Rock Creek Pharmaceuticals Inc. (fka RCPIQ)

[Buddhahead]

The Inflammation Link: NF-?B Remains a Difficult but Intriguing Target in OncOnline, ane de Lartigue, PhD
Published in Oncline: Friday, June 28, 2013

Excerpts:
"Second-generation proteasome inhibitors act at a lower concentration with lower toxicity and can be administered orally. These include carfilzomib (Kyprolis), which was recently approved for the treatment of patients with multiple myeloma who have received at least two prior therapies, including bortezomib, following clinical trials in which nearly one-quarter of patients experienced complete or partial disappearance of their tumors with a median duration of response of 7.8 months."

"Other strategies to target NF-?B activation include using inhibitors of the upstream signaling pathways mentioned above. Many of these were not conceived as NF-?B inhibitors but have subsequently shown NF-?B inhibitory activity. Among them is an antibody against the ligand that binds to RANK, one of the main activators of NF-?B signaling. Denosumab (Xgeva) has been approved since 2010 for the prevention of skeletal-related events in patients with bone metastases from solid tumors.

NF-?B undergoes numerous types of posttranslational modification, including acetylation, which regulates its activity. The histone deacetylase enzyme HDAC3 acts directly on Rel-A to enable its association with I?Ba, and the sirtuins are a family of deacetylase enzymes, with several members that act on NF-?B. Thus, HDAC inhibitors provide a potential therapeutic means of indirectly inhibiting NF?B. Vorinostat (Zolinza) and romidepsin (Istodax) are two such agents, both approved for the treatment of cutaneous T-cell lymphoma. Sirtuin inhibitors have also drawn a significant amount of attention and are currently in preclinical development.

Nonsteroidal anti-inflammatory drugs such as ibuprofen, aspirin, and indomethacin have been shown to suppress NF-?B activation, though their exact mechanism of action is not fully understood. A number of natural products with anti-inflammatory properties are also potent inhibitors of NF-?B. These include the polyphenolic compounds curcumin and resveratrol, which are undergoing phase II and phase I clinical testing, respectively, in a number of different cancer types.

Finally, since the noncanonical NF-?B pathway was discovered, it has been increasingly recognized as an important arm of NF-?B signaling. The activity of IKKß inhibitors has been shown to be somewhat limited in vivo; this could be because these inhibitors only target the canonical pathway, and there may be compensatory activity by the noncanonical pathway. With this in mind, a dual inhibitor of both pathways is being developed, which targets all five members of the NF-?B gene family. PBS-1086 is currently being examined in preclinical studies and has demonstrated potent cytotoxicity in multiple myeloma cell lines."


Article at:
http://www.onclive.com/publications/oncology-live/2013/june-2013/the-inflammation-link-nf-b-remains-a-difficult-but-intriguing-target/3#sthash.D7LrvB17.dpuf