New data shows RTA 402 potently blocks NF-kB in cancer cells through inhibition of IKK
BY OUR PHARMA CORRESPONDENT
April 10, 2006
Reata Pharmaceuticals, Inc. published a new paper demonstrating that RTA 402 (also known as CDDO-Me) potently inhibits the activity of nuclear factor kappa-B (NF-kB) activated by tumor necrosis factor (TNF) and other inflammatory agents in a variety of cancer cells. RTA 402 was shown to suppress NF-kB activity by inhibiting the activation of IkB alpha kinase (IKK).
Researchers from the University of Texas M.D. Anderson Cancer Center in their paper published in the March 15, 2006 edition of Clinical Cancer Research, demonstrated that the synthetic triterpenoids being developed by Reata Pharmaceuticals, Inc. potently inhibit activation of NF-kB and suppress the expression of many cancer-associated genes regulated by this transcription factor. NF-kB controls expression of genes involved in regulation of cellular survival, proliferation, differentiation, and inflammation. It has been shown to promote tumor initiation, progression, and resistance to radiation and chemotherapy and is widely recognized as an important target for new anti-cancer therapies.
The study demonstrated that RTA 402 potently inhibited both constitutive and inducible NF-kB in human leukemia cell lines as well as in tissue samples taken from cancer patients. These effects occurred in cells activated by a variety of agents including TNF, interlukin-1 beta, phorbol ester, okadaic acid, hydrogen peroxide, lipopolysaccharide, and cigarette smoke. RTA 402 suppressed the activity of NF-kB by inhibiting activation of the protein IKK. Inhibition of IKK correlated with suppression of NF-kB dependent genes that prevent apoptosis (IAP2, cFLIP, TRAF1, survivin, and bcl- 2), promote proliferation (cyclin D1, COX-2, and c-myc), and promote angiogenesis (VEGF and MMP-9).
The investigators also demonstrated that RTA 402 suppressed NF-kB activation induced by common chemotherapy agents including cisplatin, doxorubicin, and Taxol and that it enhanced the cytotoxic effects of these therapies as well as of TNF. The authors concluded that the proven apoptotic, antiproliferative, anti-angiogenic, and antiinflammatory activities of RTA 402 may be mediated through suppression of NFkB and its gene products.
Inhibitors of NF-kB are believed to hold great promise for treating a variety of diseases including cancer. In rigorous preclinical studies, RTA 402 has been shown to inhibit growth and cause regression of cancerous tumors as a single agent and in combination with radiation and chemotherapy. Remarkably, RTA 402 simultaneously suppresses radiation and chemotherapy-induced toxicities in normal tissues. It caused minimal toxicity in non-human primates when administered orally at very high doses, although it was well absorbed and reached high concentrations in a wide variety of tissues. Reata recently initiated a phase 1 clinical trial of RTA 402 capsules in patients with solid tumors, lymphoma, or myeloma at the University of Texas M.D. Anderson Cancer Center. Initiation efforts are also underway at the Dana-Farber Cancer Institute. This trial will set a safe human dose for RTA 402, and will also provide insights into efficacy and side effects of the drug.
Reata Pharmaceuticals, Inc. is a biopharmaceutical company focused on developing novel treatments for cancer, inflammation, and neurodegenerative diseases. Founded in 2002, Reata is developing five distinct classes of cancer drugs licensed from leading academic institutions. The company has three drugs in phase 1 clinical development -- RTA 744 for primary brain cancers, RTA 401 for leukemias, and RTA 402 for solid tumors and lymphoid malignancies. Reata is matching its clinical and preclinical drug development programs with a best-of-class drug discovery platform to identify small molecule chaperones that can prevent pathogenic misfolding of p53, SOD, and Tau, proteins involved in cancer and neurodegenerative disease.