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Establishment of a Human Multiple Myeloma Xenograft Model in the Chicken to Study Tumor Growth, Invasion and Angiogenesis
Published on: May 1, 2015
A novel selective small-molecule PI3K inhibitor is effective against human multiple myeloma in vitro and in vivo
1Department of Dermatology, Venereology and Allergology, University Medical Center, Georg August University, Göttingen, Germany.
Abstract:
Developing effective therapies against multiple myeloma (MM) is an unresolved challenge. Phosphatidylinositol-3-kinase (PI3K) activation may be associated with tumor progression and drug resistance, and inhibiting PI3K can induce apoptosis in MM cells. Thus, targeting of PI3K is predicted to increase the susceptibility of MM to anticancer therapy. The lead compound of a novel class of PI3K inhibitors, BAY80-6946 (IC50=0.5 nM against PI3K-α), was highly efficacious in four different MM cell lines, where it induced significant antitumoral effects in a dose-dependent manner. The compound inhibited cell cycle progression and increased apoptosis (P<0.001 compared with controls). Moreover, it abrogated the stimulation conferred by insulin-like growth-factor-1, a mechanism relevant for MM progression. These cellular effects were paralleled by decreased Akt phosphorylation, the main downstream target of PI3K. Likewise, profound antitumoral activity was observed ex vivo, as BAY80-6946 significantly inhibited proliferation of freshly isolated myeloma cells from three patients (P<0.001 compared with vehicle). In addition, BAY80-6946 showed convincing in vivo activity against the human AMO-1 and MOLP-8 myeloma cell lines in a preclinical murine xenograft model, where treatment with 6 mg/kg every other day for 2 weeks reduced the cell numbers by 87.0% and 69.3%, respectively (P<0.001 compared with vehicle), without overt toxicity in treated animals.
Insights
A novel phosphatidylinositol-3-kinase (PI3K) inhibitor, BAY80-6946, effectively reduced multiple myeloma (MM) cell growth and induced apoptosis. This PI3K targeting agent demonstrated significant anti-tumor activity in preclinical models, offering a promising new avenue for MM therapy.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Multiple myeloma (MM) remains a therapeutic challenge with tumor progression and drug resistance.
- Phosphatidylinositol-3-kinase (PI3K) pathway activation is implicated in MM progression and resistance.
- Targeting PI3K may enhance MM cell susceptibility to anticancer treatments.
Purpose of the Study:
- To evaluate the efficacy of a novel PI3K inhibitor, BAY80-6946, against multiple myeloma.
- To investigate the molecular mechanisms underlying BAY80-6946's anti-myeloma effects.
- To assess BAY80-6946's anti-tumor activity in preclinical MM models.
Main Methods:
- In vitro studies using multiple myeloma cell lines to assess anti-proliferative and apoptotic effects.
- Analysis of cell cycle progression and downstream signaling, including Akt phosphorylation.
- Ex vivo evaluation on primary patient myeloma cells and in vivo xenograft studies in mice.
Main Results:
- BAY80-6946 demonstrated potent anti-myeloma activity in vitro, inducing apoptosis and inhibiting cell cycle progression in a dose-dependent manner.
- The compound abrogated insulin-like growth-factor-1 stimulation and decreased Akt phosphorylation.
- Significant anti-tumor efficacy was observed ex vivo in patient-derived cells and in vivo in a murine xenograft model with no overt toxicity.
Conclusions:
- BAY80-6946 is a highly efficacious PI3K inhibitor with significant anti-myeloma activity.
- Targeting PI3K with BAY80-6946 represents a promising therapeutic strategy for multiple myeloma.
- Further clinical investigation of BAY80-6946 for MM treatment is warranted.
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