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Targeted Therapies for Multiple Myeloma Tutorial

Introduction

In This Section:

Targeted Therapies—Overview

Targeted therapies are transforming the way people treat cancer. These carefully designed drugs have already begun to make personalized medicine a reality and will continue to help doctors tailor cancer treatment based on the characteristics of each individual's cancer.

Image of health care providers looking at a medical chart.

It is important that health care professionals become familiar with the concept of targeted therapies so they can communicate with their patients about these new approaches and help patients make better-informed treatment decisions.

Multiple Myeloma Tutorial—Objectives

This tutorial focuses on the variety of targeted therapies that have been and are being developed to treat multiple myeloma.

By completing this tutorial, you will learn the answers to the following questions.

  • What molecules and pathways in multiple myeloma cells are being targeted?
  • What agents are being developed to target these molecules and pathways?
  • Which targeted therapies are currently approved by the FDA for treatment of multiple myeloma?
  • How can I find clinical trials of targeted therapies for multiple myeloma?

Multiple Myeloma Background

Multiple myeloma is a cancer that begins in plasma cells, which are a type of white blood cell. In this cancer, abnormal plasma cells, called myeloma cells, accumulate in the bone marrow and may eventually interfere with the production and function of normal blood cells. Myeloma cells may also collect in the solid part of the bone.

An outline of a human body with a skeleton is shown on the left. An inset circle coming from the body shows a plasma cell and a few red blood cells.

The disease is called multiple myeloma because it affects many of the marrow-containing bones in the body, including arm and leg bones, the pelvis, ribs, vertebrae, and skull. Treatment for multiple myeloma depends on the stage of the disease and the patient's symptoms. Patients who do not have any symptoms may not undergo treatment but will be monitored closely by their doctor.

A health care provider is shown talking to a patient in a hospital bed.

Standard treatment for multiple myeloma includes chemotherapy and the administration of steroids. Because these treatments destroy both myeloma cells and normal cells, many patients also receive blood stem cell transplants.

In recent years, new treatments for multiple myeloma have come into wide use. These include Thalidomid® or Synovir® (thalidomide) and the related drug Revlimid® (lenalidomide), which are immune system modulators that have antiangiogenic activity, as well as the targeted agent Velcade® (bortezomib), which will be discussed in this tutorial. Preclinical experiments and clinical trials are under way to evaluate additional targeted therapies and to find out how best to use these drugs in combination with each other and with standard therapies.

This is a split screen image. A magnified view of stained blood cells is shown on the left and the gloved hands of a researcher doing an experiment are shown on the right. The screen text reads, 'Studies are under way to evaluate targeted therapies for multiple myeloma.'

This tutorial describes several strategies being pursued for the treatment of multiple myeloma. Many of these strategies are also relevant for, and being tested in, other types of cancer.

Inhibition of the NF-kB Pathway

In This Section:

NF-kB in Normal Cells

The balance between the synthesis and degradation of key regulatory proteins determines the activities of several cellular signaling pathways. The ubiquitin-proteasome system is one mechanism cells use to degrade damaged or unneeded proteins. This system targets proteins involved in such key cellular processes as cell proliferation, growth, and survival.

The cytoplasm and nucleus of a cell are shown. A large cylindrical-shaped protein complex in the cytoplasm is labeled 'proteasome.' A small protein labeled 'protein' linked to small red circles labeled 'ubiquitin' is shown near the proteasome. The screen text reads, 'The ubiquitin-proteasome system is one mechanism cells use to degrade damaged or unneeded proteins.'

One example of a protein that is regulated by the ubiquitin-proteasome system is NF-kB. NF-kB is normally sequestered in the cell's cytoplasm by a protein called Inhibitor of NF-kB, or IkB. In this state, the NF-kB pathway is inactive.

The cytoplasm and nucleus of a cell are shown. A proteasome is present in the cytoplasm. Two proteins labeled 'IkB' and 'NF-kB' are in a complex in the cytoplasm. The IkB-NFkB complex is gray, indicating that it is inactive.

A number of signaling pathways activate NF-kB. They do so by phosphorylating IkB, which makes it a target for ubiquitinylation. The added ubiquitin molecules mark IkB for degradation by proteasomes.

The nucleus and cytoplasm of a cell are shown. A proteasome is shown in the cytoplasm. Small globular structures representing proteins in two signaling pathways are shown glowing, indicating that the signaling pathways are active. The pathways end near the IkB-NFkB complex.

The nucleus and cytoplasm of a cell are shown. A proteasome is shown in the cytoplasm. The IkB-NFkB complex has moved toward the proteasome. Small red circles representing ubiquitin have been added to IkB. NFkB is gray, indicating that it is inactive.

Once IkB has been degraded, NF-kB is free to move to the cell's nucleus, where it helps induce expression of a number of genes that promote cell survival and proliferation.

The nucleus and cytoplasm of a cell are shown. A proteasome is shown in the cytoplasm. IkB is now represented by a long yellow strand, indicating that the protein has been unfolded. The unfolded IkB is entering the proteasome. NFkB is now separate from IkB and is colored, indicating that it is active. NFkB is moving toward the nucleus of the cell.

NF-kB in Cancer Cells

The NF-kB signaling pathway is highly active in multiple myeloma as well as in many other cancers.

The nucleus and cytoplasm of a cell are shown. Two proteasomes are shown in the cytoplasm. One active NfKB protein is shown moving away from an IkB protein that is being degraded by a proteasome. An activated signaling pathway is shown phosphorylating another IkB protein that is in complex with NFkB. The screen text reads, 'The NF-kB pathway is highly active in most myelomas.'

Inhibition of this pathway has been shown to undermine the survival of myeloma cells, making NF-kB an attractive therapeutic target.

Inhibiting NF-kB

Interfering with the activity of the ubiquitin-proteasome system is one strategy for inhibiting NF-kB activity in cancer cells. For reasons not fully understood, cancer cells seem to be more sensitive to proteasome inhibition than normal cells.

Velcade® (bortezomib) is an example of a proteasome inhibitor. Velcade® binds strongly to the proteasome, preventing it from degrading IkB and other target proteins. This allows IkB to accumulate in the cytoplasm and keep NF-kB in its inactive state.

The cytoplasm of a cell is shown. A proteasome is present. An IkB-NFkB complex is near the proteasome; however, IkB is not being degraded by the proteasome because the proteasome is bound by a small purple ball representing the drug Velcade. The screen text reads, 'Velcade prevents the proteasome from degrading IkB and other target proteins.'

The reduction in NF-kB activity and the modification of other signaling pathways upon proteasome inhibition collectively reduce cell proliferation and increase the apoptosis of multiple myeloma cells.

A mass of green tumor cells is shown in the middle of a sheet of pink normal cells. Several of the cancer cells have fragmented into small gray vesicles, indicating that they have undergone apoptosis. The screen text reads, 'Proteasome inhibition reduces NF-kB activity and increases apoptosis.'

Velcade® has been approved by the FDA for the treatment of multiple myeloma based on evidence from clinical trials that the drug can delay disease progression and increase overall survival in myeloma patients.

Velcade® continues to be studied in clinical trials for multiple myeloma and other cancers as both a single agent and in combination with standard therapies, including immune system modulators such as Thalidomid® and Synovir®, and other targeted therapies.

More Information

Proteasome Inhibitors

This table lists several proteasome inhibitors that are being tested in clinical trials for multiple myeloma. Agents that have been approved by the FDA for treatment of multiple myeloma are marked with an asterisk. For more information on types of targeted therapies, see Understanding Targeted Therapies: An Overview.

 Research NameGeneric NameTrade Name(s)Drug Type
Proteasome InhibitorsPS-341BortezomibVelcade®*Small molecule
 PR-171Carfilzomib--Small molecule


Self Test

Questions

  1. Velcade® directly inhibits NF-kB.
    1. True
    2. False

Answers

  1. Correct Answer: b
    1. True - Incorrect.
      Velcade® inhibits NF-kB indirectly by interfering with the activity of the cell's proteasome. Inhibition of the proteasome will alter the activity of several signaling pathways, not only the NF-kB signaling pathway.
    2. False - Correct.
      Velcade® inhibits NF-kB indirectly by interfering with the activity of the cell's proteasome. Inhibition of the proteasome will alter the activity of several signaling pathways, not only the NF-kB signaling pathway.

Inhibition of Heat Shock Protein 90 (HSP90)

In This Section:

HSP90 in Normal Cells

Heat shock proteins, or HSPs, are called molecular chaperones because they help maintain the stability and activity of cellular proteins by modulating their three-dimensional shapes.

A close-up view of the cytoplasm of a normal cell is shown. A dimer of two yellow proteins labeled 'HSP (Heat Shock Protein)' is present in the cytoplasm. The screen text reads, 'HSPs influence the activity and stability of cellular proteins.'

HSP90, like most heat shock proteins, acts as part of a multiprotein complex that includes other molecular chaperones. HSP90 stabilizes its so-called client proteins so they can participate more effectively in their signaling pathways. Thus, although not a signaling molecule itself, HSP90 can enhance the activity of certain signaling pathways.

A close-up view of the cytoplasm of a normal cell is shown. The yellow HSP dimer is labeled 'HSP90' and is associated with three other proteins labeled 'Chaperones.'

A close-up view of a normal cell membrane and cytoplasm is shown. The HSP90-chaperone complex is associated with a small blue protein labeled 'Client Protein.' An activated signaling pathway is shown downstream of the client protein, indicating that the chaperone complex is helping to maintain the client protein pathway in an active state. The screen text reads, 'HSP90 stabilizes its client proteins, which can enhance their signaling activity.'

HSP90 and other heat shock proteins also help stabilize cellular proteins in the presence of environmental stresses, such as increased temperatures or glucose deprivation, that can threaten cell survival.

HSP90 in Cancer Cells

Multiple myeloma cells and many other types of cancer cells have more HSP90 than normal cells. This is most likely because cancer cells must cope with numerous external and internal stressors that are not experienced by normal cells, such as low levels of oxygen or mutation of important regulatory proteins.

This is a split-screen image with a green multiple myeloma cell on the left and a pink normal cell on the right. Yellow proteins labeled 'HSP90' are visible in the cytoplasm of both cells, but significantly more HSP90 proteins are present in the multiple myeloma cell.

There is evidence that HSP90 is an integral part of the machinery that allows cancer cells to grow uncontrollably. Its client proteins are associated with processes that contribute to all of the hallmarks of cancer: growth factor independence, resistance to antigrowth signals, unlimited replicative potential, tissue invasion and metastasis, avoidance of apoptosis, and angiogenesis. Because HSP90 supports many of the biochemical mechanisms used by cancer cells to survive and grow, drugs that interfere with HSP90 may provide better cancer control than drugs that target only a single pathway.

A close-up view of a cancer cell membrane and cytoplasm is shown. The HSP90-chaperone complex is associated with a small blue protein labeled 'Client Protein.' An activated signaling pathway is shown downstream of the client protein, indicating that the chaperone complex is helping to maintain the client protein pathway in an active state.

Inhibiting HSP90

HSP90 inhibitors have been examined in preclinical models of multiple myeloma and other types of cancer. These studies have shown that HSP90 inhibitors reduce the viability of myeloma cells, even those that are resistant to standard therapies for this cancer.

A mass of green cancer cells labeled 'Multiple Myeloma Cells' is shown. Small purple dots labeled 'HSP90 Inhibitors' are shown around and in the myeloma cells.

As expected, numerous proteins and pathways are affected by HSP90 inhibitors, including many suspected to play a role in multiple myeloma. One protein affected by HSP90 inhibition is Akt. The HSP90 complex binds to and stabilizes Akt in cancer cells, allowing the protein to promote cell proliferation and survival.

A close-up view of a cancer cell membrane and cytoplasm is shown. The HSP90-chaperone complex is associated with a small blue protein labeled 'Akt.' An activated signaling pathway is shown downstream of Akt. The pathway is labeled 'Proliferation/Survival Pathway.'

However, in the presence of an HSP90 inhibitor, the interaction between HSP90 and Akt is altered. As a result, Akt becomes a target for ubiquitinylation and degradation by proteasomes, a fate shared by many other HSP90 client proteins when the activity of this molecular chaperone is inhibited.

A close-up view of a proteasome is shown. A blue protein labeled 'Akt Protein' is nearby. The Akt protein is linked to several small red circles labeled 'Ubiquitin.'

Although no HSP90 inhibitors have been approved by the FDA, several are being tested in clinical trials of multiple myeloma.

More Information

HSP90 Inhibitors

This table lists several HSP90 inhibitors that have been or are being tested in clinical trials for multiple myeloma. To date, none of these agents has been approved by the FDA for treatment of multiple myeloma. For more information on types of targeted therapies, see Understanding Targeted Therapies: An Overview.

 Research NameGeneric NameTrade Name(s)Drug Type
HSP90 InhibitorsKOS-1022 (also called 17-DMAG)Alvespimycin--Small molecule
 KOS-953 (also called 17-AAG)Tanespimycin--Small molecule
 AUY922----Small molecule


Self Test

Questions

  1. HSP90 supports cell survival by activating Akt.
    1. True
    2. False

Answers

  1. Correct Answer: b
    1. True - Incorrect.
      HSP90 does not activate Akt. Rather, the HSP90 complex stabilizes Akt. Although this increased stability makes it more likely that Akt will be activated by other signaling molecules, HSP90 cannot directly activate Akt.
    2. False - Correct.
      HSP90 does not activate Akt. Rather, the HSP90 complex stabilizes Akt. Although this increased stability makes it more likely that Akt will be activated by other signaling molecules, HSP90 cannot directly activate Akt.

Inhibition of Histone Deacetylases (HDACs)

In This Section:

HDACs in Normal Cells

The activity of proteins can be altered in several ways, including by chemical modification. Phosphorylation is one common type of modification. Another common modification is acetylation, in which acetyl chemical groups are added to proteins.

A close-up view of a blue protein in the cytoplasm of a normal cell is shown. The protein is linked to three red globular structures representing acetyl groups. The image is labeled 'Acetylation.'

Acetylation--and deacetylation, the removal of acetyl groups--can influence the stability or function of proteins or alter their capacity to interact with other molecules.

A close-up view of a blue protein in the cytoplasm of a normal cell is shown. The three red globular structures representing acetyl groups have dissociated from the protein. The image is labeled 'Deacetylation.'

One group of proteins that is frequently modified by acetylation is the histone family. Histones are proteins that interact closely with DNA and help package it inside the nucleus.

A close-up view of a strand of DNA is shown. The yellow DNA is wrapped around several blue protein complexes labeled 'Histones.'

Genes located within regions of the tightly wound DNA that is associated with unacetylated histones are usually not expressed because the DNA is so tightly packaged that they are inaccessible to the cellular machinery that drives gene expression. Acetylation of histones loosens the close association between these proteins and DNA, thereby allowing the DNA structure to relax. Consequently, other proteins are able to reach the DNA and activate gene expression.

A close-up view of DNA wrapped around two histone complexes is shown. Several acetyl groups are linked to the histones. A protein complex representing the cellular machinery that drives gene expression is associated with the DNA between two histones.

On the other hand, gene expression can be shut down if cellular enzymes called histone deacetylases, or HDACs, remove the acetyl groups from the histones.

A close-up view of DNA associated with histones is shown. Green proteins representing histone deacetylases are associated with the histones and acetyl groups are shown moving away from the histones. The cell's gene expression machinery is moving away from the DNA.

Although named for their interaction with histones, HDACs participate in the regulation of acetylation of a wide variety of proteins that are involved in virtually all cellular processes.

HDACs in Cancer Cells

The activities and expression of many proteins implicated in cancer are regulated by acetylation. The importance of acetylation in cancer is illustrated by the finding that cancer cells cultured in the laboratory undergo cell cycle arrest and ultimately die when treated with HDAC inhibitors, whereas normal cells are relatively unaffected.

This is a split-screen image with a mass of pink normal cells shown on the left and a mass of green tumor cells shown on the right. Small green dots representing HDAC inhibitors are shown surrounding both cell masses. The normal cells are viable, but several of the cancer cells have undergone apoptosis, which is indicated by small gray vesicles. The screen text reads, 'Inhibition of HDACs causes death of cancer cells.'

Inhibiting HDACs

The apoptotic death of myeloma cells in response to treatment with HDAC inhibitors is likely due to changes in the activities and expression of numerous proteins. For example, through their effects on histones, HDAC inhibitors are thought to promote expression of p21, a cell cycle inhibitor, and Bax, a protein that promotes apoptosis.

A mass of green tumor cells is shown in the middle of the screen. The cells are surrounded by small purple dots representing HDAC inhibitors. Several of the tumor cells are undergoing apoptosis.

A close-up view of DNA associated with acetylated histones is shown. A green histone deacetylase protein associated with a green molecule representing an HDAC inhibitor is shown near the DNA. One section of DNA is glowing, indicating that the genes in this region are being expressed. The glowing DNA is labeled 'Expression of p21 and Bax genes.'

In addition, HDAC inhibitors affect the activity of HSP90, one of a number of cytoplasmic proteins regulated by acetylation. Acetylated HSP90 is unable to form stable complexes with its client proteins, leading to their degradation by proteasomes.

Small protein fragments are shown coming out of the end of the cylindrical proteasome complex. This represents the Akt protein being degraded by the proteasome because the HSP90 was unable to stabilize it.

HDAC inhibitors in combination with standard chemotherapy or other targeted therapies are being tested in clinical trials of multiple myeloma.

More Information

HDAC Inhibitors

This table lists several HDAC inhibitors that have been or are being tested in clinical trials for multiple myeloma. To date, none of these agents have been approved by the FDA for treatment of multiple myeloma, although vorinostat has been approved for another cancer, cutaneous T-cell lymphoma. For more information on types of targeted therapies, see Understanding Targeted Therapies: An Overview.

 Research NameGeneric NameTrade Name(s)Drug Type
HDAC InhibitorsSAHA (suberoyl anilide hydroxamic acid)VorinostatZolinza®Small molecule
 PXD101Belinostat--Small molecule
 MS-275Entinostat--Small molecule
 LBH589Panobinostat--Small molecule
 FK228Romidepsin (also called depsipeptide)--Small molecule
 ITF2357----Small molecule
 PCI-24781----Small molecule
 Sodium phenylbutyrate----Small molecule


Self Test

Questions

  1. Acetylation of proteins can:
    1. Reduce protein stability
    2. Modify protein-protein interactions
    3. Modify gene expression
    4. All of the above

Answers

  1. Correct Answer: d
    1. Reduce protein stability - Partially correct.
      There is a better answer.
    2. Modify protein-protein interactions - Partially correct.
      There is a better answer.
    3. Modify gene expression - Partially correct.
      There is a better answer.
    4. All of the Above - Correct.
      Protein acetylation can influence protein stability and protein-protein interactions. Acetylation of histones can also have an effect on gene expression.

Summary and Conclusions

In This Section:

Finding the Right Combinations

Because multiple signaling pathways are often disrupted in cancer cells, many clinical trials are testing combinations of targeted therapies. It is hoped that targeting multiple pathways might reduce the development of drug-resistant tumor cells.

For example, HSP90 inhibitors are being tested in combination with the proteasome inhibitor Velcade® (bortezomib) in clinical trials of myeloma. Preclinical studies have shown that myeloma cells treated with Velcade® produce more HSP90 to help protect themselves from the stress caused by the accumulation of undegraded proteins. Inhibiting HSP90 caused the cells to be more sensitive to the apoptotic effects of Velcade®.

This is a split-screen image. A mass of green cancer cells is shown on the left. Some of the cancer cells are undergoing apoptosis. The right side of the screen is a magnified view of the cytoplasm of one of the cancer cells. A proteasome bound to Velcade is shown in the cytoplasm. There are also several HSP90 dimers present in the cytoplasm.

Combination approaches that include one or more targeted therapies are almost certainly the future of cancer treatment. The possibilities are exciting, but clinical trials are needed to establish optimal dosages and schedules for combination therapies.

Two researchers in white laboratory coats are shown. The screen text reads, 'Clinical trials are needed to develop effective combination therapies for cancer.'

Accessing Targeted Therapies for Multiple Myeloma

One targeted therapy for treatment of multiple myeloma--Velcade®--has already been approved by the FDA. Click on the Additional Information link at the bottom of the screen to read about the approved uses of Velcade®.

A square icon labeled 'Targeted Therapies' is shown on the left side of the screen. The icon includes symbols for antibodies, vaccines, and small molecules. The word Velcade is shown on the right of the screen. A stamped overlay on the screen reads, 'FDA approved.'

Several other targeted therapies are being developed for use against multiple myeloma. Doctors should consider whether a clinical trial of innovative targeted therapies might be a good option for their patients.

More Information

Velcade®

Bortezomib (Velcade®)

  • Mechanism: proteasome inhibitor
  • Indications: treatment of patients with multiple myeloma and some patients with mantle cell lymphoma

Finding Clinical Trials

Targeted therapies for multiple myeloma are in all phases of clinical study.

There are a number of ways to find clinical trials. The National Cancer Institute's Web site--www.cancer.gov/clinicaltrials--contains information about clinical trials sponsored by the National Cancer Institute, pharmaceutical companies, medical centers, and other groups from around the world. For information on cancer clinical trials being conducted at the National Institutes of Health Clinical Center, visit www.bethesdatrials.cancer.gov. Information about clinical trials can also be found on the ClinicalTrials.gov Web site, which is operated and maintained by the U.S. National Library of Medicine.

Cancer patients and their families may also contact NCI's Cancer Information Service (CIS) if they have questions about cancer and clinical trials. The CIS can be reached by calling 1-800-4-CANCER. Or, patients can use the Live Chat feature on the Cancer.gov Web site.