Related Experiment Videos

Isoform specific inhibitors of PI3 kinase in glioma

Qi-Wen Fan1, William A Weiss

  • 1Department of Neurology, Pediatrics, Neurological Surgery, and Brain Tumor Research Center, Comprehensive Cancer Center, San Francisco, California 94143, USA.

Cell Cycle (Georgetown, Tex.)
|November 15, 2006
PubMed

Insights

Targeting the PI3 kinase pathway in cancer is promising. Dual inhibition of PI3Kalpha and mTOR effectively suppressed glioma cell proliferation, suggesting a new therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • The phosphoinositide 3-kinase (PI3K) pathway is frequently activated in human cancers, making it a key target for drug development.
  • The PI3K family comprises multiple isoforms with diverse roles, and identifying the most effective targets for cancer therapy remains a challenge.

Purpose of the Study:

  • To investigate the efficacy of targeting specific PI3K isoforms and related kinases in glioma, a cancer with high PI3K pathway activation.
  • To evaluate the potential of dual inhibition strategies for cancer treatment.

Main Methods:

  • Screening of drug-like molecules targeting the PI3K enzyme family in glioma models.
  • Assessment of the effects of inhibiting PI3Kalpha and mTOR on glioma cell proliferation.

Main Results:

  • PI3Kalpha was identified as a major driver of malignant progression in glioma.
  • Inhibition of PI3Kalpha alone was insufficient to halt glioma cell growth.
  • A single agent targeting both PI3Kalpha and mTOR effectively inhibited glioma cell proliferation by disrupting feedback loops.

Conclusions:

  • Dual inhibition of PI3Kalpha and mTOR represents a promising therapeutic strategy for glioma.
  • Targeting multiple nodes within the PI3K pathway, including feedback mechanisms, is essential for maximal therapeutic effect in cancer.

Related Concept Videos

PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a rapamycin-insensitive companion...
The JAK-STAT Signaling Pathway01:20

The JAK-STAT Signaling Pathway

Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...
Phosphoinositides and PIPs01:42

Phosphoinositides and PIPs

Phosphoinositides are a group of phospholipids containing a glycerol backbone with two fatty acid chains and a phosphate attached to a myoinositol sugar ring. The inositol head group extends into the cytoplasm, where it is modified by adding phosphate groups to form phosphatidylinositol phosphates or PIPs.
Different phosphoinositides are synthesized and recruited on the cytosolic face of the plasma membrane. The localization of specific phosphoinositides concentrated in separate membrane...
Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
Dipeptidyl Peptidase 4 Inhibitors01:23

Dipeptidyl Peptidase 4 Inhibitors

Dipeptidyl peptidase 4 (DPP-4) is a serine protease widely distributed in the body. It's involved in the inactivation of GLP-1 and GIP hormones, which are crucial for insulin regulation. DPP-4 inhibitors, such as sitagliptin (Januvia), saxagliptin (Onglyza), linagliptin (Tradjenta), alogliptin (Nesina), and vildagliptin (Galvus), help increase the proportion of active GLP-1, enhancing insulin secretion. These inhibitors work by competitively binding to DPP-4. This binding causes a significant...