Hepatocyte growth factor activator inhibitor-1 (HAI-1) is a type I transmembrane protein and inhibitor of several serine proteases, including hepatocyte growth factor activator and matriptase. The protein is essential for development as knockout mice die in utero due to placental defects caused by misregulated extracellular proteolysis. HAI-1 contains two Kunitz-type inhibitor domains (Kunitz), which are generally thought of as a functionally self-contained protease inhibitor unit. This is not the case for HAI-1, where our results reveal how interdomain interactions have evolved to stimulate the inhibitory activity of an integrated Kunitz. Here we present an x-ray crystal structure of an HAI-1 fragment covering the internal domain and Kunitz-1. The structure reveals not only that the previously uncharacterized internal domain is a member of the polycystic kidney disease domain family but also how the two domains engage in interdomain interactions. Supported by solution small angle x-ray scattering and a combination of site-directed mutagenesis and functional assays, we show that interdomain interactions not only stabilize the fold of the internal domain but also stimulate the inhibitory activity of Kunitz-1. By completing our structural characterization of the previously unknown N-terminal region of HAI-1, we provide new insight into the interplay between tertiary structure and the inhibitory activity of a multidomain protease inhibitor. We propose a previously unseen mechanism by which the association of an auxiliary domain stimulates the inhibitory activity of a Kunitz-type inhibitor (i.e. the first structure of an intramolecular interaction between a Kunitz and another domain).
EORTC-1506-STBSG was a prospective, multicentric, randomised, open-label phase 2 trial to assess the efficacy and safety of second-line nintedanib versus ifosfamide in patients with advanced, inoperable metastatic soft tissue sarcoma (STS). The primary end-point was progression-free survival. Patients/methods: Patients with a variety of STS subtypes were randomised 1:1 to nintedanib (200 mg b.i.d. p.o. until disease progression) or ifosfamide (3 g/m 2 i.v. days 1e3, every 21 days for 6 cycles). A Korn design was applied aiming to detect an improvement in median progression-free survival (mPFS) from 3 to 4.5 months (HR Z 0.667). An interim look was incorporated to stop the trial for futility if <19 of the first 36 patients treated with nintedanib were progression-free at week 12. Results: At the interim analysis, among the first 36 eligible and evaluable patients randomised for nintedanib, only 13 (36%) were progression-free at week 12. The trial was closed for further accrual as per protocol. In total, 80 patients were randomised (40 per treatment group). The mPFS was 2.5 months (95% CI: 1.5e3.4) for nintedanib and 4.4 months (95% CI: 2.9e6.7) on ifosfamide (adjusted HR Z 1.56 [80% CI: 1.14e2.13], p Z 0.070). The median overall survival was 13.7 months (95% CI: 9.4e23.4) on nintedanib and 24.1 months (95% CI: 10.9eNE) on ifosfamide (adjusted HR Z 1.65 [95%CI:0.89e3.06], p Z 0.111). The clinical benefit rate for nintedanib and ifosfamide was 50% versus 62.5% (p Z 0.368), respectively. Common treatment-related adverse events (all grades) were diarrhoea (35.9% of patients), fatigue (25.6%) and nausea (20.5%) for nintedanib; and fatigue (52.6%), nausea (44.7%) and vomiting, anorexia and alopecia (28.9% each) for ifosfamide. Conclusion:The trial was stopped for futility. The activity of nintedanib did not warrant further exploration in non-selected, advanced STSs.
TPS607 Background: There are currently limited treatment options for patients with HR+ EBC who have discontinued adjuvant treatment with aromatase inhibitors (AIs) due to treatment-related toxicity. Amcenestrant is an optimized oral selective estrogen receptor degrader (SERD) with potent dual activity which antagonizes and degrades the ER resulting in inhibition of the ER signalling pathway. Preliminary clinical evidence from the phase 1/2 AMEERA-1 trial has demonstrated meaningful antitumour activity and a favourable safety profile of amcenestrant in the treatment of HR+ advanced breast cancer (Linden HM, Campone M, Bardia A, et al: Abstract PD8-08: A phase 1/2 study of SAR439859, an oral selective estrogen receptor (ER) degrader (SERD), as monotherapy and in combination with other anti-cancer therapies in postmenopausal women with ER-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC): AMEERA-1. SABCS 2020 PD8-08). Methods: AMEERA-6 is a prospective, randomized, international, double-blind, double-dummy, phase 3 study. 3738 patients will be randomized 1:1 to receive either amcenestrant 200 mg daily or tamoxifen 20 mg daily. Eligible patients are pre-or postmenopausal women or men with HR+ EBC (stage IIB-III) who have received at least 6 months of adjuvant AIs (at least 3 months in the adjuvant setting if they have received prior neoadjuvant AI therapy) and discontinued them within 30 months of initiation due to treatment-related toxicity. Participants will be centrally assessed to have ER+ and/or PgR+ (≥10% positive stained cells) status by immunohistochemistry assay. Prior use of adjuvant CDK4/6 inhibitors are allowed. Patients are eligible irrespective of HER2 status; for patients with HER2-positive disease adjuvant anti-HER2 treatment and chemotherapy must be completed prior to randomization. Stratification factors include: duration of AI therapy, HER2 status, prior chemotherapy, prior CDK4/6 inhibitors, geographic region, and menopausal status. Planned treatment duration is 5 years. Patients will be followed-up for 10 years from randomization. The primary endpoint is invasive breast cancer-free survival (IBCFS). Invasive disease-free survival is a key secondary endpoint, while other secondary endpoints include distant relapse-free survival (RFS), locoregional RFS, overall survival, breast-cancer specific survival, safety, patient reported outcomes and pharmacokinetics. Adherence to treatment is an exploratory endpoint. AMEERA-6 opened for recruitment in January 2022. Clinical trial information: NCT05128773.
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