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Targeted Therapies for Lymphoma Tutorial

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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.

This image shows a doctor talking with a patient.

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.

Lymphoma Tutorial—Objectives

This tutorial focuses on the variety of targeted therapies that have been and are being developed to treat lymphoma. By completing this tutorial, you will learn the answers to the following questions.

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

Lymphoma Background

Lymphoma is a cancer that begins in cells of the immune system called lymphocytes. Lymphoma occurs when B or T cells acquire changes that allow them to grow uncontrollably. The abnormal cells accumulate in the lymph nodes or other parts of the lymphatic system.

This image shows an outline of a human body on the left with the lymphatic system highlighted. To the right of the body, a normal B and T cell are shown with an arrow leading to a mass of green cancer cells.

This image shows an outline of a human body on the left with the lymphatic system highlighted. To the right of the body, a normal B and T cell are shown with an arrow leading to a mass of green cancer cells.

There are two types of lymphoma: Hodgkin and non-Hodgkin lymphoma. The majority of Hodgkin lymphomas are classical Hodgkin lymphomas, which consist of characteristic cells called Reed-Sternberg cells. Another much more rare type of Hodgkin lymphoma is nodular lymphocyte-predominant Hodgkin lymphoma.

There are several types of non-Hodgkin lymphoma. The most common are B cell cancers called diffuse large B cell lymphoma and follicular lymphoma. Other B cell non-Hodgkin lymphomas include Burkitt lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, and mantle cell lymphoma. T cell non-Hodgkin lymphomas include mycosis fungoides, anaplastic large cell lymphoma, and precursor T-lymphoblastic lymphoma.

Targeting CD20

In This Section:

CD20 in Normal Cells

B cells at almost every stage of development express a membrane-spanning protein called CD20. The function of CD20 is not fully understood, although it is suspected to play roles in calcium regulation and B cell development.

The head and torso of a human body are shown on the left, with the lymphatic system emphasized. A callout bubble coming from a lymph node shows a close-up view of a B cell. In the membrane of the B cell is an embedded protein labeled CD20.

The head and torso of a human body are shown on the left, with the lymphatic system emphasized. A callout bubble coming from a lymph node shows a close-up view of a B cell. In the membrane of the B cell is an embedded protein labeled CD20.

CD20 in Cancer Cells

CD20 is an attractive therapeutic target for a number of reasons:

Firstly, it is expressed by nearly 90 percent of all B cell non-Hodgkin lymphomas.

This image is titled, 'B Cell Non-Hodgkin Lymphoma Patients.' On the left are 9 green figures labeled CD20-positive. On the right is one green figure labeled CD20-negative. Screen text reads, 'Expressed by nearly 90 percent of B cell non-Hodgkin lymphomas.'

This image is titled, 'B Cell Non-Hodgkin Lymphoma Patients.' On the left are 9 green figures labeled CD20-positive. On the right is one green figure labeled CD20-negative. Screen text reads, 'Expressed by nearly 90 percent of B cell non-Hodgkin lymphomas.'

Secondly, although CD20 is present on most normal B cells, the stem cells that give rise to B cells do not express the protein. This means that B cells damaged by a CD20-targeted therapy can be replaced.

In the background are several gray cells representing normal and malignant B cells that have been killed by a CD20-targeted therapy. In the foreground are several viable blue cells. One of these is labeled 'stem cell.' The other blue cells represent CD20-positive B cells that have arisen from the stem cell. The screen text on this image reads, 'Normal B cells can be regenerated.'

In the background are several gray cells representing normal and malignant B cells that have been killed by a CD20-targeted therapy. In the foreground are several viable blue cells. One of these is labeled “stem cell.” The other blue cells represent CD20-positive B cells that have arisen from the stem cell. The screen text on this image reads, “Normal B cells can be regenerated."

Finally, CD20 is not present on any other cells in the body, which makes it less likely that drugs targeting this protein will damage other tissues and organs.

A human body is shown in the center of the screen. A call-out bubble on the right shows a close-up view of a CD20-positive malignant B cell. The transmembrane protein CD20 is labeled. A black label pointing to the body states, 'Not expressed by other cells in the body.'

A human body is shown in the center of the screen. A call-out bubble on the right shows a close-up view of a CD20-positive malignant B cell. The transmembrane protein CD20 is labeled. A black label pointing to the body states, “Not expressed by other cells in the body.”

Targeting CD20

Several monoclonal antibodies have been designed to target CD20 on lymphoma cells. These include Rituxan® (rituximab), Bexxar® (tositumomab), and Zevalin® (ibritumomab tiuxetan). The mechanisms of these therapeutic antibodies vary, but all of them bind to CD20 on the surface of both normal and cancerous B cells. This tutorial discusses several proposed mechanisms of action for Rituxan® (rituximab), including antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, and apoptosis.

This image shows a close-up view of the cell membrane of a malignant B cell. A protein labeled CD20 is present in the cell membrane. A purple monoclonal antibody is bound to the extracellular portion of CD20.

This image shows a close-up view of the cell membrane of a malignant B cell. A protein labeled CD20 is present in the cell membrane. A purple monoclonal antibody is bound to the extracellular portion of CD20.

Antibody-dependent cell-mediated cytotoxicity, or ADCC, occurs when Rituxan® (rituximab) that is bound to CD20 interacts with immune system effector cells. These cells release molecules that lyse the target cell.

This image is titled 'Antibody-Dependent Cell-Mediated Cytotoxicity.' It shows a close-up view of the membrane of a malignant B cell. A CD20 protein is extruding from the B cell membrane and is bound to one of the short arms of a purple monoclonal antibody. The long arm of the antibody is bound to a protein embedded in the membrane of a blue cell that represents an immune cell. Molecules are being released from the immune cell.

This image is titled “Antibody-Dependent Cell-Mediated Cytotoxicity.” It shows a close-up view of the membrane of a malignant B cell. A CD20 protein is extruding from the B cell membrane and is bound to one of the short arms of a purple monoclonal antibody. The long arm of the antibody is bound to a protein embedded in the membrane of a blue cell that represents an immune cell. Molecules are being released from the immune cell.

Rituxan® (rituximab) is also thought to activate complement-dependent cytotoxicity, or CDC. CDC is an immune response that involves a series of proteins known as the complement system. Some of the complement proteins insert themselves into the cell membrane, compromising the integrity of the cell and leading to cell death.

This image is labeled 'Complement-Dependent Cytotoxicity.' It shows a close-up view of the membrane of a malignant B cell. The extracellular portion of CD20 is shown bound to the short arm of a monoclonal antibody. The long arm of the monoclonal antibody is bound to a series of three proteins. Five cylindrical proteins are shown embedding into the cell membrane, forming a pore. Small molecules are being released from the cell through the membrane.

This image is labeled “Complement-Dependent Cytotoxicity.” It shows a close-up view of the membrane of a malignant B cell. The extracellular portion of CD20 is shown bound to the short arm of a monoclonal antibody. The long arm of the monoclonal antibody is bound to a series of three proteins. Five cylindrical proteins are shown embedding into the cell membrane, forming a pore. Small molecules are being released from the cell through the membrane.

Rituxan® (rituximab) can also cause target cells to undergo apoptosis by shifting the balance of pro- and anti-apoptotic pathways in the cell.

A layer of pink normal cells is shown in the background and a mass of green cancer cells is shown in the foreground on the right. Several of the tumor cells are shrinking and breaking into small globules, indicating that they are undergoing apoptosis. A call-out bubble is emanating from the tumor mass; in it is a close-up view of a cancer cell beginning to undergo apoptosis.

A layer of pink normal cells is shown in the background and a mass of green cancer cells is shown in the foreground on the right. Several of the tumor cells are shrinking and breaking into small globules, indicating that they are undergoing apoptosis. A call-out bubble is emanating from the tumor mass; in it is a close-up view of a cancer cell beginning to undergo apoptosis.

Rituxan® (rituximab) was the first monoclonal antibody approved by the FDA for therapeutic use in cancer patients.

Several green figures are shown in the background. In the center is an icon containing a purple monoclonal antibody with a stamp over it reading, 'FDA approved.' Rituxan is written beneath the icon.

Several green figures are shown in the background. In the center is an icon containing a purple monoclonal antibody with a stamp over it reading, “FDA approved.” Rituxan is written beneath the icon.

It has been approved for use in combination with standard chemotherapy for treatment of CD20-expressing diffuse large B cell and follicular B cell non-Hodgkin lymphomas.

It is also approved as a single agent for certain types of CD20-positive B cell non-Hodgkin lymphomas that have relapsed or do not respond to other therapies.

Rituxan® (rituximab) and other drugs that target CD20 are also being tested in clinical trials for lymphoma.

More Information

This table lists several drugs that target CD20. Agents that have been approved by the FDA for treatment of lymphoma are marked with an asterisk. For more information on types of targeted therapies, see Understanding Targeted Therapies: An Overview.

 Research NameGeneric NameTrade NameDrug Type
CD20 Targeted Drugs--Ofatumumab (also called HuMax-CD20)Arzerra™Monoclonal antibody
 --Tositumumab*Bexxar®*Monoclonal antibody
 --Rituximab*Rituxan®*Monoclonal antibody
 --Ibritumomab Tiuxetan*Zevalin®*Monoclonal antibody
 hA20Veltuzumab--Monoclonal antibody
 AME-133v----Monoclonal antibody
 R7159----Monoclonal antibody

* Agents that have been approved by the FDA for treatment of lymphoma

Some monoclonal antibodies that target CD20 are conjugated to other molecules that will damage the CD20-expressing cell. For example, Zevalin® (ibritumomab tiuxetan) is a monoclonal antibody against CD20 that is covalently bound to a radioactive molecule called Yttrium-90. Bexxar® (tositumomab) is a monoclonal antibody conjugated to radioactive iodine.

Self Test

Questions

  1. Which of the following are mechanisms of Rituxan® (rituximab)-mediated death of lymphoma cells: .
    1. Antibody-dependent cell-mediated cytotoxicity
    2. Downregulation of CD20
    3. Apoptosis
    4. A and B
    5. A and C

Answers

  1. Correct Answer: e
    1. Partially correct.
      Rituxan is thought to induce cell death through antibody-dependent cell mediated toxicity and apoptosis as well as complement-dependent cytotoxicity.
    2. Incorrect.
      Rituxan is thought to induce cell death through antibody-dependent cell mediated toxicity and apoptosis as well as complement-dependent cytotoxicity. It does not appear to cause downregulation of CD20.
    3. Partially correct.
      Rituxan is thought to induce cell death through antibody-dependent cell mediated toxicity and apoptosis as well as complement-dependent cytotoxicity.
    4. Incorrect.
      Rituxan is thought to induce cell death through antibody-dependent cell mediated toxicity and apoptosis as well as complement-dependent cytotoxicity. It does not appear to cause downregulation of CD20.
    5. Correct.
      Rituxan is thought to induce cell death through antibody-dependent cell mediated toxicity and apoptosis as well as complement-dependent cytotoxicity.

Inhibition of Bcl-2

In This Section:

Bcl-2 in Normal Cells

The cells of the immune system must be able to rapidly expand to fight infections and then decrease in number when a threat has been overcome. One way the body controls the number of immune cells is through the carefully-controlled process of apoptosis, or programmed cell death.

A human head and torso are shown on the left with the lymphatic system highlighted. A call-out bubble coming from one of the lymph nodes shows a close-up view of several immune cells. One of the cells has undergone apoptosis, illustrated by the fact that it has broken into several gray globules.

A human head and torso are shown on the left with the lymphatic system highlighted. A call-out bubble coming from one of the lymph nodes shows a close-up view of several immune cells. One of the cells has undergone apoptosis, illustrated by the fact that it has broken into several gray globules.

The Bcl-2 family of proteins is critical for regulation of apoptosis in lymphocytes and many other cells in the body. There are both pro-survival and pro-apoptotic Bcl-2 family members. When activated, some pro-apoptotic family members, such as Bax and Bak, form pores in the outer membrane of the mitochondria, allowing the release of proteins that initiate apoptosis.

A close-up view of a mitochondrion is shown. Light blue proteins embedded in the outer mitochondrial membrane are labeled, 'Pro-survival (Bcl-2).' Red proteins embedded in the outer mitochondrial membrane are labeled, 'Pro-apoptotic (Bax/Bak).' Several red pro-apoptotic proteins have come together to form a pore in the outer membrane of the mitochondria through which small proteins are being released into the cytoplasm.

A close-up view of a mitochondrion is shown. Light blue proteins embedded in the outer mitochondrial membrane are labeled, “Pro-survival (Bcl-2).” Red proteins embedded in the outer mitochondrial membrane are labeled, “Pro-apoptotic (Bax/Bak).” Several red pro-apoptotic proteins have come together to form a pore in the outer membrane of the mitochondria through which small proteins are being released into the cytoplasm.

Pro-survival proteins such as Bcl-2 maintain the integrity of the mitochondria by preventing activation of pro-apoptotic family members.

A close-up view of a mitochondrion is shown. Light blue proteins embedded in the outer mitochondrial membrane are labeled, 'Pro-survival (Bcl-2).' Red proteins embedded in the outer mitochondrial membrane are labeled, 'Pro-apoptotic (Bax/Bak).' All of the red pro-apoptotic proteins are bound by blue pro-survival proteins, which prevent the former from forming pores in the mitochondrial membrane and inducing apoptosis.

A close-up view of a mitochondrion is shown. Light blue proteins embedded in the outer mitochondrial membrane are labeled, “Pro-survival (Bcl-2).” Red proteins embedded in the outer mitochondrial membrane are labeled, “Pro-apoptotic (Bax/Bak).” All of the red pro-apoptotic proteins are bound by blue pro-survival proteins, which prevent the former from forming pores in the mitochondrial membrane and inducing apoptosis.

Other pro-apoptotic Bcl-2 family members called BH3-only proteins promote apoptosis by preventing the inhibitory activity of Bcl-2 and other pro-survival family members. This allows pro-apoptotic family members to form pores in the outer mitochondrial membrane and initiate cell death.

A close-up view of a mitochondrion is shown. Light blue proteins embedded in the outer mitochondrial membrane are labeled, 'Pro-survival (Bcl-2).' Red proteins embedded in the outer mitochondrial membrane are labeled, 'Pro-apoptotic (Bax/Bak).' Small circular red proteins bound to Bcl-2 are labeled, 'Pro-apoptotic (BH3-only).'

A close-up view of a mitochondrion is shown. Light blue proteins embedded in the outer mitochondrial membrane are labeled, “Pro-survival (Bcl-2).” Red proteins embedded in the outer mitochondrial membrane are labeled, “Pro-apoptotic (Bax/Bak).” Small circular red proteins bound to Bcl-2 are labeled, “Pro-apoptotic (BH3-only).” Several red pro-apoptotic Bax/Bak proteins have come together to form a pore in the outer membrane of the mitochondria through which small proteins are being released into the cytoplasm.

 

Bcl-2 in Cancer Cells

Bcl-2 family members have been widely implicated in cancer. Elevated levels of Bcl-2 have been identified in a number of lymphoma types. Increased expression of the Bcl-2 gene can be caused by chromosomal translocation, gene amplification, DNA hypomethylation, and loss of regulatory microRNA expression. When levels of Bcl-2 are high, pro-apoptotic proteins cannot form pores in the mitochondrial membrane. This allows cells to ignore signals to undergo apoptosis, which may contribute to the formation and growth of tumors.

A close-up view of a mitochondrion is shown. Light blue proteins embedded in the outer mitochondrial membrane are labeled, 'Pro-survival (Bcl-2).' Red proteins embedded in the outer mitochondrial membrane are labeled, 'Pro-apoptotic (Bax/Bak).' All of the red pro-apoptotic proteins are bound by blue pro-survival proteins, which prevent the former from forming pores in the mitochondrial membrane and inducing apoptosis.

A close-up view of a mitochondrion is shown. Light blue proteins embedded in the outer mitochondrial membrane are labeled, “Pro-survival (Bcl-2).” Red proteins embedded in the outer mitochondrial membrane are labeled, “Pro-apoptotic (Bax/Bak).” All of the red pro-apoptotic proteins are bound by blue pro-survival proteins, which prevent the former from forming pores in the mitochondrial membrane and inducing apoptosis. Screen text reads, “Elevated levels of Bcl-2 allow cells to ignore signals to undergo apoptosis.”

For example, high levels of Bcl-2 help cancer cells survive after they have been damaged by chemotherapeutic drugs. This may help explain why elevated expression of Bcl-2 is associated with poor prognosis of non-Hodgkin lymphoma patients.

A layer of pink normal cells is shown in the background and a mass of green tumor cells is in the foreground. Small yellow molecules representing chemotherapeutic drugs are present. The tumor cells are not undergoing apoptosis in response to the chemotherapy.

A layer of pink normal cells is shown in the background and a mass of green tumor cells is in the foreground. Small yellow molecules representing chemotherapeutic drugs are present. The tumor cells are not undergoing apoptosis in response to the chemotherapy.

 

Inhibiting Bcl-2

There are numerous ongoing efforts to interfere with Bcl-2 and its fellow pro-survival family members to help restore the sensitivity of cancer cells to pro-apoptotic signals. Several small molecules—including one called ABT-263—have been designed to mimic BH3-only proteins. These BH3 mimetics bind to Bcl-2 and some other pro-survival family members, allowing Bax and other pro-apoptotic proteins to create pores in the outer mitochondrial membrane and commit the cell to apoptotic death.

A close-up view of a mitochondrion is shown. Light blue proteins embedded in the outer mitochondrial membrane are labeled, 'Pro-survival (Bcl-2).' Red proteins embedded in the outer mitochondrial membrane are labeled, 'Pro-apoptotic (Bax/Bak).' Small circular purple molecules bound to Bcl-2 are labeled, 'Pro-apoptotic ABT-263 (BH3-only mimetic).'

A close-up view of a mitochondrion is shown. Light blue proteins embedded in the outer mitochondrial membrane are labeled, “Pro-survival (Bcl-2).” Red proteins embedded in the outer mitochondrial membrane are labeled, “Pro-apoptotic (Bax/Bak).” Small circular purple molecules bound to Bcl-2 are labeled, “Pro-apoptotic ABT-263 (BH3-only mimetic).” Several red pro-apoptotic Bax/Bak proteins have come together to form a pore in the outer membrane of the mitochondria through which small proteins are being released into the cytoplasm.

ABT-263 induces death of lymphoma cells grown in cell culture and can also inhibit tumor growth in mouse models of lymphoma.

There have also been a number of promising results from preclinical studies of ABT-263 in combination with other therapies, including standard chemotherapeutic regimens, Rituxan® (rituximab), and the mTOR inhibitor rapamycin. ABT-263 and other Bcl-2 inhibitors are being tested in clinical trials for lymphomas and other types of cancer.

A group of green figures represent clinical trials participants. Three gray boxes on the left of the screen are labeled, 'Phase 0,' 'Phase I,' and 'Phase II' and are connected by arrows. Screen text reads, 'Bcl-2 inhibitors are being tested in clinical trials for lymphomas and other types of cancer.'

A group of green figures represent clinical trials participants. Three gray boxes on the left of the screen are labeled, “Phase 0,” “Phase I,” and “Phase II” and are connected by arrows. Screen text reads, “Bcl-2 inhibitors are being tested in clinical trials for lymphomas and other types of cancer.”

More Information

This table lists several drugs that target Bcl-2 family members.

 Research NameGeneric NameTrade NameDrug Type
Bcl-2 targeted drugs--Oblimersen sodiumGenasense®Antisense oligonucleotide
 AT-101Gossypol (levo gossypol)--Small molecule
 GX15-070Obatoclax--Small molecule
 ABT-263----Small molecule

None of the agents listed on this table have been approved by the FDA for treatment of lymphoma; however, all of these drugs are being tested in clinical trials for lymphoma and/or other types of cancer. For more information on types of targeted therapies, see Understanding Targeted Therapies: An Overview.

Specificity of Bcl-2 inhibitors: Most small molecule Bcl-2 inhibitors also bind to and inhibit other pro-survival Bcl-2 family members, including Bcl-XL, Bcl-w, and Mcl-1. ABT-263 binds with high affinity to Bcl-2, Bcl-XL, and Bcl-w, but interacts weakly with Mcl-1.

 

Antisense oligonucleotides anti-Bcl-2 drugs: Genasense® is an antisense oligonucleotide (short piece of single-stranded DNA) that targets Bcl-2 messenger RNA. When Genasense® is present, the Bcl-2 messenger RNA cannot be translated into Bcl-2 protein and is instead degraded. The result is lower levels of Bcl-2 protein in the cell, which makes the cell more susceptible to apoptosis.

Self Test

Questions

  1. BH3 mimetics directly induce apoptosis.
    1. True
    2. False

Answers

  1. Correct Answer: b
    1. True - Incorrect.
      BH3 mimetics interfere with the activity of pro-survival proteins, which allows pro-apoptotic proteins to initiate cell death.
    2. False - Correct.
      BH3 mimetics interfere with the activity of pro-survival proteins, which allows pro-apoptotic proteins to initiate cell death.

Inhibiting the PI3K/Akt/mTOR Signaling Pathways

In This Section:

PI3K/Akt/mTOR Signaling in Normal Cells

mTOR is a critical regulator of several normal cell processes in numerous cell types, including cells of the immune system. Several other proteins—including PI3-kinase, Akt and PTEN—play roles in mTOR signaling.

A cross-section of a cell is shown, including the membrane and some cytoplasm. Proteins in the cytoplasm are labeled PTEN, PI3-kinase, mTOR, and Akt.

A cross-section of a cell is shown, including the membrane and some cytoplasm. Proteins in the cytoplasm are labeled PTEN, PI3-kinase, mTOR, and Akt.

PI3-kinase is an enzyme that phosphorylates certain phospholipids of the cell membrane. Once phosphorylated, these phospholipids bind to a protein called Akt. Akt then becomes phosphorylated and activated. This triggers activation of several downstream signaling pathways, which increases cell survival, proliferation, and cell growth.

A cross-section of a cell is shown, including the membrane and some cytoplasm. The protein Akt is associated with a phospholipid in the cell membrane. Arrows representing signaling pathways extend from Akt and are labeled 'Increased Survival,' 'Increased Proliferation,' and 'Increased Growth.'

A cross-section of a cell is shown, including the membrane and some cytoplasm. The protein Akt is associated with a phospholipid in the cell membrane. Arrows representing signaling pathways extend from Akt and are labeled “Increased Survival,”” “Increased Proliferation,” and “Increased Growth.”

One important player in the growth and proliferation pathways is mTOR. When activated by Akt, mTOR promotes cell growth and proliferation by stimulating protein synthesis.

A cross-section of a cell is shown, including the membrane and some cytoplasm. The protein Akt is associated with a phospholipid in the cell membrane. Arrows representing signaling pathways extend from Akt and are labeled 'Increased Survival,' 'Increased Proliferation,' and 'Increased Growth.' The mTOR protein is shown as part of the 'Increased Growth' and 'Increased Proliferation' pathways. The label 'Increased Protein Synthesis' indicates how mTOR participates in these pathways.

A cross-section of a cell is shown, including the membrane and some cytoplasm. The protein Akt is associated with a phospholipid in the cell membrane. Arrows representing signaling pathways extend from Akt and are labeled “Increased Survival,” “Increased Proliferation,” and “Increased Growth.” The mTOR protein is shown as part of the “Increased Growth” and “Increased Proliferation” pathways. The label “Increased Protein Synthesis” indicates how mTOR participates in these pathways.

In addition to receiving signals from Akt, mTOR monitors the cell’s environment for the presence of growth factors and nutrients. If the cell needs additional resources, mTOR can increase nutrient uptake and promote angiogenesis. mTOR can also increase the activity of Akt, thus enhancing the other downstream effects of this protein.

A cross-section of a cell is shown, including the membrane and some cytoplasm. The protein Akt is associated with a phospholipid in the cell membrane. Arrows representing signaling pathways extend from Akt and are labeled 'Increased Survival,' 'Increased Proliferation,' and 'Increased Growth.' The mTOR protein is shown as part of the 'Increased Growth' and 'Increased Proliferation' pathways. Small blue molecules outside the cell are labeled, 'Growth Factors, Nutrients' and a blue arrow leads into the cell

A cross-section of a cell is shown, including the membrane and some cytoplasm. The protein Akt is associated with a phospholipid in the cell membrane. Arrows representing signaling pathways extend from Akt and are labeled “Increased Survival,” “Increased Proliferation,” and “Increased Growth.” The mTOR protein is shown as part of the “Increased Growth” and “Increased Proliferation” pathways. Small blue molecules outside the cell are labeled, “Growth Factors, Nutrients” and a blue arrow leads into the cell from these molecules to mTOR, indicating that mTOR monitors levels of these molecules. Arrows leading from mTOR are labeled “Increased Nutrient Uptake” and “Increased Angiogenesis.”

Because mTOR and its signaling partners are so powerful, the cell has mechanisms in place to regulate them. One important watchdog is PTEN. PTEN removes the phosphate groups added to membrane phospholipids by PI3-kinase. This prevents activation of Akt and its downstream pathways.

The Akt and mTOR pathways are shown, but are gray, indicating that they are inactive. The protein PTEN is associated with a membrane phospholipid and Akt has dissociated from the membrane.

The Akt and mTOR pathways are shown, but are gray, indicating that they are inactive. The protein PTEN is associated with a membrane phospholipid and Akt has dissociated from the membrane.

PI3K/Akt/mTOR Signaling in Cancer Cells

The signaling pathway that includes mTOR is highly active in many cancer cells. This can be the result of amplification or mutation of the PI3-kinase gene, amplification or mutation of the Akt gene, or loss of function of PTEN. Increased activity of some growth factor receptors can also enhance the activity of the pathway.

A cross section of a green cancer cell is shown, including the cell membrane and cytoplasm. Akt, mTOR, PI3-kinase and PTEN are shown to indicate that alterations in these proteins have been found in cancer.

A cross section of a green cancer cell is shown, including the cell membrane and cytoplasm. Akt, mTOR, PI3-kinase and PTEN are shown to indicate that alterations in these proteins have been found in cancer.

In addition, growth and proliferation of many types of cancer, including lymphomas, are driven by proteins and cell processes that depend on proteins regulated by mTOR.

Inhibiting PI3K/Akt/mTOR Signaling

Drugs targeting PI3-kinase, Akt, and mTOR are being tested in preclinical models and clinical trials. One mTOR inhibitor is a small molecule called rapamycin. Rapamycin enters the cell and binds to a protein called FKBP12.

A close-up of a cancer cell is shown. A pathway containing Akt and mTOR is shown activated. The small molecule rapamycin, represented by a small purple oval, is bound to a protein labeled FKBP12.

A close-up of a cancer cell is shown. A pathway containing Akt and mTOR is shown activated. The small molecule rapamycin, represented by a small purple oval, is bound to a protein labeled FKBP12.

This complex binds to and inhibits mTOR. Inhibition of mTOR with rapamycin has been found to inhibit proliferation of several types of lymphoma cells.

A close-up of a cancer cell is shown with a pathway containing Akt and mTOR visible. A complex of rapamycin bound to FKBP12 is interacting with mTOR. Elements of the signaling pathway downstream of mTOR are gray, indicating that rapamycin-FKBP12 prevents mTOR from activating downstream pathway members.

A close-up of a cancer cell is shown with a pathway containing Akt and mTOR visible. A complex of rapamycin bound to FKBP12 is interacting with mTOR. Elements of the signaling pathway downstream of mTOR are gray, indicating that rapamycin-FKBP12 prevents mTOR from activating downstream pathway members.

mTOR inhibitors, including rapamycin, are being tested in clinical trials for lymphoma.

A group of green figures on the right of the screen represent clinical trials participants. Three gray boxes on the left of the screen are labeled, 'Phase 0,' 'Phase I,' and 'Phase II' and are connected by arrows.

A group of green figures on the right of the screen represent clinical trials participants. Three gray boxes on the left of the screen are labeled, “Phase 0,” “Phase I,” and “Phase II” and are connected by arrows.

Some of these trials are using mTOR inhibitors in combination with standard therapies or other targeted therapies, such as Rituxan®. Researchers are also working to develop assays to identify patients in whose tumors mTOR or its signaling partners are highly activated because these patients may be more likely to benefit from treatment with combinations of therapies that include mTOR inhibitors.

Two researchers are shown in the laboratory looking at the results of an experiment.

More Information

This table lists several drugs that target mTOR and its signaling partners.

 Research NameCommon NameTrade NameType of Targeted Therapy
mTOR inhibitorsRAD-001EverolimusCertican®Small molecule
 --Rapamycin
(also called sirolimus)
Rapamune®Small molecule
 CCI-779TemsirolimusTorisel®Small molecule
 AP23573Deforolimus--Small molecule
 OSI-027----Small molecule
Akt inhibitorsKRX-0401Perifosine­--Small molecule
 --Triciribine--Small molecule
 GSK690693----Small molecule
PI3-kinse inhibitorsBGT226----Small molecule
 CAL-101----Small molecule

To date, none of these agents are approved by the FDA for treatment of lymphoma; however, all of these drugs are being tested in clinical trials for lymphoma and/or other types of cancer. For more information on types of targeted therapies, see Understanding Targeted Therapies: An Overview.

Self Test

Questions

  1. mTOR is involved in the following cellular process(es):
    1. Protein synthesis
    2. Nutrient uptake
    3. Both A and B

Answers

  1. Correct Answer: c
    1. Partially correct.
      mTOR does play a role in protein synthesis, but it can also influence a cell’s uptake of nutrients.
    2. Partially correct.
      mTOR does play a role in nutrient uptake, but it also influences protein synthesis.
    3. Correct.
      mTOR is involved in both protein synthesis and nutrient uptake.

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 called 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.'

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.'

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.'

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 DNA associated with unacetylated histones are usually not expressed because the DNA is so tightly packaged it is 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.

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.

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. Acetylation appears to play an important role in cutaneous T cell lymphomas, or CTCLs, which are non-Hodgkin lymphomas that affect the skin. Whereas most normal cells are relatively unaffected by HDAC inhibitors, these drugs induce apoptosis of CTCL cell lines and peripheral blood lymphocytes from CTCL patients.

This is a split-screen image. On the left is a mass of normal cells and on the right is a mass of tumor cells. Both types of cells are being treated with HDAC inhibitors represented by small purple molecules. The normal cells appear to be unaffected by the HDAC inhibitors, but several of the cancer cells are undergoing apoptosis, evidenced by the fact that they are splitting into gray globules. Screen text reads, 'Inhibition of HDACs causes death of CTCL cells.'

This is a split-screen image. On the left is a mass of normal cells and on the right is a mass of tumor cells. Both types of cells are being treated with HDAC inhibitors represented by small purple molecules. The normal cells appear to be unaffected by the HDAC inhibitors, but several of the cancer cells are undergoing apoptosis, evidenced by the fact that they are splitting into gray globules. Screen text reads, 'Inhibition of HDACs causes death of CTCL cells.'

Inhibiting HDACs

The apoptotic death of CTCL cells in response to HDAC inhibitors is likely due to changes in the activities and expression of multiple 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 close-up view of DNA associated with acetylated histones is shown. A green histone deacetylase protein associated with a purple 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.'

A close-up view of DNA associated with acetylated histones is shown. A green histone deacetylase protein associated with a purple 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.”

HDAC inhibitors also affect the activity of a number of cytoplasmic proteins that are regulated by acetylation. One HDAC inhibitor, Zolinza® (vorinostat), has been approved by the FDA for treatment of patients with CTCL that has progressed, persisted, or recurred during or after two systemic therapies.

A male patient is shown sitting on a hospital bed. A health care professional is standing at the side of the bed.

Zolinza® (vorinostat) and other HDAC inhibitors are currently being studied in clinical trials of CTCL and other types of lymphoma.

Several green figures are shown in the background. Five gray ovals labeled Phase 0, Phase I, Phase II, Phase III, and Phase IV are shown in the upper left-hand corner. Screen text reads, 'HDAC inhibitors are being tested in clinical trials of lymphoma.'

Several green figures are shown in the background. Five gray ovals labeled “Phase 0,” “Phase I,” “Phase II,” “Phase III,” and “Phase IV” are shown in the upper left-hand corner. Screen text reads, “HDAC inhibitors are being tested in clinical trials of lymphoma.”

More Information

This table lists several HDAC inhibitors that are being tested in clinical trials for lymphoma.

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

Drugs that have been approved by the FDA for treatment of lymphoma are marked with an asterisk. For more information on types of targeted therapies, see Understanding Targeted Therapies: An Overview.

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. Partially correct.
      There is a better answer.
    2. Partially correct.
      There is a better answer.
    3. Partially correct.
      There is a better answer.
    4. 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

Since 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, an mTOR inhibitor is being tested in combination with Rituxan® (rituximab), the monoclonal antibody that interacts with CD20. Preclinical studies have shown that diffuse large B cell lymphoma cells treated with an mTOR inhibitor are more sensitive to the cytotoxic effects of Rituxan® (rituximab).

A middle-aged male patient is shown sitting in a chair in a doctor’s office. He is talking to two health care professionals—a man seated in a chair and a woman standing next to him.

 

Accessing Targeted Therapies for Lymphoma

A few targeted therapies have already been approved by the FDA for treatment of lymphoma. For a list of these drugs and their approved uses, click on the Additional Information link at the bottom of the screen.

An icon in the middle of the screen contains an image of an antibody and small molecules. The icon is labeled 'Targeted Therapies.' A stamp over the icon reads, 'FDA approved.'

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

A male and female researcher are shown.

More Information

Approved Targeted Drugs

Targeted therapies that are approved by the FDA for the treatment of lymphoma:

Rituximab (Rituxan®)

  • Mechanism: The antibody binds to the CD20 antigen on B lymphocytes and recruits immune effector functions to mediate B cell lysis in vitro; possible mechanisms of cell lysis include complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity. The antibody has also been shown to induce apoptosis in vitro.

Indications:

  • As a single agent for treatment of patients with relapsed or refractory, low-grade or follicular, CD20-positive B cell non-Hodgkin lymphoma
  • In combination with CVP (cyclophosphamide, vincristine, and prednisone) chemotherapy for treatment of patients with previously-untreated follicular, CD20-positive, B cell non-Hodgkin lymphoma
  • As a single agent for treatment of patients with non-progressing, low-grade, CD20-positive, B cell non-Hodgkin lymphoma who have been previously treated with CVP (cyclophosphamide, vincristine, and prednisone) chemotherapy
  • In combination with CHOP (cyclophosphamide, doxorubicin hydrochloride [hydroxydaunorubicin], vincristine [Oncovin®], and prednisone) or other anthracycline-based chemotherapy regimens for treatment of patients with previously-untreated diffuse large B cell, CD20-positive non-Hodgkin lymphoma

Ibritumomab tiuxetan (Zevalin®)

  • Mechanism: The antibody binds specifically to the CD20 antigen on B lymphocytes. The beta emission from Y-90 (yttrium-90) induces cellular damage by the formation of free radicals in the target and neighboring cells.
  • Indications: As part of the Zevalin therapeutic regimen for treatment of relapsed or refractory, low-grade or follicular B-cell non-Hodgkin lymphoma, including patients with rituximab refractory follicular non-Hodgkin lymphoma

Tositumomab (Bexxar®)

  • Mechanism: The antibody binds specifically to the CD20 antigen on B lymphocytes. Possible mechanisms of action include induction of apoptosis, complement-dependent cytotoxicity, and antibody-dependent cellular cytotoxicity. Additionally, cell death is associated with ionizing radiation from I-131 (iodine-131).
  • Indications: The Bexxar therapeutic regimen is indicated for treatment of patients with CD20 antigen-expressing relapsed or refractory, low grade, follicular, or transformed non-Hodgkin lymphoma, including patients with rituximab-refractory non-Hodgkin lymphoma. The Bexxar therapeutic regimen is not indicated for the initial treatment of patients with CD20-positive non-Hodgkin lymphoma.

Vorinostat (Zolinza®)

  • Mechanism: Histone deacetylase inhibitor
  • Indications: Indicated for treatment of cutaneous manifestations in patients with cutaneous T cell lymphoma who have progressive, persistent, or recurrent diseases on or following two systemic therapies.
 

Finding Clinical Trials

Targeted therapies for lymphoma 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.