Epithelioid inflammatory myofibroblastic sarcoma (eIMS) is characterised by perinuclear ALK localisation, CD30 expression and early relapse despite crizotinib treatment. We aimed to identify ...therapies to prevent and/or treat ALK inhibitor resistance.
Malignant ascites, from an eIMS patient at diagnosis and following multiple relapses, were used to generate matched diagnosis and relapse xenografts.
Xenografts were validated by confirmation of RANBP2-ALK rearrangement, perinuclear ALK localisation and CD30 expression. Although brentuximab-vedotin (BV) demonstrated single-agent activity, tumours regrew during BV therapy. BV resistance was associated with reduced CD30 expression and induction of ABCB1. BV resistance was reversed in vitro by tariquidar, but combination BV and tariquidar treatment only briefly slowed xenograft growth compared with BV alone. Combining BV with either crizotinib or ceritinib resulted in marked tumour shrinkage in both xenograft models, and resulted in prolonged tumour-free survival in the diagnosis compared with the relapse xenograft.
CD30 is a therapeutic target in eIMS. BV efficacy is limited by the rapid emergence of resistance. Prolonged survival with combination ALK and CD30-targeted-therapy in the diagnosis model provides the rationale to trial this combination in eIMS patients at diagnosis. This combination could also be considered for other CD30-positive, ALK-rearranged malignancies.
Background: Only 2 small studies have examined the use of glucagon-like peptide-1 (GLP-1) receptor agonists with U-500 insulin, with mixed results. Moreover, there are no studies to our knowledge ...that have investigated use of sodium-glucose cotransporter-2 (SGLT-2) inhibitors with U-500 insulin therapy. Objective: This research was designed to determine the effectiveness of GLP-1 agonists and SGLT-2 inhibitors in patients already taking U-500 insulin. Methods: A retrospective chart review was conducted on patients using U-500 insulin to which a GLP-1 agonist or SGLT-2 inhibitor was added as their treatment protocol. The primary outcome measure was change in glycosylated hemoglobin (A1C) after 3 to 6 months on the additional therapy. Secondary outcomes included A1C change at 12 months, changes in total daily dose (TDD) of U-500 insulin, body mass index (BMI) and body weight from baseline, and episodes of hypoglycemia. Results: A total of 17 patients were included in the review. The combination of a GLP-1 agonist and/or SGLT-2 inhibitor with U-500 insulin resulted in significant reductions in A1C (0.84%, P = 0.004) and TDD of U-500 insulin (33.5 units, P = 0.031) at the 3- to 6-month interval. Furthermore, statistically significant decreases in mean BMI and body weight were observed 12 months postbaseline. Hypoglycemia occurred in the majority of patients (64.7%). Conclusion and Relevance: This is the first study to examine SGLT-2 inhibitors in combination with U-500 insulin therapy. Clinically, the addition of a GLP-1 agonist and/or SGLT-2 inhibitor can improve A1C and decrease TDD, BMI, and body weight.
Marine Protected Areas (MPAs) provide an important tool for conservation of marine ecosystems. To be most effective, these areas should be strategically located in a manner that supports ecosystem ...function. To inform marine spatial planning and support strategic establishment of MPAs within the California Current System, we identified areas predicted to support multispecies aggregations of seabirds ("hotspots"). We developed habitat-association models for 16 species using information from at-sea observations collected over an 11-year period (1997-2008), bathymetric data, and remotely sensed oceanographic data for an area from north of Vancouver Island, Canada, to the USA/Mexico border and seaward 600 km from the coast. This approach enabled us to predict distribution and abundance of seabirds even in areas of few or no surveys. We developed single-species predictive models using a machine-learning algorithm: bagged decision trees. Single-species predictions were then combined to identify potential hotspots of seabird aggregation, using three criteria: (1) overall abundance among species, (2) importance of specific areas ("core areas") to individual species, and (3) predicted persistence of hotspots across years. Model predictions were applied to the entire California Current for four seasons (represented by February, May, July, and October) in each of 11 years. Overall, bathymetric variables were often important predictive variables, whereas oceanographic variables derived from remotely sensed data were generally less important. Predicted hotspots often aligned with currently protected areas (e.g., National Marine Sanctuaries), but we also identified potential hotspots in Northern California/Southern Oregon (from Cape Mendocino to Heceta Bank), Southern California (adjacent to the Channel Islands), and adjacent to Vancouver Island, British Columbia, that are not currently included in protected areas. Prioritization and identification of multispecies hotspots will depend on which group of species is of highest management priority. Modeling hotspots at a broad spatial scale can contribute to MPA site selection, particularly if complemented by fine-scale information for focal areas.
Biomarkers which better match anticancer drugs with cancer driver genes hold the promise of improved clinical responses and cure rates. We developed a precision medicine platform of rapid ...high‐throughput drug screening (HTS) and patient‐derived xenografting (PDX) of primary tumor tissue, and evaluated its potential for treatment identification among 56 consecutively enrolled high‐risk pediatric cancer patients, compared with conventional molecular genomics and transcriptomics. Drug hits were seen in the majority of HTS and PDX screens, which identified therapeutic options for 10 patients for whom no targetable molecular lesions could be found. Screens also provided orthogonal proof of drug efficacy suggested by molecular analyses and negative results for some molecular findings. We identified treatment options across the whole testing platform for 70% of patients. Only molecular therapeutic recommendations were provided to treating oncologists and led to a change in therapy in 53% of patients, of whom 29% had clinical benefit. These data indicate that in vitro and in vivo drug screening of tumor cells could increase therapeutic options and improve clinical outcomes for high‐risk pediatric cancer patients.
Synopsis
A precision diagnostic platform integrating genomics and transcriptomics with drug testing of patient's primary tumor cells in high throughput drug screening (HTS) and patient‐derived xenograft (PDX) was established to improve identification of therapies in high‐risk pediatric cancer patients.
Treatment options could be identified for 70% of patients across the four‐part platform.
HTS provided orthogonal proof of drug efficacy suggested by molecular analyses and identified many new drug responses without prior molecular hallmarks.
Effective treatments were observed in more than half of PDX models.
There was a strong correlation between HTS and PDX results, and the clinical responses in patients.
A precision diagnostic platform integrating genomics and transcriptomics with drug testing of patient's primary tumor cells in high throughput drug screening (HTS) and patient‐derived xenograft (PDX) was established to improve identification of therapies in high‐risk pediatric cancer patients.
Summary Natural regeneration of farmland areas following landuse change has the potential to reinstate native vegetation and landscape processes across larger scales than intentional works. However, ...few examples of large‐scale natural regeneration have been reported from southern Australia. In this study we use historical air photos to document the rate of establishment of natural regeneration in central Victoria following a change from agricultural to rural residential land use. In 2009, regrowth patches occupied 8185 ha, or 12.3% of the cleared landscape in the study region, mostly on relatively low fertility soils. Most of this area (6216 ha) supported Cassinia shrubland, with eucalypts encroaching as patches get older. On average, native vegetation has regenerated over nearly 1800 ha every decade since the mid‐1960s. If this trend continues, regrowth will occupy 20% of infertile soils on private land by 2025. This region now appears to support one of the largest examples of old field succession recorded from south‐eastern Australia. Regrowth patches are likely to provide many conservation benefits, although little information exists on habitat values provided by regrowth shrublands. Since regeneration is on private land, perceptions of whether regrowth is ‘good’ or ‘bad’ will vary according to landholder goals, as will future management of regrowth patches. Consequently, considerable ecological and social research is required to understand the ecosystem services and disservices which regrowth provides to both landholders and biota.
Leptin, the protein product of the adipose tissue-specific ob (obese) gene (1), reduces the body weight, adiposity and food intake of obese ob/ob mice on peripheral or central injection (2, 3, 4). ...125Ileptin binding has been detected in mouse choroid plexus (5), from which a leptin receptor gene was expression cloned (5). The gene has at least 6 splice variants (6, 7). Leptin receptor mRNA was localized in the hypothalamus by in situ hybridization being particularly abundantly expressed in the arcuate nucleus (8). There is evidence linking the physiological effects of injected leptin with hypothalamic neuropeptide Y (9, 10) (NPY), which has potent central effects on food intake and energy balance (11), and is also expressed in the arcuate nucleus. Here we report dual in situ hybridization studies for leptin receptor and NPY gene expression in the mouse arcuate nucleus, where the majority of cells examined expressed both genes. This provides the first direct evidence that leptin acts on cells that express NPY mRNA.
Abstract
Rationale: Inflammatory myofibroblastic tumors (IMTs) are a particularly rare type of soft tissue sarcoma comprised of myofibroblastic spindle cells and an accompanying inflammatory ...infiltrate. There is an unmet clinical need for effective treatment regimens for patients diagnosed with IMT with anaplastic lymphoma kinase (ALK) rearrangement, who relapse following ALK inhibitor (ALKi) therapy or who present with aggressive disease. Fusion of RAN Binding Protein 2 (RANBP2) with ALK in IMT is associated with aggressive disease and has been correlated with tumor cell expression of CD30. This study investigated CD30 as a potential therapeutic target in IMT and the efficacy of the CD30-targeted antibody-monomethyl auristatin E conjugate, Brentuximab Vedotin (BV).
Methods and Results: In a cohort of five recent IMT patients at the Sydney Children’s Hospital, RANBP2-ALK fusion was identified in three patients (IMT1, IMT2 and IMT3) by RNA capture sequencing, while patients IMT4 and IMT5 (who did not relapse) harbored CLTC-ALK or SEC31A-ALK fusions respectively. Expression of CD30 was confirmed two of three RANBP2-ALK fusion positive tumors by immunohistochemistry. We established cell cultures and xenografts from malignant ascites of IMT1, at diagnosis (IMT1A) and at relapse (IMT1D) after treatment with ALKi’s and low dose chemotherapy. CD30 expression was retained in the cell cultures and xenograft tumors, as demonstrated by flow cytometry and tumor histology. BV was investigated as a potential treatment for IMT with RANBP2-ALK fusion. BV reduced IMT1A and IMT1D cell viability in vitro in resazurin cell viability assays. IMT1A and IMT1D xenograft mice had a partial response to BV which significantly (p<0.0001) prolonged survival compared to untreated controls. However, tumors eventually recurred. Resistance to BV correlated with upregulation of P-glycoprotein and reduced CD30 antigen expression in cells from treated IMT xenograft tumors. The combination of the ALK inhibitor crizotinib with BV has also been investigated. In vivo, the combination of crizotinib and BV resulted in complete resolution of tumor and significantly (p<0.0001) improved survival compared to the individual agents.
Conclusion: CD30 is a promising therapeutic target in RANBP2-ALK-rearranged IMT. BV successfully reduced IMT cell viability in vitro and prolonged survival in IMT xenografted mice, both as a single agent and when given in combination with crizotinib. Since BV is current clinical use for the treatment of Hodgkin lymphoma it may be possible to rapidly translate these findings into clinical practice for the treatment of IMT.
Citation Format: Ashleigh M. Fordham, James Blackburn, Erin E. Heyer, Jinhan Xie, Emily V. Mould, Andrew J. Gifford, Lisa T. Morgan, Carol Wadham, Mitali Fadia, Jamie I. Fletcher, Karen L. MacKenzie, Toby N. Trahair. Targeting CD30 as a novel treatment strategy in RANBP2-ALK-rearranged inflammatory myofibroblastic tumor abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4824.
In the sheep, it has been shown that the pars tuberalis of the pituitary may mediate the photoperiodic control of seasonal changes in prolactin secretion. High concentrations of melatonin receptors ...are present on the ovine pars tuberalis and melatonin is known to inhibit forskolin-stimulated cyclic AMP production in this tissue. Other hormonal inputs to the ovine pars tuberalis have not yet been identified. In the rat mRNA for the IGF-I receptor has been identified in the pars tuberalis using in situ hybridization. In order to define whether IGF-I may influence the function of the ovine pars tuberalis the presence of receptors for IGF-I has been investigated. Using in vitro autoradiography specific 125IIGF-I binding was found in high concentrations over the ovine pars tuberalis particularly associated with certain of the capillaries. Homogenate receptor assays showed saturable specific binding of 125IIGF-I with a mean dissociation constant (Kd) of 0.5 +/- 0.1 nM (n = 4). Competition studies revealed a rank order of potency of IGF-I > IGF-II > > > insulin, in displacing 125IIGF-I binding, indicative of a mixed population of IGF-I and IGF-II/mannose-6-phosphate receptors and insulin-like growth factor binding proteins (IGFBPs). Cross-linking of 125IIGF-I to pars tuberalis membrane homogenates and analysis by SDS-PAGE under reducing conditions confirmed the presence of both IGF-I receptors and binding proteins. Autophosphorylation of a 97 kDa substrate, compatible with the beta-sub-unit of the IGF-I receptor, was increased in the presence of IGF-I, indicating the existence of functional IGF-I receptors on the ovine pars tuberalis. In contrast in the rat 125IIGF-I binding was restricted to the median eminence region of the brain and was not detectable over the pars tuberalis.
Summary Natural regeneration of farmland areas following landuse change has the potential to reinstate native vegetation and landscape processes across larger scales than intentional works. However, ...few examples of large-scale natural regeneration have been reported from southern Australia. In this study we use historical air photos to document the rate of establishment of natural regeneration in central Victoria following a change from agricultural to rural residential land use. In 2009, regrowth patches occupied 8185ha, or 12.3% of the cleared landscape in the study region, mostly on relatively low fertility soils. Most of this area (6216ha) supported Cassinia shrubland, with eucalypts encroaching as patches get older. On average, native vegetation has regenerated over nearly 1800ha every decade since the mid-1960s. If this trend continues, regrowth will occupy 20% of infertile soils on private land by 2025. This region now appears to support one of the largest examples of old field succession recorded from south-eastern Australia. Regrowth patches are likely to provide many conservation benefits, although little information exists on habitat values provided by regrowth shrublands. Since regeneration is on private land, perceptions of whether regrowth is 'good' or 'bad' will vary according to landholder goals, as will future management of regrowth patches. Consequently, considerable ecological and social research is required to understand the ecosystem services and disservices which regrowth provides to both landholders and biota.
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