Highlights of This Issue Free

The polypeptide hormone prolactin (PRL) has been associated with mammary tumorigenesis in both rodents and humans. Damiano and colleagues examined the ability of the humanized anti-prolactin receptor (PRLR) monoclonal antibody LFA102 to neutralize PRLR function using several cancer models. LFA102 potently abrogated PRLR signaling and displayed significant antitumor effects in two tumor xenograft models in vivo. LFA102 also enhanced the efficacy of the aromatase inhibitor letrozole in an ER+ mammary tumor model when administered in combination. Attacking the PRL-PRLR signaling axis with LFA102 is potentially an unexploited avenue for treating breast cancer and other PRL-dependent diseases.

The metabolic inactivation of 2-Methoxyestradiol (2-ME2) by glucuronidation and oxidation elucidates its poor bioavailability, thus making it an ineffective anticancer drug. Kambhampati and colleagues designed a novel prodrug of 2-ME2 by modifying the chemical structure of 2-ME2 at two positions, namely, at the 3- and the 17-positions. The resultant double prodrug of 2-ME2 (2-ME2-PD1) is endogenously converted to the active drug, releasing significantly higher systemic concentration of 2-ME2 in animals and mimics the anticancer properties of 2-ME2 by disrupting intracellular microtubules. Thus, the orally bioavailable 2-ME2-PD1 is an ideal candidate to test the true therapeutic potential of 2-ME2 in cancers.

Antiapoptotic proteins, such as survivin and Mcl-1, are commonly overexpressed in gliomas. To address the role of these mediators in apoptosis resistance, Jane and colleagues analyzed the effects of YM-155, a survivin suppressant, in a panel of glioma cell lines. YM-155 inhibited survival, enhanced ABT-737-induced cytotoxicity, and downregulated survivin and Mcl-1 in a cell line-dependent manner. Downregulation of Mcl-1 using short hairpin RNA also enhanced ABT-737-induced killing. Sensitivity to YM-155 alone and with ABT-737 inversely correlated with EGFR activation status and was enhanced by inhibition of EGFR signaling, highlighting the relevance of multitargeted therapies to overcome the diverse resistance mechanisms of these tumors.