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Background Pancreatic cancer is a refractory malignancy, and the development of a new effective treatment strategy is needed. We generated a dendritic cell vaccine by culturing monocytes obtained by apheresis of blood from each patient, inducing their differentiation into dendritic cells, and pulsing with tumor antigen peptides. However, the clinical efficacy of the vaccine has not been established. We therefore decided to conduct an exploratory clinical trial of dendritic cell vaccine loaded with Wilms’ tumor gene 1 peptides (TLP0-001) as a potential new treatment for patients with advanced pancreatic cancer refractory to standard chemotherapy. Methods This is an investigator-initiated, double-blind, comparative trial. The patients were allocated to two groups in a 1:1 ratio through a central registration by dynamic allocation. A total of 185 patients with inoperable or metastatic pancreatic cancer who were refractory or intolerant to standard primary chemotherapy with gemcitabine plus nab-paclitaxel will be allocated to secondary treatment either with placebo in combination with S-1 (the control group) or TLP0-001 in combination with S-1 (the investigational product group). The primary objective of this trial is to evaluate the safety and efficacy (as measured by overall survival) of the investigational product by comparing the two groups. This clinical trial will be performed in accordance with Japanese Good Clinical Practice guidelines. Discussion Clinical trials of the standard regimen, including gemcitabine, for advanced pancreatic cancer are ongoing worldwide. However, a strategy for after the primary treatment has not been established. We therefore decided to conduct this study to evaluate the safety and efficacy of TLP0-001 as a secondary treatment for pancreatic cancer in anticipation of the approval of this new drug in Japan. This trial is conducted with full consideration of safety, as it is the first-in-human clinical trial of TLP0-001; thus, the trial will be conducted only at the Second Department of Surgery at Wakayama Medical University until the safety is confirmed by interim analysis. We plan to conduct a multicenter trial at 18 institutions in Japan after confirmation of the safety. Trial registration University Hospital Medical Information Network Clinical Trials Registry, UMIN000027179 . Registered on 9 April 2017.

The Wilms tumor gene WT1 is expressed at high levels in leukemic blast cells in most acute myeloid and lymphoblastic leukemias. In myelodysplastic syndrome, WT1 mRNA expression levels increase along with disease progression; thus, WT1 mRNA is a tumor marker for leukemic blast cells. WT mRNA is also expressed at high levels in various types of solid cancers, including cancers of the lung, breast, colon and pancreas. Patients with WT1-expressing tumors produce antibodies and cytotoxic T-lymphocytes against WT1 protein, indicating that WT1 protein is highly immunogenic and a promising tumor antigen. Major histocompatibility complex class I-restricted cytotoxic T-lymphocyte and class II-restricted helper epitopes of WT1 protein were identified, and clinical studies of cancer immunotherapy using these cytotoxic T-lymphocyte epitope peptides were performed without significant adverse effect and with clinical results promising enough to encourage further clinical trials. The clinical efficacy of cancer immunotherapy targeting the WT1 protein should be clarified by a large-scale clinical study.

Either WT1 or leukemia-associated aberrant immune phenotypes (LAIPs) was one of the minimal residual disease (MRD) parameters used to predict leukemia relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We first evaluated the clinical value of various positive MRD standards for accurately indicating relapse based on WT1 and FCM data in adult patients with acute leukemia (AL). In total, 824 AL patients treated with allo-HSCT were enrolled in this study. We compared the sensitivity and specificity of diverse, multiple-criteria MRD prognostic standards based on WT1 and FCM assays. Higher sensitivity was achieved without a loss of specificity when MRDco+, which was defined as two consecutive WT1 0.6 + or FCM+ or both WT1 0.6 + and FCM+ in the same sample within a year posttransplantation, was used as the positive MRD standard. Similar results were observed, even in 484 patients who had both abnormal WT1 and LAIPs values before transplant. A multivariate analysis showed that MRDco+ was an independent risk factor for leukemia relapse after transplant in both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). The combined use of FCM and WT1 monitoring could distinguish between patients with low and high risks of relapse. Various positive MRD standards were useful for guiding intervention.

The Wilms' tumor gene Wt1 is known for its important functions during genitourinary and mesothelial formation. Here we show that Wt1 is necessary for neuronal development in the vertebrate retina. Mouse embryos with targeted disruption of Wt1 exhibit remarkably thinner retinas than age‐matched wild‐type animals. A large fraction of retinal ganglion cells is lost by apoptosis, and the growth of optic nerve fibers is severely disturbed. Strikingly, expression of the class IV POU‐domain transcription factor Pou4f2 (formerly Brn‐3b), which is critical for the survival of most retinal ganglion cells, is lost in Wt1 −/− retinas. Forced expression of Wt1 in cultured cells causes an up‐regulation of Pou4f2 mRNA. Moreover, the Wt1(−KTS) splice variant can activate a reporter construct carrying 5′‐regulatory sequences of the human POU4F2 . The lack of Pou4f2 and the ocular defects in Wt1 −/− embryos are rescued by transgenic expression of a 280 kb yeast artificial chromosome carrying the human WT1 gene. Taken together, our findings demonstrate a continuous requirement for Wt1 in normal retina formation with a critical role in Pou4f2‐dependent ganglion cell differentiation.

High expression of the Wilms' tumor gene (WT1) in acute myeloid leukemia (AML) has been considered as a sensitive marker of minimal residual disease (MRD). The present study investigated the significance of quantitative analysis of WT1 mRNA, combined with multiparameter flow cytometry (MFC) regarding its efficacy and prognostic as well as relapse prediction value for leukemia patients with hematopoietic stem cell transplantation. Reverse-transcription quantitative polymerase chain reaction analysis demonstrated that the expression of WT1 in the initial and relapse group was significant higher than that in the complete remission (CR) group (P<0.01). WT1 and the donor chimerism were negatively correlated (r=−0.73, P<0.05). In all AML patients, WT1 was the highest in the M3 subtype and the lowest in the M1 subtype. Follow-up of 12 AML patients demonstrated that WT1 gene expression levels markedly decreased after CR, but obviously increased after relapse, as did the rate of the leukemia cells detected by MFC. The combined usage of MFC and WT1 monitoring contributed to an improved detection rate of relapse (91.7%), and may be used to monitor MRD, assess the treatment efficacy and prognosis, and predict the risk of recurrence in leukemia patients without specific molecular markers after allogeneic hematopoietic stem cell transplantation.

Wilms tumour is the most common renal malignancy of childhood. The disease is curable in the majority of cases, albeit at considerable cost in terms of late treatment-related effects in some children. However, one in ten children with Wilms tumour will die of their disease despite modern treatment approaches. The genetic changes that underpin Wilms tumour have been defined by studies of familial cases and by unbiased DNA sequencing of tumour genomes. Together, these approaches have defined the landscape of cancer genes that are operative in Wilms tumour, many of which are intricately linked to the control of fetal nephrogenesis. Advances in our understanding of the germline and somatic genetic changes that underlie Wilms tumour may translate into better patient outcomes. Improvements in risk stratification have already been seen through the introduction of molecular biomarkers into clinical practice. A host of additional biomarkers are due to undergo clinical validation. Identifying actionable mutations has led to potential new targets, with some novel compounds undergoing testing in early phase trials. Avenues that warrant further exploration include targeting Wilms tumour cancer genes with a non-redundant role in nephrogenesis and targeting the fetal renal transcriptome.Wilms tumour is the most common renal malignancy of childhood. Here, the authors review the genetic landscape of Wilms tumour and discuss how precision medicine guided by genomic information might lead to new therapeutic approaches and improve patient survival.

To determine the role of the Wilms' tumor gene WT1 in tumorigenesis of solid tumors, expression of the WT1 gene was examined in 34 solid tumor cell lines (four gastric cancer cell lines, five colon cancer cell lines, 15 lung cancer cell lines, four breast cancer cell lines, one germ cell tumor cell line, two ovarian cancer cell lines, one uterine cancer cell line, one thyroid cancer cell line, and one hepatocellular carcinoma cell line) by means of quantitative reverse transcriptase‐polymerase chain reaction. WT1 gene expression was detected in three of the four gastric cancer cell lines, all of the five colon cancer cell lines, 12 of the 15 lung cancer cell lines, two of the four breast cancer cell lines, the germ cell tumor cell line, the two ovarian cancer cell lines, the uterine cancer cell line, the thyroid cancer cell line, and the hepatocellular carcinoma cell line. Therefore, of the 34 solid tumor cell lines examined, 28 (82%) expressed WT1. Three cell lines expressing WT1 (gastric cancer cell line AZ‐521, lung cancer cell line OS3, and ovarian cancer cell line TYK‐nu) were further analyzed for mutations and/or deletions in the WT1 gene by means of single‐strand conformation polymorphism analysis. However, no mutations or deletions were detected in the region of the WT1 gene ranging from the 3/end of exon 1 to exon 10 (the WT1 gene consists of 10 exons) in these three cell lines. Furthermore, when AZ‐521, OS3, and TYK‐nu cells were treated with WT1 antisense oligomers, the growth of these cells was significantly inhibited in association with a reduction in WT1 protein levels. Furthermore, constitutive expression of the transfected WT1 gene in cancer cells inhibited the antisense effect of WT1 antisense oligomer on cell growth. These results indicated that the WT1 gene plays an essential role in the growth of solid tumors and performs an oncogenic rather than a tumor‐suppressor gene function.

The wild‐type Wilms’ tumor gene WT1 is overexpressed in human primary leukemia and in a wide variety of solid cancers. All of the four WT1 isoforms are expressed in primary cancers and each is considered to have a different function. However, the functions of each of the WT1 isoforms in cancer cells remain unclear. The present study demonstrated that constitutive expression of the WT1 17AA(–)/KTS(–) isoform induces morphological changes characterized by a small‐sized cell shape in TYK‐nu.CP‐r (TYK) ovarian cancer cells. In the WT1 17AA(–)/KTS(–) isoform‐transduced TYK cells, cell–substratum adhesion was suppressed, and cell migration and in vitro invasion were enhanced compared to that in mock vector‐transduced TYK cells. Constitutive expression of the WT1 17AA(–)/KTS(–) isoform also induced morphological changes in five (one gastric, one esophageal, two breast and one fibrosarcoma) of eight cancer cell lines examined. No WT1 isoforms other than the WT1 17AA(–)/KTS(–) isoform induced the phenotypic changes. A decrease in α‐actinin 1 and cofilin expression and an increase in gelsolin expression were observed in WT1 17AA(–)/KTS(–) isoform‐transduced TYK cells. In contrast, co‐expression of α‐actinin 1 and cofilin or knockdown of gelsolin expression by small interfering RNA restored WT1 17AA(–)/KTS(–) isoform‐transduced TYK cells to a phenotype that was comparable to that of the parent TYK cells. These results indicated that the WT1 17AA(–)/KTS(–) isoform exerted its oncogenic functions through modulation of cytoskeletal dynamics. The present results may provide a novel insight into the signaling pathway of the WT1 gene for its oncogenic functions. (Cancer Sci 2006; 97: 259–270)

The Wilms' tumor gene, WT1, is a tumor marker for leukemic blast cells. The WT1 expression levels were examined for 57 patients with myelodysplastic syndromes (MDS) (refractory anemia (RA), 35; RA with excess of blasts (RAEB) 14; RAEB in transformation (RAEB-t), six; and MDS with fibrosis, two) and 12 patients with acute myeloid leukemia (AML) evolved from MDS. These levels significantly increased in proportion to the disease progression of MDS from RA to overt AML via RAEB and RAEB-t in both bone marrow (BM) and peripheral blood (PB). WT1 expression levels in PB significantly correlated with the evolution of RAEB or RAEB-t to overt AML within 6 months. Therefore, WT1 expression levels in PB were superior to those in BM for early prediction of the evolution to AML by means of quantitation of the WT1 expression levels. Furthermore, WT1 expression in PB of patients with overt AML evolved from MDS was significantly decreased by effective chemotherapy or allogeneic stem cell transplantation and became undetectable in long-term survivors. These results clearly showed that WT1 expression levels are a tumor marker for preleukemic or leukemic blast cells of MDS and thus reflect the disease progression of MDS. Therefore, monitoring of WT1 expression levels has made continuous assessment of the disease progression of MDS possible, as well as the prediction of the evolution of RAEB or RAEB-t to overt AML within 6 months. The results also showed that quantitation of WT1 expression levels is useful for diagnosis of minimal residual disease of MDS with high sensitivity, thus making it possible to evaluate the efficacy of treatment for MDS.

Key Points WT1 and WTX seem to function as tumour suppressor genes (TSGs) in Wilms' tumours, but questions have arisen about these labels. The lack of an increased frequency of Wilms' tumours or other malignancies in patients with osteopathia striata congenita with cranial sclerosis (OSCS) with WTX germline mutations initially challenged its designation as a TSG, but a recent observation of Wilms' tumour precursor lesions in a patient with OSCS supports this label. In Wilms' tumours, WT1 conforms to a TSG label: patients heterozygous for WT1 germline mutations are predisposed to Wilms' tumour and WT1 is inactivated in tumours. These data link loss of WT1 function with enhanced cell viability and/or proliferation. By contrast, ablation of WT1 at the initial stages of kidney development results in apoptosis and renal agenesis, indicating that it has a crucial role in maintaining cell viability. In some leukaemias, the increased expression of WT1 compared with normal bone marrow cells, along with some reports of WT1 expression being a marker of poor prognosis, suggest that WT1 functions as an oncogene. By contrast, observations of WT1 inactivating mutations in leukaemias suggest it functions as a TSG. WT1 has important roles in regulating normal differentiation in various organs and cell types. During both nephrogenesis and haematopoiesis, loss of WT1 or overexpression of WT1 is associated with differing phenotypic consequences, depending on the differentiation status of the cell. The oncogenic or tumour suppressive effect of WT1 alteration is likely to be a result of how a cell at a particular stage of development responds to perturbations in normal differentiation. In short, either label may be misleading and/or inadequate when used to describe the function of WT1 . Genes mutated in Wilms' tumours include oncogenes, tumour suppressor genes and WT1 , which sometimes behaves as an oncogene and sometimes behaves as a tumour suppressor gene. This Review analyses, among other things, what it would take for WT1 to fall into one or the other category. Genes identified as being mutated in Wilms' tumour include TP53 , a classic tumour suppressor gene (TSG); CTNNB1 (encoding β-catenin), a classic oncogene; WTX , which accumulating data indicate is a TSG; and WT1 , which is inactivated in some Wilms' tumours, similar to a TSG. However, WT1 does not always conform to the TSG label, and some data indicate that WT1 enhances cell survival and proliferation, like an oncogene. Is WT1 a chameleon, functioning as either a TSG or an oncogene, depending on cellular context? Are these labels even appropriate for describing and understanding the function of WT1 ?