FZD10-targeted α-radioimmunotherapy with 225Ac-labeled OTSA101 achieves complete remission in a synovial sarcoma model

Synovial sarcomas are rare tumors arising in adolescents and young adults. The prognosis for advanced disease is poor, with an overall survival of 12-18 months. Frizzled homolog 10 (FZD10) is overexpressed in most synovial sarcomas, making it a promising therapeutic target. The results of a phase 1 trial of β-radioimmunotherapy (RIT) with the 90Y-labeled anti-FZD10 antibody OTSA101 revealed a need for improved efficacy. The present study evaluated the potential of α-RIT with OTSA101 labeled with the α-emitter 225Ac. Competitive inhibition and cell binding assays showed that specific binding of 225Ac-labeled OTSA101 to SYO-1 synovial sarcoma cells was comparable to that of the imaging agent 111In-labeled OTSA101. Biodistribution studies showed high uptake in SYO-1 tumors and low uptake in normal organs, except for blood. Dosimetric studies showed that the biologically effective dose (BED) of 225Ac-labeled OTSA101 for tumors was 7.8 Bd higher than that of 90Y-labeled OTSA101. 90Y- and 225Ac-labeled OTSA101 decreased tumor volume and prolonged survival. 225Ac-labeled OTSA101 achieved a complete response in 60% of mice, and no recurrence was observed. 225Ac-labeled OTSA101 induced a larger amount of necrosis and apoptosis than 90Y-labeled OTSA101, although the cell proliferation decrease was comparable. The BED for normal organs and tissues was tolerable; no treatment-related mortality or obvious toxicity, except for temporary body weight loss, was observed. 225Ac-labeled OTSA101 provided a high BED for tumors and achieved a 60% complete response in the synovial sarcoma mouse model SYO-1. RIT with 225Ac-labeled OTSA101 is a promising therapeutic option for synovial sarcoma

Knockdown of COPA, Identified by Loss-of-Function Screen, Induces Apoptosis and Suppresses Tumor Growth in Mesothelioma Mouse Model

AbstractMalignant mesothelioma is a highly aggressive tumor arising from serosal surfaces of the pleura and is triggered by past exposure to asbestos. Currently, there is no widely accepted treatment for mesothelioma. Development of effective drug treatments for human cancers requires identification of therapeutic molecular targets. We therefore conducted a large-scale functional screening of mesothelioma cells using a genome-wide small interfering RNA library. We determined that knockdown of 39 genes suppressed mesothelioma cell proliferation. At least seven of the 39 genes—COPA, COPB2, EIF3D, POLR2A, PSMA6, RBM8A, and RPL18A—would be involved in anti-apoptotic function. In particular, the COPA protein was highly expressed in some mesothelioma cell lines but not in a pleural mesothelial cell line. COPA knockdown induced apoptosis and suppressed tumor growth in a mesothelioma mouse model. Therefore, COPA may have the potential of a therapeutic target and a new diagnostic marker of mesothelioma

Defective repair of radiation-induced DNA damage is complemented by a CHORI-230-65K18 BAC clone on rat chromosome 4

AbstractThe Long Evans cinnamon (LEC) rat is highly susceptible to X-irradiation due to defective DNA repair and is thus a model for hepatocellular carcinogenesis. We constructed a bacterial artificial chromosome (BAC) contig of rat chromosome 4 completely covering the region associated with radiation susceptibility. We used transient and stable transfections to demonstrate that defective DNA repair in LEC cells is fully complemented by a 200-kb BAC, CHORI-230-65K18. Further analysis showed that the region associated with radiation susceptibility is located in a 128,543-bp region of 65K18 that includes the known gene Rpn1. However, neither knockdown nor overexpression of Rpn1 indicated that this gene is associated with radiation susceptibility. We also mapped three ESTs (TC523872, TC533727, and CB607546) in the 128,543-bp region, suggesting that 65K18 contains an unknown gene associated with X-ray susceptibility in the LEC rat

Low HER2 expression is a predictor of poor prognosis in stage I triple-negative breast cancer

IntroductionTriple-negative breast cancer (TNBC) is negative for hormone receptors and human epidermal growth factor receptor 2 (HER2). In stage I TNBC, adjuvant therapy or follow-up are performed according to risk factors, but clinical trial data is scarce. In recent years, it has been reported that HER2-low cases (1+/2+ and in situ hybridization negative) have different prognoses than HER2-0 cases. However, the risk of recurrence and risk factors in this HER2-low population for stage I TNBC have not yet been investigated.MethodsHerein, out of 174 patients with TNBC who underwent surgery from June 2004 to December 2009 at the National Cancer Center Hospital (Tokyo), we retrospectively examined 42 cases diagnosed as T1N0M0 TNBC after excluding those treated with preoperative chemotherapy.ResultsAll patients were female, the median age was 60.5 years, and 11 cases were HER2-low and 31 cases were HER2-0. The median follow-up period was 121 months. Postoperative adjuvant therapy was administered in 30 patients and recurrence occurred in 8 patients. HER2-low cases showed a significantly shorter disease-free survival (HR: 7.0; 95% CI: 1.2– 40.2; P=0.0016) and a trend towards shorter overall survival (hazard ratio [HR]: 4.2, 95% confidence interval [CI]: 0.58–31.4) compared with that of HER2-0 cases. HER2 was also identified as a factor for poor prognosis from the point- estimated values in univariate and multivariate analyses after confirming that there was no correlation between the other factors.ConclusionFor patients with stage I TNBC, the HER2-low population had a significantly worse prognosis than the HER2-0 population

A tyrosine-kinase inhibitor enhanced antitumor effects of ROBO1-targeted radioimmunotherapy in an SCLC mouse model

ROBO1 is a membrane protein that is frequently expressed in small cell lung cancer (SCLC). We previously reported our radioimmunotherapy (RIT) agent 90Y-labeled anti-ROBO1 IgG showed significant anti-tumor effects such as tumor shrinkage, but the tumors showed regrowth, suggesting the necessity for more effective therapy. Here, we evaluated the efficacy of a combination therapy of the RIT agent and a tyrosine-kinase inhibitor nintedanib in SCLC xenograft mice. Four groups of SCLC xenograft mice were treated with saline (control), nintedanib alone, RIT alone, and a combination of RIT and nintedanib, respectively. In the nintedanib alone group, no anti-tumor effects such as tumor growth suppression were observed. The RIT alone group and the combination group showed remarkable tumor shrinkage and prolonged survival compared with the control group. Tumor regrowth was observed in all 6 cases in the RIT alone group and 1 of 6 cases in the combination group by 100 days post-treatment. These results suggest that the tyrosine-kinase inhibitor nintedanib enhances anti-tumor effects of RIT with 90Y-labeled anti-ROBO1 IgG. The combination has the potential as an option for SCLC treatment.第79回日本癌学会学術総

Assessment of 4DST uptake and Ki-67 index in patients with lung tumor in comparison with FDG uptake.

Objective: A novel radiopharmaceutical, 4’-[methyl-11C]-thiothymidine (4DST), has been developed as an in vivo cell proliferation marker based on the DNA incorporation method. The purpose of this study was to evaluate 4DST uptake in patients with lung tumor and to correlate the results with proliferative activity and tumor grade, in comparison with 18F-FDG (FDG).Methods: Investigations of 4DST and FDG PET/CT were performed retrospectively in 23 lesions of 22 patients with lung tumor (18 male and 4 femal, mean age; 67.4+/- 8.6 y.o., median; 69 y.o.). The maximum standardized uptake value (SUVmax) for tumor were calculated. Histopathological diagnosis was proven by surgery when the clinical diagnosis was malignancy. Others were diagnosed as benign lung nodule by clinically follow-up. Proliferative activity as indicated by the Ki-67 index was estimated in tissue specimens.Results: Of 23 lung tumors examined, 19 lesions were malignant tumor (SqCC; 5, Adenoca.; 14), other 4 lesion were benign after surgery or clinical course observation. In 4DST PET/CT study, SUVmax were 3.04 in malignant lesion (2.89 for SqCC, 3.10 for Adenoca.) and 1.87 in benign lesion, respectively (P<0.05). In FDG PET/CT study, SUVmax were 5.62 in malignant lesion (7.46 for SqCC, 4.96 for Adenoca.) and 4.48 in benign lesion, respectively (n.s.). Linear regression analysis between 4DST and FDG indicated a correlation for SUVmax (R2 = 0.30, P<0.01). The Expression of Ki-67 of SqCC was 32.4 +/- 7.44 and that of Adeno ca. was 24.64 +/- 29.84, respectively (n.s.). Linear regression analysis indicated a correlation between FDG and Ki-67 index of or SUVmax (R2 = 0.50, P<0.005), however a significant correlation between FDG and Ki-67 index was not found in this population of this study. In several case of adenocarcinoma, mixed subtype, were relatively low Ki-67 index while the SUVmax of 4DST were high.Conclusion: 4DST PET/CT is feasible for imaging of lung tumors, as well as FDG PET/CT.世界核医学会(WFNMB2018

A Case of Novel Mutation of HNF1B in Maturity-onset Diabetes of the Young Type 5 (MODY5)

Maturity-onset diabetes of the young (MODY) is both a genetically and clinically heterozygous type of diabetes mellitus characterized by early onset (often before 25 y

Wnt1 induces osteoblastic changes in a well‐established osteolytic skeletal metastatic model derived from breast cancer

Abstract Background Osteoblastic skeletal metastasis is frequently observed in prostate cancer. An effective therapy has not been developed due to the unclear molecular mechanism. The Wnt family is involved in various biological phenomena including bone metabolism. There is no direct evidence that the family causes osteoblastic skeletal metastasis. Aims The present study aims to evaluate whether overexpressed Wnt induces osteoblastic bone metastasis in a well‐established osteolytic bone metastatic model. Methods and Results The breast cancer‐derived 5a‐D‐Luc‐ZsGreen cells were transfected with Wnt1, Wnt3A, and Wnt5A expression vectors, producing stably highly expressing cells. These cells were intracardially transplanted in nude mice. Bone metastasis development was confirmed by fluorescence imaging. Hind‐limb bones including metastasis were dissected and visualized through micro‐CT imaging. After imaging, sections were stained with hematoxylin and eosin (H&E), and immunohistochemically stained with an anti‐SATB2 antibody. Luminescent imaging confirmed mice with bone metastases in the hind limbs. Micro‐CT imaging found an osteoblastic change only in bone metastasis of mice transplanted with Wnt1‐expressing cells. This was confirmed on H&E‐stained sections. SATB2 immunostaining showed differentiated osteoblasts were at the site of bone metastases in the diaphysis. SATB2 in the Wnt/β‐catenin pathway activated by overexpressed Wnt1 could induce osteoblastic change. Conclusion Our findings provided direct evidence Wnt1 is involved in osteoblastic bone metastasis development. Our model would be a powerful tool for further elucidating molecular mechanisms underlying the disease and developing effective therapies