September 2007 Molecular Cancer Therapeutics Highlights

Selected Articles from the September 1, 2007 Issue

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View the Table of Contents for the September 2007 issue of Molecular Cancer Therapeutics

Branched Neurotensin Peptides Increase Drug Selectivity

Falciani et al.

Page 2441

Receptors for endogenous peptides are over-expressed in different human tumors and might be suitable for tumor targeting. Falciani and colleagues developed stable tetra-branched peptides containing the 8–13 sequence of human Neurotensin (NT) linked to different units for tumor therapy or imaging. Fluorescent molecules were used to monitor receptor binding and internalisation in human adenocarcinoma cells. Linking of chemotherapic molecules to branched peptides resulted in a dramatic increase in drug selectivity. NT-Methotrexate produced a 60% reduction of tumor growth in mice, with respect to animals treated with the free drug. The strategy can be seen as a general method to target receptors that are over-expressed in tumors.

Targeting RAF and TOR Decreases Glioma Growth

Hjelmeland et al.

Page 2449

The pro-tumorigenic RAS/RAF/MAPK and PI3K/AKT/TOR pathways have been separately targeted for novel cancer therapies. However, the failure of most monotherapies to cure cancers indicates that combinatorial therapies may be beneficial. LBT613 and RAD001 (everolimus) are low molecular weight inhibitors currently in pre-clinical development that are designed to target RAF and TOR, respectively. Hjelmeland and colleagues determined that dual targeting of RAF and target of rapamycin (TOR) activities with the combination of LBT613 and RAD001 decreased the proliferation and invasion of multiple human glioma cell lines. These data demonstrated that RAF and TOR inhibitors can cooperate to reduce tumor cell growth and may be useful in combination for cancer therapy.

PX-866 Inhibits PI 3-kinase Signaling

Howes et al.

Page 2505

Phosphoinositide-3-kinases are emerging as attractive targets for anti-tumor drug discovery. The recently developed PI 3-kinase inhibitor, PX-866, displays significant anti-tumor activity in xenograft models. In order to further define the mechanistic basis of tumor growth inhibition by PX-866, Howes and colleagues examined the effects of PX-866 in both monolayer and three-dimensional culture of human tumor cell lines. The 3-D spheroid culture model was more predictive of PI 3-kinase inhibitor activity than monolayer culture, and PX-866 showed a more persistent inhibition of PI 3-kinase signaling compared to wortmannin. Their results suggested that utilization of PI 3-kinase inhibitors as monotherapy may induce primarily stable disease and that curative treatments should include combination therapy with cytotoxic chemotherapeutic agents or modalities.

PI3K Inhibitors Block Platelet GPIIb/IIIa Receptor Activation

Bowers et al.

Page 2600

Phosphoinositide 3-kinases play a pivotal role in controlling vital cellular functions. Reportedly, some cancers display aberrant PI 3-kinase activity, providing a target for new cancer treatments. A drug activity biomarker assay would be very useful in the evaluation of these new agents. Bowers and colleagues selected platelets as surrogate target cells for the biomarker assay due to abundant PI 3-kinase that controls platelet GPIIb/IIIa receptor activation. Platelet flow cytometry revealed that pretreatment with PI 3-kinase inhibitors blocked this activation and was mirrored by anti-tumor effects in mouse models. Their data suggested that this approach might be useful for evaluating such drugs in the clinic.

September 2007 Molecular Cancer Therapeutics Highlights

Selected Articles from the September 1, 2007 Issue

Branched Neurotensin Peptides Increase Drug Selectivity

Targeting RAF and TOR Decreases Glioma Growth

PX-866 Inhibits PI 3-kinase Signaling

PI3K Inhibitors Block Platelet GPIIb/IIIa Receptor Activation

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