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Treatment Options > Targeted Therapies > Types of Targeted Therapies

Proteasome Inhibitors

Neha Vapiwala, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: July 22, 2004

In Part Two of our series on biologic therapies, we are performing an in-depth review of the major targeted therapies that are currently making headlines around the world.

Here, we will address bortezomib, the signature drug in a new class of targeted therapies called proteasome inhibitors. Please feel free to refer as needed to Part One, which presented the basic science principles behind targeted therapies and outlined all of the major classes of molecular inhibitors. Remember that the drugs have both generic and trade names, but we will use primarily the generic name in the following discussions.

Background

Bortezomib is the first drug in the proteasome inhibitor class of anti-cancer agents to enter clinical trials. As discussed in Part One of this series, the proteasome is a protein complex that exists in all cells and plays a critical role in breaking down other proteins. The proteins destined for degradation typically regulate the cell cycle, new blood vessel growth (angiogenesis), cell adhesion, cytokine production, and programmed cell death (apoptosis), among other important cellular processes. These processes are important to the growth and survival of tumor cells. Bortezomib binds and reversibly inhibits the proteasome. By doing so, it disrupts normal cellular processes, leading to chaos in the cell and prompting the cell to die. Laboratory studies suggest that normal cells are less susceptible to damage from periodic proteasome inhibition; because bortezomib inhibition is reversible, normal cells tend to recover from its effects. In contrast, cancer cells tend to go "haywire" when proteasomes are inhibited even for a short time, and this typically results in programmed cell death.

Multiple myeloma (also called myeloma) is a hematologic cancer, meaning it starts in the blood. It is a cancer of the plasma cell, which is part of the immune system and helps make the antibodies (immunoglobulins) we need to help fight infection and disease. It is the second most common blood cancer (non-Hodgkin's lymphoma is first). It represents about 1% of all cancers and about 2% of all cancer deaths. About 45,000 Americans currently have myeloma, and the American Cancer Society states that about 14,600 new cases are diagnosed every year in the US.

Bortezomib appears to act on myeloma cells both directly as well as indirectly (through inhibition of their growth and survival by acting on the surrounding bone). Many propose that bortezomib's anti-myeloma activity is due in large part to its ability to block a key survival protein called nuclear factor κB (NF- κB). NF-κB is located inside the cell and plays a role in switching on certain genes. These genes then lead to production of proteins involved in cell growth. NF-κB also sends a message for cells to make and put certain molecules on their surface. In the case of myeloma, these surface molecules let the myeloma tumor cells stick to the bone marrow. By sticking there, the myeloma cells trigger the bone marrow to help them grow, and thus a vicious cycle of tumor growth is created.
When bortezomib blocks NF-κB, it prevents myeloma cell growth and favors myeloma cell death.

Current FDA-Approved Indications

Bortezomib is indicated for the treatment of multiple myeloma patients who have received at least two prior therapies and have demonstrated disease progression on the last therapy. In other words, it is used as third-line therapy in myeloma patients who have demonstrated resistance to their last treatment.