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Breast tumors generally consist of a diverse population of cells with varying gene expression profiles. Breast tumor heterogeneity is a major factor contributing to drug resistance, recurrence, and metastasis after chemotherapy. Antibody-drug conjugates (ADCs) are emerging chemotherapeutic agents with striking clinical success, including T-DM1 for HER2-positive breast cancer. However, these ADCs often suffer from issues associated with intratumor heterogeneity. Here, we show that homogeneous ADCs containing two distinct payloads are a promising drug class for addressing this clinical challenge. Our conjugates show HER2-specific cell killing potency, desirable pharmacokinetic profiles, minimal inflammatory response, and marginal toxicity at therapeutic doses. Notably, a dual-drug ADC exerts greater treatment effect and survival benefit than does co-administration of two single-drug variants in xenograft mouse models representing intratumor HER2 heterogeneity and elevated drug resistance. Our findings highlight the therapeutic potential of the dual-drug ADC format for treating refractory breast cancer and perhaps other cancers. Intratumor heterogeneity in breast cancer can limit the clinical success of antibody-drug conjugates (ADCs). In this study, the authors develop dual payload Her2-ADCs that show potent anti-tumor activity against heterogeneous breast tumors in vivo.

Abstract Rodent brain tumor models have been useful for developing effective therapies for glioblastomas (GBMs). In this review, we first discuss the 3 most commonly used rat brain tumor models, the C6, 9L, and F98 gliomas, which are all induced by repeated injections of nitrosourea to adult rats. The C6 glioma arose in an outbred Wistar rat and its potential to evoke an alloimmune response is a serious limitation. The 9L gliosarcoma arose in a Fischer rat and is strongly immunogenic, which must be taken into consideration when using it for therapy studies. The F98 glioma may be the best of the 3 but it does not fully recapitulate human GBMs because it is weakly immunogenic. Next, we discuss a number of mouse models. The first are human patient-derived xenograft gliomas in immunodeficient mice. These have failed to reproduce the tumor-host interactions and microenvironment of human GBMs. Genetically engineered mouse models recapitulate the molecular alterations of GBMs in an immunocompetent environment and “humanized” mouse models repopulate with human immune cells. While the latter are rarely isogenic, expensive to produce, and challenging to use, they represent an important advance. The advantages and limitations of each of these brain tumor models are discussed. This information will assist investigators in selecting the most appropriate model for the specific focus of their research.

Tumor suppressive microRNAs (miRNAs) are increasingly implicated in the development of anti-tumor therapy by reprogramming gene network that are aberrantly regulated in cancer cells. This study aimed to determine the therapeutic potential of putative tumor suppressive miRNA, miR-138, against glioblastoma (GBM). Whole transcriptome and miRNA expression profiling analyses on human GBM patient tissues identified miR-138 as one of the significantly downregulated miRNAs with an inverse correlation with CD44 expression. Transient overexpression of miR-138 in GBM cells inhibited cell proliferation, cell cycle, migration, and wound healing capability. We unveiled that miR-138 negatively regulates the expression of CD44 by directly binding to the 3′ UTR of CD44. CD44 inhibition by miR-138 resulted in an inhibition of glioblastoma cell proliferation in vitro through cell cycle arrest as evidenced by a significant induction of p27 and its translocation into nucleus. Ectopic expression of miR-138 also increased survival rates in mice that had an intracranial xenograft tumor derived from human patient-derived primary GBM cells. In conclusion, we demonstrated a therapeutic potential of tumor suppressive miR-138 through direct downregulation of CD44 for the treatment of primary GBM.

The gut microbiome is fundamental in neurogenesis processes. Alterations in microbial constituents promote inflammation and immunosuppression. Recently, in immune-oncology, specific microbial taxa have been described to enhance the effects of therapeutic modalities. However, the effects of microbial dysbiosis on glioma are still unknown. The aim of this study was to explore the effects of glioma development and Temozolomide (TMZ) on fecal microbiome in mice and humans. C57BL/6 mice were implanted with GL261/Sham and given TMZ/Saline. Fecal samples were collected longitudinally and analyzed by 16S rRNA sequencing. Fecal samples were collected from healthy controls as well as glioma patients at diagnosis, before and after chemoradiation. Compared to healthy controls, mice and glioma patients demonstrated significant differences in beta diversity, Firmicutes/Bacteroides (F/B) ratio, and increase of Verrucomicrobia phylum and Akkermansia genus. These changes were not observed following TMZ in mice. TMZ treatment in the non-tumor bearing mouse-model diminished the F/B ratio, increase Muribaculaceae family and decrease Ruminococcaceae family. Nevertheless, there were no changes in Verrucomicrobia / Akkermansia . Glioma development leads to gut dysbiosis in a mouse-model, which was not observed in the setting of TMZ. These findings seem translational to humans and warrant further study.

Hydrogen peroxide (H 2 O 2 ) induces oxidative stress and cytotoxicity, and can be used for treating cancers in combination with radiotherapy. A product comprising H 2 O 2 and sodium hyaluronate has been developed as a radiosensitizer. However, the effects of H 2 O 2 on antitumor immunity remain unclear. To investigate the effects of H 2 O 2 , especially the abscopal effect when combined with radiotherapy (RT), we implanted murine tumor cells simultaneously in two locations in mouse models: the hind limb and back. H 2 O 2 mixed with sodium hyaluronate was injected intratumorally, followed by irradiation only at the hind limb lesion. No treatment was administered to the back lesion. The H 2 O 2 /RT combination significantly reduced tumor growth at the noninjected/nonirradiated site in the back lesion, whereas H 2 O 2 or RT individually did not reduce tumor growth. Flow cytometric analyses of the tumor‐draining lymph nodes in the injected/irradiated areas showed that the number of dendritic cells increased significantly with maturation in the H 2 O 2 /RT combination group. In addition, analyses of tumor‐infiltrating lymphocytes showed that the number of CD8 + (cluster of differentiation 8) T cells and the frequency of IFN‐γ + (interferon gamma) CD8 + T cells were higher in the noninjected/nonirradiated tumors in the H 2 O 2 /RT group compared to those in the other groups. PD‐1 (programmed death receptor 1) blockade further increased the antitumor effect against noninjected/nonirradiated tumors in the H 2 O 2 /RT group. Intratumoral injection of H 2 O 2 combined with RT therefore induces an abscopal effect by activating antitumor immunity, which can be further enhanced by PD‐1 blockade. These findings promote the development of H 2 O 2 /RT therapy combined with cancer immunotherapies, even for advanced cancers.

Immune checkpoint inhibitors (ICIs) are effective against many advanced malignancies. However, many patients are nonresponders to immunotherapy, and overcoming this resistance to treatment is important. Boron neutron capture therapy (BNCT) is a local chemoradiation therapy with the combination of boron drugs that accumulate selectively in cancer and the neutron irradiation of the cancer site. Here, we report the first boron neutron immunotherapy (B‐NIT), combining BNCT and ICI immunotherapy, which was performed on a radioresistant and immunotherapy‐resistant advanced‐stage B16F10 melanoma mouse model. The BNCT group showed localized tumor suppression, but the anti‐PD‐1 antibody immunotherapy group did not show tumor suppression. Only the B‐NIT group showed strong tumor growth inhibition at both BNCT‐treated and shielded distant sites. Intratumoral CD8+ T‐cell infiltration and serum high mobility group box 1 (HMGB1) levels were higher in the B‐NIT group. Analysis of CD8+ T cells in tumor‐infiltrating lymphocytes (TILs) showed that CD62L‐ CD44+ effector memory T cells and CD69+ early‐activated T cells were predominantly increased in the B‐NIT group. Administration of CD8‐depleting mAb to the B‐NIT group completely suppressed the augmented therapeutic effects. This indicated that B‐NIT has a potent immune‐induced abscopal effect, directly destroying tumors with BNCT, inducing antigen‐spreading effects, and protecting normal tissue. B‐NIT, immunotherapy combined with BNCT, is the first treatment to overcome immunotherapy resistance in malignant melanoma. In the future, as its therapeutic efficacy is demonstrated not only in melanoma but also in other immunotherapy‐resistant malignancies, B‐NIT can become a new treatment candidate for advanced‐stage cancers. Boron neutron capture therapy leads to new treatment option to overcome cancer immunotherapy resistance.

Despite current progress in treatment, glioblastoma (GBM) remains a lethal primary malignant tumor of the central nervous system. Although immunotherapy has recently achieved remarkable survival effectiveness in multiple malignancies, none of the immune checkpoint inhibitors (ICIs) for GBM have shown anti-tumor efficacy in clinical trials. GBM has a characteristic immunosuppressive tumor microenvironment (TME) that results in the failure of ICIs. Oncolytic herpes simplex virotherapy (oHSV) is the most advanced United States Food and Drug Administration-approved virotherapy for advanced metastatic melanoma patients. Recently, another oHSV, Delytact ® , was granted conditional approval in Japan against GBM, highlighting it as a promising treatment. Since oncolytic virotherapy can recruit abundant immune cells and modify the immune TME, oncolytic virotherapy for immunologically cold GBM will be an attractive therapeutic option for GBM. However, as these immune cells have roles in both anti-tumor and anti-viral immunity, fine-tuning of the TME using oncolytic virotherapy will be important to maximize the therapeutic efficacy. In this review, we discuss the current knowledge of oHSV, with a focus on the role of immune cells as friend or foe in oncolytic virotherapy.

Purpose Glioblastoma is a malignant brain tumor with a poor prognosis. Genetic mutations associated with this disease are complex are not fully understood and require further elucidation for the development of new treatments. The purpose of this study was to comprehensively analyze genetic mutations in glioblastomas and evaluate the usefulness of RNA sequencing. Patients and methods We analyzed 42 glioblastoma specimens that were resected in routine clinical practice and found wild-type variants of the IDH1 and IDH2 genes. RNA was extracted from frozen specimens and sequenced, and genetic analyses were performed using the CLC Genomics Workbench. Results The most common genetic alterations in the 42 glioblastoma specimens were TP53 mutation (28.6%), EGFR splicing variant (16.7%), EGFR mutation (9.5%), and FGFR3 fusion (9.5%). Novel genetic mutations were detected in 8 patients (19%). In 12 cases (28.6%), driver gene mutations were not detected, suggesting an association with PPP1R14A overexpression. Our findings suggest the transcription factors SOX10 and NKX6-2 are potential markers in glioblastoma. Conclusion RNA sequencing is a promising approach for genotyping glioblastomas because it provides comprehensive information on gene expression and is relatively cost-effective.

Reduced expression in immortalized cells/Dickkopf-3 (REIC/Dkk-3) is a tumor suppressor and its overexpression has been shown to exert anti-tumor effects as a therapeutic target gene in many human cancers. Recently, we demonstrated the anti-glioma effects of an adenoviral vector carrying REIC/Dkk-3 with the super gene expression system (Ad-SGE-REIC). Anti-vascular endothelial growth factor treatments such as bevacizumab have demonstrated convincing therapeutic advantage in patients with glioblastoma. However, bevacizumab did not improve overall survival in patients with newly diagnosed glioblastoma. In this study, we examined the effects of Ad-SGE-REIC on glioma treated with bevacizumab. Ad-SGE-REIC treatment resulted in a significant reduction in the number of invasion cells treated with bevacizumab. Western blot analyses revealed the increased expression of several endoplasmic reticulum stress markers in cells treated with both bevacizumab and Ad-SGE-REIC, as well as decreased β-catenin protein levels. In malignant glioma mouse models, overall survival was extended in the combination therapy group. These results suggest that the combination therapy of Ad-SGE-REIC and bevacizumab exerts anti-glioma effects by suppressing the angiogenesis and invasion of tumors. Combined Ad-SGE-REIC and bevacizumab might be a promising strategy for the treatment of malignant glioma.

The clinical imaging features of photon-counting detector (PCD) computed tomography (CT) are mainly known as dose reduction, improvement of spatial resolution, and reduction of artifacts compared to energy-integrating detector CT (EID-CT). The utility of cranial and spinal PCD-CT and PCD-CT angiography (CTA) has been previously reported. CTA is a widely used technique for noninvasive evaluation. Cranial CTA is important in brain tumors, especially glioblastoma; it evaluates whether the tumor is highly vascularized prior to an operation and helps in the diagnosis and assessment of bleeding risk. Spinal CTA has an important role in the estimation of feeders and drainers prior to selective angiography in the cases of spinal epidural arteriovenous fistulas and spinal tumors, especially in hemangioblastoma. So far, EID-CTA is commonly performed in an adjunctive role prior to selective angiography; PCD-CTA with high spatial resolution can be an alternative to selective angiography. In the cases of cerebral aneurysms, flow diverters are important tools for the treatment of intracranial aneurysms, and postoperative evaluation with cone beam CT with angiography using diluted contrast media is performed to evaluate stent adhesion and in-stent thrombosis. If CTA can replace selective angiography, it will be less invasive for the patient. In this review, we present representative cases with PCD-CT. We also show how well the cranial and spinal PCD-CTA approaches the accuracy of angiographic and intraoperative findings.