NF-kB plays an important role in the progression of breast cancer. Elevated levels of NF-kB have been demonstrated in breast cancer, with normal levels in the surrounding tissue. NF-kB is an anti-apoptotic factor. It is involved in the activation of genes responsible for angiogenesis, metastasis and preventing apoptosis. Regulation of the NF-kB pathway occurs through the protein IkB. It is normally found in the cytoplasm bound to IkB. Activation results in the ubiquination and degradation of IkB. The NF-kB pathway can be altered through proteasome inhibition. In addition to NF-kB, p21 and p27 play important roles in the cell cycle. Both promote cell cycle arrest. The expression of these genes can be altered in carcinogenesis. Similar to NF-kB, they are controlled by proteasome. The proteasome serves an important role in cell cycle regulation. It normally degrades proteins marked by ubiquination. Inhibition of proteasome results in the accumulation of ubiquinated proteins, including p21 and p27. NF-kB activity decreases with proteasome inhibition. PS-341 is a proteasome inhibitor. It has been shown to have clinical activity in cell cultures and xenograft models. PS-341 has been shown to decrease NF-kB activity and downregulate NF-k controlled genes. PS-341 also results in the accumulation of p21 and p27. Phase I trials have shown the agent to have antitumor activity, both alone and in combination. The combination of PS-341 and doxorubicin has been demonstrated to have activity in a xenograft model, without altering toxicity of either agent. This application proposes to examine the clinical efficacy of PS-341/doxrubicin when used at treatment for patients with metastatic breast cancer. It consists of a phase II trial with clinical and biologic endpoints. The primary clinical endpoint is overall response rate. The biologic endpoints seek to assess the biologic affect of PS-341. Five endpoints will be assessed: a) 20S proteasome inhibition; b) accumulation of ubiquinated protein conjugates; c) p21 and p27 protein levels; d) UPA levels and e) VEGF levels.
