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View the Table of Contents for the October 1 issue of Cancer Research.
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The NF2 gene is mutated in neurofibromatosis type 2, a dominantly inherited cancer disorder. Merlin, the protein coded by the NF2 gene, has been shown to function as an inhibitor of the p21-activated kinases (Paks). Thus, it is plausible that merlin’s tumor suppressive function might be mediated, at least in part, via inhibition of the Paks. Yi and colleagues show that Pak1 activity is increased in a significant fraction of primary schwannomas. Inhibition of Pak1–3 significantly reduced cell growth rates in NIH3T3 cells expressing a dominant-negative form of merlin and inhibited the ability of these cells to form tumors in vivo. These results suggest that inhibiting Paks would be a beneficial approach for the development of therapeutics for the treatment of neurofibromatosis type 2.
Serra et al. Page 8022 The PI3K signaling pathway plays a central role in diverse cellular functions including proliferation, growth, survival, and metabolism, and genetic aberrations of this pathway are among the most commonly encountered in human cancer. Serra and colleagues show that NVP-BEZ235, a dual inhibitor of PI3K and downstream mammalian target of rapamycin (mTOR), inhibited proliferation and inhibited the activation of several downstream effectors in a panel of breast cancer cells of different origin and mutation status. NVP-BEZ235 was also able to inhibit proliferation of trastuzumab-resistant modified HER2-amplified BT474 cells. In xenografts of one of these, BT474 H1047R, NVP-BEZ235 inhibited PI3K signaling and had potent antitumor activity. In treated animals, there was complete inhibition of PI3K signaling in the skin at pharmacologically active doses, suggesting that skin may serve as a surrogate tissue for pharmacodynamic studies.
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Horton et al. Page 8049 CD19 is an excellent target for antibody-based therapies of B-cell neoplasms due to its pan–B cell expression profile. To develop a highly cytotoxic anti-CD19 antibody (XmAb5574), Horton and colleagues employed protein engineering to increase the affinity of the Fc domain for Fcγ receptors on immune effector cells. In vitro, XmAb5574 displayed dramatically increased tumor cytotoxicity via direct and indirect effector functions relative to the wild-type Fc analog antibody and, in vivo, significantly reduced tumor growth in lymphoma xenograft mouse models. These results suggest that the humanized antibody XmAb5574 warrants clinical evaluation as an immunotherapeutic for CD19+ hematological malignancies.
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