Inhibition of wild-type p53-expressing AML by novel small molecule HDM2 inhibitor, CGM097

The tumor suppressor, p53, is a key regulator of apoptosis and functions upstream in the apoptotic cascade by both indirectly and directly regulating Bcl-2 family proteins. In cells expressing wild-type (wt) p53, the Human Double Minute 2 (HDM2) protein binds to p53 and blocks its activity. Inhibition of HDM2:p53 interaction activates p53 and causes apoptosis or cell cycle arrest. We have characterized the novel HDM2 inhibitor, CGM097, as having significant activity against wt p53-expressing acute myeloid leukemia (AML). Specifically, CGM097 potently and selectively inhibited the proliferation of human AML cell lines and primary AML cells expressing wt p53, but not mutant p53, in a target-specific manner. Several patient samples that harbored mutant p53 were comparatively unresponsive to CGM097. Synergy was observed when CGM097 was combined with FLT3 inhibition against mutant FLT3-expressing cells, as well as when combined with MEK inhibition in cells with activated MAPK signaling. Finally, CGM097 was effective in reducing leukemia burden in vivo. Taken together, these data suggest that CGM097 might be a promising treatment for AML characterized as harboring wt p53 as a single agent, as well as possibly in combination with another targeted therapy using tyrosine kinase inhibitors (TKIs) against oncogenes that drive AML

Inhibition of wild-type p53-expressing AML by the novel small molecule HDM2 inhibitor CGM097

The tumor suppressor p53 is a key regulator of apoptosis and functions upstream in the apoptotic cascade by both indirectly and directly regulating Bcl-2 family proteins. In cells expressing wild-type (WT) p53, the HDM2 protein binds to p53 and blocks its activity. Inhibition of HDM2:p53 interaction activates p53 and causes apoptosis or cell-cycle arrest. Here, we investigated the ability of the novel HDM2 inhibitor CGM097 to potently and selectively kill WT p53-expressing AML cells. The antileukemic effects of CGM097 were studied using cellbased proliferation assays (human AML cell lines, primary AML patient cells, and normal bone marrow samples), apoptosis, and cell-cycle assays, ELISA, immunoblotting, and an AML patient-derived in vivo mouse model. CGM097 potently and selectively inhibited the proliferation of human AML cell lines and the majority of primary AML cells expressing WT p53, but not mutant p53, in a target-specific manner. Several patient samples that harbored mutant p53 were comparatively unresponsive to CGM097. Synergy was observed when CGM097 was combined with FLT3 inhibition against oncogenic FLT3-expressing cells cultured both in the absence as well as the presence of cytoprotective stromal-secreted cytokines, as well as when combined with MEK inhibition in cells with activated MAPK signaling. Finally, CGM097 was effective in reducing leukemia burden in vivo. These data suggest that CGM097 is a promising treatment for AML characterized as harboring WT p53 as a single agent, as well as in combination with other therapies targeting oncogene-activated pathways that drive AML

SORCS1 Alters Amyloid Precursor Protein Processing and Variants May Increase Alzheimer's Disease Risk

OBJECTIVE: Sorting mechanisms that cause the amyloid precursor protein (APP) and the β-secretases and γ-secretases to colocalize in the same compartment play an important role in the regulation of Aβ production in Alzheimer’s disease (AD). We and others have reported that genetic variants in the Sortilin-related receptor (SORL1) increased the risk of AD, that SORL1 is involved in trafficking of APP, and that under expression of SORL1 leads to overproduction of Aβ. Here we explored the role of one of its homologs, the sortilin-related VPS10 domain containing receptor 1 (SORCS1), in AD. METHODS: We analyzed the genetic associations between AD and 16 SORCS1–single nucleotide polymorphisms (SNPs) in 6 independent data sets (2,809 cases and 3,482 controls). In addition, we compared SorCS1 expression levels of affected and unaffected brain regions in AD and control brains in microarray gene expression and real-time polymerase chain reaction (RT-PCR) sets, explored the effects of significant SORCS1-SNPs on SorCS1 brain expression levels, and explored the effect of suppression and overexpression of the common SorCS1 isoforms on APP processing and Aβ generation. RESULTS: Inherited variants in SORCS1 were associated with AD in all datasets (0.001 < p < 0.049). In addition, SorCS1 influenced APP processing. While overexpression of SorCS1 reduced γ-secretase activity and Aβ levels, the suppression of SorCS1 increased γ-secretase processing of APP and the levels of Aβ. INTERPRETATIONS: These data suggest that inherited or acquired changes in SORCS1 expression or function may play a role in the pathogenesis of AD

Cross‐sectional and longitudinal evaluation of plasma glial fibrillary acidic protein to detect and predict clinical syndromes of Alzheimer's disease

Abstract Introduction This study examined plasma glial fibrillary acidic protein (GFAP) as a biomarker of cognitive impairment due to Alzheimer's disease (AD) with and against plasma neurofilament light chain (NfL), and phosphorylated tau (p‐tau)181+231. Methods Plasma samples were analyzed using Simoa platform for 567 participants spanning the AD continuum. Cognitive diagnosis, neuropsychological testing, and dementia severity were examined for cross‐sectional and longitudinal outcomes. Results Plasma GFAP discriminated AD dementia from normal cognition (adjusted mean difference = 0.90 standard deviation [SD]) and mild cognitive impairment (adjusted mean difference = 0.72 SD), and demonstrated superior discrimination compared to alternative plasma biomarkers. Higher GFAP was associated with worse dementia severity and worse performance on 11 of 12 neuropsychological tests. Longitudinally, GFAP predicted decline in memory, but did not predict conversion to mild cognitive impairment or dementia. Discussion Plasma GFAP was associated with clinical outcomes related to suspected AD and could be of assistance in a plasma biomarker panel to detect in vivo AD