Cancer cells are characterized by well-known hallmarks: limitless and self-promoting growth, avoidance of programmed cell death (apoptosis), stimulation of new blood vessel growth (angiogenesis), and the ability to remodel surrounding tissues to facilitate invasion and metastasis. Many of these same characteristics are present in inflamed tissue on a temporary basis, allowing the host to fight off infection and heal damaged tissue. Avoidance of apoptosis prevents host cells from being killed by high levels of reactive oxygen species (ROS), such as hydrogen peroxide, that are generated by macrophages and other immune cells to kill invading pathogens. Rapid cell growth, angiogenesis, and tissue remodeling are vital for wound repair and recovery of normal tissue function. In normal tissue these processes are eventually turned off, whereas in cancer or chronic inflammation and autoimmune diseases they are continually active. This has led to the classic description of cancer as "a wound that does not heal."
Many of these tumor-promoting inflammatory processes are regulated by NF-κB and STAT3, which are constitutively activated in many cancers. When activated, both NF-kB and STAT3 increase the expression of a wide variety of anti-apoptotic proteins such as BCL-XL, angiogenic factors such as VEGF, inflammatory cytokines such as IL-6, and tissue remodeling enzymes such as MMP-9. In addition, chronic activation of STAT3 is believed to play a critical role in the ability of tumors to evade detection and destruction by the immune system. Consequently, each of these proteins is a major target for the development of new cancer therapies. By inhibiting both, AIMs offer a particularly attractive profile of activity. An extensive series of published studies has shown that they are potent inhibitors of angiogenesis, processes of invasion and metastasis, cell proliferation, and chemically induced carcinogenesis. In addition, they have been shown to enhance the tumor-killing properties of standard chemotherapy drugs, radiation, and a number of targeted therapies. This profile, combined with their outstanding tolerability in human clinical studies, shows great promise for the use of AIMs in combination therapy.
Reata is developing RTA 402 an oral once daily therapy, for the treatment of cancer. RTA 402 is currently in Phase 2 trials for solid tumors. In clinical studies to date, RTA 402 has been exceptionally well tolerated and has demonstrated a highly favorable degree of disease control. Inhibition of NF-kB and STAT3 activity, induction of Nrf2 activity, inhibition of metastasis, and significant reductions in circulating levels of inflammatory cytokines and pro-angiogenic proteins have been documented in this study.
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