The concept of synthetic lethality applies to cells with impaired HR, which are further subjected to PARP-1/2 inhibition. The resulting single-stranded DNA breaks ultimately

lead to an accumulation of double-strand breaks that cannot be effectively repaired, culminating in complex chromosomal alterations and increased levels of apoptosis [30]. Indeed, Cass et al. have reported on the improvement in survival in patients with BRCA-associated ovarian carcinoma treated with cisplatin, and more recently, Fogelman et al. reported a case of a pancreatic adenocarcinoma patient with CDK inhibitor germline BRCA-2 mutation who demonstrated complete pathologic response to the PARP-inhibitor, IDH inhibitor BSI-201 [31] and [32]. Henessy et al. recently investigated the frequency of somatic and germline BRCA-1/2 mutations in ovarian cancer and attempted to correlated these findings to progression-free survival after treatment with cisplatin [33]. Interestingly, 30% of all patients had either germline or somatic BRCA-1/2 mutations and these patients had a concordant significant improvement in clinical outcomes relative to patients not harboring these mutations. These data suggest that PARP-inhibitor therapy may be most appropriate not only for the 17% of pancreatic cancer patients who harbor

BRCA-1/2 germline mutations, but also those harboring somatic mutations in other proteins involved in HR repair, such as mutated partner and ligand of BRCA2 (PALB2) and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) [34] and [35]. Based on the results presented herein, as well as the clinical success of PARP-inhibitors to date, we have initiated a Phase 1 study investigating the maximum tolerated dose, safety and toxicity of ABT-888 with full dose gemcitabine and intensity modulated radiotherapy in patients with locally advanced PDAC. We thank Blum-Kovler, the Pancreatic Cancer Action Network, the AACR Career Development Award, and the Claudio X. Gonzalez Family Foundation. “
“This review highlights the function of hyponitroxia

as a proneoplastic effector, Thalidomide summarizes therapeutic strategies to increase intratumoral nitric oxide (NO) to mitigate, at least in part, the effect of hyponitroxia on angiogenesis and malignant progression, and makes the case for hyponitroxia a high-priority target in cancer therapy that may be as, if not more, important than hypoxia. As in tumors, NO also plays an important role in normal tissues. Under physiological conditions, low levels of NO are produced from L-arginine by constitutively expressed NO synthase in neuronal cells (nNOS, also known as NOS1) and endothelial cells (eNOS or NOS3) [1], which contribute to the regulation of normal physiological processes through cell signaling (Figure 1).