Research progress of peptide receptor radionuclide therapy combined with other drugs in the treatment of neuroendocrine tumors / 中华核医学与分子影像杂志

Peptide receptor radionuclide therapy (PRRT) is a nuclear medicine method that uses radionuclide-labeled somatostatin analogs (SSAs) to image and treat tumors overexpressing somatostatin receptor (SSTR). For the treatment of neuroendocrine tumors (NETs), PRRT alone can achieve a high disease control rate (DCR), but with a low disease response rate (DRR). Studies have shown that, PRRT combined with SSAs such as octreotide and lanreotide, PRRT combined with chemotherapy drugs such as 5-fluorouracil, capecitabine and temozolomide, PRRT combined with targeted drugs such as tarazopinib, everolimus and heat shock protein inhibitors, PRRT combined with immune drugs such as navumab, and the combination of 177Lu-1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacceticacid (DOTA)-Tyr3-octreotide (TOC)/DOTA- D-Phe1-Tyr3-Thr8-octreotide (TATE) and 90Y-DOTATOC/DOTATATE, are promising to improve the efficacy of PRRT in the treatment of NETs with tolerable side effects. These PRRT combinations demonstrate an encouraging potential to improve clinical outcomes in NETs patients, and more prospective randomized clinical trials are needed to further validate current findings.

Advances in the somatostatin receptor-targeting imaging and peptide receptor radionuclide therapy for pheochromocytomas and paragangliomas / 中华核医学与分子影像杂志

Pheochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumors leading to serious complications in the cardiovascular system. As somatostatin receptor (SSTR) is highly expressed in PPGL, SSTR-targeting imaging, particularly PET/CT based on 68Ga-labelled somatostatin analog represented by 68Ga-1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid- D-Phe1-Tyr3-Thr8-octreotide (DOTATATE), becomes an important tool for location and assessment of systemic metastases. Treatments for metastatic PPGL are limited. Peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE provides a new therapeutic option for patients with inoperable PPGL and demonstrates satisfying efficacy. This article summarizes the advances of SSTR-targeting imaging and PRRT in the diagnosis and treatment of PPGL.

Eficacia de lutecio-177 DOTATATE/TOC en pacientes con tumores neuroendocrinos bien diferenciados en estado avanzado. Ensayo clínico fase II / Efficacy of Lutetium-177 DOTATATE/TOC in Advanced Neuroendocrine Tumors

Resumen Introducción: En 2009, el Instituto Nacional de Cancerología (INC) elaboró el 177Lu-DOTATATE/TOC. El propósito del estudio fue demostrar la eficacia de estos radiopéptidos en el tratamiento paliativo de pacientes con tumores neuroendocrinos (TNE) avanzados inoperables (metastásicos o localmente avanzados) y en progresión. Métodos: Ensayo clínico abierto fase II de un solo brazo en 13 pacientes adultos con TNE grado 1 o 2, con expresión de receptores de somatostatina en lesiones blanco demostrada por captación Krenning 3 o 4 en 99mTc-HYNIC TOC. Los pacientes fueron tratados con 177Lu-DOTATATE o 177Lu-DOTATOC (según disponibilidad) a una actividad acumulativa proyectada de 600-800 mCi dividida en 3-4 dosis cada 6-9 semanas comenzando siempre con una actividad fija de 200 mCi y dosimetría con la primera dosis. El desenlace primario fue la respuesta objetiva calculada 6 y 12 meses después de la última dosis del tratamiento. Resultados: Se incluyeron 13 pacientes (7 mujeres) de 63 ± 11,6 años con TNE avanzado inoperable y en progresión. La actividad final administrada fue de 800 mCi, 600 mCi, 400 mCi y 200 mCi en 4, 7, 1 y 1 pacientes, respectivamente. La tasa de control de enfermedad a 6 y 12 meses fue de 69,2% y 45,5%, respectivamente, logrando únicamente enfermedad estable. Fallecieron 7 pacientes, 2 de ellos en los primeros 6 meses. La mediana de supervivencia global a partir de la última dosis del radiopéptido fue de 15,7 meses. Conclusiones: Se corroboró la eficacia y la seguridad del tratamiento con los radiopéptidos en NETs avanzados.

Abstract Objectives: The National Cancer Institute first elaborated 177Lu-DOTATATE/TOC in 2009. The purpose of this study was to prove the efficacy of these radiopeptides in the palliative treatment of patients with progressive advanced inoperable neuroendocrine tumors (NETs). Methods: A single-phase phase II open clinical trial was conducted in 13 adult patients with grade 1 y 2 NETs, with expression of somatostatin receptors in target lesions proven by Krenning Score 3 or 4 uptake in 99mTc-HYNIC TOC. Patients were treated with 177Lu-DOTATATE or 177Lu-DOTATOC (depending upon availability) at a projected acumulative activitiy of 600-800 mCi divided into 3-4 doses every 6-9 weeks always beginning with a fixed activity of 200 mCi and dosimetry during the first dose. The primary outcome was objective response to therapy. Results: 13 patients (7 women) aged 63 ± 11.6 years with inoperable advanced NETs were included. The final therapeutic administered activity was 800 mCi, 600 mCi, 400 mCi and 200 mCi in 4, 7, 1 and 1 patients, respectively. The disease control rate at 6 and 12 months was 69.2% and 45.5%, respectively, only obtaining stable disease. Six patients died, 2 of them in the first 6 months. Median overall survival was 15.7 months from the last treatment dose. Conclusions: The efficacy of the treatment with 177Lu-DOTATATE or 177Lu-DOTATOC radiopeptides elaborated in-house was confirmed, becoming a management alternative for patients with advanced NETs.

Preparation and preliminary biological evaluation of 177Lu-NOTATATE / 中华核医学与分子影像杂志

Objective:To explore the optimal labeling conditions of 177Lu-1, 4, 7-triazacyclononane-1, 4, 7-triacetic acid (NOTA)- D-Phe1-Tyr3-Thr8-octreotide (TATE), and evaluate its biodistribution and imaging characteristics in mice. Methods:The reaction temperature, pH, reaction time and other labeling conditions were changed to realize the rapid labeling of NOTATATE by 177Lu. The optimal labeling conditions, radiochemical purity, in vitro stability, plasma protein binding rate, and lipid-water partition coefficient were determined. Twenty-four normal KM mice were divided into 6 groups by random number table method. After injected with 3.7 MBq 177Lu-NOTATATE through tail vein, they were sacrificed at 0.5, 1, 4, 24 h and 4, 6 d respectively to research the biological distribution (injection dose rate per gram of tissue percentage, %ID/g). Six normal mice were randomly divided into 2 groups and injected with 11.1 MBq 177Lu-NOTATATE and 177Lu-1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid (DOTA)TATE, respectively. SPECT planar imaging was performed at 1, 2, 3 h after injection. Another 8 mice were divided into 4 groups, injected with 3.7, 7.4, 18.5 MBq 177Lu-NOTATATE and saline respectively for an acute toxicity test. Results:At pH 5 and reaction temperature between 95 ℃ and 100 ℃ for 15 min, the labeling rate could reach more than 98%. After being placed in human serum for 24 h, the radiochemical purity was still higher than 95%. The plasma protein binding rate of 177Lu-NOTATATE was (58.6±1.9)% and the lipid-water partition coefficient was 0.048±0.014. In normal mice, the concentration of radioactivity is mainly in the liver, kidney and spleen, especially in the kidney (up to (29.120±1.204) %ID/g after 0.5 h of injection), which is less distributed in the blood and excreted rapidly. Compared with 177Lu-DOTATATE, 177Lu-NOTATATE was excreted faster by the kidney. The toxicity study results revealed that no damage was observed in mice of each group, and no obvious damage or inflammatory changes were observed in organ tissue sections. Conclusions:The optimal labeling condition of 177Lu-NOTATATE were determined in this study. The physical, chemical, and biological properties of 177Lu-NOTATATE were proved to be good and safe, and it was excreted faster by the kidney than 177Lu-DOTATATE. The results of this study lay a foundation for further clinical transformation research.

Association between the expression of somatostatin receptors and pathological features, prognosis in hepatocellular carcinoma / 临床肝胆病杂志

Objective To investigate the expression of somatostatin receptors (SSTRs) in hepatocellular carcinoma (HCC) tissue and its association with clinicopathological features and prognosis of HCC.Methods HCC samples were collected from 80 patients who visited Third Hospital of PLA and Department of Hepatobiliary Surgery in The Second Affiliated Hospital of Dalian Medical University and who underwent hepatectomy from July 2012 to December 2014 and were diagnosed with HCC based on postoperative pathology (trial group).Another 80 patients who were suspected of liver disease and were not diagnosed with HCC by liver biopsy were enrolled as control group.RT-PCR and immunohistochemistry were used to measure the mRNA and protein expression of SSTR-2 and SSTR-3.The t-test was used for comparison of continuous data between groups,the chi-square test was used for comparison of categorical data between groups,the Kaplan-Meier method was used to analyze patients' survival,and the Cox regression analysis was used to investigate the influencing factors for the prognosis of HCC patients.Results The control group had significantly higher mRNA and protein expression of SSTR-2 and SSTR-3 than the trial group (t =6.456 and 8.128,x2 =7.992 and 9.157,all P ＜ 0.05).The univariate analysis showed that the mRNA expression of SSTR-2 and SSTR-3 was significantly correlated with tumor nodule (t =6.533 and 5.041,both P ＜ 0.05),degree of tumor differentiation (t =4.672 and 4.013,both P ＜ 0.05),depth of infiltration (t =6.735 and 7.019,both P ＜ 0.05),viral hepatitis (t =4.929 and 4.535,both P ＜ 0.05),alcoholic hepatitis (t =4.032 and 4.362,both P ＜ 0.05),and diabetes (t =4.372 and 6.293,both P ＜ 0.05),and the protein expression of SSTR-2 and SSTR-3 was significantly correlated with tumor nodule (x2 =25.223 and 15.399,both P ＜ 0.05),degree of tumor differentiation (x2 =7.535 and 10.944,both P ＜ 0.05),and depth of infiltration (x2 =22.520 and 9.968,both P ＜ 0.05).Compared with the group with positive expression of SSTR-2 and SSTR-3,the group with negative expression had significantly lower cumulative postoperative disease-free survival rate (P =0.015 and 0.004) and postoperative overall survival rate (P =0.009 and ＜ 0.001).The Cox model analysis showed that protein expression of SSTR-2 and SSTR-3,the number of tumor nodules,liver cirrhosis,and vein infiltration in HCC tissue were independent risk factors for overall survival after HCC surgery (P ＜ 0.05).Conclusion HCC patients have lower expression of SSTR-2 and SSTR-3 than non-HCC patients,and such low expression is closely associated with invasion/metastasis and poor prognosis of HCC.SSTRs may be the markers for the prognosis of HCC.

Somatostatin receptor scintigraphy of orbital inflammatory pseudotumor associated with systemic vasculitis / 中华核医学与分子影像杂志

Objective To explore the value of somatostatin receptor scintigraphy(SRS) in evaluating the immune activity of orbital inflammatory pseudotumor associated with systemic vasculitis.Methods Twenty-five patients with orbital inflammatory pseudotumor associated with systemic vasculitis (10 males,15 females,average age:(51.2± 14.2) years) underwent SRS.The uptake ratio (UR) of orbital inflammatory pseudotumor was obtained.(1) Patients were divided into group A (with immune activity) and group B (without immune activity) according to Birmingham vasculitis activity score (BVAS).The difference of UR between the 2 groups was compared by two-sample t test.The difference of UR before and after treatment in 12 patients was also compared.(2) Based on the results by BVAS,ROC curve was used to obtain the cut-off value of UR,as well as the diagnostic efficiency and Youden index.The consistency between SRS and BVAS was calculated.(3)Patients were divided into two groups according to the cut-off value of UR and the prognosis difference between them was compared by Fisher exact test.(4)The expression of SSTR2 and SSTR5 was observed by immunohistochemistry.Results (1) UR in group A was significantly higher than that in group B (2.09±0.44 vs 1.32±0.46,t =5.94,P＜0.01).After glucocorticoids treatment,the UR in group A reduced significantly (t=4.07,P＜0.01),but not in group B (t=1.76,P＞0.05).(2)ROC curve analysis identified UR cut-off value as 1.66,with the sensitivity of 87.5％,specificity of 95.7％,positive predictive value of 95.2％,negative predictive value of 88.0％,accuracy of 91.3％ and Youden index of 83.2％.The consistency between SRS and BVAS was strong (Kappa =0.840).(3) The prognosis was significantly different between patients with UR≥ 1.66 and UR＜1.66 (P＜0.05).(4) The immunohistochemical results revealed high expression of SSTR2 and SSTR5 in inflammatory cells in patients with immune activity.Conclusion SRS has potential value in evaluating the immune activity of orbital inflammatory pseudotumor associated with systemic vasculitis.

Pasireotide in tumor diagnosis and treatment by translational medicine / 国际肿瘤学杂志

The somatostatin analogue pasireotide is a new type of protein which is the first therapeutic agent targeted to the pituitary.Pasireotide can prevent adrenocorticotropic hormone release and inhibit the growth of tumor cells after coupling with somatostatin receptor of the target cell membranes.Pasireotide has a high binding affinity for most of somatostatin receptor (SSTR) subtypes and in particular for SSTR5.Pasireotide can paly an important role in the new round of new targets for individualized diagnosis and treatment of tumors through the studies of translational medicine.

The regulatory effect of ginsenoside Rg3 on expression of somatostatin receptor in lung carcinoma allografts in mice and its significance / 肿瘤

Objective: To investigate the inhibitory effects of ginsenoside Rg3 on the growth and metastasis of lung carcinoma allografts in mice, and to explore the possible mechanism. Methods: The mice bearing a metastatic variant of Lewis lung carcinoma were established, and then they were randomized to receive 0.9% sodium chloride solution (as a control), DDP (cisplatin), and ginsenoside Rg3 from the fourth day after transplant, respectively. Until the twenty-fourth day after transplant, the mice were sacrificed. The subcutaneous tumor was dissected, and the lung was removed. The inhibitory rate of tumor growth and the number of metastatic foci on the lung surface were counted. The expressions of SSTR (somatostatin receptor), VEGF (vascular endothelial growth factor) and PCNA (proliferation cell nuclear antigen) in subcutaneous tumor were examined by immunohistochemistry. The apoptosis was detected by TUNEL (terminal transferase-mediated dUTP nick end-labeling) method. Results: The inhibitory rates of tumor growth in DDP-treated group and the ginsenoside Rg3-treated group were 39.20% and 54.86%, respectively (P < 0.01). The numbers of metastatic foci on the lung surface in DDP-treated group and the ginsenoside Rg3-treated group were decreased by 30.25% and 58.57%, respectively (P < 0.05). The expression level of SSTR and the apoptosis index in the ginsenoside Rg3- treated group were higher than those in the control group and the DDP-treated group (P < 0.01), while the expression level of VEGF and the proliferation index of PCNA in the ginsenoside Rg3-treated group were decreased as compared with the control group and the DDP-treated group (P < 0.01, P < 0.05). Conclusion: Ginsenoside Rg3 can inhibit the growth and metastasis of lung carcinoma allografts in mice. The mechanism may be associated with the overexpression of SSTR. Copyright © 2012 by TUMOR.

Role of (68)Ga-DOTATOC PET/CT in the Evaluation of Primary Pulmonary Carcinoids

BACKGROUND/AIMS: Although carcinoid tumors usually have good prognosis, early and specific diagnosis is important. Computed tomography and magnetic resonance imaging do not provide findings that are specific for carcinoids, and somatostatin receptor scintigraphy suffers from low spatial resolution. 18-Fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) has limited sensitivity for carcinoids due to low uptake of the marker. A PET/CT system that uses the somatostatin receptor-based PET tracer 1,4,7,10-tetraazacyclododecane-N(I),N(II),N(III),N(IIII)-tetraacetic acid (D)-Phe(1)-thy(3)-octreotide ((68)Ga-DOTATOC) has also been used in the evaluation of carcinoids, although information regarding its use for the detection of primary pulmonary carcinoids is limited. Thus, we investigated the value of (68)Ga-DOTATOC PET/CT for the diagnosis of primary pulmonary carcinoid tumors. METHODS: This was a retrospective analysis of patients with primary pulmonary tumors who underwent (68)Ga-DOTATOC PET/CT. All the patients had a histopathologic diagnosis of carcinoid. The rate of detection of primary pulmonary carcinoid tumors using (68)Ga-DOTATOC PET/CT was assessed. RESULTS: Twenty patients were diagnosed as having carcinoid, and 19 tumors showed significant uptake on (68)Ga-DOTATOC (detection rate, 95%). The maximal standardized uptake value (SUV(max)) ranged from 1.1 to 66, with a median value of 21.6. In one patient, (68)Ga-DOTATOC PET/CT revealed additional lesions. CONCLUSIONS: Our results demonstrate that (68)Ga-DOTATOC PET/CT is useful in the evaluation of primary pulmonary carcinoids and should be included in the diagnostic work-up of these patients.

In vitro distribution and receptor scintigraphy of somatostatin receptor 2 subtypes in small cell lung cancer / 肿瘤

Objective: To investigate the distribution of somatostatin receptor 2 subtype (SSTR2) in small cell lung cancer (SCLC) in vitro and the value of 99mTc-octreotide scintigraphy for SCLC diagnosis in vivo. Methods: The distribution of SSTR2 was detected by electron microscopic autoradiography (EMR) using 125I octreotide. 99mTc-octreotide (0.15 mL, 16.8 MBq) was injected into nude mice via tail veins and 99mTc-octreotide scintigraphy was observed. Results: The tagged rates of cellular sliver grains were 95.0% (19/20) and 85.0% (16/20) at 30 min and 120 min, respectively. The difference was significant (P < 0.05). Sliver grains were distributed in the membranes at 30 min and located in the nucleolus and cytoplasm at 120 min. The numbers of sliver grains in the control group (addition of over Tyr 3-octreotide) were remarkably less than those of group 30 min and 120 min. The scintigraphy of the tumors in 5 nude mice was positively displayed at 4 h postinjection of 99mTc octreotide. Conclusions: SSTR2 is over-expressed in SCLC. Radiolabeled octreotide scintigraphy may become a novel detection method for early diagnosis of SCLC.

Effects of hSSTR2 gene in vitro transfection on differential proteins expression in pancreatic cancer cell line Panc-1 / 中华胰腺病杂志

Objective To study the effects of hSSTR2 gene in vitro transfection on differential proteins expression in pancreatic cancer cell line Panc-1 and search new sensitive therapeutic targets of pancreatic cancer. Methods The full length hSSTR2 cDNA was introduced into pancreatic cancer cell line Panc-1 by adenovirus vector ( Ad. CMV. hSSTR2. GFP) mediated transfection. The differential expressed proteins between the hSSTR2 transfection group, vector control and mock control were isolated and screened by 2D-DIGE analysis. Protein identification was performed by peptide mass finger printing with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF/TOF). Results The hSSTR2 gene was transfected into Panc-1 pancreatic cancer cells in vitro successfully, and fluorescence difference protein expression patterns were established between hSSTR2 negative and positive expression of Panc-1 cell. Analysis by DeCyder v6.5 software showed a total of 18 protein spots ( > 1.3-fold) and these protein spots were identified by mass spectrometry as 13 proteins. Proteins with lower abundance levels included GMP synthase, stress induced phosphoprotein 1, glutamate dehydrogenase 1, Septin-11, vimentin, Isocitrate dehydrogenase [NAD] subunit alpha, Import inner membrane translocase subunit TIM50. Proteins with high abundance levels included Elongation factor 1-alpha-1, Isoform M2 of Pyruvate kinase isozymes M1/M2, Enoyl-CoA hydratase,tripartite motif-containing 28 protein, Mitofilin, HSP105. Conclusions The proteins expression changed after hSSTR2 gene in vitro transfection in Panc-1 cells, and the function of difference proteins involved the process of metabolism of sugar, fat and nucleic acid, and the regulation of cell growth. The present study paved the way for searching new sensitive therapeutic targets of pancreatic cancer.

Preparation of magnetic resonance molecular probe for breast cancer detection in vitro / 北京大学学报(医学版)

0.05).There was remarkable low signal intensity on T2-weighed imaging and no evident artifacts for molecular probe when the concentration of Fe2+ was 20 mg/L.The least number of labeled cells detected by MR in vitro was 6?106 when the concentration of Fe2+ was 20 mg/L.Conclusion:Molecular probe,SPIO-OCT,can effectively label breast cells which express SSTR.The reasonable Fe2+ concentration of labeled cells and imaging was 20 mg/L.There is a correlation between MR signal intensity in vitro and the number of labeled cells.

Adenoviral-mediated somatostatin receptor subtype 2 gene transfer inhibits pancreatic cancer xenografts / 中国实用内科杂志

Objective To construct recombinant adenovirus carrying the gene of human somatostatin receptor subtype 2(SSTR2),to investigate its effect on growth of human pancreatic cancer xenografts in nude mice,and to further elucidate the underlying mechanisms.Methods The recombinant adenovirus coding for human SSTR2(Ad-SSTR2)and reporter gene LacZ(Ad-LacZ)were generated by site-specific recombination from Jun 1,2004 to Dec 10,2005.Human pancreatic cancer cell line was implanted subcutaneously into nude mice;normal saline(control group),Ad-LacZ(reporter gene control group)and Ad-SSTR2(experimental group)were injected into pancreatic cancer xenografts,respectively.The tumor volume and weight were measured.RTPCR and Western blot were used to determine the expression of SSTR2 after pancreatic cancer xenografts were infected with Ad-SSTR2.The expression level of ERK2 and ras proteins were assessed by Western blot.Results The virus titer of Ad-SSTR2 and Ad-LacZ was 6.0?1012pfu/L and 6.5?1012pfu/L,respectively.SSTR2 mRNA and protein were detected after Ad-SSTR2 infected pancreatic cancer xenografts.Growth of pancreatic cancer was significantly inhibited in the experimental group as compared with the control group.The growth inhibitory rate was 48.2%(P

Construction and expression of recombinant adenovirus vector encoding human somatostatin receptor type 2 / 中国病理生理杂志

AIM: To construct recombinant adenovirus vector carrying the gene of human somatostatin receptor type 2(SSTR2) for gene therapy of pancreatic carcinoma.METHODS: SSTR2 cDNA was inserted into adenovirus shuttle plasmid pDC316,named pDC316-SSTR2.pDC316-SSTR2 was cotransfected with rescue plasmid pBHGlox(delta) E1,3Cre into 293 cells by liposome reagent.Ad-SSTR2 was generated by site-specific recombination and confirmed by PCR.Ad-SSTR2 was propagated in 293 cells and purified.The titer of viral stock was determined by end-point dilution assay.Western blotting was used to determine the expression of SSTR2 protein after human pancreatic carcinoma cell capan-2 was infected with recombinant adenovirus.RESULTS: pDC316-SSTR2 was successfully constructed.Recombinant adenovirus Ad-SSTR2 was acquired by pDC316-SSTR2 and pBHGlox(delta) E1,3Cre cotransfected into 293 cells.Ad-SSTR2 was characterized by PCR.The virus titer was 6.0?10~(12) pfu/L.SSTR2 protein was detected after adenovirus infected capan-2 48 h with Western blotting.CONCLUSION: The recombinant adenovirus vector encoding human SSTR2 is successfully constructed and correctly expressed in pancreatic carcinoma cells.This investigation provides the basis for study of gene therapy of pancreatic carcinoma.