Halofuginone inhibits TGF-β/BMP signaling and in combination with zoledronic acid enhances inhibition of breast cancer bone metastasis

More efficient therapies that target multiple molecular mechanisms are needed for the treatment of incurable bone metastases. Halofuginone is a plant alkaloid-derivative with antiangiogenic and antiproliferative effects. Here we demonstrate that halofuginone is an effective therapy for the treatment of bone metastases, through multiple actions that include inhibition of TGFβ and BMP-signaling., Halofuginone blocked TGF-β-signaling in MDA-MB-231 and PC3 cells showed by inhibition of TGF-β–induced Smad-reporter, phosphorylation of Smad-proteins, and expression of TGF-β-regulated metastatic genes. Halofuginone increased inhibitory Smad7-mRNA and reduced TGF-β-receptor II protein. Proline supplementation but not Smad7-knockdown reversed halofuginone-inhibition of TGF-β-signaling. Halofuginone also decreased BMP-signaling. Treatment of MDA-MB-231 and PC3 cells with halofuginone reduced the BMP-Smad-reporter (BRE)4, Smad1/5/8-phosphorylation and mRNA of the BMP-regulated gene Id-1. Halofuginone decreased immunostaining of phospho-Smad2/3 and phospho-Smad1/5/8 in cancer cells in vivo., Furthermore, halofuginone decreased tumor-take and growth of orthotopic-tumors. Mice with breast or prostate bone metastases treated with halofuginone had significantly less osteolysis than control mice. Combined treatment with halofuginone and zoledronic-acid significantly reduced osteolytic area more than either treatment alone. Thus, halofuginone reduces breast and prostate cancer bone metastases in mice and combined with treatment currently approved by the FDA is an effective treatment for this devastating complication of breast and prostate-cancer

Tumor-expressed adrenomedullin accelerates breast cancer bone metastasis

INTRODUCTION: Adrenomedullin (AM) is secreted by breast cancer cells and increased by hypoxia. It is a multifunctional peptide that stimulates angiogenesis and proliferation. The peptide is also a potent paracrine stimulator of osteoblasts and bone formation, suggesting a role in skeletal metastases-a major site of treatment-refractory tumor growth in patients with advanced disease. METHODS: The role of adrenomedullin in bone metastases was tested by stable overexpression in MDA-MB-231 breast cancer cells, which cause osteolytic bone metastases in a standard animal model. Cells with fivefold increased expression of AM were characterized in vitro, inoculated into immunodeficient mice and compared for their ability to form bone metastases versus control subclones. Bone destruction was monitored by X-ray, and tumor burden and osteoclast numbers were determined by quantitative histomorphometry. The effects of AM overexpression on tumor growth and angiogenesis in the mammary fat pad were determined. The effects of AM peptide on osteoclast-like multinucleated cell formation were tested in vitro. A small-molecule AM antagonist was tested for its effects on AM-stimulated ex vivo bone cell cultures and co-cultures with tumor cells, where responses of tumor and bone were distinguished by species-specific real-time PCR. RESULTS: Overexpression of AM mRNA did not alter cell proliferation in vitro, expression of tumor-secreted factors or cell cycle progression. AM-overexpressing cells caused osteolytic bone metastases to develop more rapidly, which was accompanied by decreased survival. In the mammary fat pad, tumors grew more rapidly with unchanged blood vessel formation. Tumor growth in the bone was also more rapid, and osteoclasts were increased. AM peptide potently stimulated bone cultures ex vivo; responses that were blocked by small-molecule adrenomedullin antagonists in the absence of cellular toxicity. Antagonist treatment dramatically suppressed tumor growth in bone and decreased markers of osteoclast activity. CONCLUSIONS: The results identify AM as a target for therapeutic intervention against bone metastases. Adrenomedullin potentiates osteolytic responses in bone to metastatic breast cancer cells. Small-molecule antagonists can effectively block bone-mediated responses to tumor-secreted adrenomedullin, and such agents warrant development for testing in vivo

Wide-field dynamic astronomy in the near-infrared with Palomar Gattini-IR and DREAMS

There have been a dramatic increase in the number of optical and radio transient surveys due to astronomical transients such as gravitational waves and gamma ray bursts, however, there have been a limited number of wide-field infrared surveys due to narrow field-of-view and high cost of infrared cameras, we present two new wide-field near-infrared fully automated surveyors; Palomar Gattini-IR and the Dynamic REd All-sky Monitoring Survey (DREAMS). Palomar Gattini-IR, a 25 square degree J-band imager that begun science operations at Palomar Observatory, USA in October 2018; we report on survey strategy as well as telescope and observatory operations and will also providing initial science results. DREAMS is a 3.75 square degree wide-field imager that is planned for Siding Spring Observatory, Australia; we report on the current optical and mechanical design and plans to achieve on-sky results in 2020. DREAMS is on-track to be one of the first astronomical telescopes to use an Indium Galium Arsenide (InGaAs) detector and we report initial on-sky testing results for the selected detector package. DREAMS is also well placed to take advantage and provide near-infrared follow-up of the LSST

Halofuginone inhibits the establishment and progression of melanoma bone metastases

Transforming growth factor (TGF-β) derived from bone fuels melanoma bone metastases by inducing tumor secretion of pro-metastatic factors that act on bone cells to change the skeletal microenvironment. Halofuginone is a plant alkaloid derivative that blocks TGF-β signaling with antiangiogenic and antiproliferative properties. Here, we demonstrate for the first time that halofuginone therapy decreases development and progression of bone metastasis caused by melanoma cells through inhibition of TGF-β signaling. Halofuginone treatment of human melanoma cells inhibited cell proliferation, phosphorylation of SMAD proteins in response to TGF-β, and TGF-β-induced SMAD-driven transcription. In addition, halofuginone reduced expression of TGF-β target genes that enhance bone metastases, including PTHrP, CTGF, CXCR4, and IL11. Also, cell apoptosis was increased in response to halofuginone. In nude mice inoculated with 1205Lu melanoma cells, a preventive protocol with halofuginone inhibited bone metastasis. The beneficial effects of halofuginone treatment were comparable to those observed with other anti-TGF-β strategies, including systemic administration of SD208, a small molecule inhibitor of TGF-β receptor I kinase, or forced overexpression of Smad7, a negative regulator of TGF-β signaling. Furthermore, mice with established bone metastases treated with halofuginone had significantly less osteolysis than mice receiving placebo assessed by radiographys. Thus, halofuginone is also effective in reducing the progression of melanoma bone metastases. Moreover, halofuginone treatment reduced melanoma metastasis to the brain, showing the potential of this novel treatment against cancer metastasis

Brain energy metabolism: A roadmap for future research

Although we have learned much about how the brain fuels its functions over the last decades, there remains much still to discover in an organ that is so complex. This article lays out major gaps in our knowledge of interrelationships between brain metabolism and brain function, including biochemical, cellular, and subcellular aspects of functional metabolism and its imaging in adult brain, as well as during development, aging, and disease. The focus is on unknowns in metabolism of major brain substrates and associated transporters, the roles of insulin and of lipid droplets, the emerging role of metabolism in microglia, mysteries about the major brain cofactor and signaling molecule NAD+, as well as unsolved problems underlying brain metabolism in pathologies such as traumatic brain injury, epilepsy, and metabolic downregulation during hibernation. It describes our current level of understanding of these facets of brain energy metabolism as well as a roadmap for future research

Wide-field dynamic astronomy in the near-infrared with Palomar Gattini-IR and DREAMS

There have been a dramatic increase in the number of optical and radio transient surveys due to astronomical transients such as gravitational waves and gamma ray bursts, however, there have been a limited number of wide-field infrared surveys due to narrow field-of-view and high cost of infrared cameras, we present two new wide-field near-infrared fully automated surveyors; Palomar Gattini-IR and the Dynamic REd All-sky Monitoring Survey (DREAMS). Palomar Gattini-IR, a 25 square degree J-band imager that begun science operations at Palomar Observatory, USA in October 2018; we report on survey strategy as well as telescope and observatory operations and will also providing initial science results. DREAMS is a 3.75 square degree wide-field imager that is planned for Siding Spring Observatory, Australia; we report on the current optical and mechanical design and plans to achieve on-sky results in 2020. DREAMS is on-track to be one of the first astronomical telescopes to use an Indium Galium Arsenide (InGaAs) detector and we report initial on-sky testing results for the selected detector package. DREAMS is also well placed to take advantage and provide near-infrared follow-up of the LSST

Palomar Gattini-IR: Survey overview, data processing system, on-sky performance and first results

Palomar Gattini-IR is a new wide-field, near-infrared (NIR) robotic time domain survey operating at Palomar Observatory. Using a 30 cm telescope mounted with a H2RG detector, Gattini-IR achieves a field of view (FOV) of 25 sq. deg. with a pixel scale of 8.”7 in J-band. Here, we describe the system design, survey operations, data processing system and on-sky performance of Palomar Gattini-IR. As a part of the nominal survey, Gattini-IR scans ≈7500 square degrees of the sky every night to a median 5σ depth of 15.7 AB mag outside the Galactic plane. The survey covers ≈15,000 square degrees of the sky visible from Palomar with a median cadence of 2 days. A real-time data processing system produces stacked science images from dithered raw images taken on sky, together with point-spread function (PSF)-fit source catalogs and transient candidates identified from subtractions within a median delay of ≈4 hr from the time of observation. The calibrated data products achieve an astrometric accuracy (rms) of ≈0.”7 with respect to Gaia DR2 for sources with signal-to-noise ratio > 10, and better than ≈0.”35 for sources brighter than ≈12 Vega mag. The photometric accuracy (rms) achieved in the PSF-fit source catalogs is better than ≈3% for sources brighter than ≈12 Vega mag and fainter than the saturation magnitude of ≈8.5 Vega mag, as calibrated against the Two Micron All Sky Survey catalog. The detection efficiency of transient candidates injected into the images is better than 90% for sources brighter than the 5σ limiting magnitude. The photometric recovery precision of injected sources is 3% for sources brighter than 13 mag, and the astrometric recovery rms is ≈0.”9. Reference images generated by stacking several field visits achieve depths of ≳16.5 AB mag over 60% of the sky, while it is limited by confusion in the Galactic plane. With a FOV ≈40× larger than any other existing NIR imaging instrument, Gattini-IR is probing the reddest and dustiest transients in the local universe such as dust obscured supernovae in nearby galaxies, novae behind large columns of extinction within the galaxy, reddened microlensing events in the Galactic plane and variability from cool and dust obscured stars. We present results from transients and variables identified since the start of the commissioning period