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Co-administration with A1M does not influence apoptotic response of ¹⁷⁷Lu-octreotate in GOT1 neuroendocrine tumors.

ABSTRACT: Recombinant α₁-microglobulin (A1M) is a proposed radioprotector during ¹⁷⁷Lu-octreotate therapy of neuroendocrine tumors (NETs). To ensure a maintained therapeutic effect, we previously demonstrated that A1M does not affect the ¹⁷⁷Lu-octreotate induced decrease in GOT1 tumor volume. However, the underlying biological events of these findings are still unknown. The aim of this work was to examine the regulation of apoptosis-related genes in GOT1 tumors short-time after i.v. administration of ¹⁷⁷Lu-octreotate with and without A1M or A1M alone. Human GOT1 tumor-bearing mice received 30 MBq ¹⁷⁷Lu-octreotate or 5 mg/kg A1M or co-treatment with both. Animals were sacrificed after 1 or 7 days. Gene expression analysis of apoptosis-related genes in GOT1 tissue was performed with RT-PCR. In general, similar expression patterns of pro- and anti-apoptotic genes were found after ¹⁷⁷Lu-octreotate exposure with or without co-administration of A1M. The highest regulated genes in both irradiated groups compared to untreated controls were FAS and TNFSFRS10B. Administration of A1M alone only resulted in significantly regulated genes after 7 days. Co-administration of A1M did not negatively affect the transcriptional apoptotic response of ¹⁷⁷Lu-octreotate in GOT1 tumors.

SUBMITTER: Rassol N

PROVIDER: S-EPMC10115890 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Co-administration with A1M does not influence apoptotic response of 177Lu-octreotate in GOT1 neuroendocrine tumors.

Rassol Nishte N Andersson Charlotte C Pettersson Daniella D Al-Awar Amin A Shubbar Emman E Kovács Anikó A Åkerström Bo B Gram Magnus M Helou Khalil K Forssell-Aronsson Eva E

Scientific reports 20230419 1

Recombinant α1-microglobulin (A1M) is a proposed radioprotector during 177Lu-octreotate therapy of neuroendocrine tumors (NETs). To ensure a maintained therapeutic effect, we previously demonstrated that A1M does not affect the 177Lu-octreotate induced decrease in GOT1 tumor volume. However, the underlying biological events of these findings are still unknown. The aim of this work was to examine the regulation of apoptosis-related genes in GOT1 tumors short-time ...[more]

PMID: 37076494

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Project description:BackgroundPatients with advanced midgut neuroendocrine tumors who have had disease progression during first-line somatostatin analogue therapy have limited therapeutic options. This randomized, controlled trial evaluated the efficacy and safety of lutetium-177 (177Lu)-Dotatate in patients with advanced, progressive, somatostatin-receptor-positive midgut neuroendocrine tumors.MethodsWe randomly assigned 229 patients who had well-differentiated, metastatic midgut neuroendocrine tumors to receive either 177Lu-Dotatate (116 patients) at a dose of 7.4 GBq every 8 weeks (four intravenous infusions, plus best supportive care including octreotide long-acting repeatable [LAR] administered intramuscularly at a dose of 30 mg) (177Lu-Dotatate group) or octreotide LAR alone (113 patients) administered intramuscularly at a dose of 60 mg every 4 weeks (control group). The primary end point was progression-free survival. Secondary end points included the objective response rate, overall survival, safety, and the side-effect profile. The final analysis of overall survival will be conducted in the future as specified in the protocol; a prespecified interim analysis of overall survival was conducted and is reported here.ResultsAt the data-cutoff date for the primary analysis, the estimated rate of progression-free survival at month 20 was 65.2% (95% confidence interval [CI], 50.0 to 76.8) in the 177Lu-Dotatate group and 10.8% (95% CI, 3.5 to 23.0) in the control group. The response rate was 18% in the 177Lu-Dotatate group versus 3% in the control group (P<0.001). In the planned interim analysis of overall survival, 14 deaths occurred in the 177Lu-Dotatate group and 26 in the control group (P=0.004). Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia occurred in 1%, 2%, and 9%, respectively, of patients in the 177Lu-Dotatate group as compared with no patients in the control group, with no evidence of renal toxic effects during the observed time frame.ConclusionsTreatment with 177Lu-Dotatate resulted in markedly longer progression-free survival and a significantly higher response rate than high-dose octreotide LAR among patients with advanced midgut neuroendocrine tumors. Preliminary evidence of an overall survival benefit was seen in an interim analysis; confirmation will be required in the planned final analysis. Clinically significant myelosuppression occurred in less than 10% of patients in the 177Lu-Dotatate group. (Funded by Advanced Accelerator Applications; NETTER-1 ClinicalTrials.gov number, NCT01578239 ; EudraCT number 2011-005049-11 .).

Project description:Tumor dosimetry was performed for 177Lu-DOTATATE with the aims of better understanding the range and variation of the tumor-absorbed doses (ADs), how different dosimetric quantities evolve over the treatment cycles, and whether this evolution differs depending on the tumor grade. Such information is important for radiobiologic interpretation and may inform the design of alternative administration schemes. Methods: The data came from 41 patients with neuroendocrine tumors (NETs) of grade 1 (n = 23) or 2 (n = 18) who had received between 2 and 9 treatment cycles. Dosimetry was performed for 182 individual lesions, giving a total of 880 individual AD assessments across all cycles. Hybrid planar-SPECT/CT imaging was used, including quantitative SPECT reconstruction, voxel-based absorbed-dose-rate calculation, semiautomatic image segmentation, and partial-volume correction. Linear mixed-effect models were used to analyze changes in tumor ADs over cycles, absorbed-dose rates and activity concentrations on day 1, effective half-times, and tumor volumes. Tumors smaller than 8 cm3 were excluded from analyses. Results: Tumor ADs ranged between 2 and 77 Gy per cycle. On average, the AD decreased over the cycles, with significantly different rates (P < 0.05) of 6% and 14% per cycle for grade 1 and 2 NETs, respectively. The absorbed-dose rates and activity concentrations on day 1 decreased by similar amounts. The effective half-times were less variable but shorter for grade 2 than for grade 1 (P < 0.001). For grade 2 NETs, the tumor volumes decreased, with a similar tendency in grade 1. Conclusion: The tumor AD, absorbed-dose rate, and activity uptake decrease, in parallel with tumor volumes, between 177Lu-DOTATATE treatment cycles, particularly for grade 2 NETs. The effective half-times vary less but are lower for grade 2 than grade 1 NETs. These results may indicate the development of radiation-induced fibrosis and could have implications for the design of future treatment and dosimetry protocols.

Project description:BackgroundNeuroblastoma (NB) is one of the most frequently diagnosed tumors in infants. NB is a neuroendocrine tumor type with various characteristics and features, and with diverse outcome. The most malignant NBs have a 5-year survival rate of only 40-50%, indicating the need for novel and improved treatment options. 177Lu-octreotate is routinely administered for treatment of neuroendocrine tumors overexpressing somatostatin receptors (SSTR). The aim of this study was to examine the biodistribution of 177Lu-octreotate in mice bearing aggressive human NB cell lines, in order to evaluate the potential usefulness of 177Lu-octreotate for treatment of NB.MethodsBALB/c nude mice bearing CLB-BAR, CLB-GE or IMR-32 tumor xenografts (n = 5-7/group) were i.v. injected with 0.15 MBq, 1.5 MBq or 15 MBq 177Lu-octreotate and sacrificed 1 h, 24 h, 48 h and 168 h after administration. The radioactivity concentration was determined for collected tissue samples, tumor-to-normal-tissue activity concentration ratios (T/N) and mean absorbed dose for each tissue were calculated. Immunohistochemical (IHC) staining for SSTR1-5, and Ki67 were carried out for tumor xenografts from the three cell lines.ResultsHigh 177Lu concentration levels and T/N values were observed in all NB tumors, with the highest for CLB-GE tumor xenografts (72%IA/g 24 h p.i.; 1.5 MBq 177Lu-octreotate). The mean absorbed dose to the tumor was 6.8 Gy, 54 Gy and 29 Gy for CLB-BAR, CLB-GE and IMR-32, respectively, p.i. of 15 MBq 177Lu-octreotate. Receptor saturation was clearly observed in CLB-BAR, resulting in higher concentration levels in the tumor when lower activity levels where administered. IHC staining demonstrated highest expression of SSTR2 in CLB-GE, followed by CLB-BAR and IMR-32.ConclusionT/N values for all three human NB tumor xenograft types investigated were high relative to previously investigated neuroendocrine tumor types. The results indicate a clear potential of 177Lu-octreotate as a therapeutic alternative for metastatic NB.

Project description:BackgroundPeptide receptor radionuclide therapy (PRRT) utilizes somatostatin receptor (SSR) overexpression on neuroendocrine tumors (NET) to deliver targeted radiotherapy. Intensity of uptake at imaging is considered related to efficacy but has low sensitivity. A pretreatment strategy to determine individual PRRT response remains a key unmet need. NET transcript expression in blood integrated with tumor grade provides a PRRT predictive quotient (PPQ) which stratifies PRRT "responders" from "non-responders". This study clinically validates the utility of the PPQ in NETs.MethodsThe development and validation of the PPQ was undertaken in three independent 177Lu-PRRT treated cohorts. Specificity was tested in two separate somatostatin analog-treated cohorts. Prognostic value of the marker was defined in a cohort of untreated patients. The developmental cohort included lung and gastroenteropancreatic [GEP] NETs (n = 72) from IRST Meldola, Italy. The majority were GEP (71%) and low grade (86% G1-G2). Prospective validation cohorts were from Zentralklinik Bad Berka, Germany (n = 44), and Erasmus Medical Center, Rotterdam, Netherlands (n = 42). Each cohort included predominantly well differentiated, low grade (86-95%) lung and GEP-NETs. The non-PRRT comparator cohorts included SSA cohort I, n = 28 (100% low grade, 100% GEP-NET); SSA cohort II, n = 51 (98% low grade; 76% GEP-NET); and an untreated cohort, n = 44 (64% low grade; 91% GEP-NET). Baseline evaluations included clinical information (disease status, grade, SSR) and biomarker (CgA). NET blood gene transcripts (n = 8: growth factor signaling and metabolism) were measured pre-therapy and integrated with tumor Ki67 using a logistic regression model. This provided a binary output: "predicted responder" (PPQ+); "predicted non-responder" (PPQ-). Treatment response was evaluated using RECIST criteria [Responder (stable, partial and complete response) vs Non-Responder)]. Sample measurement and analyses were blinded to study outcome. Statistical evaluation included Kaplan-Meier survival and standard test evaluation analyses.ResultsIn the developmental cohort, 56% responded to PRRT. The PPQ predicted 100% of responders and 84% of non-responders (accuracy: 93%). In the two validation cohorts (response: 64-79%), the PPQ was 95% accurate (Bad Berka: PPQ + =97%, PPQ- = 93%; Rotterdam: PPQ + =94%, PPQ- = 100%). Overall, the median PFS was not reached in PPQ+ vs PPQ- (10-14 months; HR: 18-77, p < 0.0001). In the comparator cohorts, the predictor (PPQ) was 47-50% accurate for SSA-treatment and 50% as a prognostic. No differences in PFS were respectively noted (PPQ+: 10-12 months vs. PPQ-: 9-15 months).ConclusionThe PPQ derived from circulating NET specific genes and tumor grade prior to the initiation of therapy is a highly specific predictor of the efficacy of PRRT with an accuracy of 95%.

Dataset Information

Co-administration with A1M does not influence apoptotic response of ¹⁷⁷Lu-octreotate in GOT1 neuroendocrine tumors.

Publications

Co-administration with A1M does not influence apoptotic response of <sup>177</sup>Lu-octreotate in GOT1 neuroendocrine tumors.

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