Binding of human Cdc123 to eIF2γ Cardenal Peralta, Cristina; Vandroux, Paul; Neumann-Arnold, Lea ...
Journal of structural biology,
09/2023, Letnik:
215, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Display omitted
•Crystal structure of human Cdc123 bound to domain 3 of eIF2γ.•ATP is required for human Cdc123 function in eIF2 assembly.•Model of the mechanism of action of human Cdc123.•Structural ...support for understanding eIF2γ mutations responsible for MEHMO diseases.
Eukaryotic initiation factor 2 (eIF2) plays a key role in protein synthesis and in its regulation. The assembly of this heterotrimeric factor is facilitated by Cdc123, a member of the ATP grasp family that binds the γ subunit of eIF2. Notably, some mutations related to MEHMO syndrome, an X-linked intellectual disability, affect Cdc123-mediated eIF2 assembly. The mechanism of action of Cdc123 is unclear and structural information for the human protein is awaited. Here, the crystallographic structure of human Cdc123 (Hs-Cdc123) bound to domain 3 of human eIF2γ (Hs-eIF2γD3) was determined. The structure shows that the domain 3 of eIF2γ is bound to domain 1 of Cdc123. In addition, the long C-terminal region of Hs-Cdc123 provides a link between the ATP and Hs-eIF2γD3 binding sites. A thermal shift assay shows that ATP is tightly bound to Cdc123 whereas the affinity of ADP is much smaller. Yeast cell viability experiments, western blot analysis and two-hybrid assays show that ATP is important for the function of Hs-Cdc123 in eIF2 assembly. These data and recent findings allow us to propose a refined model to explain the mechanism of action of Cdc123 in eIF2 assembly.
Background.
Angiosarcomas account for <2% of all soft tissue sarcomas. This subtype is one of the most aggressive forms of soft tissue sarcoma. The prognosis for angiosarcoma patients in the advanced ...phase remains poor with current cytotoxic agents (progression‐free survival PFS time of ∼4 months and overall survival OS time of ∼8 months). We investigated the antitumor activity of sorafenib in patients with metastatic or advanced angiosarcomas in a phase II trial.
Methods.
We conducted a stratified phase II trial. The primary endpoint was the progression‐free rate (PFR) at 9 months according to the Response Evaluation Criteria in Solid Tumors. A two‐stage design (optimal Simon design) was used. Patients received sorafenib (400 mg twice daily) for 9 months until unacceptable toxicity or tumor progression. Central pathological and radiological reviews were performed. Data on stratum A (superficial angiosarcoma) and stratum B (visceral angiosarcoma) are currently available. This trial is registered with ClinicalTrials.gov (identifier, NCT00874874).
Findings.
Strata A and B recruited 26 and 15 patients, respectively. The median age was 63 years (range, 31–82 years), with 17 male and 24 female patients. Fourteen cases arose in irradiated fields. Thirty patients (73.0%) had been pretreated with conventional chemotherapy. No unexpected toxicity occurred. The PFR at 9 months was 3.8% in stratum A and 0.0% in stratum B. The median PFS times were 1.8 months and 3.8 months, respectively, whereas the median OS times were 12.0 months and 9.0 months, respectively. No responses were observed in chemotherapy‐naïve patients, whereas a 40% tumor control rate and 23% response rate were observed in the pretreated population. In this cohort, no activating mutation of the KDR gene (exons 15, 16, 24) was detected.
Interpretation.
Sorafenib showed limited antitumor activity in pretreated patients only, for both visceral and superficial angiosarcoma, but tumor control was of short duration.
摘要
研究背景. 血管肉瘤在所有软组织肉瘤中所占比例不足2％。这种亚型是恶性程度最高的软组织肉瘤之一。接受目前的细胞毒性药物治疗的晚期血管肉瘤患者预后仍然较差无进展生存期(PFS)大约为4个月，总生存期(OS)大约为8个月。我们在II期临床试验中研究了索拉非尼治疗转移性或晚期肉瘤的抗肿瘤活性。
方法. 我们进行了分层II期临床试验。根据实体瘤疗效评价标准，主要终点为9个月时的无进展率（PFR）。采用两阶段设计（Simon最佳设计）。患者接受9个月的索拉非尼（400 mg，每天两次），直至出现不可接受的毒性或肿瘤进展。进行中心病理和影像学评价。目前得到了A层（浅表性血管肉瘤）和B层（内脏血管肉瘤）的数据。这项试验在ClinicalTrials.gov进行了注册（标识号，NCT00874874）。
结果. A层和B层分别纳入26和15例患者。年龄中位数为63岁（范围31‐82岁），男性患者17例，女性患者24例。共14例病灶出现在照射野。30例患者（73.0％）既往接受过常规化疗。未发生意外的毒性反应。9个月的A层和B层的PFR分别为3.8％和0.0％，中位PFS分别为1.8个月和3.8个月，而中位OS分别为12.0个月和9.0个月。既往无化疗史的患者表现为无缓解，而接受过化疗的患者，表现出40％的肿瘤控制率和23％的缓解率。在受试患者中，未检测到KDR基因（外显子15，16，24）的激活突变。
结论. 索拉非尼仅对既往接受过化疗的内脏和浅表性血管肉瘤患者表现出有限的抗肿瘤活性，但肿瘤控制作用的持续时间短暂。
The antitumor activity of sorafenib in patients with metastatic or advanced angiosarcomas was investigated in a phase II trial. Sorafenib showed limited antitumor activity in pretreated patients only, but tumor control was of short duration.
Brain metastases from sarcomatous lesions pose a management challenge owing to their rarity and the histopathological heterogeneity. Prognostic indices such as the Graded Prognostic Assessment (GPA) ...index have been developed for several primary tumour types presenting with brain metastases (e.g. lung, breast, melanoma), tailored to the specifics of different primary histologies and molecular profiles. Thus far, a prognostic index to direct treatment decisions is lacking for adult sarcoma patients with brain metastases.
We performed a multicentre analysis of a national group of expert sarcoma tertiary centres (French Sarcoma Group, GSF-GETO) with the participation of one Canadian and one Swiss centre. The study cohort included adult patients with a diagnosis of a bone or soft tissue sarcoma presenting parenchymal or meningeal brain metastases, managed between January 1992 and March 2012. We assessed the validity of the original GPA index in this patient population and developed a disease-specific Sarcoma-GPA index.
The original GPA index is not prognostic for sarcoma brain metastasis patients. We have developed a dedicated Sarcoma-GPA index that identifies a sub-group of patients with particularly favourable prognosis based on histology, number of brain lesions and performance status.
The Sarcoma-GPA index provides a novel tool for sarcoma oncologists to guide clinical decision-making and outcomes research.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In most countries, reference chemotherapy for osteosarcoma is MAP regimen (M = high-dose methotrexate, AP = doxorubicin-cisplatinum). In France, the standard preoperative chemotherapy for ...children/adolescents combines M and etoposide-ifosfamide (EI), based on the OS94-trial. We report the safety and efficacy results of patients ≤25 years treated with preoperative M-EI regimen enroled in the French OS2006-study, between 2007 and 2014.
Treatment comprised preoperative chemotherapy with the 7 M-courses and 2 EI-courses, then surgery and postoperative chemotherapy assigned by risk's groups: standard-risk (good histological response without metastases) received 12 M-courses, 3 EI-courses; high-risk (poor histologic response, initial metastases or unresectable primary) received 5 M-courses alternated with 5 AP-courses. 253 patients were randomised to receive (n = 128) or not (n = 125) zoledronate.
409/522 patients enroled in the OS2006 study who received preoperative M-EI were analysed. Median age was 14.3 years (4.7–24.5), with 55 patients aged 18–25 years. Primary tumour location was limb in 383 patients (94%) and 85 (21%) presented metastases. Median chemotherapy duration was 37.4 weeks. 381 (96%) patients underwent surgery, 258 patients (65%) had a good histologic response. 187/324 patients (58%) with localised disease did not receive doxorubicin nor cisplatinum. Toxicity was evaluated in the randomised study: most patients experienced ≥1 severe toxicity (grade IV haematological or grade III/IV extra-haematological). Median follow-up was 4.8 years, and 168 patients had events. Five-year event-free survival was 56% (95% CI, 51–62%) and overall survival 71% (66–76%).
M-EI regimen/strategy was feasible for patient aged ≤25 years with survival rates are comparable to those obtained with MAP regimen.
•Paediatric and young adult methotrexate-based chemotherapy regimen of OS2006 protocol.•Event-free survival and overall survival rates were similar to those with standard Methotrexate-Doxorubicin-Cisplatinum (MAP) regimen used worldwide.•First-line treatment with doxorubicin and cisplatinum was avoided in 58% patients with localised tumours.
The response of desmoid tumors (DTs) to chemotherapy is evaluated with Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) in daily practice and clinical trials. MRI shows early ...change in heterogeneity in responding tumors due to a decrease in cellular area and an increase in fibronecrotic content before dimensional response. Heterogeneity can be quantified with radiomics. Our aim was to develop radiomics-based response criteria and to compare their performances with clinical and radiologic response criteria.
Forty-two patients (median age, 38.2 years) were included in this retrospective multicenter study because they presented with progressive DT and had an MRI examination at baseline, which we refer to as "MRI-0," and an early MRI evaluation performed after the first chemotherapy cycle (mean time after first chemotherapy cycle, 3 months SD, 28 days), which we refer to as "MRI-1." After signal intensity normalization, voxel size standardization, discretization, and segmentation of DT volume on fat-suppressed contrast-enhanced T1-weighted imaging, 90 baseline and delta 3D radiomics features were extracted. Using cross-validation and least absolute shrinkage and selection operator-penalized Cox regression, a radiomics score was generated. The performances of models based on the radiomics score, modified Response Evaluation Criteria in Solid Tumors, European Association for the Study of the Liver criteria, Cheson criteria, Choi criteria, and revised Choi criteria from MRI-0 to MRI-1 to predict progression-free survival (PFS, as defined by RECIST 1.1) were assessed with the concordance index. The results were adjusted for performance status, tumor volume, prior chemotherapy, current chemotherapy, and β-catenin mutation.
There were 10 cases of progression. The radiomics score included four variables. A high score indicated a poor prognosis. The radiomics score independently correlated with PFS (adjusted hazard ratio = 5.60,
= 0.003), and none of the usual response criteria independently correlated with PFS. The prognostic model based on the radiomics score had the highest concordance index (0.84; 95% CI, 0.71-0.96).
Quantifying early changes in heterogeneity through a dedicated radiomics score could improve response evaluation for patients with DT undergoing chemotherapy.
11555
Background: Results of the double-blind randomized phase 2 trial (NCT01900743), showed that regorafenib (REG) is an active treatment in patients (pts) previously treated with chemotherapy for ...an NASTS (cohorts B-leiomyosarcoma, C-synovial sarcoma, D-other sarcoma, Mir 2016), and in pts previously treated with pazopanib (PAZ) (cohort E, Penel 2019). We now present an updated analysis of progression-free survival (PFS) in all NASTS pts to assess the heterogeneity of treatment effect according to histological subtype and prior exposure to PAZ. Methods: Pts received REG 160 mg/d, 21/28 d, or placebo (PB). Pts receiving PB were offered optional cross over in case of centrally confirmed disease progression. The primary endpoint was PFS, according to RECIST-1.1, based on full blinded central review of imaging (including a re-review for cohorts B, C and D, because first analysis was based on a partial central review in these cohorts). Overall survival (OS) was a secondary endpoint. We performed a pooled analysis of cohorts B, C, D and E, on the intent-to-treat dataset, including a multivariate analysis with interaction terms to assess the heterogeneity of treatment effect according to covariates. Results: From 06/2013 to 10/2017, 175 pts were randomized (87 REG vs 88 PB; 56, 27, 55, 37 pts in cohorts B, C, D and E, respectively). The median age was 59 yrs (range, 20-81). There were 101 women (58%). Histological subtype was leiomyosarcoma in 80 pts (LMS; 41 REG vs 39 PB; 56 in cohort B and 24 in cohort E), synovial sarcoma in 28 (SS; 13 REG vs 15 PB; 27 in cohort C and 1 in cohort E), and other sarcoma in 67 (33 REG vs 34 PB; 55 in cohort D and 12 in cohort E). The median number of prior lines of systemic treatment was 2 (range, 1-6). Overall, 43 pts had received prior PAZ (21 REG vs 22 PB). Out of 88 pts assigned to PB, 69 switched to REG after progression (79%). We confirmed a significant PFS-benefit associated with REG in multivariate analysis of the pooled study population, with a HR = 0.48 (95%CI, 0.35–0.66, p < 0.001); median PFS = 2.1 vs 1.0 months, respectively. This benefit appears significant in each histological subtype. However, we observed a borderline interaction between histological subtype and treatment effect (p = 0.09): PFS benefit appears larger in pts with SS (HR = 0.21, 0.10-0.48, p < 0.001) and other sarcoma (HR = 0.49, 0.30-0.81, p = 0.006) than in LMS (HR = 0.59, 0.37-0.93, p = 0.022). PFS benefit appears rather homogeneous across strata of pts with vs without prior exposure to PAZ (interaction test, p = 0.26). Overall, in this study, regorafenib does not show any statistically significant OS-benefit (HR = 0.77, 0.57–1.05, p = 0.10), likely due to the fact that 79% of PB pts crossed over to REG at progression. Conclusions: The present study confirms the clinical PFS benefit associated with regorafenib in all NASTS pts, regardless of prior treatment with pazopanib. Clinical trial information: NCT01900743.
Abstract Aim The French Sarcoma Group performed this retrospective analysis of the ‘RetrospectYon’ database with data of patients with recurrent advanced soft tissue sarcoma (STS) treated with ...trabectedin 1.5 mg/m2 as a 24-h infusion every three weeks. Methods Patients who achieved non-progressive disease after six initial cycles could receive long-term trabectedin treatment until disease progression. Results Overall, 885 patients from 25 French centres were included. Patients received a median of four trabectedin cycles (range: 1–28). The objective response rate was 17% (six complete/127 partial responses) and 50% ( n = 403) of patients had stable disease for a disease control rate of 67%. After a median follow-up of 22.0 months, median progression-free survival (PFS) and overall survival (OS) were 4.4 and 12.2 months, respectively. After six cycles, 227/304 patients with non-progressive disease received trabectedin until disease progression and obtained a significantly superior median PFS (11.7 versus 7.6 months, P < 0.003) and OS (24.9 versus 16.9 months, P < 0.001) compared with those who stopped trabectedin treatment. Deaths and unscheduled hospitalisation attributed to drug-related events occurred in 0.5% and 9.4% of patients, respectively. Conclusion The results of this real-life study demonstrate that treatment with trabectedin of patients with STS yielded comparable or improved efficacy outcomes versus those observed in clinical trials. A long-term treatment with trabectedin given until disease progression is associated with significantly improved PFS and OS.
This prospective nationwide cohort study aimed to investigate desmoid-type fibromatosis (DF) outcomes, focusing on the prognostic value of CTNNB1 mutations.
ALTITUDES (NCT02867033) was a nationwide ...prospective cohort study of DF diagnosed between January 2016 and December 2020. At diagnosis, CTNNB1 molecular alterations were identified using next-generation sequencing or Sanger sequencing. The primary endpoint was event-free survival (EFS) (progression, relapse, or death). We enrolled 628 patients managed by active surveillance (AS), surgical resection (SR), or systemic treatment as front-line therapy.
Overall, 516 (82.2%) patients (368 females 71.3%, median age 40.3 years range, 1-89) were eligible for analysis. In 435 (84.3%) cases, there was one CTNNB1 molecular alteration: p.T41A, p.S45F, or p.S45P. The front-line management was AS in 352 (68.2%), SR in 120 (23.3%), and systemic treatments in 44 (8.5%) patients. CTNNB1 mutation distribution was similar across the three therapeutic groups. The median follow-up period was 24.7 (range, 0.4-59.7) months. The estimated 3-year EFS rate was 66.2% (95%CI, 60.5%-71.2%). DF harboring p.S45F was significantly associated with male sex (p=0.03), non-abdominal wall sites (p=0.05), pain (p=0.007), and large tumor size (p=0.025). CTNNB1 p.S45F mutation was not significantly associated with EFS, either in univariate (hazard ratio HR=1.06; 95% confidence interval CI, 0.65-1.73; p=0.81), or in multivariate analysis (HR=0.91; 95% CI, 0.55-1.49; p=0.71).
We found that CTNNB1 mutation profile was associated with unfavorable prognostic factors but was not a prognostic factor for EFS.
Abstract Background To assess the additional value of density measurement using contrast-enhancement sequences (Choi assessment) in a real-life cohort of adult soft tissue sarcoma patients treated ...with trabectedin. Methods Eligibility criteria included adults (age ⩾18) treated between 01/2007 and 12/2011, with at least two trabectedin cycles after failure or intolerance to doxorubicin/ifosfamide. Baseline and first computed tomography (CT)-scans were centrally reviewed by an experienced radiologist. Results The retrospective cohort consists of 134 (73 female) patients treated with trabectedin 1.5 mg/m2 given as a 24-h infusion every 3 weeks. Patients received a median of five trabectedin cycles (range: 2–33) and the main cause of discontinuation was progressive disease (PD) ( n = 105, 78.4%). Response Evaluation Criteria in Solid Tumours (RECIST) assessment was feasible in 128 (95.5%) patients, with Choi assessment performed in 92 (68.7%) patients, generally due to inadequate sequences or exclusive lung metastases. Concordance between both methods was fair (Kappa = 0.290). We identified five patients with false PD (i.e. PD according to RECIST but stable disease/partial response as per Choi). Univariate analysis did not identify any predictive factors for false PD. Median overall survival (OS) of patients with PD as per RECIST but stable disease/partial response (SD/PR) according to Choi was better than for patients with PD according to both RECIST and Choi (14 months versus 8 months; p = 0.052). Conclusions Choi assessment may identify patients with false PD who achieved improved efficacy outcomes, suggesting that trabectedin may delay tumour progression even in the case of non-dimensional response. Dual size and tumour density assessment may be more suitable to evaluate responses to trabectedin in sarcoma patients as well as to improve the decision-making strategies for the continuation of trabectedin therapy.
The purpose was to describe first and subsequent relapses in patients from the OS2006/Sarcome-09 trial, to help future trial design. We prospectively collected and analysed relapse data of all French ...patients included in the OS2006/Sarcome-09 trial, who had achieved a first complete remission. 157 patients experienced a first relapse. The median interval from diagnosis to relapse was 1.7 year (range 0.5-7.6). The first relapse was metastatic in 83% of patients, and disease was not measurable according to RECIST 1.1 criteria in 23%. Treatment consisted in systemic therapy (74%) and surgical resection (68%). A quarter of the patients were accrued in a phase-II clinical trial. A second complete remission was obtained for 79 patients. Most of them had undergone surgery (76/79). The 3-year progression-free and overall survival rates were 21% and 37%, respectively. In patients who achieved CR2, the 3y-PFS and OS rates were 39% and 62% respectively. Individual correlation between subsequent PFS durations was poor. For osteosarcoma relapses, we recommend randomised phase-II trials, open to patients from all age categories (children, adolescents, adults), not limited to patients with measurable disease (but stratified according to disease status), with PFS as primary endpoint, response rate and surgical CR as secondary endpoints.
PDF
