The establishment and maintenance of tumors relies in part on the ability of cancer cells to evade cell death or apoptosis. The network of interactions between antiapoptotic and pro-apoptotic proteins of the Bcl-2 family is critical for the regulation of cell survival and death. In human cancer, antiapoptotic proteins such as Bcl-2, Bcl-xL, Mcl-1 are often expressed at high levels, which leads to increased cell survival and resistance to therapy and poor clinical prognosis. Bcl-2 is known to be a contributing factor to the development of a number of B-cell malignancies. More recently, Bcl-2 along with Bcl-xL and Mcl-1 have been shown to be overexpressed in a number of solid tumors as well.
Therefore, Bcl-2 and other antiapoptotic proteins represent attractive targets for therapeutic intervention. Combining Bcl-2 inhibitors with chemotherapy or radiation is expected to sensitize tumors to these conventional treatments and potentially to overcome issues of resistance to traditional therapy. Several companies are developing small molecule inhibitors of the Bcl-2 proteins (Table 2).
Molecular chaperones are some of the most abundant cellular proteins. They are required for both the proper folding of other proteins (referred to as client proteins) upon synthesis and their refolding under conditions of denaturing stress. Heat shock protein 90 (HSP90) is a molecular chaperone that is essential for maintaining the activity of numerous client proteins involved in the regulation of cell cycle, cell growth and survival, apoptosis, and angiogenesis. Significantly, many HSP90 client proteins include those crucial for cancer-cell proliferation and survival.
HSP90 is known to be overexpressed in tumor cells compared to normal tissues from two to tenfold. Elevated levels of HSP90 have been documented in a variety of human cancers including breast, lung, colon, and brain. Collectively, these observations make HSP90 an attractive oncology target (Table 3).
Targeting HSP90 could provide a unique way of simultaneously blocking multiple pathways involved in tumorigenesis through the depletion of oncogenic factors essential for cancer cell proliferation and survival. Inhibition of HSP90 should lead to misfolding of client proteins, their destabilization, and the subsequent degradation by the proteasome-mediated pathway. Combination therapy of HSP90 inhibitors with other targeted agents and/or traditional cancer therapeutics might result in significantly enhanced efficacy especially in resistant tumors.
The proteasome is the primary component of the protein-degradation system in the cell and is involved in the regulation of a number of cellular processes including proliferation, survival, and apoptosis. Proteasome substrates comprise proteins involved in the regulation of the cell cycle, DNA repair, stress responses, apoptosis, as well as misfolded and misassembled proteins.
Proteasome inhibition results in accumulation of these proteins in the cell and subsequent cell death. The proteasome is a validated target for cancer therapy. Currently, Velcade® (Takeda Pharmaceuticals recently acquired the drug through its takeover of Millenium Pharmaceuticals), approved for the treatment of multiple myeloma and mantel cell lymphoma, is the only proteasome inhibitor on the market.
Despite the clinical successes of Velcade, a significant number of patients fall into the relapsed/refractory category. Inconvenient dosing (twice a week IV injection) and painful peripheral neuropathy limit Velcade use. Newer agents targeting the proteasome could potentially address these issues.
Two new proteasome inhibitors are currently in clinical development: carfilzomib PR-171 (Proteolix) and NPI-0052 (Nereus). Compared to Velcade, carfilzomib and NPI-0052 belong to distinct chemical classes, are irreversible inhibitors, and have different selectivities against the three proteolytic components of the proteasome. It is too early to tell though whether broad-spectrum inhibition or more selective proteolytic activity inhibition will result in better safety and/or efficacy profile for a proteasome-targeting agent.