Gene Summary

Gene:CASR; calcium sensing receptor
Summary:The protein encoded by this gene is a plasma membrane G protein-coupled receptor that senses small changes in circulating calcium concentration. The encoded protein couples this information to intracellular signaling pathways that modify parathyroid hormone secretion or renal cation handling, and thus this protein plays an essential role in maintaining mineral ion homeostasis. Mutations in this gene are a cause of familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia. [provided by RefSeq, Aug 2017]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:extracellular calcium-sensing receptor
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: CASR (cancer-related)

Mensali N, Myhre MR, Dillard P, et al.
Preclinical assessment of transiently TCR redirected T cells for solid tumour immunotherapy.
Cancer Immunol Immunother. 2019; 68(8):1235-1243 [PubMed] Free Access to Full Article Related Publications
Off-target toxicity due to the expression of target antigens in normal tissue or TCR cross-reactivity represents a major risk when using T cell receptor (TCR)-engineered T cells for treatment of solid tumours. Due to the inherent cross-reactivity of TCRs it is difficult to accurately predict their target recognition pre-clinically. It has become evident that direct testing in a human being represents the best evaluation of the risks. There is, therefore, a clear unmet need for assessing the safety of a therapeutic TCR in a more controllable manner than by the injection of permanently modified cellular products. Using transiently modified T cells combined with dose escalation has already been shown feasible for chimeric antigen receptor (CAR)-engineered T cells, but nothing is yet reported for TCR. We performed a preclinical evaluation of a therapeutic TCR transiently expressed in T cells by mRNA electroporation. We analyzed if the construct was active in vitro, how long it was detectable for and if this expression format was adapted to in vivo efficacy assessment. Our data demonstrate the potential of mRNA engineered T cells, although less powerful than permanent redirection, to induce a significant response. Thus, these findings support the development of mRNA based TCR-therapy strategies as a feasible and efficacious method for evaluating TCR safety and efficacy in first-in-man testing.

Dusek J, Skoda J, Holas O, et al.
Stilbene compound trans-3,4,5,4´-tetramethoxystilbene, a potential anticancer drug, regulates constitutive androstane receptor (Car) target genes, but does not possess proliferative activity in mouse liver.
Toxicol Lett. 2019; 313:1-10 [PubMed] Related Publications
The constitutive androstane receptor(CAR) activation is connected with mitogenic effects leading to liver hyperplasia and tumorigenesis in rodents. CAR activators, including phenobarbital, are considered rodent non-genotoxic carcinogens. Recently, trans-3,4,5,4´-tetramethoxystilbene(TMS), a potential anticancer drug (DMU-212), have been shown to alleviate N-nitrosodiethylamine/phenobarbital-induced liver carcinogenesis. We studied whether TMS inhibits mouse Car to protect from the PB-induced tumorigenesis. Unexpectedly, we identified TMS as a murine CAR agonist in reporter gene experiments, in mouse hepatocytes, and in C57BL/6 mice in vivo. TMS up-regulated Car target genes Cyp2b10, Cyp2c29 and Cyp2c55 mRNAs, but down-regulated expression of genes involved in gluconeogenesis and lipogenesis. TMS did not change or down-regulate genes involved in liver proliferation or apoptosis such as Mki67, Foxm1, Myc, Mcl1, Pcna, Bcl2, or Mdm2, which were up-regulated by another Car ligand TCPOBOP. TMS did not increase liver weight and had no significant effect on Ki67 and Pcna labeling indices in mouse liver in vivo. In murine hepatic AML12 cells, we confirmed a Car-independent proapoptotic effect of TMS. We conclude that TMS is a Car ligand with limited effects on hepatocyte proliferation, likely due to promoting apoptosis in mouse hepatic cells, while controlling Car target genes involved in xenobiotic and endobiotic metabolism.

Liu L, Ma J, Qin L, et al.
Interleukin-24 enhancing antitumor activity of chimeric oncolytic adenovirus for treating acute promyelocytic leukemia cell.
Medicine (Baltimore). 2019; 98(22):e15875 [PubMed] Related Publications
BACKGROUND: Acute promyelocytic leukaemia (APL) is a clonal disease arising by hematopoietic stem cell (HSC), which characterized by inappropriate proliferation/differentiation or survival of immature myeloid progenitors. Oncolytic adenoviruses have been under widespread investigation as anticancer agents. Recently, our data suggested that tumor cells were cured by AdCN205-IL-24, an adenovirus serotype 5-based conditionally replicating adenovirus expressing IL-24 after infection.
METHODS: In this study, we created a novel fiber chimeric oncolytic adenovirus AdCN306-IL-24 that has Ad11 tropism and approved CAR (coxsackie adenovirus receptor, CAR)-independent cell entry, which could allow development of selective cytopathic effects (CPE) in APL cells in vitro.
RESULTS: Formidable cytotoxic effect was specifically implemented in APL cells after infection with AdCN306-IL-24. The expression of IL-24 was up-regulated upon treated with accepted tumors. And the vector also induced superior cytolytic effects activity in APL cells by activation of programmed cell death.
CONCLUSIONS: Taken together, our data suggested that chimeric oncolytic adenovirus AdCN306-IL-24 could express IL-24 gene, representing a potential therapeutics for acute promyelocytic leukemia.

Wang Y, Yu W, Zhu J, et al.
Anti-CD166/4-1BB chimeric antigen receptor T cell therapy for the treatment of osteosarcoma.
J Exp Clin Cancer Res. 2019; 38(1):168 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Chimeric antigen receptor (CAR)-engineered T cells have displayed outstanding performance in the treatment of patients with hematological malignancies. However, their efficacy against solid tumors has been largely limited.
METHODS: In this study, human osteosarcoma cell lines were prepared, flow cytometry using antibodies against CD166 was performed on different cell samples. CD166-specific T cells were obtained by viral gene transfer of corresponding DNA plasmids and selectively expanded using IL-2 and IL-15. The ability of CD166.BBζ CAR-T cells to kill CD166
RESULTS: CD166 was selectively expressed on four different human osteosarcoma cell lines, indicating its role as the novel target for CAR-T cell therapy. CD166.BBζ CAR-T cells killed osteosarcoma cell lines in vitro; the cytotoxicity correlated with the level of CD166 expression on the tumor cells. Intravenous injection of CD166.BBζ CAR-T cells into mice resulted in the regression of the tumor with no obvious toxicity.
CONCLUSIONS: Together, the data suggest that CD166.BBζ CAR-T cells may serve as a new therapeutic strategy in the future clinical practice for the treatment of osteosarcoma.

Zhang R, Deng Q, Jiang YY, et al.
Effect and changes in PD‑1 expression of CD19 CAR‑T cells from T cells highly expressing PD‑1 combined with reduced‑dose PD‑1 inhibitor.
Oncol Rep. 2019; 41(6):3455-3463 [PubMed] Related Publications
CD19 chimeric antigen receptor (CAR) T cell therapy has changed the outcomes of relapsed/refractory B‑cell leukemia and lymphoma. However, its efficacy in patients with relapsed/refractory non‑Hodgkin lymphoma (NHL) has been less impressive compared with that in patients with acute lymphoid leukemia. Furthermore, immune checkpoints have a critical role in the immune system. Several clinical trials have confirmed the dramatic effects of programmed death‑1/programmed death‑ligand 1 (PD‑1/PD‑L1) inhibitors in numerous malignancies, but the immune‑associated adverse events of PD‑1/PD‑L1 inhibitors may occur in a number of systems. The aim of the present study was to investigate the combination of CD19 CAR‑T cells with a reduced dose of PD‑1 inhibitor. This method is expected to overcome the side-effects of PD‑1 inhibitors, while maintaining therapeutic efficacy. The findings demonstrated that a reduced dose of PD‑1 inhibitor did not affect the transfection rate, proliferation rate or cytokine secretion of CD19 CAR‑T cells. An interesting finding of the present study was that the number of PD‑1‑positive cells CAR‑T cells, measured by flow cytometry, declined when they were cultured in vitro, but returned to high levels with gradual prolongation of the co‑culture time of CD19 CAR‑T cells with lymphoma cells; however, there was no change in the mRNA expression of T cells and CAR‑T cells during this process. This phenomenon may be one of the reasons why the curative effect of CAR‑T cells on B‑cell lymphoma is unsatisfactory compared with B‑cell leukemia. The synergistic effect of a reduced‑dose PD‑1 inhibitor combined with CD19 CAR‑T cells from T cells highly expressing PD‑1 was confirmed in a mouse trial. Mice in the combined treatment group achieved the longest survival time. In this group, the proportion of CAR‑T cells and the level of interleukin‑6 were higher compared with those in the CAR‑T cell group. In conclusion, a reduced dose of a PD‑1 inhibitor combined with CD19 CAR‑T cells appears to be a promising treatment option for relapsed/refractory B‑NHL exhibiting high PD‑1 expression by T cells. This method may achieve good clinical efficacy while reducing the side-effects of PD‑1 inhibitors.

Mukund V, Saddala MS, Farran B, et al.
Molecular docking studies of angiogenesis target protein HIF-1α and genistein in breast cancer.
Gene. 2019; 701:169-172 [PubMed] Related Publications
Therapeutic inhibition of hypoxia inducible factor-1α (HIF-1α) action has emerged as a potential approach for managing several diseases including breast cancer (BC). Genistein has been found to exert anti-malignant activity. However, its mechanisms of action remain unknown. Studies indicate that it could act by downregulating HIF-1α. Based on these findings, we investigated whether genistein could reduce HIF-1α in BC cell lines. Furthermore, we performed molecular docking studies to characterize the sites of interaction between genistein and HIF-1α. In the present investigation, we prove, for the first time, that genistein downregulates HIF-1α in BC cells. Molecular docking analysis also revealed that genistein binds to the FIH-1 binding site of HIF-1α protein. These findings thus indicate that genistein and/or HIF-1α antagonists could be a potential treatment for BC.

Sorigue M, Sancho JM
Recent landmark studies in follicular lymphoma.
Blood Rev. 2019; 35:68-80 [PubMed] Related Publications
Follicular lymphoma (FL) is the most common indolent lymphoma. Therapeutic advances in the past decade have improved its prognosis, but some questions remain open, particularly over adapting therapy to each individual patient's disease risk. Several trials and large studies dealing with biological and therapeutic aspects of FL have been published in the past few months and may have immediate or near-future practice-changing implications. These studies include risk-assessment by gene expression profiling, the therapeutic strategy in localized FL, use of obinutuzumab or lenalidomide in the front-line setting, stem cell transplant in early treatment failure and phosphatidylinositol 3-kinase (PI3K) inhibition and chimeric antigen receptor (CAR) T-cells in multiply relapsed disease. This review aims to contextualize these studies, summarize their design and results, assess their impact, highlight related questions that remain unanswered and, finally, provide a personal view as to how they change our approach to non-transformed FL.

Ali S, Tahir M, Khan AA, et al.
Cisplatin Synergistically Enhances Antitumor Potency of Conditionally Replicating Adenovirus via p53 Dependent or Independent Pathways in Human Lung Carcinoma.
Int J Mol Sci. 2019; 20(5) [PubMed] Free Access to Full Article Related Publications
Cisplatin is ranked as one of the most powerful and commonly prescribed anti-tumor chemotherapeutic agents which improve survival in many solid tumors including non-small cell lung cancer. However, the treatment of advanced lung cancer is restricted due to chemotherapy resistance. Here, we developed and investigated survivin promoter regulating conditionally replicating adenovirus (CRAd) for its anti-tumor potential alone or in combination with cisplatin in two lung cancer cells, H23, H2126, and their resistant cells, H23/CPR, H2126/CPR. To measure the expression of genes which regulate resistance, adenoviral transduction, metastasis, and apoptosis in cancer cells, RT-PCR and Western blotting were performed. The anti-tumor efficacy of the treatments was evaluated through flow cytometry, MTT and transwell assays. This study demonstrated that co-treatment with cisplatin and CRAd exerts synergistic anti-tumor effects on chemotherapy sensitive lung cancer cells and monotherapy of CRAd could be a practical approach to deal with chemotherapy resistance. Combined treatment induced stronger apoptosis by suppressing the anti-apoptotic molecule Bcl-2, and reversed epithelial to mesenchymal transition. In conclusion, cisplatin synergistically increased the tumor-killing of CRAd by (1) increasing CRAd transduction via enhanced CAR expression and (2) increasing p53 dependent or independent apoptosis of lung cancer cell lines. Also, CRAd alone proved to be a very efficient anti-tumor agent in cancer cells resistant to cisplatin owing to upregulated CAR levels. In an exciting outcome, we have revealed novel therapeutic opportunities to exploit intrinsic and acquired resistance to enhance the therapeutic index of anti-tumor treatment in lung cancer.

Shah NN, Fry TJ
Mechanisms of resistance to CAR T cell therapy.
Nat Rev Clin Oncol. 2019; 16(6):372-385 [PubMed] Related Publications
The successes with chimeric antigen receptor (CAR) T cell therapy in early clinical trials involving patients with pre-B cell acute lymphoblastic leukaemia (ALL) or B cell lymphomas have revolutionized anticancer therapy, providing a potentially curative option for patients who are refractory to standard treatments. These trials resulted in rapid FDA approvals of anti-CD19 CAR T cell products for both ALL and certain types of B cell lymphoma - the first approved gene therapies in the USA. However, growing experience with these agents has revealed that remissions will be brief in a substantial number of patients owing to poor CAR T cell persistence and/or cancer cell resistance resulting from antigen loss or modulation. Furthermore, the initial experience with CAR T cells has highlighted challenges associated with manufacturing a patient-specific therapy. Understanding the limitations of CAR T cell therapy will be critical to realizing the full potential of this novel treatment approach. Herein, we discuss the factors that can preclude durable remissions following CAR T cell therapy, with a primary focus on the resistance mechanisms that underlie disease relapse. We also provide an overview of potential strategies to overcome these obstacles in an effort to more effectively incorporate this unique therapeutic strategy into standard treatment paradigms.

Elicin O, Cihoric N, Vlaskou Badra E, Ozsahin M
Emerging patient-specific treatment modalities in head and neck cancer - a systematic review.
Expert Opin Investig Drugs. 2019; 28(4):365-376 [PubMed] Related Publications
INTRODUCTION: Head and neck cancer (HNC) is an immunosuppressive disease that demonstrates heterogeneous molecular characteristics and features of tumor-host interaction. Beside radiotherapy and surgery, the current standard of care in systemic treatment involves the use of cytotoxic chemotherapy, monoclonal antibodies (mAbs), and tyrosine kinase inhibitors (TKIs). There are also other modalities being developed under the category of immunotherapy, but they are overshadowed by the recent advancements of immune checkpoint inhibitors.
AREAS COVERED: This systematic review covers recent advancements in 'patient-specific' treatment modalities, which can be only administered to a given patient.
EXPERT OPINION: Currently, patient-specific treatment modalities in HNC mainly consist of active immunotherapy using adoptive cell therapies and/or gene engineered vectors. Despite the slow pace of development, the interest continues in these treatment modalities. The future of HNC treatment is expected to be guided by biomarkers and personalized approaches with tailored combinations of local treatments (radiotherapy, surgery), systemic agents and immune system modulation. Systematic research is required to generate robust data and obtain a high-level of evidence for the effectiveness of such treatment modalities.

Cetani F, Saponaro F, Borsari S, Marcocci C
Familial and Hereditary Forms of Primary Hyperparathyroidism.
Front Horm Res. 2019; 51:40-51 [PubMed] Related Publications
Individuals with a familial predisposition to the development of parathyroid tumors constitute a small minority of all patients with primary hyperparathyroidism (PHPT). These familial syndromes exhibit Mendelian inheritance patterns and the main causative genes in most families have been identified. They include multiple endocrine neoplasia (MEN; types 1, 2A, and 4), hyperparathyroidism-jaw tumor (HPT-JT) syndrome, familial isolated hyperparathyroidism, familial hypocalciuric hypercalcemia (FHH), and neonatal severe PHPT. Each MEN type is associated with the various combinations of specific tumors. MEN1 is characterized by the occurrence of parathyroid, enteropancreatic, and pituitary tumors; MEN2A is characterized by medullary thyroid carcinoma and pheochromocytoma, and MEN4 is characterized by a pathological spectrum similar to that of MEN1 in association with tumors of the adrenal, kidney, and reproductive organs. HPT-JT is characterized by PHPT, ossifying fibromas of maxillary bones, kidney disease, and uterine neoplasias. The prompt diagnosis of these diseases is of great importance for planning appropriate surveillance of the mutant carriers and correct surgical management. The search for mutation is also useful for the identification of the family members who do not carry the mutation and can avoid unnecessary biochemical and instrumental evaluations. Surgery remains the treatment of choice in all familial forms except FHH.

Pepper MS, Alessandrini M, Pope A, et al.
Cell and gene therapies at the forefront of innovative medical care: Implications for South Africa.
S Afr Med J. 2018; 109(1):20-22 [PubMed] Related Publications
The fields of cell and gene therapy are moving rapidly towards providing innovative cures for incurable diseases. A current and highly topical example is immunotherapies involving T-cells that express chimeric antigen receptors (CAR T-cells), which have shown promise in the treatment of leukaemia and lymphoma. These new medicines are indicative of the changes we can anticipate in the practice of medicine in the near future. Despite their promise, they pose challenges for introduction into the healthcare sector in South Africa (SA), including: (i) that they are technologically demanding and their manufacture is resource intensive; (ii) that the regulatory system is underdeveloped and likely to be challenged by ethical, legal and social requirements that accompany these new therapies; and (iii) that costs are likely to be prohibitive, at least initially, and before economies of scale take effect. Investment should be made into finding novel and innovative ways to introduce these therapies into SA sooner rather than later to ensure that SA patients are not excluded from these exciting new opportunities.

Hu W, Zi Z, Jin Y, et al.
CRISPR/Cas9-mediated PD-1 disruption enhances human mesothelin-targeted CAR T cell effector functions.
Cancer Immunol Immunother. 2019; 68(3):365-377 [PubMed] Related Publications
The interaction between programmed cell death protein 1 (PD-1) on activated T cells and its ligands on a target tumour may limit the capacity of chimeric antigen receptor (CAR) T cells to eradicate solid tumours. PD-1 blockade could potentially enhance CAR T cell function. Here, we show that mesothelin is overexpressed in human triple-negative breast cancer cells and can be targeted by CAR T cells. To overcome the suppressive effect of PD-1 on CAR T cells, we utilized CRISPR/Cas9 ribonucleoprotein-mediated editing to disrupt the programmed cell death-1 (PD-1) gene locus in human primary T cells, resulting in a significantly reduced PD-1

Minagawa K, Al-Obaidi M, Di Stasi A
Generation of Suicide Gene-Modified Chimeric Antigen Receptor-Redirected T-Cells for Cancer Immunotherapy.
Methods Mol Biol. 2019; 1895:57-73 [PubMed] Related Publications
Chimeric antigen receptor (CAR)-redirected T-cells are a powerful tool for the treatment of several type of cancers; however, they can cause several adverse effects including cytokine release syndrome, off-target effects resulting in potentially fatal organ damage or even death. Particularly, for CAR T-cells redirected toward acute myeloid leukemia (AML) antigens myelosuppression can be a challenge. The previously validated inducible Caspase9 (iC9) suicide gene system is one of the approaches to control the infused cells in vivo through its activation with a nontherapeutic chemical inducer of dimerizer (CID). We performed a preclinical validation using a model of CD33

Bian W, Zhang H, Tang M, et al.
Potential Role of microRNA-183 as a Tumor Suppressor in Hepatocellular Carcinoma.
Cell Physiol Biochem. 2018; 51(5):2065-2072 [PubMed] Related Publications
BACKGROUND/AIMS: Disseminated tumors, known as metastases, are responsible for ninety-percent of mortality due to cancer. Epithelial to mesenchymal transition, a phenomenon required for morphological conversion of non-motile discoid shaped epithelial cells to highly motile spindle-shaped mesenchymal cells, is thought to be a pre-requisite for metastatic progression. Metastasis-associated 1 (MTA1) protein is a prime inducer of EMT and metastatic progression in all solid tumors including hepatocellular carcinoma (HCC). However, the molecular mechanisms that regulate the expression and function of MTA1 in HCC have not been elucidated.
METHODS: In silico prediction algorithms were used to find microRNAs (miRNAs) that may target MTA1. We examined the relationship between the expression of MTA1 and miR-183 using quantitative real time PCR. We also determined the levels of the MTA1 protein using immunohistochemistry. Reporter assays, in the presence and absence of the miR-183 mimic, were used to confirm MTA1 as a bona fide target of miR183. The effect of miR-183 on HCC pathogenesis was determined using a combination of in vitro migration and invasion assay, together with in vivo xenograft experiments. The correlation between miR-183 and MTA1 expression was also studied in samples from HCC patients, and in The Cancer Genome Atlas dataset.
RESULTS: Analysis of the sequence database revealed that MTA1 is a putative target of miR-183. MTA1 protein and RNA expression showed opposite trends to miR-183 expression in breast, renal, prostate, and testicular tissue samples from cancer patients, and in the metastatic HCC cell line HepG2. An inverse correlation was also observed between MTA1 (high) and miR-183 (low) expression within samples from HHC patients and in the TCGA dataset. Reporter assays in HepG2 cells showed that miR-183 could inhibit translation of a reporter harboring the wild-type, but not the mutant miR-183 3'-untranslated region (UTR). In addition, miR-183 significantly inhibited in vitro migration and invasion in HepG2 cells, and in vivo hepatic metastasis.
CONCLUSION: Our results reveal a novel post-transcriptional regulatory mechanism for MTA1 expression via miR-183, which is suppressed during HCC pathogenesis.

Rohaan MW, Wilgenhof S, Haanen JBAG
Adoptive cellular therapies: the current landscape.
Virchows Arch. 2019; 474(4):449-461 [PubMed] Free Access to Full Article Related Publications
For many cancer types, the immune system plays an essential role in their development and growth. Based on these rather novel insights, immunotherapeutic strategies have been developed. In the past decade, immune checkpoint blockade has demonstrated a major breakthrough in cancer treatment and has currently been approved for the treatment of multiple tumor types. Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TIL) or gene-modified T cells expressing novel T cell receptors (TCR) or chimeric antigen receptors (CAR) is another strategy to modify the immune system to recognize tumor cells and thus carry out an anti-tumor effector function. These treatments have shown promising results in various tumor types, and multiple clinical trials are being conducted worldwide to further optimize this treatment modality. Most successful results were obtained in hematological malignancies with the use of CD19-directed CAR T cell therapy and already led to the commercial approval by the FDA. This review provides an overview of the developments in ACT, the associated toxicity, and the future potential of ACT in cancer treatment.

Xu Q, Harto H, Berahovich R, et al.
Generation of CAR-T Cells for Cancer Immunotherapy.
Methods Mol Biol. 2019; 1884:349-360 [PubMed] Related Publications
T cells engineered with chimeric antigen receptors (CARs) are emerging as powerful cancer immunotherapies. Remarkable efficacies have been demonstrated in treating B-cell malignancies with CAR-T cells, leading to the FDA's first approval of gene therapy. Currently, numerous clinical trials for hematological malignancies and solid tumors are underway worldwide. Production of CAR-T cells with proper qualities is essential for CAR-T success in vivo. Here we detail optimized protocols for the generation of CAR-T cells for preclinical studies using lentiviral gene transfer, expansion of CAR-T cells in culture, detection of CAR expression, and evaluation of CAR-T cellular cytotoxicity in vitro.

Ti D, Niu Y, Wu Z, et al.
Genetic engineering of T cells with chimeric antigen receptors for hematological malignancy immunotherapy.
Sci China Life Sci. 2018; 61(11):1320-1332 [PubMed] Related Publications
The host immune system plays an instrumental role in the surveillance and elimination of tumors by recognizing and destroying cancer cells. In recent decades, studies have mainly focused on adoptive immunotherapy using engineered T cells for the treatment of malignant diseases. Through gene engraftment of the patient's own T cells with chimeric antigen receptor (CAR), they can recognize tumor specific antigens effectively and eradicate selectively targeted cells in an MHC-independent fashion. To date, CAR-T cell therapy has shown great clinical utility in patients with B-cell leukemias. Owing to different CAR designs and tumor complex microenvironments, genetically redirected T cells may generate diverse biological properties and thereby impact their long-term clinical performance and outcome. Meanwhile some unexpected toxicities that result from CAR-T cell application have been examined and limited the curative effects. Diverse important parameters are closely related with adoptively transferred cell behaviors, including CAR-T cells homing, CAR constitutive signaling, T cell differentiation and exhaustion. Thus, understanding CARs molecular design to improve infused cell efficacy and safety is crucial to clinicians and patients who are considering this novel cancer therapeutics. In this review, the developments in CAR-T cell therapy and the limitations and perspectives in optimizing this technology towards clinical application are discussed.

Zheng Y, Gao N, Fu YL, et al.
Generation of regulable EGFRvIII targeted chimeric antigen receptor T cells for adoptive cell therapy of glioblastoma.
Biochem Biophys Res Commun. 2018; 507(1-4):59-66 [PubMed] Related Publications
Adoptive immunotherapy using chimeric antigen receptors-modified T cells (CAR-T) is a promising approach for cancer treatment. However, CARs currently applied in the clinics cannot be effectively regulated and the safety of CAR-T cell therapies remains a major concern. To improve the safety of CAR-T cells, we designed a synthetic splitting CAR (ssCAR) that can regulate T cell functions exogenously. Epidermal growth factor receptor variant III (EGFRvIII) was used as a molecular target for ssCAR. Our results indicate that both EGFRvIII and small molecule are needed for the activation of the ssCAR-T cells. AP21967 dose-dependently increased the expression of T cell activation, production of cytokines and extent of cell lysis. In conclusion, the gene switch designed in this study allows for temporal and spatial control over engineered T cells in a dose-and time-dependent manner by AP21967. Our work demonstrates the feasibility and improved safety profile of this novel treatment approach.

Morsink LM, Walter RB, Ossenkoppele GJ
Prognostic and therapeutic role of CLEC12A in acute myeloid leukemia.
Blood Rev. 2019; 34:26-33 [PubMed] Related Publications
CLEC12A has recently been identified as an antigen, expressed on leukemic stem cells and leukemic blasts. Given the fact that this expression profile seems stable throughout diagnosis, treatment and relapse on leukemic blasts and leukemic stem cells, CLEC12A can be considered a highly potent and reliable marker for the detection of measurable residual disease and therefore applicable for risk stratification and prognostication in AML. Low CLEC12A expression on leukemic blasts seems to be independently associated with lower likelihood of achieving complete remission after 1 cycle of induction chemotherapy, shorter event free survival, as well as overall survival, indicating potential prognostic properties of CLEC12A expression itself. Lack of expression on the normal hematopoietic stem and progenitor cells, in contrast to CD123 and CD33, might result in less toxicity regarding cytopenias, making CLEC12A an interesting target for innovating immunotherapies, including monoclonal and bispecific antibodies, antibody-drug conjugates and CAR-T cells therapy.

Saetersmoen ML, Hammer Q, Valamehr B, et al.
Off-the-shelf cell therapy with induced pluripotent stem cell-derived natural killer cells.
Semin Immunopathol. 2019; 41(1):59-68 [PubMed] Related Publications
Cell therapy is emerging as a very promising therapeutic modality against cancer, spearheaded by the clinical success of chimeric antigen receptor (CAR) modified T cells for B cell malignancies. Currently, FDA-approved CAR-T cell products are based on engineering of autologous T cells harvested from the patient, typically using a central manufacturing facility for gene editing before the product can be delivered to the clinic and infused to the patients. For a broader implementation of advanced cell therapy and to reduce costs, it would be advantageous to use allogeneic "universal" cell therapy products that can be stored in cell banks and provided upon request, in a manner analogous to biopharmaceutical drug products. In this review, we outline a roadmap for development of off-the-shelf cell therapy based on natural killer (NK) cells derived from induced pluripotent stem cells (iPSCs). We discuss strategies to engineer iPSC-derived NK (iPSC-NK) cells for enhanced functional potential, persistence, and homing.

Ruella M, Xu J, Barrett DM, et al.
Induction of resistance to chimeric antigen receptor T cell therapy by transduction of a single leukemic B cell.
Nat Med. 2018; 24(10):1499-1503 [PubMed] Free Access to Full Article Related Publications
We report a patient relapsing 9 months after CD19-targeted CAR T cell (CTL019) infusion with CD19

Zhang Q, Xu J, Ding J, et al.
Bortezomib improves adoptive carbonic anhydrase IX‑specific chimeric antigen receptor‑modified NK92 cell therapy in mouse models of human renal cell carcinoma.
Oncol Rep. 2018; 40(6):3714-3724 [PubMed] Related Publications
Adoptive chimeric antigen receptor (CAR) T or NK cells offer new options for cancer treatment. Clinical results indicate that CAR‑modified T cell (CAR‑T) therapy has curative therapeutic efficacy for hematological malignancies. However, the efficacy of the therapy in most solid tumors, including advanced renal cell carcinoma (RCC), remains highly limited. New regimens, including combination of CAR‑T cells with chemical drugs, must be studied to enhance the therapeutic efficacy of CAR‑T or NK cells for solid tumors. In the present study, a carbonic anhydrase IX (CAIX)‑specific third‑generation CAR was transduced into NK92 cells by lentiviral vectors. The immune effects, including cytokine release and cytotoxicity, of the CAR‑NK92 cells against CAIX‑positive RCC cells were evaluated in vitro. Combination therapeutic effects of bortezomib and CAR‑NK92 cells were analyzed in a mouse model with human RCC xenografts. The results revealed that CAIX‑specific CAR‑NK92 cells specifically recognized in vitro cultured CAIX‑positive RCC cells and released cytokines, including IFN‑γ, perforin and granzyme B, and exhibited specific cytotoxicity. The cytotoxicity of the CAR‑NK92 cells was enhanced after treating RCC cells with bortezomib in vitro. The suppressive efficacy of bortezomib combined with CAR‑NK92 cells against established CAIX‑positive tumor xenografts was more significant than that of the monotherapy with either CAR‑NK92 cells or bortezomib. Therefore, bortezomib can enhance the effects of the CAR‑NK92 cells against RCC in vitro and in vivo. This study provided an experimental basis for the novel clinical regimen of CAIX‑specific CAR‑modified NK or T cells for the treatment of RCC.

Mollanoori H, Shahraki H, Rahmati Y, Teimourian S
CRISPR/Cas9 and CAR-T cell, collaboration of two revolutionary technologies in cancer immunotherapy, an instruction for successful cancer treatment.
Hum Immunol. 2018; 79(12):876-882 [PubMed] Related Publications
Clustered regularly interspaced short palindromic repeats/CRISPR associated nuclease9 (CRISPR/Cas9) technology, an acquired immune system in bacteria and archaea, has provided a new tool for accurately genome editing. Using only a single nuclease protein in complex with 2 short RNA as a site-specific endonuclease made it a simple and flexible genome editing tool to target nearly any genomic locus. Due to recent developments in therapeutic engineered T cell and effective responses of CD19-directed chimeric antigen receptor T cells (CART19) in patients with B-cell leukemia and lymphoma, adoptive T cell immunotherapy, particularly CAR-T cell therapy became a rapidly growing field in cancer therapy and recently Kymriah and Yescarta (CD19-directed CAR-T cells) were approved by FDA. Therefore, the combination of CRISPR/Cas9 technology as a genome engineering tool and CAR-T cell therapy (engineered T cells that express chimeric antigen receptors) may lead to further improvement in efficiency and safety of CAR-T cells. This article reviews mechanism and therapeutic application of CRISPR/Cas9 technology, accuracy of this technology, cancer immunotherapy by CAR T cells, the application of CRISPR technology for the production of universal CAR T cells, improving their antitumor efficacy, and biotech companies that invested in CRISPR technology for CAR-T cell therapy.

Zhong Q, Zhu YM, Zheng LL, et al.
Chimeric Antigen Receptor-T Cells with 4-1BB Co-Stimulatory Domain Present a Superior Treatment Outcome than Those with CD28 Domain Based on Bioinformatics.
Acta Haematol. 2018; 140(3):131-140 [PubMed] Related Publications
BACKGROUND: The second-generation CD19-chimeric antigen receptor (CAR)-T co-stimulatory domain that is commonly used in clinical practice is CD28 or 4-1BB. Previous studies have shown that the persistence of CAR-T in the 4-1BB co-stimulatory domain appears to be longer.
METHODS: The expression profile data of GSE65856 were obtained from GEO database. After data preprocessing, the differentially expressed genes (DEGs) between the mock CAR versus CD19-28z CAR T cells and mock CAR versus CD19-BBz CAR T cells were identified using the limma package. Subsequently, functional enrichment analysis of DEGs was performed using the DAVID tool. Then, the protein-protein international (PPI) network of these DEGs was visualized by Cytoscape, and the miRNA-target gene-disease regulatory networks were predicted using Webgestal.
RESULTS: A total of 18 common DEGs, 6 CD19-28z specific DEGs and 206 CD19-BBz specific DEGs were identified. Among CD19-28z specific DEGs, down-regulated PAX5 might be an important node in the PPI network and could be targeted by miR-496. In CD19-BBz group, JUN was a hub node in the PPI network and involved in the regulations of miR520D - early growth response gene 3 (EGR3)-JUN and mi-R489-AT-rich interaction domain 5A (ARID5A)-JUN networks.
CONCLUSION: The 4-1BB co-stimulatory domain might play in important role in the treatment of CAR-T via miR-520D-EGR3-JUN and miR489-ARID5A-JUN regulation network, while CD28 had a negative effect on CAR-T treatment.

Hasan A, Moscoso DI, Kastrinos F
The Role of Genetics in Pancreatitis.
Gastrointest Endosc Clin N Am. 2018; 28(4):587-603 [PubMed] Related Publications
Individuals with acute recurrent and chronic pancreatitis may have an inherited predisposition to the development of the disease. Pancreatitis in the setting of a significant family history of the disease can be classified as hereditary or familial pancreatitis. In this article, the authors closely examine the specific genes implicated in pancreatitis, investigate the role of genetic testing for diagnosis, and describe the impact of genetic testing results on clinical management.

Cohen AD
CAR T Cells and Other Cellular Therapies for Multiple Myeloma: 2018 Update.
Am Soc Clin Oncol Educ Book. 2018; 38:e6-e15 [PubMed] Related Publications
Cellular therapies are a rapidly evolving approach to myeloma treatment, which bring a unique mechanism of action with the potential to overcome drug resistance and induce long-term remissions. Two primary approaches are being studied: non-gene-modified strategies, which rely on the endogenous anti-myeloma T-cell repertoire, and gene-modified strategies, which introduce a new T-cell receptor (TCR) or a chimeric antigen receptor (CAR) to confer novel antigen specificity. CAR T cells show the greatest activity to date. Multiple antigen targets, including B-cell maturation antigen (BCMA), CD19, CD38, CD138, and SLAMF7, are being explored for myeloma, and BCMA has emerged as the most promising. Preliminary data from four phase I studies of BCMA CAR T cells, each using a different CAR construct, that involved 90 evaluable patients with relapsed/refractory disease have been reported. These data show response rates of 60% to 100%, including minimal residual disease (MRD)-negative complete remissions, at effective doses (> 10

Ushakov DS, Dorozhkova AS, Babayants EV, et al.
Expression of microRNA Potentially Regulated by AhR and CAR in Malignant Tumors of the Endometrium.
Bull Exp Biol Med. 2018; 165(5):688-691 [PubMed] Related Publications
We studied microRNA whose expression can be regulated by carcinogenic compounds. Bioinformatic analysis has detected microRNA potentially regulated by xenosensor receptors AhR (miR-28, miR-30c, miR-30e, miR-139, and miR-153) and CAR (miR-29c, miR-31, miR-185, miR-625, and miR-652). Published data indicate that these microRNAs are oncosuppressors, except miR-31 that can act as an oncogene. The expression of these microRNAs in malignant tumors of the endometrium was studied. The expression of the majority of the studied microRNAs, except miR-652, was 2-3-fold below the normal, which confirms their oncosuppressor function and indicates their involvement in the endometrial carcinogenesis and hence, allows considering them as potential markers of the disease.

Galván-Femenía I, Guindo M, Duran X, et al.
Genomic profiling in advanced stage non-small-cell lung cancer patients with platinum-based chemotherapy identifies germline variants with prognostic value in SMYD2.
Cancer Treat Res Commun. 2018; 15:21-31 [PubMed] Related Publications
OBJECTIVE: The aim of the study was to investigate the relationship between germline variations as a prognosis biomarker in patients with advanced Non-Small-Cell-Lung-Cancer (NSCLC) subjected to first-line platinum-based treatment.
MATERIALS AND METHODS: We carried out a two-stage genome-wide-association study in non-small-cell lung cancer patients with platinum-based chemotherapy in an exploratory sample of 181 NSCLC patients from Caucasian origin, followed by a validation on 356 NSCLC patients from the same ancestry (Valencia, Spain).
RESULTS: We identified germline variants in SMYD2 as a prognostic factor for survival in patients with advanced NSCLC receiving chemotherapy. SMYD2 alleles are associated to a decreased overall survival and with a reduced Time to Progression. In addition, enrichment pathway analysis identified 361 variants in 40 genes to be involved in poorer outcome in advanced-stage NSCLC patients.
CONCLUSION: Germline SMYD2 alleles are associated with bad clinical outcome of first-line platinum-based treatment in advanced NSCLC patients. This result supports the role of SMYD2 in the carcinogenic process, and might be used as prognostic signature directing patient stratification and the choice of therapy.
MICROABSTRACT: A two-Stage Genome wide association study in Caucasian population reveals germline genetic variation in SMYD2 associated to progression disease in first-line platinum-based treatment in advanced NSCLC patients. SMYD2 profiling might have prognostic / predictive value directing choice of therapy and enlighten current knowledge on pathways involved in human carcinogenesis as well in resistance to chemotherapy.

Do MH, To PK, Cho YS, et al.
Targeting CD46 Enhances Anti-Tumoral Activity of Adenovirus Type 5 for Bladder Cancer.
Int J Mol Sci. 2018; 19(9) [PubMed] Free Access to Full Article Related Publications
CD46 is generally overexpressed in many human cancers, representing a prime target for CD46-binding adenoviruses (Ads). This could help to overcome low anti-tumoral activity by coxsackie-adenoviral receptor (CAR)-targeting cancer gene therapy viruses. However, because of scarce side-by-side information about CAR and CD46 expression levels in cancer cells, mixed observations of cancer therapeutic efficacy have been observed. This study evaluated Ad-mediated therapeutic efficacy using either CAR-targeting Ad5 or CD46-targeting Ad5/35 fiber chimera in bladder cancer cell lines. Compared with normal urothelia, bladder cancer tissue generally overexpressed both CAR and CD46. While CAR expression was not correlated with disease progression, CD46 expression was inversely correlated with tumor grade, stage, and risk grade. In bladder cancer cell lines, expression levels of CD46 and CAR were highly correlated with Ad5/35- and Ad5-mediated gene transduction and cytotoxicity, respectively. In a human EJ bladder cancer xenograft mouse model, with either overexpressed or suppressed CD46 expression levels, Ad5/35-tk followed by ganciclovir (GCV) treatment significantly affected tumor growth, whereas Ad5-tk/GCV had only minimal effects. Overall, our findings suggest that bladder cancer cells overexpress both CAR and CD46, and that adenoviral cancer gene therapy targeting CD46 represents a more suitable therapy option than a CAR-targeting therapy, especially in patients with low risk bladder cancers.

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