Highlights of This Issue

DOI: Published September 2012

Notch Inhibition in Pancreatic Cancer

Mizuma et al. Page 1999

Pancreatic cancer remains a lethal malignancy. Mizuma and colleagues used a panel of pancreatic cancer cell lines and patient-derived xenografts to show that targeting Notch signaling using a γ-secretase inhibitor, MRK-003, could downregulate Notch target genes and curb tumor-initiating pancreatic cancer stem cells, resulting in the inhibition of tumor growth and potentiation of gemcitabine sensitivity. Further, they identified a gene signature, responsive to Notch inhibition, which may aid in the selection of patient subsets more likely to benefit from this therapy. These findings convincingly establish the therapeutic relevance of the Notch signaling in pancreatic cancer and have major translational implications.

Sphingosine 1-Phosphate Lyase and Prostate Cancer

Brizuela et al. Page 1841

Sphingosine 1-phosphate (S1P) is a growth-promoting, proangiogenic and anti-apoptotic sphingolipid metabolite. This study reports the decrease activity and expression in prostate tumor samples of S1P lyase, the enzyme that degrades S1P. S1P lyase expression and activity were inversely correlated with those of sphingosine kinase-1, the enzyme producing S1P, and associated with tumor grade. S1P lyase and sphingosine kinase-1 expressions were independently predictive of aggressive cancer, supporting the role of S1P in prostate cancer. By decreasing S1P content, a dual strategy aimed at stimulating S1P lyase and inhibiting sphingosine kinase-1 made prostate cancer cells remarkably sensitive to chemotherapy or radiotherapy.

ABT-888 and Platinum Drug Combinations

Clark et al. Page 1948

Targeted therapy is an emerging option for BRCA-associated breast cancer patients. This study helps to illuminate one possible synergistic combination of conventional and novel agents. Using Brca/BRCA isogenic models (in vitro and in vivo), the cytotoxic effects of ABT-888 (PARP inhibitor), cisplatin, or carboplatin single agent treatments were compared to those in combinations and Clark and colleagues found that ABT-888/carboplatin combination was associated with enhanced cytotoxicity in BRCA-deficient models and that BRCA-deficient cells depend on a greater endogenous PARP activity (than BRCA-proficient cells) for survival. A phase II clinical trial is currently comparing ABT-888/carboplatin combination versus ABT-888 alone to treat BRCA-associated breast cancer patients.

TPI-287 Reduces Brain Metastatic Colonization

Fitzgerald et al. Page 1959

Brain metastases of breast cancer appear to be increasing in incidence and are significant contributors to patient morbidity and mortality. While the taxanes constitute a backbone chemotherapy for breast cancer, they are relatively brain impermeable. Here, Fitzgerald and colleagues identify a brain permeable member of the taxane family, TPI-287. TPI-287 prevented the formation of brain metastases by 55% in a mouse model system, but was unable to shrink established lesions.