Highlights of This Issue

Abstract

Since the failure of matrix metalloproteinase (MMP) inhibitor in clinical trials, highly selective reagents that target individual MMPs have been the new focus. MMP-2 is highly expressed in bone metastatic breast cancer and drives the progression of the disease. Here, Tauro and colleagues have generated MMP-2 highly selective bone seeking MMP inhibitors (BMMPIs) based on bisphosphonates. In vivo studies reveal BMMPIs are effective in promoting the apoptosis of bone metastatic breast cancer cells and protecting against cancer induced bone disease. Given the well-tolerated nature of bisphosphonates, BMMPIs could be rapidly translated to the clinic for the treatment of skeletal malignancies such as bone metastatic breast cancer.Immune checkpoint blockade has shown promise in melanoma, with a subset of patients experiencing complete durable responses. However, the majority of patients still do not receive long-term benefit. Farren and colleagues combined immune checkpoint blockade with selinexor, a small molecule inhibitor of exportin-1 that has anti-melanoma activity of its own. This treatment combination skewed immune responses toward a Th1 type, and proved more effective in controlling tumor growth when administered at multiple schedules in a murine model. These results support further development of this novel combination of immune checkpoint blockade and small molecule nuclear export inhibitors.Selinexor (KPT-330) is a first in class nuclear transport inhibitor currently in clinical trials as an anti-cancer agent. Tyler, Servos and colleagues analyzed immune homeostasis in mice treated with selinexor and found disruptions in T cell development, a progressive loss of CD8 T cells and increases in inflammatory monocytes. Altering the frequency of drug dosing preserved normal immune function better than decreasing the dose. Overall, selinexor treatment leads to transient inhibition of T cell activation but clinically relevant once and twice weekly dosing schedules that incorporate sufficient drug holidays allow for normal CD8 T cell functioning and development of anti-tumor immunity.Stage III/IV head-and-neck squamous cell carcinomas (HNSCCs) are often treated with cisplatin-containing chemoradiation protocols. However, not all tumors respond well and biomarkers to personalize chemoradiotherapy are not available. Martens-de Kemp and colleagues performed an unbiased genome-wide functional genetic screen to identify genes that influence cisplatin response. Pathway analysis on cisplatin-sensitizing genes identified the FA/BRCA pathway as the predominant cisplatin response pathway in HNSCC cells. Expression of genes involved in this pathway predicted prognosis of (chemo-) radiation treated HNSCC patients. Biomarkers that indicate FA/BRCA pathway activity in tumors are prime candidates to predict cisplatin response in HNSCC.