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.I) Bortezomib (Velcade, PS 341 )
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.
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.
The recommended dose of bortezomib is 1.3 mg/m 2/dose administered as an intravenous (IV) injection twice weekly for 2 weeks (days 1, 4, 8, and 11). This is followed by a 10-day rest period (days 12-21). Doses are typically given on Monday and Thursday or Tuesday and Friday. This 3-week period is considered a treatment cycle.
The length of treatment is determined on an individual basis, depending on a patient's response to and tolerability of the drug. In clinical trials, patients were able to receive bortezomib for up to 8 cycles, but those who were still benefiting were allowed to continue for additional cycles.
Possible adverse side effects of bortezomib include:
1) SUMMIT Phase II trial in myeloma patients with advanced relapsed and refractory disease: Study 025
Materials & Methods
2) CREST trial, relapsed/refractory disease: Study 024
3) Study 029:
4) APEX trial (Assessment of Proteasome Inhibition for Extending Remissions) in relapsed/refractory myeloma .
Bortezomib is being evaluated in numerous early phase studies for a variety of solid cancers, including prostate, colorectal, and lung cancer, as well as other hematologic cancers, such as lymphoma and leukemia. In addition to its potential use as a single agent, laboratory research suggests that combining bortezomib with chemotherapy or radiation therapy can result in improved outcomes. The rationale behind this combination approach is to take advantage of the additive benefits of both treatments, and possibly even synergistic effects. Synergy is when two or more agents interact so that their combined effect is even greater than the sum of their individual effects.
Listed below are some of the latest clinical trials that are currently enrolling patients, along with the study sponsors. Note that while bortezomib continues to be investigated as a single agent therapy, it is increasingly being incorporated as an adjunctive agent within a whole treatment regimen. Depending on the tumor type, this regimen may contain varying combinations of chemotherapy, radiation therapy, surgery, hormonal agents, and even other targeted therapies.Multiple myeloma
For further information, please see Targeted Therapy Basics.