Tumor-specific Proteins Research Articles

Simplified Lipid Nanoparticles for Tissue- And Cell-Targeted mRNA Delivery Facilitate Precision Tumor Therapy in a Lung Metastasis Mouse Model.

mRNA-based applications have achieved remarkable success in the development of next-generation vaccines and the treatment of diverse liver diseases. Overcoming the challenge of delivering mRNA to extrahepatic tissues, especially specific cells within tissues, is crucial for precision therapy. In this study, a platform is developed for selective mRNA delivery to desired cells within tissues by combining lipid nanoparticle (LNP)-based targeted delivery with mRNA sequence-controlled expression. Through systematic optimization, a three-component LNP platform is developed, enabling targeted mRNA delivery to the lung, liver, and spleen. The incorporation of unique microRNA target sites into the mRNA scaffold further enhances control over protein translation in specific cells within the target tissue. This combined strategy, named SELECT (Simplified LNP with Engineered mRNA for Cell-type Targeting), demonstrates its efficacy in distinguishing mRNA expression between tumor and normal cells based on intracellular microRNA abundance. SELECT encapsulating mRNA encoding a tumor-specific cytotoxic protein, human ELANE, exhibits selective mRNA delivery to tumor lesions and significant inhibition of tumor growth in a mouse model of melanoma lung metastasis. Overall, SELECT has great potential as a new precision tumor treatment approach and also offers promising prospects for other mRNA therapies targeting specific cell types.

Application of serum tumor specific protein 70 for prognostic stratification in acute myeloid leukemia

Objective: To assess the value of serum tumor specific protein 70 (SP70) for prognostic stratification in acute myeloid leukemia (AML). Methods: A cohort study design was adopted. 129 newly diagnosed AML patients from September 2022 to January 2024 at the Hematology Department of the First Affiliated Hospital of Nanjing Medical University were included, as well as a control group consisted of 120 healthy individuals and 7 cases with benign hematologic diseases during the same period (total 127 cases). Clinical data were collected from Electronic Medical Records. According to the 2023 edition of the Chinese Leukemia Diagnosis and Treatment Guidelines, AML patients with good or moderate prognosis were categorized as low-to-intermediate risk, while those with poor prognosis were high-risk group. Univariate and multivariate logistic regression analyses were used to identify variables significantly associated with AML prognostic risk. ROC analysis was used to evaluate diagnostic performance. A nomogram for predicting patient prognostic risk was constructed by R 4.0.2 software, and the internal validation was performed using bootstrapping. Results: Among 129 AML patients, there were 71 males (55.0%) and 58 females (45.0%), with 42 (32.6%) classified as high-risk and 87 (67.4%) as low-intermediate risk. The high-risk group had a significantly higher median age [62 (48, 67) years] compared to the low-intermediate risk group [50 (35, 63) years, Z=-2.381, P=0.017], and a significantly higher proportion of males (30 patients, 71.4%) compared to the low-intermediate risk group (41 patients, 47.1%, χ2=6.760, P=0.009). Multivariate logistic regression analysis indicated that serum SP70 (OR=2.54, 95%CI: 1.68-3.84, P<0.001), hemoglobin (HB) (OR=0.96, 95%CI: 0.93-0.99, P<0.05), and bone marrow blast (BM blast) (OR=1.07, 95%CI: 1.02-1.13, P<0.05) were independent risk factors for high-risk prognosis in AML patients. ROC analysis showed that the area under the curve (AUC) for SP70 predicting high-risk patients was 0.908 (cut-off value of 5.74 ng/ml, 95%CI: 0.845-0.952, sensitivity 90.5%, specificity 82.8%). The combined model of serum SP70, HB, and BM blasts had an AUC of 0.931 (95%CI: 0.890-0.973); C-index=0.925 (95%CI: 0.876-0.963),with no statistically significant difference compared to serum SP70 alone (Z=1.693,P>0.05). Conclusion: Serum SP70 may be a promising non-invasive molecular biomarker for prognostic stratification in AML.

Supramolecular artificial Nano-AUTACs enable tumor-specific metabolism protein degradation for synergistic immunotherapy.

Autophagy-targeting chimera (AUTAC) has emerged as a powerful modality that can selectively degrade tumor-related pathogenic proteins, but its low bioavailability and nonspecific distribution significantly restrict their therapeutic efficacy. Inspired by the guanine structure of AUTAC molecules, we here report supramolecular artificial Nano-AUTACs (GM NPs) engineered by AUTAC molecule GN [an indoleamine 2,3-dioxygenase (IDO) degrader] and nucleoside analog methotrexate (MTX) through supramolecular interactions for tumor-specific protein degradation. Their nanostructures allow for precise localization and delivery into cancer cells, where the intracellular acidic environment can disrupt the supramolecular interactions to release MTX for eradicating tumor cells, modulating tumor-associated macrophages, activating dendritic cells, and inducing autophagy. Specifically, the induced autophagy facilitates the released GN for degrading immunosuppressive IDO to further enhance effector T cell activity and inhibit tumor growth and metastasis. This study offers a unique strategy for building a nanoplatform to advance the field of AUTAC in tumor immunotherapy.

Covalent targeted radioligands potentiate radionuclide therapy.

Targeted radionuclide therapy, in which radiopharmaceuticals deliver potent radionuclides to tumours for localized irradiation, has addressed unmet clinical needs and improved outcomes for patients with cancer1-4. A therapeutic radiopharmaceutical must achieve both sustainable tumour targeting and fast clearance from healthy tissue, which remains a major challenge5,6. A targeted ligation strategy that selectively fixes the radiopharmaceutical to the target protein in the tumour would be an ideal solution. Here we installed a sulfur (VI) fluoride exchange (SuFEx) chemistry-based linker on radiopharmaceuticals to prevent excessively fast tumour clearance. When the engineered radiopharmaceutical binds to the tumour-specific protein, the system undergoes a binding-to-ligation transition and readily conjugates to the tyrosine residues through the 'click' SuFEx reaction. The application of this strategy to a fibroblast activation protein (FAP) inhibitor (FAPI) triggered more than 80% covalent binding to the protein and almost no dissociation for six days. In mice, SuFEx-engineered FAPI showed 257% greater tumour uptake than did the original FAPI, and increased tumour retention by 13-fold. The uptake in healthy tissues was rapidly cleared. In a pilot imaging study, this strategy identified more tumour lesions in patients with cancer than did other methods. SuFEx-engineered FAPI also successfully achieved targeted β- and α-radionuclide therapy, causing nearly complete tumour regression in mice. Another SuFEx-engineered radioligand that targets prostate-specific membrane antigen (PSMA) also showed enhanced therapeutic efficacy. Considering the broad scope of proteins that can potentially be ligated to SuFEx warheads, it might be possible to adapt this strategy to other cancer targets.

Codetection of Proteins and RNAs on Extracellular Vesicles for Pancreatic Cancer Early Diagnosis.

Tumor-derived extracellular vesicles (EVs) carry tumor-specific proteins and RNAs, thus becoming prevalent targets for early cancer diagnosis. However, low expression of EV cargos and insufficient diagnostic power of individual biomarkers hindered EVs application in clinical practice. Herein, we propose a multiplex Codetection platform of proteins and RNAs (Co-PAR) for EVs. Co-PAR adopted a pair of antibody-DNA probes to recognize the same target protein, which in turn formed a double-stranded DNA. Thus, the target protein could be quantified by detecting the double-stranded DNA via qPCR. Meanwhile, qRT-PCR simultaneously quantified the target RNAs. Thus, with a regular qPCR instrument, Co-PAR enabled the codetection of multiplex proteins and RNAs, with the sensitivity of 102 EVs/μL (targeting CD63) and 1 EV/μL (targeting snRNA U6). We analyzed the coexpressions of three protein markers (CD63, GPC-1, HER2) and three RNA markers (snRNA U6, GPC-1 mRNA, miR-10b) on EVs from three pancreatic cell lines and 30 human plasma samples using Co-PAR. The diagnostic accuracy of the 6-biomarker combination reached 92.9%, which was at least 6.2% higher than that of 3-biomarker combinations and at least 13.5% higher than that of 6 single biomarkers. Co-PAR, as a multiparameter detection platform for EVs, has great potential in early disease diagnosis.

Abstract 5239: Discovery of AML associated therapeutic targets

Abstract Chimeric Antigen Receptor T-cell (CART) immunotherapy has shown significant success in the treatment of hematological malignancies. However, their efficacy in AML is limited due to the disease's genetic diversity and lack of uniform antigen targets. To identify potential AML cell-surface markers, we employed a comprehensive approach that involved the utilization of 3' single-cell RNA sequencing (scRNA-seq), bulk RNA sequencing (RNA-seq), and enhanced whole exome sequencing (eWES). A total of 21 samples were analyzed, comprising 18 distinct AML patients and 3 healthy bone marrow aspirates, serving as controls. We conducted scRNAseq on 21 samples, yielding a total of 185,106 high-quality cells, which were effectively clustered into 38 unbiased groups. Notably, tumor clusters exhibited highest copy number variations and formed separate clusters from other non-tumor immune cells. To uncover key functional pathways, we conducted pathway enrichment analysis comparing tumor cells to non-tumor cells. Our findings demonstrated a significant overrepresentation of cellular processes related to Allograft rejection, IL2/STAT5 signaling, IFN-gamma response and apoptosis. To identify AML specific markers, we performed an unbiased systematic search of the scRNAseq dataset for genes with unique expression patterns in tumor cells compared to the healthy bone marrow controls. Our analysis identified differentially expressed genes, with many genes displaying relative cell and tissue specificity. Notably, among these genes, we unveiled key potential targets with cell surface specificity, including novel markers alongside previously known ones. Noteworthy candidates, such as ADGRE2, CD33, CD123, CLEC12A, and FLT3 and understudied novel markers such as CD86, CSF1R, S100 proteins and VMP1, were prominently expressed, showcasing their potential significance as targets for engineered immunotherapy. To validate and consolidate our discoveries, we conducted a cross-referencing exercise by comparing our scRNAseq data against bulk RNA data from primary human AML samples and cell lines. Bulk global proteomics, flow cytometry-based and CART generation studies are ongoing to confirm our discoveries. Our rigorous computational and experimental approach provides valuable insights into tumor-specific cell surface proteins, which hold promise as potential targets for innovative and precision immunotherapeutic interventions in the realm of AML treatment. Citation Format: Omar M. Ibrahim, Michael P. Rettig, Reyka G. Jayasinghe, Li Ding, John F. DiPersio. Discovery of AML associated therapeutic targets [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5239.

Cancer cell membrane biomimetic composites of cisplatin prodrug for targeted eradication of circulating tumor cells in whole blood

The dissemination of circulating tumor cells in the peripheral blood circulation system plays a fundamental role in cancer recurrence and metastasis. Therefore, it is a pivotal scientific requirement to eradicate circulating tumor cells in whole blood system effectively. In this work, we provide a pH and GSH responsive drug delivery and release composites using cancer cell membrane biomimetic nanoparticles loaded with Pt(IV) prodrug (CM-Pt(IV) NPs), which exhibits high selectivity and biocompatibility. Cancer cells tend to form homogeneous aggregates by interacting with tumor-specific binding proteins on their surface. Thus, the cancer cell membrane coating possesses a homologous targeting ability to circulating tumor cells. The core nano-carrier composites loaded with Platinum(IV) agents were prepared by combining PLGA, Hyaluronic acid, and Cystamine. Within the nano-carrier composites, the S–S bond was reduced to S–H due to the high concentration of GSH present in cancer cells under an environment with a pH of 6.8. Consequently, this facilitates the release of platinum drugs that can specifically bind to cell DNA and effectively eradicate cancer cells. This highly selective delivery and precise release composites enable CM-Pt(IV) NPs to eliminate circulating tumor cells in the peripheral blood system effectively. This study provides an efficient drug delivery strategy for treating metastatic cancer.

Abstract A006: Spatial localization of Caveolin-1 protein in triple negative breast cancer is related to different molecular features

Abstract Background: Triple negative breast cancer (TNBC) is an aggressive and heterogeneous form of breast cancer with few targeted therapies and clinically used biomarkers. Caveolin-1 (CAV1) is a marker of stromal activation and vascularization. Molecular features of the tumor microenvironment (TME), important for tumor metastasis, may improve precision oncology in TNBC. CAV1 protein levels have previously been reported as a potential biomarker in breast cancer depending on their localization. Therefore, we aimed to investigate CAV1 protein levels in malignant and stromal cells of TNBC and their relation to CAV1 gene expression, clinicopathological factors, and molecular features. Methods: Tumor-specific CAV1 protein levels were evaluated with immunohistochemistry in malignant and stromal cells in tumor tissue microarrays from a cohort of 242 TNBC patients (inclusion 2010-2015, Sweden) from SCAN-B (NCT03758976). The protein levels of CAV1 in malignant and stromal cells were dichotomized as ‘strong’ (1) vs ‘negative to moderate’ (0) The CAV1 categories in malignant and stromal cells, respectively, were combined to create a joint CAV1 status with four categories: malignant/stromal cells, 0/0, 0/1, 1/0, and 1/1. Gene expression profiles from massive parallel paired-end sequencing of mRNA (RNA-seq) were available for all the tumors and from which PAM50 category and TNBC subtype were assigned. CAV1 status in malignant and stromal cells in relation to clinicopathological factors was analyzed using Chi-Square test. CAV1 mRNA expression in relation to CAV1 status in malignant and stromal cells was evaluated using Kruskal-Wallis test. Results: CAV1 status could be evaluated in 231/242 tumors. Strong CAV1 staining in malignant cells was associated with higher histological grade but no axillary lymph node involvement (both P &amp;lt;0.007). In contrast, strong CAV1 staining in stromal cells was associated with lower histological grade but axillary lymph node involvement (both P &amp;lt;0.001). Strong CAV1 staining in stromal cells was also associated with higher age at diagnosis (P =0.025). With regards to PAM50 subtypes, CAV1 in malignant cells was positively associated with the basal subtype while CAV1 in malignant cells was positively associated with the HER2 enriched subtype (P &amp;lt;0.001). Depending on localization, CAV1 expression was associated with different TNBCsubtypes. CAV1 in malignant cells was positively associated with the mesenchymal and negatively associated with the immunomodulatory subtype (P &amp;lt;0.001). CAV1 in stromal cells was positively associated with the luminal androgen (LAR) subtype (P &amp;lt;0.001). Neither CAV1 protein levels in malignant cells nor in stromal cells were correlated with CAV1 gene expression in the tumors, and the combined CAV1 status was not associated with CAV1 gene expression. Conclusion: CAV1 protein levels in malignant cells were related to different molecular features of TNBC compared to CAV1 protein levels in stromal cells. The results suggest that depending on localization, CAV1 protein levels function as two distinct biomarkers. Citation Format: Christopher Godina, Somayeh Khazaei, Mattias Belting, Johan Vallon-Christersson, Björn Nodin, Karin Jirström, Karolin Isaksson, Ana Bosch, Helena Jernström. Spatial localization of Caveolin-1 protein in triple negative breast cancer is related to different molecular features [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A006.

Oncolytic herpes simplex viruses designed for targeted treatment of EGFR-bearing tumors

Oncolytic herpes simplex viruses (oHSVs) have emerged as leading cancer therapeutic agents. Effective oHSV virotherapy may ultimately require both intratumoral and systemic vector administration to target the primary tumor and distant metastases. An attractive approach to enhancing oHSV tumor specificity is engineering the virus envelope glycoproteins for selective recognition of and infection via tumor-specific cell surface proteins. We previously demonstrated that oHSVs could be retargeted to EGFR-expressing cells by the incorporation of a single-chain antibody (scFv) at the N terminus of glycoprotein D (gD). Here, we compared retargeted oHSVs generated by the insertion of scFv, affibody molecule, or VHH antibody ligands at different positions within the N terminus of gD. When compared to the scFv-directed oHSVs, VHH and affibody molecules mediated enhanced EGFR-specific tumor cell entry, spread and cell killing invitro, and enabled long-term tumor-specific virus replication following intravenous delivery invivo. Moreover, oHSVs retargeted via a VHH ligand reduced tumor growth upon intravenous injection and achieved complete tumor destruction after intratumoral injection. Systemic oHSV delivery is important for the treatment of metastatic disease, and our enhancements in targeted oHSV design are a critical step in creating an effective tumor-specific oHSVs for safe administration via the bloodstream.

CRISPR-Cas-based biosensors for the detection of cancer biomarkers.

Along with discovering cancer biomarkers, non-invasive detection methods have played a critical role in early cancer diagnosis and prognostic improvement. Some traditional detection methods have been used for detecting cancer biomarkers, but they are time-consuming and involve materials and human costs. With great flexibility, sensitivity and specificity, the clustered regularly interspaced short palindromic repeats (CRISPR)-associated system provides a wide range of application prospects in this field. Herein, we introduce the background of the CRISPR-Cas (CRISPR-associated) system and comprehensively summarize the diagnosis strategies of cancer mediated by the CRISPR-Cas system, including four kinds of biochemical-based markers: nucleic acid, enzyme, tumor-specific protein and exosome. Furthermore, we discuss the challenges in implementing the CRISPR-Cas system in clinical applications.

Using long-read CAGE sequencing to profile cryptic-promoter-derived transcripts and their contribution to the immunopeptidome.

Recent studies have shown that the noncoding genome can produce unannotated proteins as antigens that induce immune response. One major source of this activity is the aberrant epigenetic reactivation of transposable elements (TEs). In tumors, TEs often provide cryptic or alternate promoters, which can generate transcripts that encode tumor-specific unannotated proteins. Thus, TE-derived transcripts (TE transcripts) have the potential to produce tumor-specific, but recurrent, antigens shared among many tumors. Identification of TE-derived tumor antigens holds the promise to improve cancer immunotherapy approaches; however, current genomics and computational tools are not optimized for their detection. Here we combined CAGE technology with full-length long-read transcriptome sequencing (long-read CAGE, or LRCAGE) and developed a suite of computational tools to significantly improve immunopeptidome detection by incorporating TE and other tumor transcripts into the proteome database. By applying our methods to human lung cancer cell line H1299 data, we show that long-read technology significantly improves mapping of promoters with low mappability scores and that LRCAGE guarantees accurate construction of uncharacterized 5' transcript structure. Augmenting a reference proteome database with newly characterized transcripts enabled us to detect noncanonical antigens from HLA-pulldown LC-MS/MS data. Lastly, we show that epigenetic treatment increased the number of noncanonical antigens, particularly those encoded by TE transcripts, which might expand the pool of targetable antigens for cancers with low mutational burden.

Identifying Surface Protein Markers for AML Immunotherapy

Background: Acute Myeloid Leukemia (AML) is a hematologic malignancy characterized by clonal expansion and differentiation arrest of myeloid precursor cells in the bone marrow. It results in the accumulation of abnormal and immature myeloblasts, which impairs the production of normal blood cells, including erythrocytes, leukocytes, and platelets. Chimeric Antigen Receptor T-cell therapy (CAR-T therapy) and Antibody-Drug Conjugate (ADC) immunotherapies have shown significant success in the treatment of hematological malignancies. However, their efficacy in AML is limited due to the disease's genetic diversity, lack of uniform antigen targets and immunosuppressive microenvironment. Single-cell RNA sequencing (scRNA-seq) is a powerful technique that can be utilized for surface antigen discovery in various cell types, including immune cells and cancer cells. Methods: To identify potential AML cell-surface markers, we employed a comprehensive approach that involved the utilization of 3' single-cell RNA sequencing (scRNA-seq), bulk RNA sequencing (RNA-seq), and enhanced whole exome sequencing (eWES). A total of 21 samples were analyzed, comprising 18 distinct AML patients and 3 healthy bone marrow aspirates, serving as controls. Results: Using enhanced whole exome sequencing (eWES) on tumor/normal paired samples, we defined the significant driver mutations within our sample cohort, notably DNMT3A (N=4, 21%), FLT3 (N=3, 16%), TET2 (N=3, 16%), KRAS (N=2, 11%), and GATA2 (N=2, 11%). Subsequently, we conducted scRNAseq on 21 samples, yielding a total of 185,106 high-quality cells, which were effectively clustered into 38 unbiased groups. Each sample demonstrated an average capture of 8862 cells, showcasing robust data acquisition. Our scRNAseq analysis revealed a diverse representation of major lymphoid and myeloid lineages, with prominent populations of AML blasts, T/NK cells, and progenitor cells. Notably, tumor clusters exhibited highest copy number variations and formed separate clusters from other non-tumor immune cells. To uncover key functional pathways, we conducted pathway enrichment analysis comparing tumor cells (N=131,196 cells) to non-tumor cells (N=53,910 cells). Our findings demonstrated a significant overrepresentation of cancer hallmarks, such as Allograft rejection (FDR= 0.000002), IL2/STAT5 signaling (FDR= 0.0000005), IFN-gamma response (FDR= 0.00000001) and apoptosis (FDR= 0.00000001) within the AML blasts, suggesting their potential involvement in AML pathogenesis. To identify AML specific markers, we developed analysis pipeline and performed an unbiased systematic search of the scRNAseq dataset for genes with unique expression patterns in tumor cells compared to the healthy bone marrow controls. Our analysis identified 302 differentially expressed genes, with 8 genes displaying relative cell and tissue specificity. Notably, among these genes, we unveiled key potential targets with cell surface specificity, including novel markers alongside previously known ones. Noteworthy candidates, such as CD86, CSF1R, CD33, CLEC12A, and FLT3, were prominently and significantly expressed, showcasing their potential significance as targets for engineered immunotherapy. To validate and consolidate our discoveries, we conducted a cross-referencing exercise by comparing our scRNAseq data against bulk RNA data from primary human AML samples and cell lines. Bulk global proteomics and flow cytometry-based studies are planned to confirm our genetic discoveries. Summary: Our rigorous computational and experimental approach provides valuable insights into tumor-specific cell surface proteins, which hold promise as potential targets for innovative and precision immunotherapeutic interventions in the realm of AML treatment.

Tumor-derived biomarkers predict efficacy of B7H3 antibody-drug conjugate treatment in metastatic prostate cancer models.

Antibody-drug conjugates (ADCs) are a promising targeted cancer therapy; however, patient selection based solely on target antigen expression without consideration for cytotoxic payload vulnerabilities has plateaued clinical benefits. Biomarkers to capture patients who might benefit from specific ADCs have not been systematically determined for any cancer. We present a comprehensive therapeutic and biomarker analysis of a B7H3-ADC with pyrrolobenzodiazepine(PBD) payload in 26 treatment-resistant, metastatic prostate cancer (mPC) models. B7H3 is a tumor-specific surface protein widely expressed in mPC, and PBD is a DNA cross-linking agent. B7H3 expression was necessary but not sufficient for B7H3-PBD-ADC responsiveness. RB1 deficiency and/or replication stress, characteristics of poor prognosis, and conferred sensitivity were associated with complete tumor regression in both neuroendocrine (NEPC) and androgen receptor positive (ARPC) prostate cancer models, even with low B7H3 levels. Non-ARPC models, which are currently lacking efficacious treatment, demonstrated the highest replication stress and were most sensitive to treatment. In RB1 WT ARPC tumors, SLFN11 expression or select DNA repair mutations in SLFN11 nonexpressors governed response. Importantly, WT TP53 predicted nonresponsiveness (7 of 8 models). Overall, biomarker-focused selection of models led to high efficacy of in vivo treatment. These data enable a paradigm shift to biomarker-driven trial designs for maximizing clinical benefit of ADC therapies.

ScanNeo2: a comprehensive workflow for neoantigen detection and immunogenicity prediction from diverse genomic and transcriptomic alterations.

Neoantigens, tumor-specific protein fragments, are invaluable in cancer immunotherapy due to their ability to serve as targets for the immune system. Computational prediction of these neoantigens from sequencing data often requires multiple algorithms and sophisticated workflows, which are currently restricted to specific types of variants, such as single-nucleotide variants or insertions/deletions. Nevertheless, other sources of neoantigens are often overlooked. We introduce ScanNeo2 an improved and fully automated bioinformatics pipeline designed for high-throughput neoantigen prediction from raw sequencing data. Unlike its predecessor, ScanNeo2 integrates multiple sources of somatic variants, including canonical- and exitron-splicing, gene fusion events, and various somatic variants. Our benchmark results demonstrate that ScanNeo2 accurately identifies neoantigens, providing a comprehensive and more efficient solution for neoantigen prediction. ScanNeo2 is freely available at https://github.com/ylab-hi/ScanNeo2/ and is accompanied by instruction and application data.

Ivermectin as a potential therapeutic strategy for glioma.

Ivermectin (IVM), a semi-synthetic macrolide parasiticide, has demonstrated considerable effectiveness in combating internal and external parasites, particularly nematodes and arthropods. Its remarkable ability to control parasites has earned it significant recognition, culminating in Satoshi Omura and William C. Campbell's receipt of the 2015 Nobel Prize in Physiology or Medicine for their contributions to the development of IVM. In recent years, investigations have revealed that IVM possesses antitumor properties. It can suppress the growth of various cancer cells, including glioma, through a multitude of mechanisms such as selective targeting of tumor-specific proteins, inducing programmed cell death, and modulation of tumor-related signaling pathways. Hence, IVM holds tremendous potential as a novel anticancer drug. This review seeks to provide an overview of the underlying mechanisms that enable IVM's capacity to suppress glioma. Furthermore, it aims to elucidate the challenges and prospects associated with utilizing IVM as a new anticancer agent.

Lighting the way to tumor destruction

Achieving tumor-specific protein loss remains a challenge in the delivery of proteolysis-targeting chimeras (PROTACs) as cancer therapeutics. As a solution, Wang et al. recently developed nanoformulated PROTACs (NAPs), a novel photoactivatable degradation approach. This innovative class of compounds harnesses near-infrared (NIR) light for precise PROTAC release and protein degradation in mouse tumors.

Designing Multimodal Informative Sensing with an Exosome-Mediated Signal Coupling Transduction Strategy Based on a Single-Stimulus Multiresponse Recognition Interface.

Given that exosomes released from cancer cells carry various tumor-specific proteins on their surface, they have emerged as a source of biomarkers for cancer diagnosis. However, developing accurate and reliable assays to detect exosomes in the early stages of disease with low abundance and complex systems remains challenging. Here, the prepared PDIG film has the ability to sense multiple signals from a single stimulus, in which the presence of cobalt(II) chloride and deep eutectic solvents (DES) endows PDIG with thermochromic and thermosensitive properties. Concretely, the PDIG served as the recognition interface in series with a bipolar electrode (BPE) that exhibits a highly sensitive color and conductivity response to temperature stimuli triggered by the light-harvesting probe TiO2@CNOs introduced via proximity hybridization assay triggering a rolling circle amplification strategy, resulting in the output of colorimetric, photoacoustic, and electrochemiluminescent signals for the detection of colorectal cancer exosomes. This work is expected to provide a new direction for exploring the multisignal amplification strategy of BPE, broaden the application of BPE in biological analysis, and provide new insights for developing highly information-sensing elements to ensure the multimodal coupling for cancer-specific exosome detection.

Interleukin-6-controlled, mesenchymal stem cell-based sodium/iodide symporter gene therapy improves survival of glioblastoma-bearing mice

New treatment strategies are urgently needed for glioblastoma (GBM)-a tumor resistant to standard-of-care treatment with a high risk of recurrence and extremely poor prognosis. Based on their intrinsic tumor tropism, adoptively applied mesenchymal stem cells (MSCs) can be harnessed to deliver the theranostic sodium/iodide symporter (NIS) deep into the tumor microenvironment. Interleukin-6 (IL-6) is a multifunctional, highly expressed cytokine in the GBM microenvironment including recruited MSCs. MSCs engineered to drive NIS expression in response to IL-6 promoter activation offer the possibility of a new tumor-targeted gene therapy approach of GBM. Therefore, MSCs were stably transfected with an NIS-expressing plasmid controlled by the human IL-6 promoter (IL-6-NIS-MSCs) and systemically applied in mice carrying orthotopic GBM. Enhanced radiotracer uptake by 18F-Tetrafluoroborate-PET/magnetic resonance imaging (MRI) was detected in tumors after IL-6-NIS-MSC application as compared with mice that received wild-type MSCs. Exvivo analysis of tumors and non-target organs showed tumor-specific NIS protein expression. Subsequent 131I therapy after IL-6-NIS-MSC application resulted in significantly delayed tumor growth assessed by MRI and improved median survival up to 60% of GBM-bearing mice as compared with controls. In conclusion, the application of MSC-mediated NIS gene therapy focusing on IL-6 biology-induced NIS transgene expression represents a promising approach for GBM treatment.

Three-Dimensional Histological Electrophoresis for High-Throughput Cancer Margin Detection in Multiple Types of Tumor Specimens.

Accurate identification of tumor margins during cancer surgeries relies on a rapid detection technique that can perform high-throughput detection of multiple suspected tumor lesions at the same time. Unfortunately, the conventional histopathological analysis of frozen tissue sections, which is considered the gold standard, often demonstrates considerable variability, especially in many regions without adequate access to trained pathologists. Therefore, there is a clinical need for a multitumor-suitable complementary tool that can accurately and high-throughput assess tumor margins in every direction within the surgically resected tissue. We herein describe a high-throughput three-dimensional (3D) histological electrophoresis device that uses tumor-specific proteins to identify and contour tumor margins intraoperatively. Testing on seven cell-line xenograft models and human cervical cancer models (representing five types of tissues) demonstrated the high-throughput detection utility of this approach. We anticipate that the 3D histological electrophoresis device will improve the accuracy and efficiency of diagnosing a wide range of cancers.

Systematic discovery of gene fusions in pediatric cancer by integrating RNA-seq and WGS

BackgroundGene fusions are important cancer drivers in pediatric cancer and their accurate detection is essential for diagnosis and treatment. Clinical decision-making requires high confidence and precision of detection. Recent developments show RNA sequencing (RNA-seq) is promising for genome-wide detection of fusion products but hindered by many false positives that require extensive manual curation and impede discovery of pathogenic fusions.MethodsWe developed Fusion-sq to overcome existing disadvantages of detecting gene fusions. Fusion-sq integrates and “fuses” evidence from RNA-seq and whole genome sequencing (WGS) using intron–exon gene structure to identify tumor-specific protein coding gene fusions. Fusion-sq was then applied to the data generated from a pediatric pan-cancer cohort of 128 patients by WGS and RNA sequencing.ResultsIn a pediatric pan-cancer cohort of 128 patients, we identified 155 high confidence tumor-specific gene fusions and their underlying structural variants (SVs). This includes all clinically relevant fusions known to be present in this cohort (30 patients). Fusion-sq distinguishes healthy-occurring from tumor-specific fusions and resolves fusions in amplified regions and copy number unstable genomes. A high gene fusion burden is associated with copy number instability. We identified 27 potentially pathogenic fusions involving oncogenes or tumor-suppressor genes characterized by underlying SVs, in some cases leading to expression changes indicative of activating or disruptive effects.ConclusionsOur results indicate how clinically relevant and potentially pathogenic gene fusions can be identified and their functional effects investigated by combining WGS and RNA-seq. Integrating RNA fusion predictions with underlying SVs advances fusion detection beyond extensive manual filtering. Taken together, we developed a method for identifying candidate gene fusions that is suitable for precision oncology applications. Our method provides multi-omics evidence for assessing the pathogenicity of tumor-specific gene fusions for future clinical decision making.