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Therapeutic Potency of PI3K Pharmacological Inhibitors of Gastrointestinal Cancer.

ABSTRACT: Therapeutic targeting of phosphatidyl-inositol 3-kinase (PI3K) is considered as a possible strategy in several types of cancer, including gastrointestinal ones. In vitro and in vivo studies indicated the significance of proapoptotic and antiproliferative inhibition of PI3K. Although there are many phase 1 and 2 clinical trials on PI3K inhibitors in patients with gastrointestinal cancer, the molecular mechanism of PI3K targeting PI3K/ mTOR pathway is not clear. Panclass I, isoformselective, and dual PI3K/mTOR inhibitors are under investigation. This review aimed to indicate PI3K-dependent targeting mechanisms in gastrointestinal cancer and the evaluation of related clinical data.

SUBMITTER: Hashemzadeh K

PROVIDER: S-EPMC6488499 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Therapeutic Potency of PI3K Pharmacological Inhibitors of Gastrointestinal Cancer.

Hashemzadeh Kamelia K Jokar Mohammad Hassan MH Sedighi Sima S Moradzadeh Maliheh M

Middle East journal of digestive diseases 20181121 1

Therapeutic targeting of phosphatidyl-inositol 3-kinase (PI3K) is considered as a possible strategy in several types of cancer, including gastrointestinal ones. In vitro and in vivo studies indicated the significance of proapoptotic and antiproliferative inhibition of PI3K. Although there are many phase 1 and 2 clinical trials on PI3K inhibitors in patients with gastrointestinal cancer, the molecular mechanism of PI3K targeting PI3K/ mTOR pathway is not clear. Panclass I, isoformselective, and d ...[more]

PMID: 31049177

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Project description:We have studied the tumor genomic evolution in a patient with metastatic breast cancer bearing an activating PIK3CA mutation. The patient was treated with the PI3Kα inhibitor BYL719 and achieved a lasting clinical response on BYL719, but eventually progressed to treatment and died shortly thereafter. A rapid autopsy was performed and a total of 14 metastatic lesions were collected for further analysis. In order to identify possible genetic determinants of acquired resistance to PI3Kα inhibition, we took a three-step approach. First, we examined both the primary tumor (before BYL719 treatment) and the new lung metastasis by whole genome sequencing (DNA from the spleen was used as a normal control). Then, we analyzed the primary tumor, lung metastasis, and the peri-aortic lesion that remained stable (responding) at the time of progression to BYL719 therapy by whole exome sequencing. Finally, to confirm and expand our findings, we sequenced the primary tumor and all the metastatic lesions to >500-fold coverage using a custom targeted deep-sequencing assay, MSK-IMPACT. Using this 3-step approach, we have demonstrated that patient’s lesion underwent parallel genetic evolution at multiple metastatic sites with different PTEN genomic alterations leading to a convergent PTEN- null phenotype resistant to PI3Kα inhibition. In order to expand our observations, we analyzed paired samples (pre-treatment and at progression) from six additional patients enrolled in the BYL719 trial. Acquired bi-allelic loss of PTEN was found in one additional patient treated with BYL719 whereas in two patients PIK3CA mutations present in the primary tumor were no longer detected at the time of progression. To functionally characterize our findings, inducible PTEN knockdown in sensitive cells resulted in resistance to BYL719, while simultaneous PI3K-p110β blockade reverted this resistance phenotype, both in cell lines and in PTEN-null xenografts derived from our patient. We conclude that parallel genetic evolution of separate sites with different PTEN genomic alterations leads to a convergent PTEN-null phenotype resistant to PI3Kα inhibition.

Project description:BackgroundFicus palmata (Fig), are distributed in different parts of the world, and are used in traditional medicine to treat various ailments including inflammation, tumor, epilepsy, jaundice, influenza and bacillary dysentery. The present study aimed to evaluate the antidiarrheal, antisecretary, antispasmodic, antiulcer and anti motility properties of Ficus palmata.MethodsIn-vivo, in-vitro and in-silico techniques were used to investigate various gastrointestinal effects of Ficus palmata. Antidiarrheal, antisecretary, antispasmodic, antiulcer, anti motility and molecular docking were performed using castor oil induced diarrhea and fluid accumulation, isolated tissue preparations, ethanol-HCl induced ulcer assay, charcoal meal transit time and Auto Doc Vina.ResultsFicus palmata crude extract (Fp.Cr) exhibited protection against castor oil-induced diarrhea in mice and dose-dependently inhibited intestinal fluid secretions. Fp.Cr caused relaxation of spontaneous and K+ (80 Mm)-induced contractions in isolated rabbit jejunum preparations. It showed protective effect against gastric ulcers induced by ethanol-hydrochloric acid in rats. Fp.Cr reduced distance travelled by charcoal meal in the gastrointestinal transit model in mice. The plant constituents: psoralenoside and bergapten showed high binding affinities (E-value ≥ - 6.5 Kcal/mol) against histaminergic H1, calmodulin and voltage gated L-type calcium channels, while showed moderate affinities (E-value ≥7 Kcal/mol) against dopaminergic D2, adrenergic α1, muscranic M3, mu-opioid, whereas revealed lower affinities (E-value ≥9.5 Kcal/mol) vs. muscranic M1, histaminergic H2 and H+/K+ ATPase pump. Germanicol acetate and psoralene exhibited weak affinities against aforementioned targets.ConclusionThis study reveals that Ficus palmata possesses anti-diarrheal, anti-secretory, anti-spasmodic, anti-motility and anti-ulcer activities. The various constituents reveal different binding affinities against target proteins, which mediate the gastrointestinal functions.

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Therapeutic Potency of PI3K Pharmacological Inhibitors of Gastrointestinal Cancer.

Publications

Therapeutic Potency of PI3K Pharmacological Inhibitors of Gastrointestinal Cancer.

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