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Early Research Study Using New Oral Proteasome Inhibitor Shows Promise

Home/Early Research Study Using New Oral Proteasome Inhibitor Shows Promise

Early Research Study Using New Oral Proteasome Inhibitor Shows Promise

Velcade is currently the only FDA approved proteasome inhibitor. Here is an encouraging research study using a new oral proteasome inhibitor ONX 0912, which was submitted to the internationally recocognized medical journal, Blood, April 2, 2010; accepted August 8, 2010. Here is a copy of the study abstract:

A novel orally active proteasome inhibitor ONX 0912 trigger in vitro and in vivo cytotoxicity in multiple myeloma

Dharminder Chauhan1,*, Ajita V. Singh1, Monette Aujay2, Christopher J. Kirk2, Madhavi Bandi1, Bryan Ciccarelli1, Noopur Raje1, Paul Richardson1 and Kenneth C. Anderson1
1 The LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center, Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, United States; 2 Onyx Pharmaceuticals, Emeryville, CA, United States

Abstract

Bortezomib therapy has proven successful for the treatment of relapsed, relapsed/refractory, and newly diagnosed multiple myeloma (MM). At present, bortezomib is available as an intravenous (IV) injection and its prolonged treatment is associated with toxicity and development of drug-resistance. Here we show that the novel proteasome inhibitor ONX 0912, a tripeptide epoxyketone, inhibits growth and induces apoptosis in MM cells resistant to conventional and bortezomib therapies. The anti-MM activity of ONX-0912 is associated with activation of caspase-8, caspase-9, caspase-3, and PARP, as well as inhibition of migration of MM cells and angiogenesis. ONX 0912, like bortezomib, predominantly inhibits chymotrypsin-like activity of the proteasome and is distinct from bortezomib in its chemical structure. Importantly, ONX 0912 is orally bioactive. In animal tumor model studies, ONX 0912 significantly reduced tumor progression and prolongs survival. Immununostaining of MM tumors from ONX 0912-treated mice showed growth inhibition, apoptosis, and a decrease in associated angiogenesis. Finally, ONX 0912 enhances anti-MM activity of bortezomib, lenalidomide dexamethasone, or pan-HDAC inhibitor. Taken together, our study provides the rationale for clinical protocols evaluating ONX 0912, either alone or in combination, to improve patient outcome in MM.

This could become a big deal! Not so much that the drug is in an oral form, but because, as the abstract states:

Here we show that the novel proteasome inhibitor ONX 0912, a tripeptide epoxyketone, inhibits growth and induces apoptosis in MM cells resistant to conventional and bortezomib therapies.

This statement implies that ONX 0912 may work on Velcade resistant patients. Very cool! Speed things up and get this research moving forward as soon as possible!

Feel good and keep smiling! Pat