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The Journal of Clinical Investigation Dec 2023Patients with inflammatory bowel disease (IBD) are susceptible to colitis-associated cancer (CAC). Chronic inflammation promotes the risk for CAC. In contrast, mucosal...
Patients with inflammatory bowel disease (IBD) are susceptible to colitis-associated cancer (CAC). Chronic inflammation promotes the risk for CAC. In contrast, mucosal healing predicts improved prognosis in IBD and reduced risk of CAC. However, the molecular integration among colitis, mucosal healing, and CAC remains poorly understood. Claudin-2 (CLDN2) expression is upregulated in IBD; however, its role in CAC is not known. The current study was undertaken to examine the role for CLDN2 in CAC. The AOM/DSS-induced CAC model was used with WT and CLDN2-modified mice. High-throughput expression analyses, murine models of colitis/recovery, chronic colitis, ex vivo crypt culture, and pharmacological manipulations were employed in order to increase our mechanistic understanding. The Cldn2KO mice showed significant inhibition of CAC despite severe colitis compared with WT littermates. Cldn2 loss also resulted in impaired recovery from colitis and increased injury when mice were subjected to intestinal injury by other methods. Mechanistic studies demonstrated a possibly novel role of CLDN2 in promotion of mucosal healing downstream of EGFR signaling and by regulation of Survivin expression. An upregulated CLDN2 expression protected from CAC and associated positively with crypt regeneration and Survivin expression in patients with IBD. We demonstrate a potentially novel role of CLDN2 in promotion of mucosal healing in patients with IBD and thus regulation of vulnerability to colitis severity and CAC, which can be exploited for improved clinical management.
Topics: Animals; Humans; Mice; Claudin-2; Colitis; Colitis-Associated Neoplasms; Dextran Sulfate; Disease Models, Animal; Inflammatory Bowel Diseases; Intestinal Mucosa; Mice, Inbred C57BL; Survivin
PubMed: 37815870
DOI: 10.1172/JCI170771 -
Cancer Communications (London, England) Dec 2019High-grade glioma (HGG) is a fatal human cancer. Bortezomib, a proteasome inhibitor, has been approved for the treatment of multiple myeloma but its use in glioma awaits...
BACKGROUND
High-grade glioma (HGG) is a fatal human cancer. Bortezomib, a proteasome inhibitor, has been approved for the treatment of multiple myeloma but its use in glioma awaits further investigation. This study aimed to explore the chemotherapeutic effect and the underlying mechanism of bortezomib on gliomas.
METHODS
U251 and U87 cell viability and proliferation were detected by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, tumor cell spheroid growth, and colony formation assay. Cell apoptosis and cell cycle were detected by flow cytometry. Temozolomide (TMZ)-insensitive cell lines were induced by long-term TMZ treatment, and cells with stem cell characteristics were enriched with stem cell culture medium. The mRNA levels of interested genes were measured via reverse transcription-quantitative polymerase chain reaction, and protein levels were determined via Western blotting/immunofluorescent staining in cell lines and immunohistochemical staining in paraffin-embedded sections. Via inoculating U87 cells subcutaneously, glioma xenograft models in nude mice were established for drug experiments. Patient survival data were analyzed using the Kaplan-Meier method.
RESULTS
Bortezomib inhibited the viability and proliferation of U251 and U87 cells in a dose- and time-dependent manner by inducing apoptosis and cell cycle arrest. Bortezomib also significantly inhibited the spheroid growth, colony formation, and stem-like cell proliferation of U251 and U87 cells. When administrated in combination, bortezomib showed synergistic effect with TMZ in vitro and sensitized glioma to TMZ treatment both in vitro and in vivo. Bortezomib reduced both the mRNA and protein levels of Forkhead Box M1 (FOXM1) and its target gene Survivin. The FOXM1-Survivin axis was markedly up-regulated in established TMZ-insensitive glioma cell lines and HGG patients. Expression levels of FOXM1 and Survivin were positively correlated with each other and both related to poor prognosis in glioma patients.
CONCLUSIONS
Bortezomib was found to inhibit glioma growth and improved TMZ chemotherapy efficacy, probably via down-regulating the FOXM1-Survivin axis. Bortezomib might be a promising agent for treating malignant glioma, alone or in combination with TMZ.
Topics: Adolescent; Adult; Aged; Animals; Antineoplastic Agents; Apoptosis; Bortezomib; Brain Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Down-Regulation; Female; Forkhead Box Protein M1; Gene Expression Regulation, Neoplastic; Glioma; Humans; Male; Mice, Inbred BALB C; Mice, Nude; Middle Aged; Survivin; Temozolomide; Young Adult
PubMed: 31796105
DOI: 10.1186/s40880-019-0424-2 -
Journal of Clinical Oncology : Official... Mar 2023Despite intensive treatment with surgery, radiation therapy, temozolomide (TMZ) chemotherapy, and tumor-treating fields, mortality of newly diagnosed glioblastoma (nGBM)... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Despite intensive treatment with surgery, radiation therapy, temozolomide (TMZ) chemotherapy, and tumor-treating fields, mortality of newly diagnosed glioblastoma (nGBM) remains very high. SurVaxM is a peptide vaccine conjugate that has been shown to activate the immune system against its target molecule survivin, which is highly expressed by glioblastoma cells. We conducted a phase IIa, open-label, multicenter trial evaluating the safety, immunologic effects, and survival of patients with nGBM receiving SurVaxM plus adjuvant TMZ following surgery and chemoradiation (ClinicalTrials.gov identifier: NCT02455557).
METHODS
Sixty-four patients with resected nGBM were enrolled including 38 men and 26 women, in the age range of 20-82 years. Following craniotomy and fractionated radiation therapy with concurrent TMZ, patients received four doses of SurVaxM (500 μg once every 2 weeks) in Montanide ISA-51 plus sargramostim (granulocyte macrophage colony-stimulating factor) subcutaneously. Patients subsequently received adjuvant TMZ and maintenance SurVaxM concurrently until progression. Progression-free survival (PFS) and overall survival (OS) were reported. Immunologic responses to SurVaxM were assessed.
RESULTS
SurVaxM plus TMZ was well tolerated with no serious adverse events attributable to SurVaxM. Of the 63 patients who were evaluable for outcome, 60 (95.2%) remained progression-free 6 months after diagnosis (prespecified primary end point). Median PFS was 11.4 months and median OS was 25.9 months measured from first dose of SurVaxM. SurVaxM produced survivin-specific CD8+ T cells and antibody/immunoglobulin G titers. Apparent clinical benefit of SurVaxM was observed in both methylated and unmethylated patients.
CONCLUSION
SurVaxM appeared to be safe and well tolerated. The combination represents a promising therapy for nGBM. For patients with nGBM treated in this manner, PFS may be an acceptable surrogate for OS. A large randomized clinical trial of SurVaxM for nGBM is in progress.
Topics: Male; Humans; Female; Young Adult; Adult; Middle Aged; Aged; Aged, 80 and over; Temozolomide; Glioblastoma; Survivin; Antineoplastic Agents, Alkylating; Brain Neoplasms; Adjuvants, Immunologic; Vaccines, Subunit
PubMed: 36521103
DOI: 10.1200/JCO.22.00996 -
Science Advances Mar 2020Small interfering RNA (siRNA) is a powerful tool for gene silencing that has been used for a wide range of biomedical applications, but there are many challenges facing...
Small interfering RNA (siRNA) is a powerful tool for gene silencing that has been used for a wide range of biomedical applications, but there are many challenges facing its therapeutic use in vivo. Here, we report on a platelet cell membrane-coated metal-organic framework (MOF) nanodelivery platform for the targeted delivery of siRNA in vivo. The MOF core is capable of high loading yields, and its pH sensitivity enables endosomal disruption upon cellular uptake. The cell membrane coating provides a natural means of biointerfacing with disease substrates. It is shown that high silencing efficiency can be achieved in vitro against multiple target genes. Using a murine xenograft model, significant antitumor targeting and therapeutic efficacy are observed. Overall, the biomimetic nanodelivery system presented here provides an effective means of achieving gene silencing in vivo and could be used to expand the applicability of siRNA across a range of disease-relevant applications.
Topics: Animals; Blood Platelets; Cell Line, Tumor; Cell Membrane; Coated Vesicles; Drug Carriers; Gene Knockdown Techniques; Gene Silencing; Gene Transfer Techniques; Genes, Reporter; Humans; Metal Nanoparticles; Metal-Organic Frameworks; Mice; RNA, Small Interfering; Survivin; Xenograft Model Antitumor Assays
PubMed: 32258408
DOI: 10.1126/sciadv.aaz6108 -
Cellular Signalling Oct 2023Survivin is a bifunctional protein that plays crucial roles in tumorigenesis. In the present study, we discovered that the natural product gastrodin suppressed the cell...
Survivin is a bifunctional protein that plays crucial roles in tumorigenesis. In the present study, we discovered that the natural product gastrodin suppressed the cell viability and colony formation of non-small cell lung cancer (NSCLC) cell lines A549, HCC827, and H460 in a dose-dependent manner. In addition, gastrodin enhanced the protein levels of cleaved-caspase 3 by activating the endogenous mitochondrial apoptosis pathway. Gastrodin inhibits protein kinase B (Akt)/WEE1/cyclin-dependent kinase 1 (CDK1) signaling to downregulate survivin Thr34 phosphorylation. Survivin Thr34 dephosphorylation caused by gastrodin interfered with the binding of ubiquitin-specific protease 19 (USP19), which eventually destabilized survivin. We revealed that the growth of NSCLC xenograft tumors was markedly suppressed by gastrodin in vivo. Furthermore, gastrodin overcomes pemetrexed resistance in vivo or in vitro. Our results suggest that gastrodin is a potential antitumor agent by reducing survivin in NSCLC.
Topics: Humans; Survivin; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Pemetrexed; Apoptosis; Cell Line, Tumor; Cell Proliferation; Endopeptidases
PubMed: 37586466
DOI: 10.1016/j.cellsig.2023.110851 -
Proceedings of the National Academy of... Aug 2021To identify regulators of triple-negative breast cancer (TNBC), gene expression profiles of malignant parts of TNBC (mTNBC) and normal adjacent (nadj) parts of the same...
To identify regulators of triple-negative breast cancer (TNBC), gene expression profiles of malignant parts of TNBC (mTNBC) and normal adjacent (nadj) parts of the same breasts have been compared. We are interested in the roles of estrogen receptor β (ERβ) and the cytochrome P450 family (CYPs) as drivers of TNBC. We examined by RNA sequencing the mTNBC and nadj parts of five women. We found more than a fivefold elevation in mTNBC of genes already known to be expressed in TNBC: BIRC5/survivin, Wnt-10A and -7B, matrix metalloproteinases (MMPs), chemokines, anterior gradient proteins, and lysophosphatidic acid receptor and the known basal characteristics of TNBC, sox10, ROPN1B, and Col9a3. There were two unexpected findings: 1) a strong induction of CYPs involved in activation of fatty acids (CYP4), and in inactivation of calcitriol (CYP24A1) and retinoic acid (CYP26A1); and 2) a marked down-regulation of FOS, FRA1, and JUN, known tethering partners of ERβ. ERβ is expressed in 20 to 30% of TNBCs and is being evaluated as a target for treating TNBC. We used ERβ TNBC patient-derived xenografts in mice and found that the ERβ agonist LY500703 had no effect on growth or proliferation. Expression of CYPs was confirmed by immunohistochemistry in formalin-fixed and paraffin-embedded (FFPE) TNBC. In TNBC cell lines, the CYP4Z1-catalyzed fatty acid metabolite 20-hydroxyeicosatetraenoic acid (20-HETE) increased proliferation, while calcitriol decreased proliferation but only after inhibition of CYP24A1. We conclude that CYP-mediated pathways can be drivers of TNBC but that ERβ is unlikely to be a tumor suppressor because the absence of its main tethering partners renders ERβ functionless on genes involved in proliferation and inflammation.
Topics: Amphibian Proteins; Animals; Benzopyrans; Calcitriol; Cytochrome P-450 Enzyme System; Down-Regulation; Estrogen Receptor alpha; Estrogen Receptor beta; Fatty Acids; Female; Gene Expression Regulation, Neoplastic; Humans; Mice; Neoplasms, Experimental; Random Allocation; Survivin; Transcriptome; Tretinoin; Triple Negative Breast Neoplasms; Wnt Proteins
PubMed: 34389675
DOI: 10.1073/pnas.2104162118 -
Genetic Testing and Molecular Biomarkers Sep 2022Breast cancer is the most frequently diagnosed cancer in women and ranks second among causes for cancer-related death in women. Gene technology has led to the... (Review)
Review
Breast cancer is the most frequently diagnosed cancer in women and ranks second among causes for cancer-related death in women. Gene technology has led to the recognition that breast cancer is a heterogeneous disease composed of different biological subtypes, and genetic profiling enables the response to chemotherapy to be predicted. This fact emphasizes the importance of selecting sensitive diagnostic and prognostic markers in the early disease stage and more efficient targeted treatments for this disease. One such prognostic marker appears to be survivin. Many studies have shown that survivin is strongly expressed in different types of cancers. Its overexpression has been demonstrated in breast cancer, and high activity of the survivin gene has been associated with a poor prognosis and worse survival rates.
Topics: Biomarkers, Tumor; Breast Neoplasms; Female; Humans; Inhibitor of Apoptosis Proteins; Survivin
PubMed: 36166738
DOI: 10.1089/gtmb.2021.0286 -
Molecular Cancer Therapeutics Aug 2023CD3 bispecific T-cell engagers (TCE), comprised of a tumor-targeting domain linked to a CD3 binding domain, function by bridging target-positive tumors and...
CD3 bispecific T-cell engagers (TCE), comprised of a tumor-targeting domain linked to a CD3 binding domain, function by bridging target-positive tumors and CD3-expressing effector T cells enabling redirected T cell-mediated killing of tumor cells. Although the majority of CD3 bispecific molecules in clinical development incorporate tumor-targeting antibody-based binding domains, many tumor-associated antigens derive from intracellular proteins and are not accessible to targeting via antibody. Intracellular proteins processed into short peptide fragments and presented on the cell surface by MHC proteins are recognized by T-cell receptors (TCR) on the surface of T cells. Here we describe the generation and preclinical evaluation of ABBV-184, a novel TCR/anti-CD3 bispecific composed of a highly selective soluble TCR that binds a peptide derived from the oncogene survivin (BIRC5) bound to the class I MHC allele human leukocyte antigen (HLA)-A*02:01 expressed on tumor cells, linked to a specific binder to the CD3 receptor on T cells. ABBV-184 drives an optimal distance between T cell and target cell thereby enabling sensitive recognition of low-density peptide/MHC targets. Consistent with the expression profile of survivin across a broad range of both hematologic and solid tumors, treatment of acute myeloid leukemia (AML) and non-small cell lung cancer (NSCLC) cell lines with ABBV-184 results in T-cell activation, proliferation, and potent redirected cytotoxicity of HLA-A2-positive target cell lines, both in vitro and in vivo, including patient-derived AML samples. These results indicate that ABBV-184 is an attractive clinical candidate for the treatment of patients with AML and NSCLC.
Topics: Humans; T-Lymphocytes; Carcinoma, Non-Small-Cell Lung; Survivin; Lung Neoplasms; Receptors, Antigen, T-Cell; CD3 Complex; Leukemia, Myeloid, Acute; Hematologic Neoplasms; Antibodies, Bispecific
PubMed: 37294945
DOI: 10.1158/1535-7163.MCT-22-0770 -
Oral Oncology Jan 2021Survivin is an inhibitor of apoptosis that is proposed as a target for anti-cancer therapy because of its high expression in cancer cells. It has potential as a...
INTRODUCTION
Survivin is an inhibitor of apoptosis that is proposed as a target for anti-cancer therapy because of its high expression in cancer cells. It has potential as a prognostic and predictive biomarker of response to radiation and systemic therapies. We report its expression in head and neck squamous cell carcinoma (HNSCC) and its correlation with treatment response and survival.
METHODS
We measured survivin protein expression in tumor specimens from 96 patients with HNSCC treated at Fox Chase Cancer Center, of whom 21 were p16+. Quantitative automated immunofluorescence was employed to score nuclear and cytoplasmic survivin in 5 tissue microarrays (TMAs) consisting of 316 H&N tumor cores and 107 control tissue cores. Survivin levels were then correlated to therapy response and survival outcomes.
RESULTS
Using the median score as the cutoff, overall survival (OS) was significantly shorter for the group expressing higher survivin in nuclear (p = 0.013), cytoplasmic (p = 0.018) and total compartments (p = 0.006). No correlation was seen between survivin expression and patient sex or grade of tumor, T or N stage, or p16 status. Survivin expression in metastases did not significantly differ from that in primary tumors. Levels of p53 expression showed a significant positive correlation with higher survivin expression in the cytoplasm (p = 0.0264) and total compartments (p = 0.0264), but not in the nucleus (p = 0.0729).
CONCLUSIONS
Survivin expression above the median is associated with shorter overall survival in HNSCC, including for patients treated with chemotherapy or radiation. p16 expression did not correlate with survivin levels.
Topics: Adult; Age Factors; Aged; Aged, 80 and over; Apoptosis; Cell Nucleus; Cyclin-Dependent Kinase Inhibitor p16; Cytoplasm; Disease-Free Survival; Female; Humans; Male; Middle Aged; Neoplasm Proteins; Prognosis; Sex Factors; Squamous Cell Carcinoma of Head and Neck; Survivin; Tissue Array Analysis; Treatment Outcome; Tumor Suppressor Protein p53
PubMed: 33221541
DOI: 10.1016/j.oraloncology.2020.105049 -
Expert Opinion on Drug Discovery Jul 2022Due to its unique functional impact on multiple cancer cell circuits including proliferation, apoptosis, tumor dissemination, DNA damage repair, and immune response, the... (Review)
Review
INTRODUCTION
Due to its unique functional impact on multiple cancer cell circuits including proliferation, apoptosis, tumor dissemination, DNA damage repair, and immune response, the inhibitor of apoptosis protein (IAP) survivin has gained high interest as a molecular target and a multitude of therapeutics were developed to interfere with survivin expression and functionality. First clinical evaluations of these therapeutics, however, were disappointing highlighting the need to develop advanced delivery systems of survivin-targeting therapeutics.
AREAS COVERED
This review focuses on advancements in nanocarriers to molecularly target survivin in human malignancies. A plethora of nanoparticle platforms, including liposomes, polymeric systems, dendrimers, inorganic nanocarriers, RNA/DNA nanotechnology and exosomes, are discussed in the background of survivin-tailored RNA interference, small molecule inhibitors, dominant negative mutants or survivin vaccination or combined modality treatment with chemotherapeutic drugs and photo-dynamic/photothermal strategies.
EXPERT OPINION
Novel therapeutic approaches include the use of biocompatible nanoformulations carrying gene silencing or drug molecules to directly or indirectly target proteins, allow for a more precise and controlled delivery of survivin therapeutics. Moreover, surface modification of these nanocarriers may result in a tumor entity-specific delivery. Therefore, nanomedicine exploiting survivin-tailored strategies in a multimodal background is considered the way forward to enhance the development of future personalized medicine.
Topics: Drug Delivery Systems; Drug Discovery; Humans; Nanomedicine; Nanoparticles; Nanotechnology; Neoplasms; Survivin
PubMed: 35593177
DOI: 10.1080/17460441.2022.2077329