Highlights of This Issue

Abstract

Several clinical trials are currently evaluating the efficacy of targeting Ras-dependent signals in patients with KRAS-mutant tumors. Migliardi and colleagues assessed the consequences of extracellular signal-regulated kinase (ERK) kinase (MEK) and phosphoinositide 3-kinase/mTOR inhibition in KRAS-mutant metastatic colorectal carcinomas. For this purpose they used a collection of 40 patient-derived xenografts, an experimental setting that best mimics the clinical situation and likely anticipates findings in humans. They found that concomitant blockade of MEK and PI3K/mTOR induces prevalent disease stabilization but does not result in massive tumor shrinkage. Moreover, arrest of tumor growth is short lived. These results raise a caution against the occurrence of overt and durable responses in patients with KRAS-mutant colorectal cancer treated with MEK and PI3K/mTOR inhibitors.Although BRAF inhibitors show exceptional promise in the treatment of melanoma, many mechanisms of acquired and intrinsic drug resistance have been reported. Paraiso and colleagues have demonstrated that all of the signaling proteins implicated in the escape from vemurafenib therapy are clients of HSP90, and that inhibition of HSP90 with a small-molecule inhibitor overcomes both acquired and intrinsic vemurafenib resistance by increasing the expression of BIM (Bcl-2 interacting mediator of cell death) and downregulating Mcl-1. Together, these studies suggest that the combination of vemurafenib and an HSP90 inhibitor may be a strategy to delay and/or overcome BRAF inhibitor resistance.Toxicity has been a significant barrier to acceptance of intraperitoneal chemotherapy in ovarian cancer. Chambers and colleagues undertook the first front-line trial in stage III optimally debulked ovarian cancer patients in which all drugs in combination (pemetrexed, cisplatin, and paclitaxel) were administered intraperitoneally. Intraperitoneal pemetrexed showed a pharmacokinetic advantage. At doses <1,000 mg/m2 of intraperitoneal pemetrexed, the combination was found to be very well tolerated, with minimal peripheral neuropathy or alopecia. The median progression-free survival of 30.1 months is also encouraging. This novel treatment holds promise as an intraperitoneal regimen with far less toxicity than standard intravenous/intraperitoneal cisplatin or carboplatin/taxane regimens.Histone deacetylase (HDAC) inhibitors regulate transcription of a variety of oncogenes and tumor suppressor genes. Banerji and colleagues report the results of a phase I trial of a novel oral class I specific HDAC inhibitor. In addition to toxicity, they have used proof-ofmechanism pharmacodynamic markers quantifying acetylation of histone H3 in peripheral blood mononuclear cells to recommend a phase II dose. A patient with pancreatic cancer had a partial response to CHR-3996 for over a year, and the drug is being evaluated in further trials, including a study of multiple myeloma.