Explore the vast range of titles available.

Ripretinib (DCC-2618) is a novel, type II tyrosine switch control inhibitor designed to broadly inhibit activating and drug-resistant mutations in and . Ripretinib has emerged as a promising investigational agent for the treatment of gastrointestinal stromal tumor owing to targeted inhibition of secondary resistance mutations that may develop following treatment with prior line(s) of tyrosine kinase inhibitors. Here we describe the rationale and design of intrigue (NCT03673501), a global, randomized (1:1), open-label, Phase III study comparing the safety and efficacy of ripretinib versus sunitinib in patients with advanced gastrointestinal stromal tumor following imatinib. The primary end point is progression-free survival and key secondary objectives include objective response rate and overall survival. Clinical Trial Registration: NCT03673501

Background Avapritinib, a potent inhibitor of KIT and platelet-derived growth factor receptor A (PDGFRA) tyrosine kinases, has demonstrated unprecedented clinical activity in PDGFRA D842V-mutant gastrointestinal stromal tumors (GIST). Methods This retrospective analysis compared efficacy of avapritinib in patients enrolled in the NAVIGATOR phase 1 trial (NCT02508532) with the efficacy of other tyrosine kinase inhibitors (TKIs) in patients with unresectable/metastatic PDGFRA D842V-mutant GIST enrolled in a retrospective natural history study (Study 1002). The primary endpoint was overall survival (OS) from the start of reference treatment (avapritinib for NAVIGATOR patients or first-line TKI for treatment of unresectable/metastatic GIST for Study 1002 patients); the secondary endpoint was progression-free survival (PFS). Adjusted Kaplan–Meier survival curves were compared by Cox regression. Results Fifty-six (NAVIGATOR) and 19 (Study 1002) patients with PDGFRA D842V-mutant GIST were evaluated; of the 56 patients from NAVIGATOR, a subgroup of patients treated with either 300 mg (recommended phase 2 dose) or 400 mg (maximum tolerated dose) avapritinib starting dose ( n  = 38) were analyzed separately. Patient characteristics were adjusted for imbalances by propensity score between the study groups. Inverse probability of treatment weighting-adjusted Kaplan–Meier analysis of OS showed median OS was not reached for NAVIGATOR patients treated with any of the avapritinib doses tested and was 12.6 months for Study 1002 patients; OS rate at 6/48 months was 100%/63% in NAVIGATOR and 56%/17% in Study 1002 ( P =  0.0001). In the 300/400 mg subgroup, adjusted OS rates at 6/36 months were 100%/73 and 68%/20% in Study 1002 ( P =  0.0016). Adjusted median PFS was 29.5 months in NAVIGATOR and 3.4 months in Study 1002. Conclusions In this indirect, retrospective analysis, avapritinib demonstrated more durable survival outcomes compared with other TKIs in patients with unresectable/metastatic PDGFRA D842V-mutant GIST. Trial registration The NAVIGATOR trial was registered at ClinicalTrials.gov as per July 2015, Identifier: NCT02508532 .

The hypereosinophilic syndrome, although uncommon, is difficult to treat, and the treatment has substantial toxic effects. This proof-of concept trial shows that treatment of patients with the hypereosinophilic syndrome with an anti–interleukin-5 monoclonal antibody, mepolizumab, improves clinical and laboratory outcomes. This proof-of concept trial shows that treatment of patients with the hypereosinophilic syndrome with an anti–interleukin-5 monoclonal antibody, mepolizumab, improves clinical and laboratory outcomes. The hypereosinophilic syndrome consists of several heterogeneous disorders characterized by sustained blood eosinophilia and eosinophil-related end-organ damage, with no identifiable cause, such as parasitic infection. 1 The objective of treatment is long-term reduction of blood and tissue eosinophil levels to prevent end-organ damage and thromboembolic events. Except for the myeloproliferative variant of the hypereosinophilic syndrome (associated with the Fip1-like 1–platelet-derived growth factor receptor α fusion gene [ FIP1L1–PDGFRA ]), for which imatinib mesylate is considered first-line therapy, current management is based on long-term systemic corticosteroids. 1 – 4 Eosinophil development from hematopoietic progenitors is regulated mainly by interleukin-5, 5 which has a selective role . . .

Constitutive JAK2 signaling is central to myeloproliferative neoplasm (MPN) pathogenesis and results in activation of STAT, PI3K/AKT, and MEK/ERK signaling. However, the therapeutic efficacy of current JAK2 inhibitors is limited. We investigated the role of MEK/ERK signaling in MPN cell survival in the setting of JAK inhibition. Type I and II JAK2 inhibition suppressed MEK/ERK activation in MPN cell lines in vitro, but not in Jak2V617F and MPLW515L mouse models in vivo. JAK2 inhibition ex vivo inhibited MEK/ERK signaling, suggesting that cell-extrinsic factors maintain ERK activation in vivo. We identified PDGFRα as an activated kinase that remains activated upon JAK2 inhibition in vivo, and PDGF-AA/PDGF-BB production persisted in the setting of JAK inhibition. PDGF-BB maintained ERK activation in the presence of ruxolitinib, consistent with its function as a ligand-induced bypass for ERK activation. Combined JAK/MEK inhibition suppressed MEK/ERK activation in Jak2V617F and MPLW515L mice with increased efficacy and reversal of fibrosis to an extent not seen with JAK inhibitors. This demonstrates that compensatory ERK activation limits the efficacy of JAK2 inhibition and dual JAK/MEK inhibition provides an opportunity for improved therapeutic efficacy in MPNs and in other malignancies driven by aberrant JAK-STAT signaling.

To investigate the possible role of imatinib, an inhibitor of the tyrosine kinase activity of PDGF-R, in desmoplastic small round cell tumor (DSRCT). From August 2005 to June 2009, DSRCT patients refractory to conventional treatment were enrolled. Patients received imatinib 400 mg daily. Primary end point of this open label, prospective, Phase II trial was objective response rate. Of the 13 enrolled patients, eight were evaluable for response. Median age was 20 years (range: 9-32). Objective responses at 3 months were: stable disease in one patient and progressive disease in seven patients. Imatinib showed no efficacy in the treatment of DSRCT unresponsive to conventional therapy, despite molecular-based selection of patients.

Diffuse midline gliomas with histone H3 lysine27-to-methionine mutations (H3K27M-glioma) are an aggressive type of childhood cancer with few options for treatment. Filbin et al. used a single-cell sequencing approach to study the oncogenic programs, genetics, and cellular hierarchies of H3K27M-glioma. Tumors were mainly composed of cells resembling oligodendrocyte precursor cells, whereas differentiated malignant cells were a smaller fraction. In comparison with other gliomas, these cancers had distinct oncogenic programs and stem cell–like profiles that contributed to their stable tumor-propagating potential. The analysis also identified a lineage-specific marker that may be useful in developing therapies. Science , this issue p. 331 Single-cell analyses of H3K27M glioma defines a putative developmental hierarchy that differs from other gliomas. Gliomas with histone H3 lysine27-to-methionine mutations (H3K27M-glioma) arise primarily in the midline of the central nervous system of young children, suggesting a cooperation between genetics and cellular context in tumorigenesis. Although the genetics of H3K27M-glioma are well characterized, their cellular architecture remains uncharted. We performed single-cell RNA sequencing in 3321 cells from six primary H3K27M-glioma and matched models. We found that H3K27M-glioma primarily contain cells that resemble oligodendrocyte precursor cells (OPC-like), whereas more differentiated malignant cells are a minority. OPC-like cells exhibit greater proliferation and tumor-propagating potential than their more differentiated counterparts and are at least in part sustained by PDGFRA signaling. Our study characterizes oncogenic and developmental programs in H3K27M-glioma at single-cell resolution and across genetic subclones, suggesting potential therapeutic targets in this disease.

Oligodendrocytes have been considered as a functionally homogeneous population in the central nervous system (CNS). We performed single-cell RNA sequencing on 5072 cells of the oligodendrocyte lineage from 10 regions of the mouse juvenile and adult CNS. Thirteen distinct populations were identified, 12 of which represent a continuum from Pdgfra⁺ oligodendrocyte precursor cells (OPCs) to distinct mature oligodendrocytes. Initial stages of differentiation were similar across the juvenile CNS, whereas subsets of mature oligodendrocytes were enriched in specific regions in the adult brain. Newly formed oligodendrocytes were detected in the adult CNS and were responsive to complex motor learning. A second Pdgfra⁺ population, distinct from OPCs, was found along vessels. Our study reveals the dynamics of oligodendrocyte differentiation and maturation, uncoupling them at a transcriptional level and highlighting oligodendrocyte heterogeneity in the CNS.

Avapritinib (AYVAKIT™) is a potent and selective tyrosine kinase inhibitor of platelet-derived growth factor receptor alpha (PDGFRA) and KIT activation loop mutants. It is being developed by Blueprint Medicines for the treatment of gastrointestinal stromal tumours (GIST), solid tumours and systemic mastocytosis. Avapritinib is approved in the USA for PDGFRA exon 18 (including D842V) mutant GIST and is undergoing regulatory assessment in the USA as a 4th-line treatment for GIST. Avapritinib is also undergoing regulatory assessment in the EU for PDGFRA D842V mutant GIST. This article summarizes the milestones in the development of avapritinib leading to this first approval for the treatment of adults with unresectable or metastatic GIST harbouring a PDGFRA exon 18 mutation, including PDGFRA D842V mutations. Clinical development of avapritinib is also underway for the treatment of systemic mastocytosis and late-stage solid tumours in several countries.

Platelet-derived growth subunit A (PDGFA) plays critical roles in development of glioblastoma (GBM) with substantial evidence from TCGA database analyses and in vivo mouse models. So far, only platelet-derived growth receptor α (PDGFRA) has been identified as receptor for PDGFA. However, PDGFA and PDGFRA are categorized into different molecular subtypes of GBM in TCGA_GBM database. Our data herein further showed that activity or expression deficiency of PDGFRA did not effectively block PDGFA activity. Therefore, PDGFRA might be not necessary for PDGFA function.To profile proteins involved in PDGFA function, we performed co-immunoprecipitation (Co-IP) and Mass Spectrum (MS) and delineated the network of PDGFA-associated proteins for the first time. Unexpectedly, the data showed that EPHA2 could be temporally activated by PDGFA even without activation of PDGFRA and AKT. Furthermore, MS, Co-IP, in vitro binding thermodynamics, and proximity ligation assay consistently proved the interaction of EPHA2 and PDGFA. In addition, we observed that high expression of EPHA2 leaded to upregulation of PDGF signaling targets in TCGA_GBM database and clinical GBM samples. Co-upregulation of PDGFRA and EPHA2 leaded to worse patient prognosis and poorer therapeutic effects than other contexts, which might arise from expression elevation of genes related with malignant molecular subtypes and invasive growth. Due to PDGFA-induced EPHA2 activation, blocking PDGFRA by inhibitor could not effectively suppress proliferation of GBM cells, but simultaneous inhibition of both EPHA2 and PDGFRA showed synergetic inhibitory effects on GBM cells in vitro and in vivo. Taken together, our study provided new insights on PDGFA function and revealed EPHA2 as a potential receptor of PDGFA. EPHA2 might contribute to PDGFA signaling transduction in combination with PDGFRA and mediate the resistance of GBM cells to PDGFRA inhibitor. Therefore, combination of inhibitors targeting PDGFRA and EHA2 represented a promising therapeutic strategy for GBM treatment.

PurposeThe platelet-derived growth factor (PDGF) signalling pathway is often dysregulated in cancer and PDGF-receptor expression has been linked to unfavourable prognostic factors in breast cancer (e.g. ER negativity, high Ki67 and high grade). This study aimed to evaluate the expression of PDGFRα, PDGFRβ and ligand PDGF-CC in breast cancer in relation to molecular subtypes and prognosis.MethodsProtein expression of tumour and/or stromal cell PDGFRα, PDGFRβ and PDGF-CC was evaluated in primary tumours (N = 489), synchronous lymph node metastases (N = 135) and asynchronous recurrences (N = 39) using immunohistochemistry in a prospectively maintained cohort of primary breast cancer patients included during 1999–2003. Distant recurrence-free interval (DRFi) was the primary end-point.ResultsHigh expression of all investigated PDGF family members correlated to increasing Nottingham histopathological grade and high Ki67. Tumour cells displayed high expression of PDGFRα in 20%, and PDGF-CC in 21% of primary tumours, which correlated with the triple-negative subtype (TNBC). Patients with high PDGF-CC had inferior prognosis (P = 0.04) in terms of 5-year DRFi, whereas PDGFRα was up-regulated in lymph node metastasis and recurrences compared to primary tumours. High primary tumour PDGFRα was associated with increased risk of central nervous system (CNS) recurrence.ConclusionsHigh PDGFRα and PDGF-CC expression were linked to breast cancer with an aggressive biological phenotype, e.g. the TNBC subtype, and high PDGF-CC increased the risk of 5-year distant recurrence. Tumour cell PDGFRα was significantly up-regulated in lymph node metastases and asynchronous recurrences. Our findings support an active role of the PDGF signalling pathway in tumour progression.