Somatostatin Receptor Expression Research Articles

Nanotechnology-Based Strategy for Enhancing Therapeutic Efficacy in Pancreatic Cancer: Receptor-Targeted Drug Delivery by Somatostatin Analog

A novel nanotechnology-based drug delivery system (DDS) targeted at pancreatic cancer cells was developed, characterized, and tested. The system consisted of liposomes as carriers, an anticancer drug (paclitaxel) as a chemotherapeutic agent, and a modified synthetic somatostatin analog, 5-pentacarbonyl-octreotide, a ligand for somatostatin receptor 2 (SSTR2), as a targeting moiety for pancreatic cancer. The cellular internalization, cytotoxicity, and antitumor activity of the DDS were tested in vitro using human pancreatic ductal adenocarcinoma (PDAC) cells with different expressions of the targeted SSTR2 receptors, and in vivo on immunodeficient mice bearing human PDAC xenografts. The targeted drug delivery system containing paclitaxel exhibited significantly enhanced cytotoxicity compared to non-targeted DDS, and this efficacy was directly related to the levels of SSTR2 expression. It was found that octreotide-targeted DDS proved exceptionally effective in suppressing the growth of PDAC tumors. This study underscores the potential of octreotide-targeted liposomal delivery systems to enhance the therapeutic outcomes for PDAC compared with non-targeted liposomal DDS and Paclitaxel-Cremophor® EL, suggesting a promising avenue for future cancer therapy innovations.

Defining the optimal segmentation method for measuring somatostatin receptor expressing tumor volume on 68Ga-DOTATATE positron emission tomography/computed tomography to predict prognosis in patients with gastroenteropancreatic neuroendocrine tumors.

We aimed to compare different segmentation methods used to calculate prognostically valuable volumetric parameters, somatostatin receptor expressing tumor volume (SRETV), and total lesion somatostatin receptor expression (TLSRE), measured by 68Ga-DOTATATE PET/CT and to find the optimal segmentation method to predict prognosis. Images of 34 patients diagnosed with gastroenteropancreatic neuroendocrine tumor (GEPNET) who underwent 68Ga-DOTATATE PET/CT imaging were reanalyzed. Four different threshold-based methods (fixed relative threshold method, normal liver background threshold method, fixed absolute standardized uptake value (SUV) threshold method, and adaptive threshold method) were used to calculate SRETV and TLSRE values. SRETV of all lesions of a patient was summarized as whole body SRETV (WB-SRETV) and TLSRE of all lesions of a patient was computed as whole body TLSRE (WB-TLSRE). WB-SRETVs calculated with all segmentation methods were statistically significantly associated with progression-free survival except WB-SRETVat which was calculated using adaptive threshold method. The fixed relative threshold methods calculated by using 45% (WB-SRETV45%) and 60% (WB-SRETV60%) of the SUV value as threshold respectively, were found to have statistically significant highest prognostic value (C-index = 0.704, CI = 0.622-0.786, P = 0.007). Among WB-TLSRE parameters, WB-TLSRE35%, WB-TLSRE40%, and WB-TLSRE50% had the highest prognostic value (C-index = 0.689, CI = 0.604-0.774, P = 0.008). The fixed relative threshold method was found to be the most effective and easily applicable method to measure SRETV on pretreatment 68Ga-DOTATATE PET/CT to predict prognosis in GEPNET patients. WB-SRETV45% (cutoff value of 11.8 cm3) and WB-SRETV60% (cutoff value of 6.3 cm3) were found to be the strongest predictors of prognosis in GEPNET patients.

68Ga]DOTATOC PET-derived radiomics to predict genetic background of head and neck paragangliomas: a pilot investigation.

To investigate the [68Ga]DOTATOC PET radiomic profile of head and neck paragangliomas (HNPGLs) and identify radiomic characteristics useful as predictors of succinate dehydrogenase genes (SDHx) pathogenic variants. Sporadic and SDHx HNPGL patients, who underwent [68Ga]DOTATOC PET/CT, were retrospectively included. HNPGLs were analyzed using LIFEx software, and extracted features were harmonized to correct for batch effects and confronted testing for multiple comparison. Stepwise discriminant analysis was conducted to remove redundancy and identify best discriminating features. ROC analysis was used to define optimal cut-offs. Multivariate decision-tree analysis was performed using CHAID method. 34 patients harboring 60 HNPGLs (51 SDHx in 25 patients) were included. Three sporadic and nine SDHx HNPGLs were metastatic. At stepwise discriminant analysis, both GLSZM-Zone Size Non-Uniformity (ZSNU, reflecting tumor heterogeneity) and IB-TLSRE (total lesion somatostatin receptor expression) were independent predictors of genetic status, with 96.4% of lesions and 91.6% of patients correctly classified after cross validation (p < 0.001). Among non-metastatic patients, GLSZM-ZSNU and IB-TLSRE were significantly higher in sporadic than SDHx HNPGLs (p < 0.001). No differences were revealed in metastatic patients. Decision-tree analysis highlights multifocality and IB-TLSRE as useful variables, correctly identifying 6/9 sporadic and 24/25 SDHx patients. Model failed to classify one SDHA and three sporadic patients (2 metastatic). Radiomics features GLSZM-ZSNU and IB-TLSRE appear to reflect HNPGLs SDHx status and tumor behavior (metastatic vs. non-metastatic). If validated, especially IB-TLSRE might represent a simple and time-efficient radiomic index for SDHx variants early screening and prediction of tumor behavior in HNPGL cases.

CPEB2 inhibits preeclampsia progression by regulating SSTR3 translation through polyadenylation

AimsTrophoblast cell dysfunction is one of the important factors leading to preeclampsia (PE). Cytoplasmic polyadenylation element-binding 2 (CPEB2) has been found to be differentially expressed in PE patients, but whether it mediates PE process by regulating trophoblast cell function is unclear. MethodsThe expression of CPEB2 and somatostatin receptor 3 (SSTR3) was detected by quantitative real-time PCR, Western blot (WB) and immunofluorescence staining. Cell functions were analyzed by CCK-8 assay, EdU assay, flow cytometry and transwell assay. Epithelial-mesenchymal transition (EMT)-related protein levels were detected by WB. The interaction of CPEB2 and SSTR3 was confirmed by RIP assay, dual-luciferase reporter assay and PCR poly(A) tail assay. Animal experiments were performed to explore the effect of CPEB2 on PE progression in vivo, and the placental tissues of rat were used for H&E staining, immunohistochemical staining and TUNEL staining. ResultsCPEB2 was lowly expressed in PE patients. CPEB2 upregulation accelerated trophoblast cell proliferation, migration, invasion and EMT, while its knockdown had an opposite effect. CPEB2 bound to the CPE site in the 3′-UTR of SSTR3 mRNA to suppress SSTR3 translation through reducing poly(A) tails. Besides, SSTR3 overexpression suppressed trophoblast cell proliferation, migration, invasion and EMT, while its silencing accelerated trophoblast cell functions. However, these effects could be reversed by CPEB2 upregulation and knockdown, respectively. In vivo experiments, CPEB2 overexpression relieved histopathologic changes, inhibited apoptosis, promoted proliferation and enhanced EMT in the placenta of PE rat by decreasing SSTR3 expression. ConclusionCPEB2 inhibited PE progression, which promoted trophoblast cell functions by inhibiting SSTR3 translation through polyadenylation.

Correlation between tumor invasion and somatostatin receptor subtypes in acromegaly.

The low expression of somatostatin receptor (SSTR) subtypes in somatotropinoma is associated with a poor response to somatostatin analogs (SSAs). However, the correlation between SSTRs and tumor invasion has not yet been clarified. Therefore, the authors aimed to investigate the relationship between SSTRs and tumor invasion, as well as the correlation between tumor invasiveness and pharmacological response to SSAs. A total of 102 patients with acromegaly who underwent surgery between December 2016 and December 2021 at the largest pituitary tumor surgery center in southern China were included in this retrospective study. Patients were divided into the noninvasive tumor group (Knosp grades 0-2 and Hardy-Wilson grade I or II) and invasive group (either Knosp grade 3 or 4 or Hardy-Wilson grade III or IV). The positive response to SSAs was defined by the following criteria after at least 3 months of SSA treatment: 1) ≥ 50% reduction or age- and sex-adjusted normal range of insulin-like growth factor-1 (IGF-1) level; 2) ≥ 80% reduction in or normal range of growth hormone (GH) level; or 3) > 20% reduction in tumor volume. The reference for the normal range of age- and sex-adjusted serum IGF-1 levels was derived from a survey of 2791 healthy adults (1339 males and 1452 females) in China. Demographics and clinical characteristics including tumor size, biochemical assessment, expression levels of SSTRs, and response to preoperative SSAs were compared between the invasive group and noninvasive group. Receiver operating characteristic (ROC) curve analysis was performed to assess the association between SSTR2 and tumor invasion. Compared with the noninvasive group, the invasive group presented with a larger tumor size (9.99 ± 10.41 cm3 vs 3.50 ± 4.02 cm3, p < 0.001), relatively lower SSTR2 expression (p < 0.001), and poorer response to SSAs (36.4% vs 91.7%, p < 0.001). In addition, there was a significant negative correlation between SSTR2 mRNA level and tumor size (r = -0.214, p = 0.031). However, there were no statistically significant differences in the expression of SSTR1, SSTR3, and SSTR5 between the groups. ROC analysis revealed that the low SSTR2 mRNA level was closely associated with tumor invasion (area under the curve 0.805, p < 0.0001). Tumor invasion is negatively correlated with SSTR2 level but is not associated with other SSTR subtypes. Patients with invasive tumors have a poorer response to SSA therapy, which may be due to the low level of SSTR2 expression. Therefore, SSTR2 could be considered as a routine investigative marker for aiding management of postoperative residual tumors.

Efficacy and Safety of 225 Ac-DOTATATE in the Treatment of Neuroendocrine Neoplasms With High SSTR Expression.

We aimed to evaluate the efficacy and safety of 225 Ac-DOTATATE targeted α therapy (TAT) in various neuroendocrine neoplasms (NENs) with high somatostatin receptor (SSTR) expression. This single-center prospective study included 10 patients with histologically diagnosed NENs that exhibited increased SSTR expression on 68 Ga-DOTATATE PET/CT imaging. All patients received 225 Ac-DOTATATE TAT. The primary end points were molecular imaging-based response and disease control rate (DCR), measured using the slightly modified Positron Emission Tomography Response Criteria in Solid Tumors 1.0. The secondary end points were adverse event profiles and clinical responses. The adverse event profile was determined according to the Common Terminology Criteria for Adverse Events version 5.0. Clinical response was assessed using the EORTC QLQ-C30 v3.0 (European Organization for Research and Treatment of Cancer Core Quality of Life questionnaire version 3.0). A molecular imaging-based partial response was observed in 40% of all patients, SD in 40%, PD in 20%, and DCR in 80%. The DCR was 83.3% (5/6) in patients who were previously treated with 177 Lu-DOTATATE. According to the EORTC QLQ-C30 v3.0 score, most symptoms improved after 225 Ac-DOTATATE treatment, with only diarrhea showing no improvement. Grade III/IV hematological, kidney, and liver toxicities were not observed. The median follow-up time was 14 months (7-22 months), and no deaths were reported. This initial study suggests that 225 Ac-DOTATATE is a potentially promising option for treating NENs with elevated SSTR expression, with an acceptable toxicity profile and well-tolerated adverse effects.

177 Lu-DOTATATE Salvage Therapy in Rapidly Progressing Neuroendocrine Tumor With Poor Performance Status.

Peptide receptor radionuclide therapy (PRRT) has shown to be effective and safe in metastatic gastroenteropancreatic and nongastroenteropancreatic neuroendocrine tumors. However, the selection criteria for PRRT are restricted to patients with good performance status (Eastern Cooperative Oncology Group score ≤2 or Karnofsky performance score ≥60). This denies many patients with adequate somatostatin receptor expression and biochemical profiles from the beneficial effects of PRRT on the quality of life, daily function, and overall survival. The 2 cases highlight the favorable response of PRRT in patients with metastatic neuroendocrine tumor having a very poor performance status initially.

Low-dose targeted radionuclide therapy synergizes with CAR T cells and enhances tumor response.

Ionizing radiation has garnered considerable attention as a combination partner for immunotherapy due to its potential immunostimulatory effects. In contrast to the more commonly used external beam radiation, we explored the feasibility of combining chimeric antigen receptor (CAR) T cell therapy with targeted radionuclide therapy (TRT), which is achieved by delivering β-emitting 177Lu-DOTATATE to tumor via tumor-infiltrating CAR T cells that express somatostatin receptor 2 (SSTR2). We hypothesized that the delivery of radiation to tumors could synergize with CAR T therapy, resulting in enhanced antitumor immunity and tumor response. To determine the optimal dosage and timing of 177Lu-DOTATATE treatment, we measured CAR T cell infiltration and expansion in tumors longitudinally through positron emission tomography (PET) using a SSTR2-specific positron-emitting radiotracer,18F-NOTA-Octreotide. In animals receiving CAR T cells and a low-dose (2.5 Gy) of TRT following the administration of 177Lu-DOTATATE, we observed a rapid regression of large subcutaneous tumors, which coincided with a dramatic increase in serum proinflammatory cytokines. Tumor burden was also reduced when a higher radiation dose (6 Gy) was delivered to the tumor. However, this higher dose led to cell death in both the tumor and CAR T cells. Our study suggests that there may exist an optimum range of TRT dosage that can enhance T cell activity and sensitize tumor cells to T cell killing, which may result in more durable tumor control compared to a higher radiation dose.

Identification of Wandering Masses and Tumor Heterogeneity on68Ga-DOTATATE and18F-FDG PET/CT in Metastatic Grade II Neuroendocrine Tumor with Increased Somatostatin Receptor Expression After Combined Chemotherapy and PRRT

Identification of Wandering Masses and Tumor Heterogeneity on⁶⁸Ga-DOTATATE and¹⁸F-FDG PET/CT in Metastatic Grade II Neuroendocrine Tumor with Increased Somatostatin Receptor Expression After Combined Chemotherapy and PRRT

Somatostatin receptor 2 (SSTR2) expression is associated with better clinical outcome and prognosis in rectal neuroendocrine tumors

Somatostatin analogues have recently been used as therapeutic targets for metastatic or surgically unresectable gastroenteropancreatic (GEP) neuroendocrine tumors (NETs), and associated somatostatin receptor (SSTR) expression has been well demonstrated in most GEP NETs, with the exception of rectal NETs. SSTR2 immunohistochemical expressions were evaluated in 350 surgically or endoscopically resected rectal NETs and compared to clinicopathologic factors. SSTR2 expression was observed in 234 (66.9%) rectal NET cases and associated tumors with smaller size (p = 0.001), low pT classification (p = 0.030), low AJCC tumor stage (p = 0.012), and absence of chromogranin expression (p = 0.009). Patients with rectal NET and SSTR2 expression had significantly better overall survival than those without SSTR2 expression both by univariable (p = 0.006) and multivariable (p = 0.014) analyses. In summary, approximately two-thirds of rectal NETs expressed SSTR2. SSTR2 expression was significantly associated with favorable behavior and good overall survival in patients with rectal NETs. Furthermore, SSTR2 expression can be used as prognostic factors. When metastatic disease occurs, SSTR2 expression can be used a possible target for somatostatin analogues.

Concomitant inhibition of PI3K/mTOR signaling pathways boosts antiproliferative effects of lanreotide in bronchopulmonary neuroendocrine tumor cells.

Introduction: Somatostatin analogues (SSAs) are commonly used in the treatment of hormone hypersecretion in neuroendocrine tumors (NETs), however the extent to which they inhibit proliferation is much discussed. Objective: We studied the antiproliferative effects of novel SSA lanreotide in bronchopulmonary NETs (BP-NETs). We focused on assessing whether pretreating cells with inhibitors for phosphatidylinositol 3-kinase (PI3K) and mammalian target for rapamycin (mTOR) could enhance the antiproliferative effects of lanreotide. Methods: BP-NET cell lines NCI-H720 and NCI-H727 were treated with PI3K inhibitor BYL719 (alpelisib), mTOR inhibitor everolimus and SSA lanreotide to determine the effect on NET differentiation markers, cell survival, proliferation and alterations in cancer-associated pathways. NT-3 cells, previously reported to express somatostatin receptors (SSTRs) natively, were used as control for SSTR expression. Results: SSTR2 was upregulated in NCI-H720 and NT-3 cells upon treatment with BYL719. Additionally, combination treatment consisting of BYL719 and everolimus plus lanreotide tested in NCI-H720 and NCI-H727 led to diminished cell proliferation in a dose-dependent manner. Production of proteins activating cell death mechanisms was also induced. Notably, a multiplexed gene expression analysis performed on NCI-H720 revealed that BYL719 plus lanreotide had a stronger effect on the downregulation of mitogens than lanreotide alone. Discussion/Conclusion: We report a widespread analysis of changes in BP-NET cell lines at the genetic/protein expression level in response to combination of lanreotide with pretreatment consisting of BYL719 and everolimus. Interestingly, SSTR expression reinduction could be exploited in therapeutic and diagnostic applications. The overall results of this study support the evaluation of combination-based therapies using lanreotide in preclinical studies to further increase its antiproliferative effect and ultimately facilitate its use in high-grade tumors.

Somatostatin receptor subtype 2A expression and genetics in 184 paragangliomas: a single center retrospective observational study.

Adrenal and extra-adrenal paragangliomas (PGLs) are a group of neuroendocrine tumors (NETs) with strong heterogeneity, which often express somatostatin receptor subtype 2 A (SSTR2A). However, the association between SSTR2A expression and genetic status of PGLs remains unclear. The purpose of the study was to identify whether various pathogenic variants (PVs) had an impact on SSTR2A expression in PGLs. This retrospective study included 184 patients with pathologically confirmed PGLs. The immunohistochemical expression of SSTR2A were studied in 184 tumors and PVs were tested in 159 tumor samples. Clinical and genetic data were compared in SSTR2A positive and negative PGLs. SSTR2A was positive in 63.6% (117/184) of all tumors. PGLs with negative SSTR2A were more likely to be extra-adrenal (37.0% vs 18.0%; P = 0.005) and exhibited a considerably greater proportion of PVs (75.4% vs. 49.0%; P = 0.001) than those with positive SSTR2A. Compared to those without PVs, a higher proportion of PGLs with PVs in cluster 1B (P = 0.004) and cluster 2 (P = 0.004) genes, especially VHL (P = 0.009), FGFR1 (P = 0.010) and HRAS (P = 0.007), were SSTR2A negative. SSTR2A was positive in all tumors (4/4) with SDHx PVs and in 87.5% (7/8) of metastatic PGLs. SSTR2A negativity was correlated with extra-adrenal tumor location and PVs in cluster 1B and cluster 2 genes such as VHL, FGFR1 and HRAS. Immunohistochemistry of SSTR2A should be taken into consideration in the personalized management of PGLs.

Prognostic value of FDG, PSMA, and DOTATATE uptake on PET imaging in metastatic castration-resistant prostate cancer (mCRPC).

31 Background: In mCRPC, fluorodeoxyglucose (FDG) and prostate-specific membrane antigen (PSMA) PET/CT are often used in combination for selecting patients for PSMA-radioligand therapy (PSMA-RLT). Few studies have specifically assessed the prognostic value of FDG+/PSMA- lesions, which exclude patients from PSMA-RLT. Also, little is known about the significance of somatostatin receptor expression, a potential biomarker of neuroendocrine differentiation of mCRPC, which can be assessed with DOTATATE-PET/CT. 3TMPO is a prospective study in progressing mCRPC patients who were imaged with up to 3 PET tracers. Here, we report on patient’s overall survival (OS), with respect to the presence of FDG+/PSMA- and DOTATATE+ lesions. Methods: In 3TMPO (NCT04000776, protocol in PMID 34674367), all patients had 68Ga-PSMA-617 and 18F-FDG PET/CT scans. A 68Ga-DOTATATE scan was ordered if an FDG+/PSMA- lesion was found. For all tracers, positivity was defined as lesion SUVpeak being 1.5x higher than liver SUVmean. Kaplan-Meier with log-rank test was used to assess the difference in OS between groups. Cox regression model was used to quantify the effect of factors predictive of OS. Results: The median [95% CI] OS of the 98 enrolled patients was 10.2 [8.5-11.8] mo. At least one FDG+/PSMA- lesion was found in 45 (45.9%) patients and their OS was shorter than that of the others: 5.6 [4.3-6.9] vs. not reached (p=0.0001). Six (16.2%) of 37 patients who underwent 68Ga-DOTATATE-PET had ≥1 DOTATATE+ lesion and their OS was shorter than that of patients without a DOTATATE+ lesion: 3.0 [2.2-3.7] vs. 6.4 [1.6-11.1] mo. (p=0.0004). Characteristics significantly associated with worse OS were ECOG, ISUP grade, number of metastases, number of lines of therapy, presence of visceral metastases, FDG and PSMA molecular tumor volumes (MTV) (p&lt;0.05). In a multivariate analysis adjusted for the number of metastases and of treatment lines, the presence of an FDG+/PSMA- lesion increased the risk of death (HR [95% CI]=2.4 [1.4-4.3], p=0.002), and this was also significant after adjusting for both PSMA and FDG-MTV (HR [95% CI]=2.9 [1.4-5.8], p=0.003). Conclusions: mCRPC patients harboring FDG+/PSMA- lesion(s) had a shorter OS than those who did not, and their prognosis was even poorer if they also had DOTATATE+ lesion(s). Upfront FDG/PSMA-PET followed by DOTATATE-PET might help clinicians to guide patient towards palliative care vs. further systemic therapy, including PSMA-RLT. Clinical trial information: NCT04000776 .

Somatostatin receptors and the associated intracellular machinery: the two sides of the coin.

Somatostatin receptors (SSTs) are widely expressed in pituitary tumors and neuroendocrine neoplasms (NENs) of different origins, i.e. the gastrointestinal tract and the thorax (lungs and thymus), thus representing a well-established target for medical treatment with SST ligands (SRLs). However, the response to SRLs is highly heterogeneous between tumors. Two main factors can contribute to this variability: (i) the differential SST expression among tumor types and (ii) the differential expression/modulation of the SST-related intracellular machinery. In this literature review, we provide an overview of available data on the variable expression of SSTs in pituitary tumors and NENs, together with the resulting clinical implications. Moreover, we aim to describe the complex intracellular machinery involved in SST signaling and trafficking. Particularly, we will focus on β-arrestins and describe their role in receptor internalization and recycling, as well as the various functions of these scaffold molecules in tumor pathogenesis and progression. This review highlights the interplay between membrane receptors and intracellular machinery, together with its role in determining the clinical behavior of the tumor and the response to treatment in patients with pituitary tumors or NENs.

Efficacy and tolerability of somatostatin analogues according to gender in patients with neuroendocrine tumors.

As the incidence of neuroendocrine tumors has been rising, gender differences in epidemiology and clinical behavior have emerged, and interest into a gender-driven management of these tumors has grown with the aim to improve survival and quality of life of these patients. Somatostatin Analogues represent the first line of systemic treatment of both functional and non-functional neuroendocrine tumors, through the expression of somatostatin receptors (SSTRs) in the tumor cells, and proved effective in controlling hormonal hypersecretion and inhibiting tumor growth, improving progression-free survival and overall survival of these patients. Aim of the present review is to investigate any differences by gender in efficacy and safety of SSTS-targeted therapies, that represent the mainstay treatment of neuroendocrine tumors, as they emerge from studies of varying design and intent. Although preclinical studies have provided evidence in favor of differences by gender in tumor expression of SSTR, as well as of the role of sex hormones and related receptors in modulating SSTRs expression and function, the clinical studies conducted so far have not shown substantial differences between males and females in either efficacy or toxicity of SSTR-targeted therapies, even if with sometimes inconsistent results. Moreover, in most studies gender was not a predictor of response to treatment. Studies specifically designed to address this issue are needed to develop gender-specific therapeutic algorithms, improving patients' prognosis and quality of life.

Changes in tumor-to-blood ratio as a prognostic marker for progression-free survival and overall survival in neuroendocrine tumor patients undergoing PRRT

BackgroundHistorically, patient selection for peptide receptor radionuclide therapy (PRRT) has been performed by virtue of somatostatin receptor scintigraphy (SRS). In recent years, somatostatin receptor positron emission tomography (SSTR-PET) has gradually replaced SRS because of its improved diagnostic capacity, creating an unmet need for SSTR-PET-based selection criteria for PRRT. Tumor-to-blood ratio (TBR) measurements have shown high correlation with the net influx rate Ki, reflecting the tumor somatostatin receptor expression, to a higher degree than standardized uptake value (SUV) measurements. TBR may therefore predict treatment response to PRRT. In addition, changes in semiquantitative SSTR-PET parameters have been shown to predate morphological changes, making them a suitable metric for response assessment.MethodsThe institutional database of the Department of Nuclear Medicine (University Hospital Essen) was searched for NET patients undergoing ≥ 2 PRRT cycles with available baseline and follow-up SSTR-PET. Two blinded independent readers reported the occurrence of new lesions quantified tumor uptake of up to nine lesions per patient using SUV and TBR. The association between baseline TBR and changes in uptake/occurrence of new lesions with progression-free survival (PFS) and overall survival (OS) was tested by use of a Cox regression model and log-rank test.ResultsPatients with baseline TBR in the 1st quartile had a shorter PFS (14.4 months) than those in the 3rd (23.7 months; p = 0.03) and 4th (24.1 months; p = 0.02) quartile. Similarly, these patients had significantly shorter OS (32.5 months) than those with baseline TBR in the 2nd (41.8 months; p = 0.03), 3rd (69.2 months; p < 0.01), and 4th (42.7 months; p = 0.03) quartile. Baseline to follow-up increases in TBR were independently associated with shorter PFS when accounting for prognostic markers, e.g., RECIST response (hazard ratio = 2.91 [95%CI = 1.54–5.50]; p = 0.01). This was confirmed with regard to OS (hazard ratio = 1.64 [95%CI = 1.03–2.62]; p = 0.04). Changes in SUVmean were not associated with PFS or OS.ConclusionsBaseline TBR as well as changes in TBR were significantly associated with PFS and OS and may improve patient selection and morphological response assessment. Future trials need to assess the role of TBR for therapy monitoring also during PRRT and prospectively explore TBR as a predictive marker for patient selection.

Impact of the PI3K-alpha inhibitor alpelisib on everolimus resistance and somatostatin receptor expression in an orthotopic pancreatic NEC xenograft mouse model.

The mechanistic target of rapamycin complex 1 (mTORC1) inhibitor everolimus is one of the few approved therapies for locally advanced and metastatic neuroendocrine tumours (NETs). However, after initial disease stabilisation, most patients develop resistance within 1 year. Our aim was to overcome resistance to everolimus by additional treatment with the PI3K-alpha inhibitor alpelisib in an everolimus-resistant orthotopic pancreatic neuroendocrine carcinoma xenograft mouse model. Female SCID mice underwent laparoscopic pancreatic transplantation of everolimus-sensitive (BON1KDMSO) or everolimus-resistant (BON1RR2) NET cells. Both groups were further divided into four treatment groups: placebo, everolimus, alpelisib, and everolimus + alpelisib (combination). Oral treatment was started at a tumour volume of approximately 140 mm3 and continued until 1900-2000 mm3, validated by weekly MRI. Somatostatin receptor expression and tumour viability were analysed by 68Ga-DOTATOC and 18F-FDG PET/CT. Everolimus resistance of the BON1RR2 tumours was confirmed. In the everolimus-sensitive group, everolimus alone, alpelisib alone, and combination treatment significantly prolonged survival, compared to placebo, while in the BON1RR2 group, only combination treatment significantly prolonged survival compared to placebo, but neither everolimus nor alpelisib alone. Placebo-treated everolimus-sensitive tumours grew more rapidly (median survival 45 days), compared to placebo-treated everolimus-resistant tumours (60 days). Within the everolimus-sensitive group, the combination-treated mice showed the longest median survival (52 days). Of all groups, the everolimus-resistant combination-treated group survived longest (69 days). Combination treatment with everolimus and alpelisib seems promising to overcome everolimus resistance in neuroendocrine neoplasms, and should be further examined in a clinical trial.

Effect of paclitaxel octreotide conjugate on human ovarian paclitaxel-resistant cell xenograft tumor model and the mechanism underlying reversal of paclitaxel resistance

Purpose: To determine the effect of paclitaxel octreotide conjugate (POC) on human ovarian paclitaxelresistant cell xenograft tumor model and the mechanism underlying reversal of paclitaxel resistance.&#x0D; Methods: Forty female BALB/c-nu/nu mice were subcutaneously inoculated with 106 paclitaxel-resistant cells (a2780/taxol) per mouse during the logarithmic growth phase of ovarian cancer. They were randomly divided into four groups (control, octreotide, paclitaxel and POC). Immunohistochemical streptavidin-peroxidase (SP) method was used to determine expression of nuclear proliferation antigen (PCNA) while TUNEL method was used to assess apoptosis of human ovarian cancer metastasis. Realtime polymerase chain reaction (PCR) was used to assay mRNA expression levels of somatostatin receptor 2 (SSTR2), multidrug-resistant gene (MDR1), vascular endothelial growth factor (VEGF), matrix metalloproteinase-9 (MMP-9), and acetylated tubulin (α-tubulin and β-III-tubulin), while the corresponding protein expressions were assayed using western blotting.&#x0D; Results: Immunohistochemical SP showed significantly lower PCNA levels in octreotide, paclitaxel and POC groups than in control mice, but that of POC mice was significantly reduced, relative to those of octreotide and paclitaxel groups (p &lt; 0.05). There were significantly higher expression levels of SSTR2 mRNA and protein in octreotide, paclitaxel and POC groups than in control mice, but they were significantly higher in POC group than in octreotide and paclitaxel groups (p &lt; 0.05). The mRNA and protein expressions of other factors in POC mice were significantly lower than those in both octreotide and paclitaxel groups (p &lt; 0.05).&#x0D; Conclusion: Paclitaxel-octreotide conjugate effectively inhibits the growth of a2780/taxol xenografts in nude mice, induces tumor cell apoptosis, and suppresses tumor cell growth via mechanism involving enhancement of SSTR2 expression, and decreases in levels of acetylated tubulin, matrix metalloproteinase-9, and vascular endothelial growth factor.

Sstr2 Defines the Cone Differentiation-Competent Late-Stage Retinal Progenitor Cells in the Developing Mouse Retina.

Cone cell death is a characteristic shared by various retinal degenerative disorders, such as cone-rod dystrophy, Stargardt disease, achromatopsia, and retinitis pigmentosa. This leads to conditions like color blindness and permanently impaired visual acuity. Stem cell therapy focused on photoreceptor replacement holds promise for addressing these conditions. However, identifying surface markers that aid in enriching retinal progenitor cells (RPCs) capable of differentiating into cones remains a complex task. In this study, we employed single-cell RNA sequencing to scrutinize the transcriptome of developing retinas in C57BL/6J mice. This revealed the distinctive expression of somatostatin receptor 2 (Sstr2), a surface protein, in late-stage RPCs exhibiting the potential for photoreceptor differentiation. In vivo lineage tracing experiments verified that Sstr2+ cells within the late embryonic retina gave rise to cones, amacrine and horizontal cells during the developmental process. Furthermore, Sstr2+ cells that were isolated from the late embryonic mouse retina displayed RPC markers and exhibited the capability to differentiate into cones in vitro. Upon subretinal transplantation into both wild-type and retinal degeneration 10 (rd10) mice, Sstr2+ cells survived and expressed cone-specific markers. This study underscores the ability of Sstr2 to enrich late-stage RPCs primed for cone differentiation to a large extent. It proposes the utility of Sstr2 as a biomarker for RPCs capable of generating cones for transplantation purposes.

Revisiting the usefulness of the short acute octreotide test to predict treatment outcomes in acromegaly.

We previously described that a short version of the acute octreotide test (sAOT) can predict the response to first-generation somatostatin receptor ligands (SRLs) in patients with acromegaly. We have prospectively reassessed the sAOT in patients from the ACROFAST study using current ultra-sensitive GH assays. We also studied the correlation of sAOT with tumor expression of E-cadherin and somatostatin receptor 2 (SSTR2) . A total of 47 patients treated with SRLs for 6 months were evaluated with the sAOT at diagnosis and correlated with SRLs' response. Those patients whose IGF1 decreased to <3SDS from normal value were considered responders and those whose IGF1 was ≥3SDS, were considered non-responders. The 2 hours GH value (GH2h) after s.c. administration of 100 mcg of octreotide was used to define predictive cutoffs. E-cadherin and SSTR2 immunostaining in somatotropinoma tissue were investigated in 24/47 and 18/47 patients, respectively. In all, 30 patients were responders and 17 were non-responders. GH2h was 0.68 (0.25-1.98) ng/mL in responders vs 2.35 (1.59-9.37) ng/mL in non-responders (p<0.001). GH2h = 1.4ng/mL showed the highest ability to identify responders (accuracy of 81%, sensitivity of 73.3%, and specificity of 94.1%). GH2h = 4.3ng/mL was the best cutoff for non-response prediction (accuracy of 74%, sensitivity of 35.3%, and specificity of 96.7%). Patients with E-cadherin-positive tumors showed a lower GH2h than those with E-cadherin-negative tumors [0.9 (0.3-2.1) vs 3.3 (1.5-12.1) ng/mL; p<0.01], and patients with positive E-cadherin presented a higher score of SSTR2 (7.5 ± 4.2 vs 3.3 ± 2.1; p=0.01). The sAOT is a good predictor tool for assessing response to SRLs and correlates with tumor E-cadherin and SSTR2 expression. Thus, it can be useful in clinical practice for therapeutic decision-making in patients with acromegaly.