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Wong, E. T.

Publications and source records attributed to Wong, E. T..

4 recordsLinked to original sources

Efficacy of Tumor Treating Fields (TTFields) in triple negative breast cancer cells and synergy with PARP inhibitor talazoparib

Breast cancer is the most diagnosed cancer worldwide. Triple-negative breast cancer (TNBC) is a subtype with a poor prognosis because of its aggressiveness and high likelihood of relapse, making its treatment particularly challenging. We explored the effect of Tumor Treating Fields (TTFields) as a novel treatment option for breast cancer, which can be used together with other therapies, such as PARP inhibitors. TTFields use alternating electric fields to inhibit cell growth and induce cellular damage. Our findings indicate that TTFields increase expression of the universal cell cycle CDK inhibitory protein p21(WAF1)/CDKN1A independently of TP53 mutational status. Moreover, when used together with the PARP inhibitor talazoparib, the combination further upregulates p21 protein. Both TTFields alone and together with talazoparib induce cell death as documented by PARP cleavage while reducing markers of cell growth and anti-apoptotic proteins, including p-STAT3, STAT3, and MCL-1. Additionally, TTFields together with talazoparib induce DNA damage, as indicated by increased {gamma}H2AX expression. The combination of talazoparib plus TTFields treatment decrease PDL-1 levels and given its utility in predicting response to PD-1/PD-L1 by mediating immune evasion, this raises the possibility of future combination for immune modulation in cancer therapy. Our preclinical results suggest TTFields alone or together with PARP inhibitors such as talazoparib as a promising therapeutic approach for further development for the treatment of breast cancer.

cancer biology↗

A New Method for Optimal Placement of Tumor Treating Fields Electrodes

OverviewTumor Treating Fields (TTFields) provide a non-invasive treatment option for newly diagnosed glioblastoma. While optimization of electrode placement is important to increase treatment efficacy, clinical therapy planning is done using an undisclosed and proprietary software (NovoTAL(R)), which is clinically unvalidated. This study investigates a new computational approach for optimizing TTFields electrode placement and is compared to the current clinical standard. MethodsWe developed a new computational pipeline integrating patient-specific anatomical data to optimize electrode configurations in five representative glioblastoma cases with diverse tumor locations and sizes. Two optimization strategies were employed: one maximizing electric field intensity at the tumor, and another enhancing coverage of the adjacent brain while maintaining sufficient tumor intensity. Results were compared to electrode placements generated by NovoTAL(R). Additional simulations with artificial tumors assessed the effects of tumor size and location. ResultsOptimized electrode placements improved electric field intensity in tumors by 18%-34% compared to the clinical standard. Coverage-weighted optimizations provided broader field coverage without significantly compromising tumor intensity. Smaller or surface-adjacent tumors benefited most from optimization, achieving precise targeting and enhanced coverage. Extensive randomized placement analyses highlighted the superior performance of the optimized configurations. Analysis of artificial models showed consistent improvements across varying tumor locations and sizes. ConclusionPersonalized optimization of TTFields electrode placement significantly improves electric field targeting of tumors and adjacent brain regions. This approach outperforms standardized planning software and clinical practices and supports future development of adaptive, automated strategies for individualized TTFields therapy in glioblastoma. Keypoints- Optimized TTFields array placement enhanced field intensity by 18-34% vs. clinical standard. - Optimized TTFields planning improved field coverage in tumor-adjacent regions. - Optimized TTFields planning outperformed standard methods and random placement. Importance of the studyTTFields are increasingly used as adjuvant therapy for glioblastoma. However, current individualized treatment planning relies on proprietary, undisclosed, and clinically unvalidated software, limiting transparency, optimization, and innovation in the field. This study introduces an individualized, semi-automated, and open-source method for optimal electrode placement based on standard MRI data, addressing a critical need for validated and adaptable planning tools. Our approach increased field intensity in tumors by 18-34% and achieved broader coverage compared to the standard clinical tool (NovoTAL(R)), without compromising therapeutic strength. Notably, the method also consistently outperformed extensive random electrode placements across diverse tumor types and sizes, highlighting its robustness and ability to achieve true optimal configurations. Open-source availability enhances reproducibility and clinical translation, representing a significant step toward more effective, individualized TTFields therapy. This advancement has the potential to improve outcomes for glioblastoma patients and underscores the importance of technology validation in neuro-oncology.

neuroscience↗

Enabling CAR-T Cell Immunotherapy in Glioblastoma by Modifying Tumor Microenvironment via Oncolytic Adenovirus Encoding Bispecific T Cell Engager

Recent clinical trials show that CAR-T cell therapies can initially blunt tumor growth in glioblastoma (GBM) patients. However, the tumor microenvironment activates mechanisms that inhibit tumor-killing potential of the CAR-T cells and limit their therapeutic efficacy. To counteract this, we have utilized oncolytic adenovirus (OV) Ad5-{Delta}24-RGD as a platform to overexpress a bispecific T cell engager (BiTE) targeting both T cell marker CD3 and GBM specific tumor associated antigen IL-13R2. We first demonstrated that OV-BiTE could enhance recruitment of T cells to GBM in vitro and in vivo. We then showed that intratumoral injection of OV-BiTE followed by infusion of combined EGFR- and EGFRvIII-CAR-T cells was more effective than OV-BiTE supplemented with either CAR-T therapy alone, and led to significant tumor eradication in a GBM xenograft mouse model. In conclusion, our multimodal OV-BiTE & CAR-T cell immunotherapy is capable of overcoming immunosuppressive tumor microenvironment and GBM resistance to treatment. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=160 SRC="FIGDIR/small/667708v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@c55b15org.highwire.dtl.DTLVardef@deffb2org.highwire.dtl.DTLVardef@64ff90org.highwire.dtl.DTLVardef@c65fc2_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LIOncolytic adenovirus encoding bispecific T cell engager (OV-BiTE) combines two immunotherapeutic agents into one. C_LIO_LIOV-BiTE strategy modifies tumor microenvironment and enhances recruitment of T cells to glioblastoma (GBM) in vitro and in vivo. C_LIO_LIMultimodal OV-BiTE & CAR-T cell immunotherapy effectively reduced tumor mass in a GBM xenograft mouse model and is superior to either immunotherapy alone. C_LI

cancer biology↗

Combination of Imipridone ONC201 or ONC206 with Temozolomide and Radiotherapy in triple ITR therapy reduces intracranial tumor burden and prolongs survival in an orthotopic wild-type IDH GBM mouse model

Glioblastoma remains the most lethal common primary brain tumor in adults with limited therapeutic options. TIC10/ONC201, a first-in-class imipridone we discovered, achieved meaningful therapeutic effects in phase I/II trials in patients with diffuse gliomas harboring H3K27M mutations, and currently the drug is in randomized phase III testing (ACTION trial; NCT05580562). ONC201 targets mitochondrial protease ClpP to disrupt oxidative phosphorylation and trigger the integrated stress response (ISR), TRAIL/DR5, and tumor cell death. We hypothesized that ONC201 and its analogue ONC206 synergize with temozolomide (TMZ) and ionizing radiation (IR), standard-of-care glioblastoma therapies. ONC201 enhances TMZ or IR-induced apoptosis, and cytotoxicity. ClpP-silencing suppresses ONC201-induced cytotoxicity but not TMZ or RT. Both ONC201 and ONC206 reduce expression of TMZ-resistance mediator MGMT. Suppression of MGMT protein was observed in H3K27M-mutated DIPG cell lines following treatment with ONC201 or ONC206 with or without TMZ. Cytokine profiling indicates distinct ONC201 alterations relative to TMZ suggesting distinct anti-tumor immune mechanisms. Triple IR+TMZ+ONC201 (ITR) therapy prolongs median survival to 123 days with a tail on survival curve (3-of-7 mice alive beyond 200-days) in an orthotopic U251 GBM model versus ONC201 (44-days; p=0.000197), IR (63-days; p=0.0012), TMZ (78-days; p=0.0354), ONC201+IR (55-days; p=0.0004), ONC201+TMZ (80-days; p=0.0041) and IR+TMZ (103-days; p>0.05). By 231-days, the only surviving mice were in IRT group. Our results support investigation of ONC201/ONC206 in combination with TMZ and IR (ITR) in GBM or H3K27M mutated diffuse glioma therapy.

cancer biology↗