Highlights of This Issue Free

Relapsed and refractory lymphoproliferative disorders represent an unmet clinical need requiring novel treatments. The authors conducted a phase II trial investigating clinical activity, safety, and pharmacodynamic effects of a dual-targeted therapy with the AKT inhibitor perifosine in combination with the multikinase inhibitor sorafenib. Data showed feasibility of the combination therapy with promising clinical activity in Hodgkin lymphoma. Pharmacodynamic analysis showed that the phosphorylation levels of extracellular signal-regulated kinase (ERK) and AKT in peripheral blood lymphocytes predicted clinical response and might therefore represent useful predictive biomarkers warranting further studies.

Anaplastic thyroid carcinoma (ATC) is one of the most aggressive forms of cancer, and no curative therapies are currently available. Immunotherapy based on infusion of natural killer (NK) cells has gained increased attention in recent years. Wennerberg and colleagues explored the role of NK cell responses against ATC and found that these tumors express ULBP-2 and produce CXCL10. Consequently, ATC tumors were highly susceptible to NK cell-mediated killing and chemoattracted activated NK cells. Thus, NK cell therapy could prove to be a promising novel treatment strategy for patients with ATC.

Bone marrow (BM) angiogenesis is enhanced in multiple myeloma (MM) versus monoclonal gammopathy of undetermined significance (MGUS) and entails a therapeutic target. HGF/cMET pathway is implicated in the MM pathogenesis and progression. We show that BM-derived endothelial cells from patients with active MM but not those from patients with MGUS or with benign anemia present the HGF/cMET pathway constitutively activated and operative in an autocrine fashion as an angiogenesis amplifier. Data on a novel selective cMET inhibitor, SU11274, suggest that the HGF/cMET pathway may be envisaged as a new therapeutic target for the antiangiogenic management of active MM.

PIK3CA somatic mutations play a crucial role in response to molecular-targeted therapies; however, their detection on circulating tumor cells (CTC) is challenging because CTC are heterogeneous, and cells carrying these mutations consists a minority in CTC population. In this study, Markou and colleagues designed and validated a highly sensitive and specific method for PIK3CA hotspot mutations that is based on a combination of ARMS-PCR and HRMA. They report for the first time that PIK3CA hotspot mutations are present at a relatively high frequency in CTCs, both in metastatic and early breast cancer, and that PIK3CA mutational status can change during disease recurrence or progression. Moreover, they show that the presence of PIK3CA mutations in CTC is associated with worse survival in patients with clinically confirmed metastasis. This is the very first study in which clinical significance is shown for the presence of any mutation in CTC. These findings could have extremely important significance for the therapeutic intervention because it is known that the presence of PIK3CA mutations is connected with response to molecular-targeted therapies like trastuzumab.