Adam , Phillips Joanna , Bhatia Aashim , Vossough Arastoo , George Elizabeth , Nabavizadeh Ali , Braunstein Steve , Gupta Nalin , Prados Michael , Waszak Sebastian , Boyle-Lang Janel , Molinaro Annette , Dun Matthew , Koschmann Carl , Nazarian Javad , Mueller Sabine
Published: November 2023

BACKGROUND

Subjects diagnosed with diffuse midline glioma (DMG) face extremely poor prognoses. PNOC DMG-ACT (DMG-Adaptive Combination Trial, PNOC022) is an open-label, multi-institutional, international trial that aims to investigate combination therapies for patients with DMG. Herein, we report on the combination study arm with ONC201, an orally available DRD2 and ClpP agonist, and paxalisib, a dual PI3K-mTOR inhibitor for patients who completed standard-of-care radiation (Cohort 2).

METHODS

Children and young adults aged 2-39 years were enrolled 4-14 weeks post-radiation and received maintenance therapy with weekly ONC201 (weight-based adult equivalent of 625 mg) and daily paxalisib (27mg/m2). Plasma and CSF samples for pharmacokinetics (PK) and circulating tumor DNA (ctDNA) were collected at multiple timepoints.

RESULTS

Sixty-eight patients with biopsy-proven DMG enrolled between November 2021 and June 2023 (median age 9 years [range 3-37], n=41 female [60%]). Site-determined tumor location includes 47 pontine (69%), 16 thalamic (24%), 3 spinal cord (4%) and 2 cerebellar (2%) DMGs. Median overall survival (OS) from time of diagnosis is 16.5 months (lower 95% CI 11.6 months) with a median follow-up time of 9.9 months (95% CI: 8.5, 11.4). The H3K27M mutation was found in 91% (n=50) and 9% were classified as H3K27-altered (n=5). TP53 was mutant in 50% (22/44 available). Most common grade 3 and above treatment-related adverse events were neutrophil count decreased (n=4); mucositis (n=3); and, colitis, DRESS, lymphocyte count decreased, hyperglycemia, hypokalemia (n=2). PK and ctDNA analyses are being finalized.

CONCLUSIONS

The current median OS is encouraging compared to historical controls. At the meeting, we will present updated molecular characterization and early biological correlates in association with clinical outcomes including toxicity, OS, PK, and central imaging confirmed progression-free survival.
DNAR-02. MICROGLIA IN THE GLIOBLASTOMA MICROENVIRONMENT ASSIST REPAIR OF RADIATION INDUCED DNA DAMAGE IN A CONTACT INDEPENDENT MANNER
Authors: Palavalasa Sravya , Singer Ava , Scott Andrew , Wilder-Romans Kari , Shankar Sunita , Ravikumar Visweswaran , Bhadury Sagnik , Andren Anthony , Sajjakulnukit Peter , Zhou Weihua , Lyssiotis Costas A , Rao Arvind , Al-holou Wajd , Wahl Daniel R
Published: November 2023

Rapid repair of DNA damage mediates genotoxic therapy resistance and poor prognosis in glioblastoma (GBM). The GBM tumor microenvironment (TME) is heterogenous, and we hypothesized that non-malignant cells in the GBM TME support the repair of DNA damage in glioblastoma cells. Consistent with this hypothesis, we found that GBM tumors grown intracranially in mice had rapid DNA repair and were resistant to radiation when compared to tumors of identical genotype grown extracranially in mouse flanks. Further interrogation of irradiated intracranial tumors using gamma-H2AX immunofluorescence revealed spatial heterogeneity in DNA damage repair, with spatially separate regions of rapid and slow gamma-H2AX resolution. Paired spatial transcriptomic analysis and gamma-H2AX immunofluorescence revealed that tumor regions with rapid DNA repair were rich in microglia and enriched for inflammatory response and epithelial to mesenchymal transition (EMT) pathway transcripts. Spatial transcriptomic analysis of patient tissue revealed that regions enriched in DNA damage repair pathways are also enriched for microglia and not other non-malignant cell types. Having nominated microglia, we then cocultured GBM cells and microglia and found that GBM cells cocultured with microglia repair DNA damage faster in a contact-independent manner. Hence, we show that microglia in the GBM microenvironment assist GBM cells to repair radiation induced DNA damage through inflammatory response and EMT and hence, mediate treatment resistance.
DNAR-06. RHO GTPASES AS A POTENTIAL CHEMOSENSITIZER OF TMZ AND CISPLATIN-RESISTANT GBM TUMOR CELLS THROUGH A P53-DEPENDENT MECHANISM
Authors: Forti Fabio , Magalhaes Yuli
Published: November 2023

Rho GTPases regulate cellular processes related to tumor progression and their expression/activity determines the invasiveness and aggressiveness of GBM and, despite current aggressive therapies, effective treatments remain desired. Here we proposed that Rho GTPase acts on the genomic stability of GBM and its resistance to TMZ and cisplatin drugs in a p53-dependent mechanism. We selected GBM cell lines with different p53 status – U87-MG and A172 (wt-p53), T98G and U138-MG (mut-p53) – and subjected them to Rho inhibition by C3 toxin and subsequent DNA damage by TMZ treatments or cisplatin. Bioinformatic analysis showed that prolonged exposure to cisplatin induces the transcription of regulatory genes of Rho GTPases. Pulldown assays corroborated this analysis showing an increase in Rho activity after exposure to cisplatin or TMZ. IC50 for TMZ and cisplatin, as well as survival and proliferation assays, were all decreased by Rho inhibition in wt-p53 cells, while HCR assays showed that DNA repair capacity for both genotoxic drugs is decreased by Rho inhibition only in wt-p53 cells. To verify the role of p53 in this mechanism, we knocked down p53 in U87-MG cells, thus avoiding Rho inhibition-induced chemosensitivity and impaired DNA repair. Then, U87-MG cells were subjected to various treatment regimens with low doses of TMZ or cisplatin to obtain a subpopulation of cells resistant to these drugs. Further exposure to DNA damage led to increased p53(Ser15) phosphorylation, p53 nuclear translocation, and F-actin-induced polymerization. Two TMZ-resistant cell clones were selected, both showing a significant increase in TMZ IC50 for survival, while Rho inhibition reduced IC50 in both clones, significantly reversing the acquired resistance of these cells. These results suggest that Rho GTPase plays a role in DNA repair and in the acquired GBM wt-p53 resistance to TMZ and show that this pathway may be a fragile-point against current therapies.
DNAR-12. ATR INHIBITION AS A NOVEL RADIOSENSITIZATION STRATEGY FOR GLIOBLASTOMA
Authors: Kanji Suman , Tomimatsu Nozomi , Di Cristofaro Luis Fernando Macedo , Ghamasaee Pegah , Floyd John , Mukherjee Bipasha , Burma Sandeep
Published: November 2023

Glioblastomas (GBM) are lethal brain tumors for which surgical resection followed by ionizing radiation (IR) with concurrent and adjuvant Temozolomide (TMZ) remains the mainstay of therapy. GBMs are extremely radioresistant, and radiosensitization approaches are desperately needed for these tumors. IR induces DNA double-strand breaks (DSBs), and these lesions can be repaired either by error-prone non-homologous end joining (NHEJ) or the error-free homologous recombination (HR) pathway. Research in our and other laboratories has shown that the ATR kinase promotes the HR pathway. We therefore hypothesized that ATR inhibition would block DSB repair in rapidly-dividing GBM cells that are HR dependent but not in non-dividing normal brain cells that are dependent upon NHEJ for repair. We treated a panel of GBM cell lines and normal human astrocytes with the ATR inhibitor VX-803 and/or IR and assessed for multiple endpoints including HR, DSB repair, and cell survival. We found that VX-803 blocks HR and DSB repair in GBM cells but does not significantly affect repair in non-dividing normal human astrocytes. Hence, treatment with VX-803 sensitizes GBM lines to IR in vitro as measured by the colony formation assay. Next, PDX mouse models of GBM were treated with VX-803 followed by XRT, and monitored for tumor growth and survival. We found that the drug can cross the blood-brain barrier and, in conjunction with IR, block DNA repair in intracranial tumors, attenuate tumor growth, and consequently extend survival of tumor-bearing mice. Importantly, the drug does not significantly affect DSB repair in normal brain cells indicating that ATR inhibition might selectively block repair in GBM cells, thereby minimizing normal tissue toxicity. Our results indicate that regulation of HR by ATR is critical for optimal DSB repair, especially in rapidly-dividing GBM cells, and that ATR inhibition could be used to improve GBM radiotherapy in the clinic.
DNAR-13. TARGETING THE DNA DAMAGE RESPONSE IN GLIOBLASTOMA PROPAGATING CELLS: FROM MOLECULAR MECHANISMS TO PRECISION MEDICINE
Authors: Pailas Alexandros , Neumann Katrin , Jeanty Céline , Herold-Mende Christel , Toth Reka , Nazarov Petr , Scalisi Joshua , Neirinckx Virginie , Rogister Bernard , Van Dyck Eric
Published: November 2023

Glioblastoma (GBM) is the most aggressive and lethal primary tumor of the central nervous system (CNS). Despite surgical resection and a combination of radiotherapy and alkylation chemotherapy, the median survival for patients with newly diagnosed GBM is only ~ 14 months. Among the many challenges confronting clinicians are subpopulations of tumor-propagating cells named GBM Stem-like Cells (GSCs), which have been proposed to drive treatment resistance and foster tumor relapse. At the mechanistic level, GSCs have been shown to display constitutive activation of the DNA damage response (DDR) due to chronic replication stress (RS), which enhances their ability to repair the DNA lesions induced by chemoradiation. Thus, developing new therapeutic strategies against glioblastoma is of paramount importance. Cell cycle regulation and DNA damage response are two crucial molecular networks altered in most cancer types. In this context, we have previously identified a DNA repair and cell cycle gene expression signature that results in the classification of GBM tumors in two major groups, G1 and G3, which differ in the expression of survival and proliferation pathways. Using bioinformatics analysis of the GLASS consortium database, we have created an exhaustive oncopanel of the molecular alterations defining the G1 and G3 groups. Furthermore, using G1- and G3-patient-derived GSC cell lines as experimental models, we have identified crucial differences in the mechanisms orchestrating the cell cycle, DDR, and treatment resistance between G1 and G3 cells. Finally, we have also identified group-specific therapeutic strategies combining repositioned FDA-approved drugs with the inhibition of crucial DDR factors. Our long-term goals are i) to understand the molecular basis behind the differential response to DNA damage and replication stress developed by G1 and G3 cells and ii) to propose group-specific, DDR-based combination therapies that prevent treatment resistance and promote long-lasting treatment.
DDEL-03. PHYSIOLOGICALLY BASED PHARMACOKINETIC (PBPK) MODELING OF HETEROGENEOUS DRUG PENETRATION INTO THE HUMAN BRAIN AND GLIOBLASTOMA
Authors: Li Jing , Sanai Nader , Tovmasyan Artak , Kim Seongho
Published: November 2023

BACKGROUD

Insufficient penetration of potentially effective therapeutic agents across the human blood-brain barrier (BBB) is a hurdle to the effective treatment of brain cancer. The BBB in glioblastoma is disrupted to varying extents. This study was to develop a PBPK model platform for prediction of heterogenous drug penetration into the human brain and glioblastoma.

METHODS

A 7-compartment CNS (7-CNS) PBPK model platform was developed to predict drug concentrations in the brain blood, brain parenchyma, cranial CSF, spinal CSF, and 3 tumor compartments representing infiltrating tumor (T1) with a slightly disrupted BBB, bulk tumor (T2) with a leaky BBB, and necrotic core (T3) with no blood vessels. The model accounted for brain/tumor general anatomy and regional pathophysiological differences. Drug transfer and fluid balance between compartments were described by differential equations. Simulations were performed using R programming. The model was verified by comparisons of predicted and observed tumor PK data of ribociclib and abemaciclib in glioblastoma patients.

RESULTS

For ribociclib, the model-predicted mean unbound drug brain-to-plasma ratio (Kp,uu) was 0.17, 2.2, 8.2, 24.9 in normal brain, T1, T2, and T3, respectively; the predicted Kp,uu in T1 and T2 was consistent with observed Kp,uu in non-enhancing (median, 2.0) and enhancing tumors (median, 10.1) from 12 patients. For abemaciclib, the predicted mean Kp,uu was 0.88, 1.4, 6.2, and 3.1 in normal brain, T1, T2, and T3, respectively; the predicted Kp,uu in T1 and T2 agreed with observed Kp,uu in non-enhancing (median, 2.1) and enhancing tumors (median, 7.2) from 38 patients.

CONCLUSION

The developed PBPK model platform well predicts heterogeneous drug penetration and distribution in normal human brain and different regions of glioblastoma, as verified by ribociclib and abemaciclib. It provides a mechanism-based computational modeling tool to assist the development and design of improved drugs and dosing regimens for more effective treatment of glioblastoma.
DDEL-05. PHARMACOKINETIC ASSESSMENT OF CONVECTION-ENHANCED DELIVERY OF SMALL MOLECULE DRUGS FOR H3 K27-ALTERED DIFFUSE MIDLINE GLIOMA
Authors: Rechberger Julian , Anderson Jacob , Ge Jizhi , Zhang Liang , Daniels David
Published: November 2023

H3 K27-altered diffuse midline gliomas (DMG) are uniformly lethal tumors for which no therapy has been found to be effective. The blood-brain barrier (BBB) restricts uptake and accumulation of systemically administered drugs in the brain. Convection-enhanced delivery (CED) circumvents the BBB by directly infusing therapeutics into the tumor, facilitating homogenous distribution of drugs at high local concentrations with minimal systemic toxicity. However, most drugs given by CED are rapidly cleared from the brain, severely limiting its therapeutic potential. Here, we determine the impact of drug characteristics rather than mechanism of action on compatibility with CED. Various medicinal chemistry prediction models were interrogated to define drug categories predicated on inherent physicochemical properties of the drugs. A panel of FDA-approved drugs with biologically validated activity in DMG were selected for each group: panobinostat/ponatinib, everolimus/topotecan, tolnaftate/tretinoin, and carmofur/eltrombopag. In vivo pharmacokinetic studies of these drugs delivered by CED into the pons of tumor-naïve mice showed that drugs expected to be less likely to undergo active efflux persisted at the site of infusion over prolonged periods of time. Conversely, efflux transporter (ET) substrate drugs were quickly excreted from the brain and readily detectable in the plasma following CED. Based on the observed brain and plasma concentration-time profiles, the brain exit rate constant and clearance out of the brain were much higher for ET substrate drugs compared with ET non-substrates, resulting in a significant increase in the residence time (the time spent by drugs in the brain) in the absence of ET-mediated clearance. These properties were further validated in efficacy studies in DMG animal models. The proclivity of many drugs to be rapidly effluxed from the brain after CED generates a vulnerability that can be exploited for the development of novel therapeutic regimens, such as with pharmacokinetics-informed drug selection or concomitant dosing of ET-inhibiting drugs.
DDEL-06. MICROGLIA REPAIR THE DISRUPTED BLOOD-BRAIN BARRIER FOLLOWING LOW-INTENSITY PULSED ULTRASOUND THROUGH P2RY12 SIGNALING
Authors: Habashy Karl , Arrieta Victor , Luan Yu , Kim Kwang-Soo , Dhiantravan Silpol , Najem Hinda , Gomez Mateo , Dmello Crismita , Chen Li , Saganty Ruth , Gould Andrew , Hou Ye , Heimberger Amy , Canney Michael , Stupp Roger , Yue Feng , Sonabend Adam
Published: November 2023

In a phase I clinical trial for patients with recurrent glioblastoma, we used an implantable ultrasound device for low-intensity pulsed ultrasound and microbubbles (LIPU/MB) to open the blood-brain barrier (BBB). This strategy increased parenchymal drug concentrations by 3.7- to 5.9-fold. Magnetic resonance imaging analysis with gadolinium injections at different timepoints post-sonication revealed that the BBB integrity began to restore within an hour post-sonication. To investigate the effect of LIPU/MB, we biopsied sonicated and non-sonicated peritumoral brain regions 45 minutes post-sonication before tumor resection in 7 patients. Single-cell RNA sequencing analysis revealed that sonicated microglia clustered separately and had enrichment of gene ontology terms related to the positive regulation of cell adhesion (p < 2x10-6), wound healing (p < 3x10-5), and regulation of vascular development and angiogenesis (p < 4x10-5). Upregulated genes included IL1B (log2fold-change 2.9, p < 1x10-140), PLAUR (log2fold-change 1.9, p < 2x10-177), and VEGFA (log2fold-change 1.8, p < 1x10-125). We also evaluated the spatial distribution of microglia in sonicated and non-sonicated samples by multiplex immunofluorescence. Analysis of 20 vessels per sample demonstrated that sonicated microglia accumulated around blood vessels, averaging at 14 μm from CD31+ cells, compared to 45 μm in non-sonicated biopsies (p < 0.01). Based on previous reports of P2RY12-dependent microglial migration and repair of the BBB, we evaluated the effect of P2RY12 inhibition with clopidogrel on BBB repair post-sonication in mice. Permeability assay with fluorescein revealed that the BBB was 80% (p < 0.001) and 50% (p < 0.05) more permeable at 10 and 45 minutes post-sonication in clopidogrel-treated mice, respectively. This work provides human data supporting the role of microglia in the repair of the BBB, previously described in animals, and provides preclinical and clinical evidence for the role of these cells in the rapid restoration of vascular integrity post-LIPU/MB in humans.
DDEL-08. THE OMMAYA IN LEPTOMENINGEAL DISEASE AND CENTRAL NERVOUS SYSTEM MALIGNANCIES: A RESERVOIR OF THE PAST OR SOURCE OF THE FUTURE?
Authors: Spirollari Eris , Vazquez Sima , Durkin Daniel , Fliegelman Jacob , Carpenter Austin , Dominguez Jose , Hanft Simon
Published: November 2023

Advances in systemic therapies have increased survival in patients with metastatic cancer. However, such prolonged survival has been associated with increased incidence of leptomeningeal disease (LMD), a late-stage manifestation of cancer to the leptomeninges that carries a dismal prognosis. Circumvention of the blood-brain-barrier to treat LMD can be accomplished with intraventricular therapy using an Ommaya reservoir. Our objective is to determine the indications, efficacy, and future directions of the Ommaya reservoir in LMD and CNS malignancies. A systematic review of the literature was conducted. Data extracted from articles included year of publication, study design, cancer types, and findings. The search query returned 5,338 articles, of which 94 were included. Most articles (45, 47.9%) were prospective cohort studies. Forty-one (43.6%) described retrospective chart reviews, and five (5.3%) described RCTs. Ommaya was studied as a vehicle for intrathecal chemotherapy administration (76, 80.9%), an access site for CSF sampling (12, 12.8%), or a device through which to study dosimetry and pharmacokinetics of various drugs (5, 5.3%). Most studies (50, 53.2%) explored the use of Ommaya in LMD, secondary to any cancer (62%), breast cancer (20%), lung cancer (6%), glioma (6%), lymphoma (4%), and melanoma (2%). Sixteen articles (17%) focused on the use of Ommaya in malignant glioma, 11 studies (11.7%) in CNS lymphoma, and three (3, 3.2%) evaluated the efficacy of intraventricular morphine for intractable cancer pain. Since 2011, 24 studies (64.9%) reported positive outcomes with Ommaya, and two (5.4%) did not. The literature indicates that the Ommaya is a safe and reliable option for treatment of certain malignancies and LMD. The benefit appears to be most marked in the era of multi-modality treatment for cancer, particularly breast. Most recently, and perhaps most promising, is utilization of Ommaya for CSF analysis, both in tracking therapeutic response and defining pharmacokinetics in patients with LMD.
DDEL-13. CILIA INHIBITORS SYNERGIZE WITH TEMOZOLOMIDE TO DRAMATICALLY IMPROVE SURVIVAL IN ORTHOTOPIC MURINE MODELS OF GLIOBLASTOMA
Authors: Umlauf Benjamin
Published: November 2023

Patients with malignant brain tumors such as glioblastoma face a poor prognosis with a median survival of less than two years. Recent glymphatic studies demonstrate the interconnectivity between the fluid in the brain parenchymal and ventricular spaces. We reasoned enhancing the accumulation of a drug in the cerebral spinal fluid (CSF) of the ventricular space will also enhance the accumulation of the drug in the parenchyma where a GBM resides. To improve drug accumulation in the CSF, we modulated the motility of ependymal cell cilia. Ependymal cells coat the ventricles and display motile cilia that mechanically propel CSF through the ventricular space. Impairing ciliary motion could slow down CSF turnover without affecting the overall amount of CSF in the brain and central nervous system. To test these hypotheses, we identified FDA-approved therapeutics that are known to impair airway cilia as a “side effect.” Seven candidate drugs were administered into the ventricle of mice bearing orthotopic GBM in combination with systemic temozolomide. Five of the seven cilia-inhibiting drugs significantly improved overall survival when combined with temozolomide compared to controls. The lead candidate, lidocaine, demonstrated a synergistic relationship with temozolomide, and 100% of animals treated with the combination survived to the study endpoint tumor free. We demonstrate lidocaine can impair cilia motility in vitro and in vivo. Combining intraventricular lidocaine with temozolomide is well tolerated and results in a 2.8-fold increase in brain temozolomide concentration per dose compared to controls. Finally, we validate these data in two human PDX orthotopic xenograft GBM murine models, including an un-methylated MGMT GBM that became sensitive to temozolomide with the combination treatment. These studies offer a new concept for treating malignant brain tumors and potentially a scheme to improve the treatment of additional encephalopathies in the future.
DDDR-01. P38-MAPK INHIBITOR REVERSED CISPLATIN RESISTANCE IN NON-SMALL CELL LUNG CANCER BRAIN METASTASES BY REGULATING P-GP AND BCRP OF BLOOD-TUMOR BARRIER
Authors: Liang Lun , Yu Min , Yang Shilun , Duan Hao , He Zhenqiang , Wang Zhenning , Chang Junlei , Mou Yonggao
Published: November 2023

BACKGROUND

Previous studies have shown that the blood-brain barrier (BBB) of brain metastases (BMs) is destroyed, and the neovascularization and tumor cells constitute the blood-tumor barrier (BTB). Whether the BTB plays a role in the chemotherapy resistance of BMs is lacking in-depth research. This study aims to elucidate the possible role of BTB in cisplatin resistance of BMs from non-small cell lung cancer (NSCLC).

METHODS

AND MATERIALS; A multicenter retrospective cohort study including 1177 patients with NSCLC-BMs was conducted to explore the prognosis. Immunohistochemistry and immunofluorescence staining were used to verify the expression of some BBB markers in the BTB. Animal models of BMs were constructed by cardiac injection of A549. NSCLC-BMs cell lines A549-mBrain were selected in vivo. Cisplatin susceptibility tests and CCK8 proliferation tests were performed on A549-mBrain. RNA sequencing, Western Blot and qPCR were used to explore the mechanism that might regulate cisplatin resistance in A549-mBrain.

RESULTS

Platinum-based chemotherapy did not improve the overall survival time of NSCLC-BMs. BTB in NSCLC-BMs lacked astrocytes and pericytes, but still expressed several molecular markers of BBB, such as tight junction, transcytosis, and efflux pump. The efflux pump P-gp and BCRP expressions were higher in NSCLC-BMs than those in the lung primary lesion by immunohistochemistry in patients' tumor section. The A549-mBrain showed cisplatin resistance compared with the parental A549. Besides, the expression of P-gp and BCRP were also higher in A549-mBrain than parental A549 by Western Blot and qPCR. In A549-mBrain, inhibition of the p38-MAPK signaling pathway decreased the expression of P-gp and BCRP, thus increasing the sensitivity to cisplatin.

CONCLUSION

BTB may retain some BBB function in NSCLC-BMs, in which efflux pump P-gp and BCRP expression were related to cisplatin resistance. p38-MAPK inhibitor reversed cisplatin resistance in NSCLC-BMs by regulating P-gp and BCRP.
DDDR-02. THE EFFICACY OF SOTORASIB IN KRAS-MUTATED NSCLC PATIENTS WITH BRAIN METASTASES: A RETROSPECTIVE COHORT STUDY
Authors: Lebouille-Veldman Anna , Taros Trent , Nawabi Noah , Peng Luke , Philips John
Published: November 2023

INTRODUCTION

Sotorasib has emerged as a favorable treatment option for patients with advanced KRAS-mutated non-small cell lung cancer (NSCLC) including those with brain metastases (BM). The objective of this study was to determine the efficacy of sotorasib in the treatment of pre-treated BMs in patients with NSCLC.

METHODS

This retrospective cohort study included adult patients with KRAS-mutated NSCLC with BMs who received sotorasib between April-2021 and March-2023 at Mass General Brigham Hospitals. Intracranial progression-free survival (ICPFS) and overall survival (OS) were the primary endpoints and were explored using Kaplan Meier analyses for three groups of patients: patients with active BMs and no local therapy (1), patients with active BMs with local treatment within one month of sotorasib initiation (2) and patients with radiographically stable BMs following previous local treatment (3).

RESULTS

31 patients with NSCLC and BMs were included (23% male). Mean age at start of sotorasib was 60. 87% of patients had primary lung adenocarcinoma, and 68% of patients had between 1 and 4 BMs when they started sotorasib. Differences in survival distributions for ICPFS for patients in each of the three groups were statistically significant, χ2(2) = 7.600, p = 0.022. Median ICPFS was 3 months (95% CI: 0 – 8.9) from start of sotorasib for group 1, 5 months (0-11.5) group 2, and 15 months (0-33.5) for group 3. Median OS was 4 months (0-8.8) for group 1, 6 months (0-13.7) for group 2, and 12 months (3.6-20.4) for group 3. 55% of patients experienced intracranial progression on sotorasib, including 39% of patients who had stable BMs at sotorasib initiation.

CONCLUSION

The results of this study indicate that while sotorasib does have intracranial activity, a multimodal approach to BM therapy is still warranted, as are future studies with larger patient samples, controls, and extended follow up.
DDDR-03. DRUG REPURPOSING VIA ULTRA-HIGH THROUGHPUT 3D SPHEROIDS SCREENING FOR HUMAN SCHWANNOMA
Authors: Lei Kecheng , Tora Muhibullah , Lakhina Yuliya , Zhang Michelle , Qui Min , Fu Haian , Du Yuhong , Boulis Nicholas
Published: November 2023

Schwannoma is the most common benign peripheral nerve tumor occurring sporadically or as part of neurofibromatosis syndromes. While surgical resection can be used as the primary treatment option for Schwannoma, patients could face life-long repeated surgeries due to recurrence of syndromes that decreases the quality of life. Thus, non-invasive treatments for Schwannoma are highly demanded. To discover novel therapeutics for non-invasive Schwannoma treatment, in this project, we leveraged the benefits of drug repurposing high-throughput screening (HTS) of FDA-approved drugs using 3D spheroids derived from Schwannoma patient samples. Both 2D primary cells and 3D primary spheroids models were developed from an IRB-approved tumor bank of schwannoma patient samples. The 3D spheroids were validated to recapitulate the features of patient tumors. We then conducted an ultra-HTS(uHTS) in 1536-well format of 2036 FDA-approved drugs on the growth and viability of Schwannoma patient-derived 3D spheroids. Seven FDA-approved drugs were identified from the pilot screen to inhibit the growth of Schwannoma patient-derived 3D spheroids. These drugs offer potential to serve as pharmacotherapeutics for Schwannoma non-invasive treatment. Our results have demonstrated the capability of a drug repurposing strategy for Schwannoma using uHTS and a patient-derived tumor bank. We further demonstrated that patient-derived drug sensitivity signatures could be encoded from the screening data to enable clustering of patients, which accounts for heterogeneity in Schwannoma and avoids "one-size-fits-all" solutions in future non-invasive Schwannoma treatment studies.
DDDR-04. TRANSIENT SUPPRESSION OF XPO1 ACTIVITY IS SUFFICIENT FOR SELINEXOR-INDUCED CYTOTOXICITY IN GLIOBLASTOMA CELLS LINES
Authors: Tang Yongjian , Sprinzen Lisa , Terada Yukinori , Pieper Russell
Published: November 2023

Inhibitors of the nuclear export protein exportin 1 (XPO1i) show promise in the treatment of leukemias and solid tumors, including brain tumors. XPO1i such as Selinexor reversibly bind and inhibit XPO1 activity, resulting in a lethal nuclear accumulation of a variety of XPO1 substrates. Although XPO1i activity has been suggested to require prolonged suppression of XPO1 activity, this point has not been directly addressed. To do so we generated glioblastoma and patient-derived glioblastoma xenograft cells that express either endogenous wild-type (WT) XPO1 or endogenous WT XPO1 plus a doxycycline-inducible point-mutant form of XPO1 (C528S) that exhibits full XPO1 activity but cannot bind or be inhibited by Selinexor. These cells were then incubated with doxycycline before, or at various time after, the initiation of continuous Selinexor exposure, after which the ability of C528S XPO1 to rescue cells from Selinexor-induced toxicity could be determined. All four glioblastoma cell lines examined were drug-sensitive (IC50 < 600nM) and exhibited a dose-dependent nuclear retention of the XPO1 substrate RanBP1 following Selinexor exposure. Induced expression of C528S led to a doubling of XPO1 protein levels (WT plus C528S), and variable increases in Selinexor IC50, from 3-fold in GBM43 cells to 12,000-fold in LN229 cells. While induction of C528S expression prior to, or up to 8 h after, Selinexor exposure completely prevented Selinexor-induced cytotoxicity, cells could not be rescued after a 24 hr Selinexor exposure. Furthermore, the resistance provided by prolonged expression of C528S, or by shRNA-mediated suppression of XPO1 levels, was nearly 10-fold less than that provided by complete CRISPR-based replacement of WT XPO1 with C528S. These results therefore show that a transient suppression of XPO1 activity is sufficient for Selinexor-induced cytotoxicity in glioblastoma cells, and suggest that the Selinexor-induced lethality results from a combination of loss of XPO1 activity and Selinexor-XPO1 complex formation.
DDDR-05. TARGETED INHIBITION OF DNA REPAIR AND SURVIVAL SIGNALING IN DIFFUSE INTRINSIC PONTINE GLIOMAS
Authors: Barravecchia Ivana , Sharma Monika , Teis Robert , Cruz Jeanette , Mumby Rachel , Ziemke Elizabeth , Espinoza Carlos , Krishnamoorthy Varunkumar , Magnuson Brian , Ljungman Mats , Koschmann Carl , Whitehead Christopher , Sebolt-Leopold Judith , Galban Stefanie
Published: November 2023

Therapeutic resistance remains a major obstacle to successful clinical management of Diffuse Intrinsic Pontine Glioma (DIPG), a high-grade pediatric tumor of the brain stem. In nearly all patients, available therapies fail to prevent progression. Innovative combinatorial therapies that penetrate the blood-brain barrier and lead to long-term control of tumor growth are desperately needed. We identified mechanisms of resistance to radiotherapy, the standard of care for DIPG. Based on these findings, we rationally designed a brain-penetrant small molecule, MTX-241F, that is a highly selective inhibitor of EGFR and PI3 kinase family members, including the DNA repair protein DNA-PK. Preliminary studies demonstrate that micromolar levels of this inhibitor can be achieved in murine brain tissue and that MTX-241F exhibits promising single-agent efficacy and radiosensitizing activity in patient-derived DIPG neurospheres. Its physiochemical properties include high exposure in the brain, indicating excellent brain penetrance. Since radiotherapy results in double-strand breaks that are repaired by homologous recombination (HR) and non-homologous DNA end joining (NHEJ), we have tested the combination of MTX-241F with an inhibitor of ATM to achieve blockade of HR and NHEJ, respectively, with or without radiotherapy. When HR blockers were combined with MTX-241F and radiotherapy, synthetic lethality was observed, providing impetus to explore this combination in clinically relevant models of DIPG. Our data provide proof-of-concept evidence to support advanced development of MTX-241F for the treatment of DIPG. Future studies will be designed to inform rapid clinical translation to ultimately impact patients diagnosed with this devastating disease.