Administration Of Temozolomide Research Articles

An Injury-like Signature of the Extracellular Glioma Metabolome

Aberrant metabolism is a hallmark of malignancies including gliomas. Intracranial microdialysis enables the longitudinal collection of extracellular metabolites within CNS tissues including gliomas and can be leveraged to evaluate changes in the CNS microenvironment over a period of days. However, delayed metabolic impacts of CNS injury from catheter placement could represent an important covariate for interpreting the pharmacodynamic impacts of candidate therapies. Intracranial microdialysis was performed in patient-derived glioma xenografts of glioma before and 72 h after systemic treatment with either temozolomide (TMZ) or a vehicle. Microdialysate from GBM164, an IDH-mutant glioma patient-derived xenograft, revealed a distinct metabolic signature relative to the brain that recapitulated the metabolic features observed in human glioma microdialysate. Unexpectedly, catheter insertion into the brains of non-tumor-bearing animals triggered metabolic changes that were significantly enriched for the extracellular metabolome of glioma itself. TMZ administration attenuated this resemblance. The human glioma microdialysate was significantly enriched for both the PDX versus brain signature in mice and the induced metabolome of catheter placement within the murine control brain. These data illustrate the feasibility of microdialysis to identify and monitor the extracellular metabolome of diseased versus relatively normal brains while highlighting the similarity between the extracellular metabolome of human gliomas and that of CNS injury.

The combination of temozolomide and perifosine synergistically inhibit glioblastoma by impeding DNA repair and inducing apoptosis

Temozolomide (TMZ) is widely utilized as the primary chemotherapeutic intervention for glioblastoma. However, the clinical use of TMZ is limited by its various side effects and resistance to chemotherapy. The present study revealed the synergistic inhibition of glioblastoma through the combined administration of TMZ and perifosine. This combination therapy markedly diminished BRCA1 expression, resulting in the suppression of DNA repair mechanisms. Furthermore, the combination of TMZ and perifosine elicited caspase-dependent apoptosis, decreasing glioblastoma cell viability and proliferation. The observed synergistic effect of this combination therapy on glioblastoma was validated in vivo, as evidenced by the substantial reduction in glioblastoma xenograft growth following combined treatment with TMZ and perifosine. In recurrent glioma patients, higher BRCA1 expression is associated with worse prognosis, especially the ones that received TMZ-treated. These findings underscore the potent antitumor activity of the AKT inhibitor perifosine when combined with TMZ and suggest that this approach is a promising strategy for clinical glioblastoma treatment.

133 BMAL1 is Upregulated in Pediatric High-Grade Gliomas

INTRODUCTION: Pediatric high-grade gliomas (pHGG) are highly invasive brain tumors with poor survival outcomes, and novel therapeutic approaches are urgently needed. Recently, a retrospective study found timing of Temozolomide administration affects survival in adult patients with glioblastoma (Damato et al. 2021). There has, however, been limited exploration into circadian gene expression in pediatric gliomas. METHODS: We analyzed expression of BMAL1, a key circadian gene, in pediatric gliomas using bioinformatic approaches, Western blotting, and immunocytochemistry (ICC). We first compared BMAL1 expression in pLGGs and pHGGs using published publicly available data from cBioPortal for Cancer Genomics. Immunoblotting was utilized to determine BMAL1 protein expression levels in patient specimens of pHGG, pLGG and cortex from epilepsy surgery. Immunocytochemistry on synchronized primary tumor lines was used to show localization of BMAL1 protein. RESULTS: Using data from cBioPortal, we found significantly higher expression of BMAL1 in pHGGs compared to pLGGs (0.349 + 1.05 vs 0.0545 + 0.666, p < 0.001). Western blotting showed increased expression of BMAL1 in HGG tumor specimens compared to LGG and cortical specimens. Immunostaining demonstrated cellular localization of BMAL1. CONCLUSIONS: In this study, we found that the circadian gene BMAL1 is expressed in pHGGs, and that expression is higher in pHGGs compared to pLGGs and cortex. Next steps will be to understand how timing of Temozolomide in relationship to the circadian cycle affects tumor cell survival.

Treatment of glioblastoma in Greenlandic patients

ABSTRACTGlioblastoma (GBM), WHO grade IV, is the most common primary malignant brain tumour among adults with a devastating overall survival of 14–22 months. Standard treatment of GBM includes maximum safe resection, radiotherapy plus concomitant and adjuvant temozolomide (TMZ), given over a period of approximately 9 months. Treatment and follow-up for Greenlandic patients with GBM are managed at Rigshospitalet (RH), Copenhagen. Greenlandic GBM patients, therefore, travel back and forth to RH, often unaccompanied, and challenged by cognitive failure or other symptoms from their disease and/or treatment. Few Greenlandic patients are diagnosed with GBM annually, but considering the poor prognosis and short remaining lifespan, it would be preferable to limit their travels. TMZ is administrated as capsules. Health personnel at Queen Ingrid’s Hospital (DIH), Nuuk, are trained in treating other oncological diseases and handling side effects. Hence, it could be investigated whether administration of adjuvant TMZ at DIH could be feasible after personnel education as well as economic consideration and compensation, in close collaboration with neuro oncologists at RH. In this article, we describe the Greenlandic cancer treatment, and the typical workflow from diagnosis of GBM to treatment to progression.

Therapeutic Potential of Resveratrol for Glioma: A Systematic Review and Meta-Analysis of Animal Model Studies

Gliomas are aggressive malignant brain tumors, with poor prognosis despite available therapies, raising the necessity for finding new compounds with therapeutic action. Numerous preclinical investigations evaluating resveratrol’s anti-tumor impact in animal models of glioma have been reported; however, the variety of experimental circumstances and results have prevented conclusive findings about resveratrol’s effectiveness. Several databases were searched during May 2023, ten publications were identified, satisfying the inclusion criteria, that assess the effects of resveratrol in murine glioma-bearing xenografts. To determine the efficacy of resveratrol, tumor volume and animal counts were retrieved, and the data were then subjected to a random effects meta-analysis. The influence of different experimental conditions and publication bias on resveratrol efficacy were evaluated. Comparing treated to untreated groups, resveratrol administration decreased the tumor volume. Overall, the effect’s weighted standardized difference in means was −2.046 (95%CI: −3.156 to −0.936; p-value < 0.001). The efficacy of the treatment was observed for animals inoculated with both human glioblastoma or rat glioma cells and for different modes of resveratrol administration. The combined administration of resveratrol and temozolomide was more effective than temozolomide alone. Reducing publication bias did not change the effectiveness of resveratrol treatment. The findings suggest that resveratrol slows the development of tumors in animal glioma models.

Overcoming chemotherapy resistance in low-grade gliomas: A computational approach.

Low-grade gliomas are primary brain tumors that arise from glial cells and are usually treated with temozolomide (TMZ) as a chemotherapeutic option. They are often incurable, but patients have a prolonged survival. One of the shortcomings of the treatment is that patients eventually develop drug resistance. Recent findings show that persisters, cells that enter a dormancy state to resist treatment, play an important role in the development of resistance to TMZ. In this study we constructed a mathematical model of low-grade glioma response to TMZ incorporating a persister population. The model was able to describe the volumetric longitudinal dynamics, observed in routine FLAIR 3D sequences, of low-grade glioma patients acquiring TMZ resistance. We used the model to explore different TMZ administration protocols, first on virtual clones of real patients and afterwards on virtual patients preserving the relationships between parameters of real patients. In silico clinical trials showed that resistance development was deferred by protocols in which individual doses are administered after rest periods, rather than the 28-days cycle standard protocol. This led to median survival gains in virtual patients of more than 15 months when using resting periods between two and three weeks and agreed with recent experimental observations in animal models. Additionally, we tested adaptive variations of these new protocols, what showed a potential reduction in toxicity, but no survival gain. Our computational results highlight the need of further clinical trials that could obtain better results from treatment with TMZ in low grade gliomas.

Advances in mitophagy and mitochondrial apoptosis pathway-related drugs in glioblastoma treatment.

Glioblastoma (GBM) is the most common malignant tumor of the central nervous system (CNS). It is a leading cause of death among patients with intracranial malignant tumors. GBM exhibits intra- and inter-tumor heterogeneity, leading to drug resistance and eventual tumor recurrence. Conventional treatments for GBM include maximum surgical resection of glioma tissue, temozolomide administration, and radiotherapy, but these methods do not effectively halt cancer progression. Therefore, development of novel methods for the treatment of GBM and identification of new therapeutic targets are urgently required. In recent years, studies have shown that drugs related to mitophagy and mitochondrial apoptosis pathways can promote the death of glioblastoma cells by inducing mitochondrial damage, impairing adenosine triphosphate (ATP) synthesis, and depleting large amounts of ATP. Some studies have also shown that modern nano-drug delivery technology targeting mitochondria can achieve better drug release and deeper tissue penetration, suggesting that mitochondria could be a new target for intervention and therapy. The combination of drugs targeting mitochondrial apoptosis and autophagy pathways with nanotechnology is a promising novel approach for treating GBM.This article reviews the current status of drug therapy for GBM, drugs targeting mitophagy and mitochondrial apoptosis pathways, the potential of mitochondria as a new target for GBM treatment, the latest developments pertaining to GBM treatment, and promising directions for future research.

Lymphoproliferative disorder during temozolomide therapy; a representative case of a formidable complication and management challenges

BackgroundLymphoproliferative disorder represents a heterogeneous clinicopathological spectrum characterized by uncontrolled proliferation of lymphocytes. Immunodeficiency is a major trigger of its development. While induction of immunodeficiency is a well-known adverse effect of temozolomide therapy, development of lymphoproliferative disorder following temozolomide therapy has not previously been described.Case presentationA patient with brainstem glioma developed constitutional symptoms, pancytopenia, splenomegaly and generalized lymphadenopathy during the 2nd cycle of maintenance therapy following induction therapy with temozolomide. Epstein-Barr virus-infected lymphocytes were observed histopathologically and “other iatrogenic immunodeficiency-associated lymphoproliferative disorder” (OIIA-LPD) was diagnosed. Although discontinuation of temozolomide led to rapid remission, relapse was observed 4 months later. CHOP chemotherapy was induced, resulting in secondary remission. Vigilant follow-up for another 14 months showed radiologically stable brainstem glioma and no further recurrence of OIIA-LPD.ConclusionsThis is the first report documenting OIIA-LPD during temozolomide administration. Timely diagnosis of the disease and discontinuation of the causative agent were considered to be the management of choice. Close monitoring for relapse should be continued. Finding a balance between glioma management and controlling the remission of OIIA-LPD remains to be clarified.

Hyaluronic acid/chitosan-coated poly (lactic-co-glycolic acid) nanoparticles to deliver single and co-loaded paclitaxel and temozolomide for CD44+oral cancer cells

Oral cancer has a poor survival rate despite comprehensive therapy. Current treatments result in acute side effects and fail to eliminate an aggressive group of cells overexpressing CD44. Such cells are capable of tumour initiating, self-renewal, invasion and metastasis, resulting in tumour relapse and resistance. This study aims to synthesise and characterise hyaluronic acid/chitosan-coated poly (lactic-co-glycolic acid) nanoparticles and assess their effectiveness in delivering Paclitaxel and Temozolomide to human tongue squamous cell carcinoma cell line that expresses high CD44 levels, in terms of cell cytotoxicity and apoptosis. This study also assesses the coordinated administration of Paclitaxel and Temozolomide and whether they exhibit significant synergistic cell inhibition effects with reduced introduced drug concentration if co-delivered simultaneously. Nanoparticles were synthesised with solvent evaporation method and characterised to assess their size, homogeneity, and zeta potential. Cell viability assay and real-time cell analysis were performed to examine the cell inhibitory effect of the drug-loaded nanoparticles. Cell apoptosis and cell cycle alteration were detected, and reactive oxygen species induction, mitochondrial membrane potential, and expressed genes associated with cell inhibition and death were evaluated. The synthesised nanoparticles had a nano-sized diameter of 260.40±11.54 nm, a positive zeta potential of +14.31±1.37 mV and a low polydispersity index value of 0.15±0.03. Paclitaxel, Temozolomide, and their combination have inhibited cell proliferation with half maximal inhibitory concentrations of 4 nM, 1000 μM and 2nM:300 μM, respectively. Compared to free drugs, the single-loaded and co-loaded drugs induced more cytotoxicity. Paclitaxel and Temozolomide showed a considerable synergistic inhibitory effect which was discovered to be more significant when the drugs were loaded in the nanoparticles. Drug-loaded nanoparticles were verified to induce higher cell apoptosis rates, cell proportion arrested at the S-phase of the cell cycle, reactive oxygen species generation, mitochondrial collapse and expression of genes associated with cellular inhibition and death than free drugs. These results demonstrate that the established nanoparticles could be a potential candidate for oral cancer therapy since they could deliver and improve the efficacy of single and dual drugs against oral cancer cells.

Comparative Study of Extremely Low-Frequency Electromagnetic Field, Radiation, and Temozolomide Administration in Spheroid and Monolayer Forms of the Glioblastoma Cell Line (T98).

Glioblastoma is the most common primary malignant tumor of the central nervous system. The patient's median survival rate is 13.5 months, so it is necessary to explore new therapeutic approaches. Extremely low-frequency electromagnetic field (EMF) has been explored as a noninvasive cancer treatment. This study applied the EMF with previous conventional chemoradiotherapy for glioblastoma. In this study, we evaluated the cytotoxic effects of EMF (50 Hz, 100 G), temozolomide (TMZ), and radiation (Rad) on gene expression of T98 glioma cell lines in monolayer and spheroid cell cultures. Treatment with Rad and EMF significantly increased apoptosis-related gene expression compared to the control group in monolayers and spheroids (p<0.001). The expression of apoptotic-related genes in monolayers was higher than the similar spheroid groups (p<0.001). We found that treatment with TMZ and EMF could increase the gene expression of the autophagy cascade markers compared to the control group (p<0.001). Autophagy-related gene expression in spheroids was higher than in the similar monolayer group (p<0.001). We demonstrated that coadministration of EMF, TMZ, and Rad significantly reduced cell cycle and drug resistance gene expression in monolayers and spheroids (p<0.001) compared to the control group. The combinational use of TMZ, Rad and, EMF showed the highest antitumor activity by inducing apoptosis and autophagy signaling pathways and inhibiting cell cycle and drug resistance gene expression. Furthermore, EMF increased TMZ or radiation efficiency.

Delta-radiomics Entropy Based on Tumor Heterogeneity Concept – Response Predictor to Irradiation for Unresectable/recurrent Glioblastoma

Although adjuvant radiotherapy in combination with Temozolomide administration has clearly demonstrated the benefit in improving the prognosis of patients with multiforme glioblastoma, radiotherapy as only treatment or in combination with systemic treatment is one of the best supportive in unresectable cases. For recurrent cases, the salvage radiotherapy option (re-irradiation) can be chosen in carefully selected cases so that the benefit is greater than the toxicities. Radiomics, a new subdomain of artificial intelligence (AI), relies on advanced analysis in high-resolution medical imaging to establish diagnostic, prognostic and predictive models for clinical medicine. The variation of the delta-radiomics parameters analyzed within a tumor volume may be via tumor heterogeneity indirectly correlated with the response to treatment. The aim of the study is to propose a delta-radiomic based on entropy algorithm to allow the non-invasive pre-therapeutic identification of patients with unresectable or recurrent multiform glioblastoma who will benefit from irradiation and/or salvage re-irradiation.

ACT-1 A PROSPECTIVE MULTICENTER PHASE I/IIA STUDY OF PREOPERATIVE NEOADJUVANT BEVACIZUMAB FOR NEWLY DIAGNOSED GLIOBLASTOMA

Abstract Background Preoperative neoadjuvant bevacizumab (neoBev) reduces enhancement and perifocal edema by inhibition of angiogenesis and vascular permeability for glioblastoma (GBM). The aim of this study was to investigate safety and efficacy of neoBev for newly diagnosed GBM through an exploratory prospective multi-center study. METHODS &amp; PATIENTS 15 patients with newly diagnosed GBM were enrolled in the present study. Eligibility was a patient with a brain tumor representing with ring-shaped enhancement and perifocal edema on magnetic resonance imaging (MRI). Based on neuroimage of typical GBM, neoBev and temozolomide (TMZ) were administered prior to craniotomy. Two weeks after neoBev, the tumor volume on T1-weighted gadolinium enhancement (T1Gd) and fluid attenuated inversion recovery (FLAIR) were assessed. Three to four weeks after neoBev and TMZ administration, patients underwent surgical resection. The primary endpoint was feasibility and safety, and the secondary endpoint was efficacy. Adverse events including systemic toxicity and wound healing delay during radiation (RT), TMZ, and Bev combined therapy were carefully monitored throughout clinical course including extent of resection. RESULTS Average of tumor regression rate two weeks after neoBev on T1Gd and FLAIR were 37.0% and 54.0%, respectively. Cerebral blood flow and cerebral blood volume were reduced after neoBev. Patients underwent surgical resection safely without excess blood loss due to less vascular and less degree of brain swelling. Two patients underwent awake surgery without any complications. Postoperative MRI showed that the all tumors were totally removed except one with multiple invasive tumors. Histological diagnosis of all patients was GBM, IDH-1 wild-type. Postoperative course was uneventful without neurological deficit and adverse effects except one postoperative hematoma in the resection cavity and one wound infection due to wound dehiscence. CONCLUSION Preoperative neoBev for newly diagnosed GBM might contribute to safe surgery. Clinical outcome of this therapeutics is now currently under investigation.

A case of psoriasiform drug eruption caused by temozolomide

AbstractPsoriasiform drug eruption is defined as condition similar to psoriasis triggered by drug administration, including de novo development of psoriasis or exacerbation of pre‐existing psoriasis. Herein, we describe a 52‐year‐old Japanese woman, who developed disseminated psoriasiform lesions following administration of temozolomide, a remedy for glioblastoma, although cutaneous adverse events by this drug was very rare. In addition, we assume that altered inflammatory signals associated with psoriasis, such as activation of signal transducer and activator of transcription 3 (STAT3), might be involved in the underlying pathomechanism of drug eruption caused by temozolomide.

Combination therapy with interferon-gamma as a potential therapeutic medicine in rat's glioblastoma: A multi-mechanism evaluation

BackgroundThis study assessed the effects of single or combined administration of temozolomide (TMZ) and interferon-gamma (IFN-ᵞ) on anxiety-like behaviors, balance disorders, learning and memory, TNF-α, IL-10, some oxidant and antioxidants factors with investigating the toll-like receptor-4 (TLR4) and p-CREB signaling pathway in C6-induced glioblastoma of rats. Methods40 male Sprague-Dawley rats bearing intra-caudate nucleus (CN) culture medium or C6 inoculation were randomly divided into five groups as follows: Sham, Tumor, TMZ, IFN-ᵞ and a TMZ + IFN-ᵞ combination. The open-field test (OFT), elevated plus maze (EPM), rotarod, and passive avoidance test (PAT) were done on days 14–17. On day 17 after tumor implantation, brain tissues were extracted for histopathological evaluation. TNF-α, IL-10, SOD, GPX, TAC, MDA, the protein level of TLR4 and p-CREB was measured. ResultsCombination therapy inhibited the growth of the tumor. Treatment groups alleviated tumor-induced anxiety-like behaviors and improved imbalance and memory impairment. SOD, GPX, and TAC decreased in the tumor group. The combination group augmented GPX and TAC. MDA decreased in treatment groups. TMZ, IFN-ᵞ reduced tumor-increased TNF-α and IL-10 level. The combination group declined TNF-α level in serum and IL-10 level in serum and brain. Glioblastoma induced significant upregulation of TLR4 and p-CREB in the brain which inhibited by IFN-ᵞ and TMZ+ IFN-ᵞ. ConclusionThe beneficial effects of TMZ, IFN-ᵞ, and TMZ+ IFN-ᵞ on neurocognitive functioning of rats with C6-induced glioblastoma may be mediated via modulating oxidative stress, reduced cytokines, and the downregulation of expression of TLR4 and p-CREB. Combination treatment appears to be more effective than single treatment.

Circadian Clock Genes Act as Diagnostic and Prognostic Biomarkers of Glioma: Clinic Implications for Chronotherapy.

Gliomas are the most common primary intracranial tumors and closely related to circadian clock. Due to the high mortality and morbidity of gliomas, exploring novel diagnostic and early prognostic markers is necessary. Circadian clock genes (CCGs) play important roles in regulating the daily oscillation of biological processes and the development of tumor. Therefore, we explored the influences that the oscillations of circadian clock genes (CCGs) on diagnosis and prognosis of gliomas using bioinformatics. In this work, we systematically analyzed the rhythmic expression of CCGs in brain and found that some CCGs had strong rhythmic expression; the expression levels were significantly different between day and night. Four CCGs (ARNTL, NPAS2, CRY2, and DBP) with rhythmic expression were not only identified as differentially expressed genes but also had significant independent prognostic ability in the overall survival of glioma patients and were highly correlated with glioma prognosis in COX analysis. Besides, we found that CCG-based predictive model demonstrated higher predictive accuracy than that of the traditional grade-based model; this new prediction model can greatly improve the accuracy of glioma prognosis. Importantly, based on the four CCGs' circadian oscillations, we revealed that patients sampled at night had higher predictive ability. This may help detect glioma as early as possible, leading to early cancer intervention. In addition, we explored the mechanism of CCGs affecting the prognosis of glioma. CCGs regulated the cell cycle, DNA damage, Wnt, mTOR, and MAPK signaling pathways. In addition, it also affects prognosis through gene coexpression and immune infiltration. Importantly, ARNTL can rhythmically modulated the cellular sensitivity to clinic drugs, temozolomide. The optimal point of temozolomide administration should be when ARNTL expression is highest, that is, the effect is better at night. In summary, our study provided a basis for optimizing clinical dosing regimens and chronotherapy for glioma. The four key CCGs can serve as potential diagnostic and prognostic biomarkers for glioma patients, and ARNTL also has obvious advantages in the direction of glioma chronotherapy.

Abstract 1661: Development of a patient-derived glioblastoma model in the transgenic Rag2 Null rat: In vivo imaging, histology, and combination therapy assessment

Abstract An important obstacle to translating promising drug treatments against glioblastoma (GBM) to the clinic is lack of resistant GBM animal models that more accurately parallel the clinical course of GBM drug resistance found in patients. In this project, a recurrent patient derived intracranial GBM tumor model (GB10) was developed for the first time in the novel Rag2 Null transgenic rat to establish a reproducible preclinical brain tumor model. Histologic characterization confirmed markers of high nuclear proliferation (30% Ki67) and presence of neovascularity (3% Von Willebrand Factor VIII) in all tumors. Serial in vivo imaging was performed to determine a clinically relevant late stage of tumor across all rats before initiation of treatment, accounting for heterogeneity of tumor size and growth rate characteristics. Overall survival was measured following oral administration of control, Temozolomide (TMZ), or combination therapy with TMZ and Idasanutlin. Eighteen Rag2 Null rats were intracranially implanted with GB10, a well characterized, recurrent cell line from the Mayo Clinic Brain Tumor Patient-Derived Xenograft National Resource. Bi-weekly high resolution, 2-dimensional T2 magnetic resonance imaging (2DT2 MRI) was performed on a Bruker 9.4 tesla scanner until tumor volume reached 30 µL. 14 days later, simultaneous positron emission tomography and magnetic resonance imaging (PET MRI) was performed on each rat with three dimensional T1 post-contrast (3DT1 CE), amino acid-based 18F-Flouroethyltyrosine (18F-FET), and amide proton transfer-chemical exchange saturation transfer (amide-CEST). Measured tumor parameters included volumetry (3DT1 CE), metabolic activity (18F-FET), and mobile phase intracellular protein content (amide-CEST), to confirm late-stage viable tumors of similar size (15.3 mm^2 +/-1.38 based on SEM, N=16) and metabolism (2:1 ratio of activity of tumor relative to contralateral control brain tissue). Two rats were removed: 1 died prematurely of infection and 1 had extra-axial tumor location. Oral treatment groups were as follows: Control (N= 5), TMZ (N=6) or TMZ + Idasanutlin (N=5). Kaplan Meier survival curves for the TMZ treated group (80.2+/-4.1 days) and combined TMZ + Idasanutlin group (93.8+/-6.2 days) were both significantly increased (P&amp;lt;0.001) compared to control (67.4+/-4.5 days). Survival for the TMZ + Idasanutlin treated group was also significantly increased (P&amp;lt;0.001) relative to TMZ treated group indicating efficacy of combination therapy. In conclusion, a robust, resistant, patient derived GBM animal model was developed using serial, high field, non-invasive, multimodality, molecular imaging along with histopathologic analysis. Feasibility of assessing treatment response was also demonstrated with both a standard of care and experimental combination therapy, in the late stage of GBM growth. Citation Format: Luke R. Jackson, Megan R. Masi, Hamideh zarrinmayeh, Sudip K. Das, Mark A. Green, Scott E. Snyder, Nian Wang, Karen Pollok, Gary D. Hutchins, Elizabeth R. Butch, Michael C. Veronesi. Development of a patient-derived glioblastoma model in the transgenic Rag2 Null rat: In vivo imaging, histology, and combination therapy assessment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1661.

Abstract 1086: PEGylated talazoparib enhances therapeutic window of its combination with temozolomide in Ewing sarcoma

Abstract Introduction: The Ewing family of sarcomas is the fourth most common highly malignant childhood cancer. Current standard therapy is relatively ineffective for relapsed and metastatic Ewing sarcoma predominantly due to development of resistance to chemotherapeutics. Nanoparticle-formulated drugs are reported to increase uptake into tumor tissue, while reducing drug access to normal tissues, because of reduced permeability of normal vasculature. This potentially leads to lower dose exposure in normal tissues and reduced toxicity. The purpose of this study was to evaluate the antitumor activity of the PEGylated poly(ADP) ribose polymerase 1/2 (PARP1/2) inhibitor talazoparib combined with the DNA alkylating agent temozolomide (TMZ) in Ewing sarcoma xenograft models and other pediatric cancers. Method:. We evaluated the preclinical efficacy of PEGylated talazoparib (PEG~TLZ), alone or in combination with TMZ, in Ewing sarcoma and glioblastoma patient derived xenograft (PDX) models. Additional solid tumor models, such as rhabdomyosarcoma, Wilms tumor, malignant rhabdoid tumor, osteosarcoma, and synovial sarcoma were evaluated using a novel single mouse testing approach. PEG~TLZ was administered as a single administration intraperitoneally to mice bearing subcutaneous tumors at a single dose of 5 - 20 µmol/kg alone, or at 10 µmol/kg on day 1 combined with TMZ administered orally at 40 mg/kg starting on day 3 or 4 for 5 consecutive days. Results: Mice bearing Ewing sarcoma and MGMT-deficient glioblastoma xenografts tolerated PEG~TLZ+TMZ with minimal toxicity and achieved maintained complete response (MCR). The time-separated drug administration schedule of the single dose of PEG~TLZ followed by the 5-day TMZ treatment demonstrated objective responses in Ewing sarcoma, rhabdoid tumor, rhabdomyosarcoma, and glioblastoma PDX models. Conclusion: We evaluated the range of PEG~TLZ+TMZ activity among pediatric solid tumor panels using conventional and single-mouse testing approaches, and demonstrated that PEG~TLZ combined with delayed TMZ administration enhances the therapeutic window of the treatment compared to free TLZ. From the clinical standpoint, the single intravenous administration of PEG~TLZ could be advantageous for treating infants and young children. Citation Format: Vanessa Del Pozo, Andrew J. Robles, Shaun Fontaine, Qianqian Liu, Joel E. Michalek, Peter J. Houghton, Raushan Kurmasheva. PEGylated talazoparib enhances therapeutic window of its combination with temozolomide in Ewing sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1086.

Targeting the Axl and mTOR Pathway Synergizes Immunotherapy and Chemotherapy to Butylidenephthalide in a Recurrent GBM.

Background The role of inherent tumor heterogeneity and an immunosuppressive microenvironment in therapeutic resistance has been determined to be of importance for the better management of glioblastoma multiforme (GBM). Some studies have suggested that combined drugs with divergent mechanisms may be promising in treating recurrent GBM. Methods Intracranial sustained (Z)-n-butylidenephthalide [(Z)-BP] delivery through Cerebraca Wafers (CWs) to eliminate unresectable brain tumors was combined with the administration of temozolomide (TMZ), pembrolizumab, and cytokine-induced killer (CIK) cells for treating a patient with recurrent glioblastoma. Neurological adverse events and wound healing delay were monitored for estimating tolerance and efficacy. Response Assessment in Neuro-Oncology criteria were applied to evaluate progression-free survival (PFS); further, the molecular characteristics of GBM tissues were analyzed, and the underlying mechanism was investigated using primary culture. Results Intracerebral (Z)-BP in residual tumors could not only inhibit cancer stem cells but also increase interferon gamma levels in serum, which then led to the regression of GBM and an immune-responsive microenvironment. Targeting receptor tyrosine kinases, including Axl and epidermal growth factor receptor (EGFR), and inhibiting the mechanistic target of rapamycin (mTOR) through (Z)-BP were determined to synergize CIK cells in the presence of pembrolizumab and TMZ in recurrent GBM. Therefore, this well-tolerated regimen could simultaneously block multiple cancer pathways, which allowed extended PFS and improved quality of life for 22 months. Conclusion Given the several unique functions of (Z)-BP, greater sensitivity of chemotherapy and the synergism of pembrolizumab and CIK cells could have affected the excellent prognosis seen in this patient with recurrent GBM.

Glioblastoma That Does Not Improve with Standard Treatment: Standard and Personalized Treatment Making The Most of Limited Modalities

The standard treatment for glioblastoma is maximal surgical resection followed by postoperative temozolomide administration combined with radiation therapy. Although treatment outcomes have improved in recent years, glioblastoma remains a fatal malignant brain tumor. In addition to standard treatment, it is important to understand the characteristics of additional therapies or limited therapeutic modalities, such as bevacizumab, photodynamic therapy, BCNU wafers, tumor treating fields, and genomic medicine. Furthermore, combination therapy should be applied, depending on the individual patient's condition, to treat this intractable disease.

A natural carotenoid crocin exerts antidepressant action by promoting adult hippocampal neurogenesis through Wnt/β-catenin signaling

IntroductionAdult hippocampal neurogenesis (AHN) is acknowledged to play a critical role in depression. Emerging evidence suggests that the Wnt/β-catenin pathway can modulate hippocampal neurogenesis. Crocin, a natural carotenoid, possesses antidepressant property. Yet, how it affects neurogenesis and exerts antidepressant response remains unknown. ObjectiveTo explore the role of AHN and Wnt/β-catenin in the antidepressant action of crocin. MethodsDepressive-related behaviors, including sucrose preference test (SPT), tail suspension test (TST), forced swimming test (FST), and sexual behaviors were performed following crocin treatment. Neurogenesis was characterized via immunohistochemistry, immunofluorescence, Golgi staining and electrophysiology approach. Wnt/β-catenin signaling was examined with western blot analysis. The role of AHN Wnt/β-catenin cascade in crocin’s antidepressant response was assessed by conditional removal of glial fibrillary acidic protein (GFAP)-expressing newborn neural cells, temozolomide administration, microinfusion of Dkk1 or viral-mediated shRNA of Wnt3a. ResultsCrocin decreased the immobility duration in TST and FST without impairing the performance in sexual behaviors. Crocin boosted the proliferation and differentiation of progenitors, and promoted dendritic maturation and functional integration of hippocampal newborn neurons. Conditional removal of GFAP-expressing neural cells or temozolomide administration impaired the antidepressant response of crocin. Additionally, Wnt/β-catenin signaling was promoted following crocin treatment. In chronic unpredictable mild stress (CUMS) murine model, crocin treatment displayed antidepressant response in SPT, FST and TST, and restored the neurogenesis levels and Wnt/β-catenin signaling impaired by CUMS. Infusion of Dickkopf-1 (DKK1) or knockdown of Wnt3a in the hippocampus impaired the antidepressant response of crocin. ConclusionCrocin exerted antidepressant response, which was dependent on enhancement of AHN and activation of the Wnt/β-catenin pathway.