This article aimed to investigate the correlations among SKA3 expression and prognosis, clinical relevance, tumor immunity, and RNA-binding protein (RBP)-involved mechanisms for overall survival (OS) in lung adenocarcinoma (LUAD). To explore the SKA3 expression level in LUAD by analyzing the genomic data as well as related clinical characteristics from the database of TCGA. Nomogram and gene set enrichment analysis (GSEA) were applied, respectively, to evaluate the performance of SKA3 in LUAD. Correlations between SKA3 and immunity and RBP-involved mechanisms were also performed. SKA3 had a higher expression level in LUAD samples than in adjacent normal lung samples, with shorter survival times in the high-SKA3-expressed LUAD subgroup (P < 0.05). qRT-PCR results remained consistent (P < 0.05). Uni-/multivariate Cox analyses revealed that SKA3 could have independent prognostic ability for LUAD (both P < 0.05). The nomogram model constructed with clinical pathological parameters and SKA3 expression levels predicted OS rates for LUAD and GSEA revealed SKA3-related pathways. In aspects of tumor immunity, SKA3 was significantly involved with tumor neoantigen burden, tumor mutational burden, immune cell pathways, and immune checkpoint inhibitor (ICI) molecules (all P < 0.05). The CellMiner database also found significant correlations between SKA3 and the antitumor drug sensitivity of chemotherapy, fenretinide, and PX-316. Besides, a total of nine LncRNA/RBP/SKA3 networks were revealed in LUAD for their RBP-involved mechanisms. SKA3 could serve as a potential biomarker for OS prognosis and immunotherapy in LUAD. LncRNA/RBP/SKA3 networks were identified in LUAD for their RBP-involved mechanisms, paving the way for further experimental verifications.

01 Oct 2006·Cancer Chemotherapy and PharmacologyQ4 · MEDICINE

The skin and hair as surrogate tissues for measuring the target effect of inhibitors of phosphoinositide-3-kinase signaling

Q4 · MEDICINE

Article

Author: Ashley R. Winkler ; Lynn Kirkpatrick ; Amanda F. Baker ; Ryan Williams ; Nathan T. Ihle ; Garth Powis

BACKGROUNDThe purpose of the study was to evaluate the use of phospho-Akt in mouse and human skin as a surrogate target for tumor phospho-Akt to measure the effect of antitumor inhibitors of phosphatidylinositol-3-kinase (PI-3-K)/Akt (protein kinase B) signaling.METHODThe expression of phosphoSer473-Akt was quantitatively assessed by Western blotting in human HT-29 colon, MCF-7 breast, A-549 non small cell lung tumor xenografts in mice, and by immunohistochemistry in mouse skin and human hair.RESULTSThe pattern of PI-3-K isoforms in human hair keratinocytes was similar to that in tumor but mouse hair keratinocytes showed a different pattern. A high level of phospho-Akt staining was present in keratinocytes of the external root sheath of the hair and was inhibited by the PI-3-K inhibitor PX-866 administered to mice, and in human hair exposed to PX-866 in culture. The inhibition of phospho-Akt by PX-866 in mouse hair keratinocytes was greater than inhibition of phospho-Akt in HT-29 and A-549 xenografts in the same mice. Phospho-Akt in mouse hair keratinocytes was inhibited by the Akt inhibitor PX-316 to a lesser degree than in MCF-7 tumor xenografts.CONCLUSIONSHair offers a way of measuring the effects of PI-3-K signaling inhibitors and, in cancer patients, may provide a readily obtainable surrogate tissue for assessing PI-3-K and phospho-Akt inhibition in tumor.

01 Jan 2004·Oncology Research Featuring Preclinical and Clinical Cancer TherapeuticsQ2 · MEDICINE

In Vivo Molecular Pharmacology and Antitumor Activity of the Targeted Akt Inhibitor PX-316

Q2 · MEDICINE

Article

Author: Baker, Amanda F. ; Powis, Garth ; Gard, Jaime M. ; Kirkpatrick, Lynn ; Stamper, Chelsea ; Ihle, Nathan ; George, Benjamin L. ; Coon, Amy ; Williams, Ryan ; Meuillet, Emmanuelle J. ; Mahadevan, Daruka

Akt, a serine/threonine kinase that promotes cell survival, is activated by binding of its pleckstrin homology (PH) domain to membrane phosphatidylinositol (PtdIns)-3-phosphates formed by PtdIns-3-kinase. D-3-Deoxy-phosphatidyl-myo-inositols that cannot be phosphorylated on the 3-position of the myo-inositol group are inhibitors of the Akt PH domain. The most active compound is D-3-deoxy-phosphatidyl-myo-inositol 1-[(R)-2-methoxy-3-octadecyloxypropyl hydrogen phosphate] (PX-316). PX-316 administered intraperitoneally to mice at 150 mg/kg inhibits Akt activation in HT-29 human tumor xenografts up to 78% at 10 h with recovery to 34% at 48 h. Phosphorylation of GSK-3beta, a downstream target of Akt, is also inhibited. There is no decrease in PtdIns(3,4,5)-trisphosphate levels by PX-316, showing it is not an inhibitor of PtdIns-3-K in vivo. Gene expression profiling of HT-29 tumor xenografts shows many similarities between the effects of PX-316 and the PtdIns-3-K inhibitor wortmannin, with downregulation of several ribosomal-related genes, while PX-316 uniquely increases the expression of a group of mitochondrial-related genes. PX-316 has antitumor activity against early human MCF-7 breast cancer and HT-29 colon cancer xenografts in mice. PX-316 formulated in 20% hydroxypropyl-beta-cyclodextrin for intravenous administration is well tolerated in mice and rats with no hemolysis and no hematological toxicity. Thus, PX-316 is the lead compound of a new class of potential agents that inhibit Akt survival signaling.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Discovery	US	Cascadian Therapeutics LLC	-

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