Targeting ALDH1A1 Stem Cells in Ovarian Cancer
Landen et al., Page 3186
In this study, Landen and colleagues have shown an association with ALDEFLUOR activity and both platinum and taxane resistance, and that ALDEFLUOR-positive ovarian cancer cells have increased tumorigenicity and differentiation potential compared to the ALDEFLUOR-negative population. More importantly, they have shown in vivo that platinum therapy increases the ALDH1A1 population and that targeting ALDH1A1 sensitizes resistant cell lines to platinum or taxane-based therapy. Targeting this special subpopulation may be required to achieve durable cures in ovarian cancer.
Vorinostat Reduces Tumor Growth in Bone
Pratap et al., Page 3210
Histone deacetylase inhibitors, such as vorinostat, are promising treatments for breast and prostate cancers where metastatic bone disease is a prevalent complication. To examine the benefit of this drug on tumor growth in bone and protection against osteolysis, Pratap and colleagues treated SCID mice with intratibial tumors formed from human cells. Vorinostat significantly reduced tumor growth by 33%. However, in the nontumor bearing contralateral limb or limbs from tumor-free mice, significant trabecular bone loss occurred. The mechanism involved induced levels of bone resorbing factors. These findings suggest that HDAC inhibitors should be used in patients in combination with bisphosphonates.
Predictive Biomarkers for Selumetinib in CRC
Tentler et al., Page 3351
Colorectal cancer (CRC) patients with KRAS activating mutations have been shown to be refractory to epidermal growth factor receptor (EGFR)-directed therapies. As this patient group represents a substantial fraction of CRC cases, there is an emerging need for novel agents and predictive biomarkers of response for the treatment of KRAS mutant CRC. Tentler and colleagues used gene array data from KRAS mutant CRC cell lines, cell line xenografts, and direct human CRC tumor explants to develop a predictive classifier for response to the MEK 1/2 inhibitor selumetinib (AZD6244). Interestingly, gene set enrichment analysis showed that upregulation of the Wnt signaling pathway was a major, functional mediator of resistance to selumetinib. These findings have potentially important clinical implications for early clinical trial design as well as rational combination strategies for KRAS mutant CRC.