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Targeted Therapies for Breast Cancer 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. 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.

Image of doctor talking to patient.

Breast Cancer Tutorial—Objectives

Image of young female patient in a hospital bed with healthcare providers surrounding her.

This tutorial focuses on targeted therapies that have been and are being developed to treat breast cancer, including small molecules and monoclonal antibodies. By completing this tutorial, you will learn the answers to the following questions:

  • What pathways in breast cancer cells are being targeted?
  • What agents are being developed to target these pathways?
  • Which targeted therapies are currently approved by the U.S. Food and Drug Administration (FDA) for treating breast cancer?
  • How can I find clinical trials that are evaluating targeted therapies for breast cancer?

Breast Cancer Treatment Background

Treatment for breast cancer depends on the stage of the disease, but often includes surgery, radiation therapy, and chemotherapy. Some targeted therapies, including antihormone therapies and Herceptin® (trastuzumab), have also become part of standard treatment for breast cancer when a patient's tumor expresses the targets of these drugs. Preclinical experiments and clinical trials are currently underway to evaluate additional targeted therapies and find out how best to use these drugs in combination with each other and standard therapies.

Inhibition of Estrogen Signaling

In This Section:

Estrogen Signaling in Normal Cells

Some of the earliest targeted therapies were aimed at disrupting the activity of the hormone estrogen in breast cancer cells.

In premenopausal women, estrogen is made primarily in the ovaries. However, estrogen is also made in smaller amounts by other tissues, including adipose (fat) tissue and the breast. Estrogen travels through the circulatory system to reach its target organs, which include the breast.

This is an image of a female body. Circulating estrogen is represented by small pink dots throughout the body. The ovaries are highlighted in pink to indicate that they are the primary source of estrogen in the female body.

During normal human development, the menstrual cycle, and pregnancy and lactation, estrogen and other hormones stimulate the growth and development of epithelial cells in the breast.

This is a side-view of a breast. The ductal system of the breast is shown extending from the nipple.

Estrogen is a steroid hormone that can easily cross the plasma membrane of the cell and then enter the cell's nucleus. Once inside the nucleus, estrogen binds to estrogen receptor proteins. The estrogen-receptor complex then binds to specific sequences of DNA and regulates the expression of numerous genes involved in cell growth.

A cross-section of a cell is shown. In the nucleus of the cell, estrogen, represented by pink spheres, is bound to estrogen receptor, represented by gray structures.

Estrogen Signaling in Cancer Cells

Many years ago, it was discovered that removal of the ovaries led to the regression of some breast tumors. It is now known that this occurred because the tumors were dependent on estrogen for growth.

A silhouette of a woman's body is shown in the background. A call-out bubble in the foreground shows a close-up view of breast tissue with a green mass in the middle representing a breast tumor.

Approximately 75% of breast tumors rely on estrogen. These tumors are referred to as "estrogen dependent." Tumors that do not rely on estrogen for growth are called "estrogen independent."

Estrogen dependence can usually be predicted by the presence of estrogen receptors in tumor cells. The estrogen receptor protein can be detected in breast tumor biopsy specimens using a technique known as immunohistochemical staining. Tumor cells that express estrogen receptors--called ER positive--are usually estrogen dependent. Tumors that lack estrogen receptors--called ER negative--are usually estrogen independent.

This is a split-screen image. The left panel is labeled, 'ER Positive: Estrogen Dependent.' There is a silhouette of a woman's body in the background covered with a picture of breast tissue stained for estrogen receptor. Cells with estrogen receptor are colored brown. The right panel is labeled, 'ER Negative: Estrogen Independent.' There is a silhouette of a woman's body in the background covered with a picture of breast tissue. There is a lack of brown staining, indicates  estrogen receptor is not present

Inhibiting Estrogen Signaling

Two different types of antihormone therapies are used to treat women with ER-positive breast tumors: selective estrogen receptor modulators and aromatase inhibitors.

Selective estrogen receptor modulators, or SERMs, which include drugs such as tamoxifen, compete with estrogen for binding to the estrogen receptor. When tamoxifen is bound to the estrogen receptor, estrogen is unable to bind, and estrogen signaling is disrupted.

This image shows a close-up view of the nucleus of a green cancer cell. Estrogen receptor, represented by a gray structure, is bound to a purple sphere representing tamoxifen. Estrogen, represented by a pink sphere, is unable to bind to estrogen receptor because of the presence of tamoxifen.

Aromatase inhibitors, which include drugs such as anastrozole, interfere with the body's ability to make estrogen. They do so by blocking the activity of aromatase, an enzyme needed for the final steps of estrogen production. Aromatase inhibitors do not work very efficiently in premenopausal women because the ovaries make too much aromatase. Therefore, they are used mainly in postmenopausal women.

Anti-hormone therapies such as tamoxifen and anastrozole can be used to treat most stages of breast cancer. Women with early-stage breast cancer are usually treated with surgery followed by antihormone therapy and radiation therapy, and sometimes chemotherapy.

A silhouette of a woman is shown on the left. A green mass in her right breast represents a breast tumor. On the right, a heading reads, 'Early-Stage Breast Cancer.' Bullets below the heading include surgery, anti-hormone therapy, radiation therapy, and chemotherapy.

Women with inoperable, metastatic breast cancer are often given antihormone therapy, with or without chemotherapy.

A silhouette of a woman is shown on the left. Her lymph nodes are highlighted. A green mass in her right breast represents a breast tumor. Additional green masses in other locations represent metastatic breast cancer cells in the lymph nodes, lung, and brain.

Antihormone therapies can also be used to reduce the risk of developing breast cancer. Tamoxifen and another selective estrogen receptor modulator, raloxifene, and several aromatase inhibitors have been found to reduce the risk of breast cancer among women at high risk for the disease.

More Information

Estrogen Activity

The following table lists several drugs that target estrogen activity and have been approved by the FDA for treatment of breast cancer and/or reduction of risk of breast cancer.

 Generic NameTrade Name(s)Type of Targeted Therapy
Selective estrogen receptor modulatorsTamoxifenNolvadex® Soltamox®Small molecule
 RaloxifeneEvista®Small molecule
 ToremifeneFareston®Small molecule
 FulvestrantFaslodex®Small molecule
Aromatase inhibitorsAnastrozoleArimidex®Small molecule
 ExemestaneAromasin®Small molecule
 LetrozoleFemara®Small molecule

Many drugs, including tamoxifen, that inhibit estrogen receptors in the breast can actually activate estrogen receptors in other tissues. For example, tamoxifen can activate estrogen receptors in the bone and endometrium. This is why these agents are called "selective estrogen receptor modulators," or SERMs, rather than estrogen receptor inhibitors. For more information on estrogen receptors and SERMs, visit NCI's Understanding Cancer Series: Estrogen Receptors/SERMs at http://www.cancer.gov/cancertopics/understandingcancer/estrogenreceptors.

For more information on types of targeted therapies, see Understanding Targeted Therapies: An Overview at http://www.cancer.gov/cancertopics/understandingcancer/targetedtherapies.

Self Test

Questions

  1. Aromatase inhibitors act directly on the estrogen receptor.
    1. True
    2. False

Answers

  1. Correct Answer: b
    1. True - Incorrect.
      Aromatase inhibitors interfere with the activity of aromatase, the enzyme responsible for the final steps of estrogen production. They do not interact directly with the estrogen receptor.
    2. False - Correct.
      Aromatase inhibitors interfere with the activity of aromatase, the enzyme responsible for the final steps of estrogen production. They do not interact directly with the estrogen receptor.


Inhibition of HER2

In This Section:

Inhibition of HER2

The epidermal growth factor receptor family consists of four cell surface receptors: EGF receptor, also called HER1; HER2/neu; HER3; and HER4. Binding of specific growth factors, or ligands, to three of these receptors causes them to interact, or dimerize, either with a receptor of the same type or with another family member. HER2 is called an "orphan receptor" because it does not interact directly with any ligand. Instead, it dimerizes with ligand-bound EGF receptor, HER3, or HER4.

A cross-section of a cell is shown, including the cell membrane, cytoplasm, and nucleus. There are several proteins of different colors spanning the membrane. Some of the proteins are labeled EGFR/HER1, HER2, HER3, and HER4.

A cross-section of a cell is shown in the background. A call-out circle in the foreground shows a magnified view of two proteins--EGFR and HER2--embedded in the membrane. EGFR is interacting with a growth factor and has dimerized with HER2.

Receptor dimerization activates signaling pathways inside the cell. These pathways lead to cell growth, proliferation, and survival.

A cross-section of a normal cell is shown in the background. EGFR has dimerized with HER and two HER2 receptors have dimerized. Active signaling pathways are coming from both pairs of dimerized receptors.

HER2 in Cancer Cells

The HER2 gene is amplified in 20% of breast cancers. This means that the cells of these cancers have extra copies of the HER2 gene. Breast cancers with amplified HER2 genes, referred to as HER2-positive cancers, make more HER2 protein than HER2-negative cancers.

This is a split-screen image. On the right is a normal cell in the background with a close-up view of chromosome 17 in an inset circle in the foreground. There is a single yellow band on the chromosome labeled, 'HER2 gene.' On the left is a cancer cell that overexpresses HER2 in the background. An inset circle in the foreground shows chromosome 17 with six yellow bands labeled, 'HER2 genes,' indicating that the HER2 gene has been amplified in the cancer cell.

The extra HER2 protein causes increased signal pathway activation, which contributes to the uncontrolled growth and survival of these cancers.

A cross-section of a cancer cell with many membrane-spanning receptors is shown. Three pairs of receptors represent activated, dimerized receptors. These dimers have activated intracellular signaling pathways, represented by a string of glowing yellow oval shapes.

Breast tumors that overexpress HER2 protein are more aggressive than other breast tumors. Patients with these tumors have a poorer prognosis and decreased chance of survival compared with patients whose tumors do not overexpress HER2.

Inhibiting HER2

Researchers have developed multiple strategies for interfering with HER2 signaling. These include a small molecule called lapatinib as well as monoclonal antibodies.

The screen is titled, 'Interfering with HER2 Signaling.' A silhouette of a woman is shown on the left side of the screen. Two icons are shown on the right side of the screen. The first icon, labeled 'Small Molecules,' shows three small purple ovoid shapes. The second icon, labeled 'Monoclonal Antibodies,' shows a single purple Y-shape.

Herceptin® (trastuzumab) is a monoclonal antibody that binds to HER2. This prevents the receptor from activating the pathways that promote the proliferation and survival of breast cancer cells.

This image shows a layer of pink normal with an embedded mass of green cancer cells. An inset circle in the foreground shows a close-up view of a cancer cell with multiple receptors spanning the cell membrane. A purple antibody is bound to one of the receptors and is preventing the receptor from interacting with another membrane-spanning receptor. An intracellular signaling pathway is colored gray to indicate that it is inactive.

Herceptin® (trastuzumab) may also interfere with cancer cell growth by activating an immune response.

This image shows a layer of pink normal with an embedded mass of green cancer cells. There are purple antibodies bound to the surface of some of the cancer cells. These antibodies have attracted blue immune cells that are releasing molecules that will damage nearby cells.

Herceptin® (trastuzumab) is used to treat breast cancer only if the tumor overexpresses HER2. It has been approved by the FDA for the treatment of metastatic breast cancer in combination with or following administration of standard chemotherapy. Herceptin® (trastuzumab) has also been approved by the FDA as an adjuvant treatment for some earlier-stage breast cancers. Adjuvant therapy is treatment given after primary therapy--for example, surgery--to increase the chances of long-term survival.

More Information

Herceptin

Herceptin® (trastuzumab) is approved by the FDA for the adjuvant treatment of HER2-overexpressing breast cancer that is either (1) axillary lymph node-positive or (2) axillary lymph node-negative with at least one high-risk feature (e.g., estrogen receptor/progesterone receptor-negative, pathologic tumor size greater than 2 cm, Grade 2-3, age less than 35 years):

Herceptin® (trastuzumab) is also approved by the FDA for use:

  • In combination with paclitaxel for first-line treatment of HER2-overexpressing metastatic breast cancer.
  • As a single agent for treatment of HER2-overexpressing breast cancer in patients who have received one or more chemotherapy regimens for metastatic disease.

More Information

Drugs that target EGFR family members (HER1 and HER2)

 Generic NameTrade NameDrug Type
EGFR (HER1) inhibitorsCetuximabErbitux®Monoclonal antibody
 LapatinibTykerb®*Small molecule
 GefitinibIressa®Small molecule
 ErlotinibTarceva®Small molecule
HER2 inhibitorsTrastuzumabHerceptin®*Monoclonal antibody
 PertuzumabOmnitarg™Monoclonal antibody
 LapatinibTykerb®*Small molecule

* Agents that have been approved by the FDA for treatment of breast cancer and/or reduction of risk of breast cancer

The small molecule inhibitors--Tykerb® (lapatinib), Iressa® (gefitinib), and Tarceva® (erlotinib)--interfere with the kinase activity of their target proteins. The monoclonal antibodies--Erbitux® (cetuximab), Herceptin® (trastuzumab), and Omnitarg™(pertuzumab)--interact with the extracellular portion of their target receptor proteins and prevent receptor interaction with growth factor and/or dimerization with other receptors.

For more information on types of targeted therapies, see Understanding Targeted Therapies: An Overview at http://www.cancer.gov/cancertopics/understandingcancer/targetedtherapies.

Self Test

Questions

  1. Possible mechanisms of action of Herceptin® (trastuzumab) include:
    1. Activation of an immune response.
    2. Reduction of circulating levels of growth factor.
    3. Both A and B.

Answers

  1. Correct Answer: a
    1. Correct.
      Herceptin® (trastuzumab) is thought to activate an immune response called antibody-dependent cell-mediated cytotoxicity. Other possible mechanisms of action include preventing the dimerization of EGFR family receptors, increasing the rate of degradation of HER2, and preventing the extracellular domain of HER2 from being processed properly.
    2. Incorrect.
      Herceptin® (trastuzumab) interacts with HER2, which is a cell surface receptor, and does not influence levels of circulating growth factor. Potential mechanisms of action of trastuzumab include activating an immune response, preventing the dimerization of EGFR family receptors, increasing the rate of degradation of HER2, and preventing the extracellular domain of HER2 from being processed properly.
    3. Incorrect.
      Trastuzumab interacts with HER2, which is a cell surface receptor, and does not influence levels of circulating growth factor. Potential mechanisms of action of Herceptin® (trastuzumab) include activation of an immune response, preventing the dimerization of EGFR receptors, increasing the rate of degradation of HER2, and preventing the extracellular domain of HER2 from being processed properly.

Inhibition of Insulin-Like Growth Factor Signaling

In This Section:

IGF Signaling in Normal Cells

The insulin-like growth factor—or IGF—signaling pathway plays an important role in normal breast development and during pregnancy and lactation. The IGF signaling pathway can be activated by two growth factors, IGF1 and IGF2. When one of these binds to an IGF1 receptor, the receptor activates downstream signaling pathways inside the cell. These signaling pathways regulate cell growth, proliferation, and differentiation.

A cross-section of a cell is shown, including the cell membrane, cytoplasm, and nucleus. There are many blue growth factors outside the cells, some labeled 'IGF1' and 'IGF2.' There are several membrane-spanning proteins.

IGF Signaling in Cancer Cells

There is strong evidence that alteration of IGF signaling plays a role in breast cancer. Preclinical studies in cell culture and animal models suggest that dysregulation of the IGF signaling pathway promotes the transformation, survival, growth, and metastasis of breast cancer cells. Epidemiologic studies have found that premenopausal women with breast cancer have high levels of circulating IGF1. And immunohistochemical staining has revealed that the IGF1 receptor is overexpressed in nearly half of all breast cancers.

A green cancer cell is shown. There are many growth factors circulating outside the cell and several membrane-spanning receptors visible. The frame is labeled, 'Premenopausal women with breast cancer have high levels of circulating IGF1.'

Furthermore, there is evidence that the IGF signaling pathway participates in crosstalk with other signaling pathways, such as those activated by EGF receptor, HER2, VEGF receptor, and mTOR.

Inhibiting IGF Signaling

There are several potential strategies for targeting the IGF pathway. One approach is to use hormone inhibitors to reduce circulating levels of IGF1 and IGF2.

A green cancer cell is shown. There are several membrane-spanning receptors visible. The number of circulating growth factors is decreased compared to the previous image. Some of the growth factors are labeled, 'Target IGF1.'

Other agents are being developed to directly target either IGF1 or the IGF1 receptor.

A green cancer cell is shown. There are several membrane-spanning receptors visible, some labeled, 'Target IGF1R.'

Several monoclonal antibodies are being developed to target the IGF1 receptor. These antibodies may prevent IGF1 or IGF2 from binding to the receptor and, thus, prevent activation of the pathway. They also appear to reduce levels of IGF1 receptor.

This image shows a cross-section of a green cancer cell in the background. An inset circle in the foreground shows a close-up view of the cancer cell with two receptors spanning the cell membrane. A purple antibody is bound to the receptors and preventing the receptors from interacting with a growth factor. An intracellular signaling pathway visible in the cell in the background is colored gray to indicate that it is inactive.

Several monoclonal antibodies directed against IGF1 receptor and small-molecule inhibitors of this receptor are currently being tested in breast cancer patients in Phase I and Phase II clinical trials. Many of these trials are testing these agents in combination with standard chemotherapy drugs, antihormone therapies, or drugs that target HER2 or mTOR.

More Information

IGF1R

The IGF signaling pathway is very complex, with a number of receptor types as well as IGF-binding proteins that modulate the interaction of IGFs with their receptors. One complicating aspect of inhibiting the IGF1 receptor (IGF1R) is its similarity to the insulin receptor. This similarity makes it particularly challenging to develop small molecules that inhibit the kinase activity of IGF1R but not the insulin receptor. However, because insulin signaling is critical for maintaining normal physiological processes, it is very important that anti-IGF1R therapies do not interfere with the insulin receptor.

The following table lists several monoclonal antibodies that target insulin-like growth factor receptor that are being studied in clinical trials.

 Research NameGeneric NameTrade NameDrug Type
IGF1R inhibitorsIMC-A12Cixutumumabn/aMonoclonal antibody
 CP-751,871Figitumumabn/aMonoclonal antibody
 AVE1642n/an/aMonoclonal antibody
 AMG-479n/an/aMonoclonal antibody
 R1507n/an/aMonoclonal antibody

For more information on types of targeted therapies, see Understanding Targeted Therapies: An Overview at http://www.cancer.gov/cancertopics/understandingcancer/targetedtherapies.

Self Test

Questions

  1. The IGF1R is commonly mutated in breast cancer.
    1. True
    2. False

Answers

  1. Correct Answer: b
    1. True - Incorrect.
      There is no evidence that IGF1R mutations contribute to breast cancer. However, breast tumors may express high levels of normal IGF1R.
    2. False - Correct.
      There is no evidence that IGF1R mutations contribute to breast cancer. However, breast tumors may express high levels of normal IGF1R, leading to increased activity of the pathway.

Inhibition of PARP

In This Section:

PARP in Normal Cells

When a normal cell's DNA is damaged or mutated, several cellular mechanisms can come into play to detect and repair the alterations. If the DNA is repaired successfully, the cell survives. However, if the DNA cannot be repaired, the cell will undergo a form of cellular suicide called apoptosis rather than risk passing on flawed genetic information to progeny cells.

On the left of the screen, a normal cell is shown with a red starburst in the nucleus. An arrow to the right leads to an icon labeled, 'damage,' and showing DNA with a single-strand break and a red starburst. Two arrows extend from the damage icon. The first is labeled 'Successful Repair and leads to a pink cell labeled 'Cell Survival.' The second arrow is labeled 'Failure to Repair' and leads to a group of gray spheres labeled 'Cell Suicide (Apoptosis).'

One protein involved in repairing damaged DNA is poly(ADP ribose) polymerase 1, or PARP1. When a strand of DNA is broken, or nicked, PARP1 moves to the site of damage and becomes activated. It then recruits a team of DNA repair proteins that work together to mend the broken strand of DNA.

A close-up view of a cell nucleus is shown. A group of proteins representing DNA repair proteins is shown interacting with the DNA. Screen text reads, 'PARP is important for DNA damage repair.'

PARP in Cancer Cells

Many standard cancer treatments, including many chemotherapy drugs and radiation therapy, damage the DNA of rapidly dividing cancer cells. If PARP is able to help repair the damage caused by these agents, tumor cells may be more likely to survive and grow.

A cross-section of a cancer cell is shown. Screen text reads, 'Chemotherapy drugs and radiation therapies damage the DNA of rapidly dividing cancer cells.' A white haze entering the cell is labeled 'Radiation.' The DNA in the nucleus has been damaged and is labeled with the damage icon (a picture of DNA with a broken strand and a red starburst). A yellow protein representing PARP is in the nucleus.

A cross-section of a cancer cell is shown. Screen text reads, 'PARP may help cancer cells repair damage and survive.' Five DNA repair proteins are visible in the nucleus near the DNA. The DNA is intact, indicating that it has been repaired by PARP and the other DNA repair proteins.

Inhibiting PARP

However, preclinical studies suggest that standard therapies combined with PARP inhibitors may be more effective than standard therapies alone. If cancer cells are exposed to a PARP inhibitor, the protein will be unable to respond when the cell's DNA is damaged by treatments such as chemotherapy. The presence of unrepaired DNA damage will make the cell more likely to undergo apoptosis.

A layer of pink normal cells is shown with a mass of green cancer cells in the middle. Small yellow dots near all of the cells represent standard chemotherapeutic drugs. A call-out bubble in the foreground shows the nucleus of a cancer cell containing damaged DNA. PARP is present in the nucleus and is associated with a PARP inhibitor.

Clinical trials studying PARP inhibitors in combination with standard chemotherapeutic agents in breast cancer are currently under way.

This image is titled, 'PARP Inhibitors.' On the left side of the screen, there is a bulleted list that reads, 'Used in combination with standard therapies.' There are also three gray boxes labeled 'Phase 0,' 'Phase I,' and 'Phase II' and connected by arrows. On the right side of the screen is group of green female figures representing breast cancer patients.

It is also possible that PARP inhibitors could be effective as single agents against tumors with inherent DNA repair defects, such as breast tumors with mutations in the DNA repair proteins BRCA1 or BRCA2. Preclinical studies have shown that breast tumor cells carrying BRCA mutations undergo an arrest of the cell cycle and apoptosis when exposed to PARP inhibitors, whereas cells with normal BRCA proteins survive and continue to grow.

This is a split-screen image. A mass of cells on the left side is labeled 'Normal BRCA' and a mass on the right side is labeled 'Mutant BRCA' and has a mutation icon associated with it (DNA with starburst and labeled 'mutation'). Purple dots representing PARP inhibitors are circulating around both cell masses. The cells with mutant BRCA are undergoing apoptosis upon exposure to the PARP inhibitors, but the normal BRCA cells remain viable.

Several PARP inhibitors are currently being tested in clinical trials involving women with BRCA mutation-associated breast cancer.

This image is titled, 'PARP Inhibitors.' On the left side of the screen, there is a bulleted list that reads, 'Tested in BRCA mutation-associated breast cancer.' There are also three gray boxes labeled 'Phase 0,' 'Phase I,' and 'Phase II' and connected by arrows. On the right side of the screen is group of green female figures representing breast cancer patients.

More Information

PARP

Several drugs that target PARP are currently being tested in clinical studies.

 Research NameGeneric NameTrade NameDrug Type
PARP inhibitorsABT-888n/an/aSmall molecule
 AG014699n/an/aSmall molecule
 BSI-201n/an/aSmall molecule
 AZD2281n/an/aSmall molecule

For more information on types of targeted therapies, see Understanding Targeted Therapies: An Overview at http://www.cancer.gov/cancertopics/understandingcancer/targetedtherapies.

Self Test

Questions

  1. Women whose breast tumors have mutations in BRCA1 or BRCA2 overexpress PARP.
    1. True
    2. False

Answers

  1. Correct Answer: b
    1. True - Incorrect.
      There is no evidence that BRCA-mutation-associated tumors have increased expression of PARP. However, it appears that cancer cells with BRCA1 or BRCA2 mutations are more sensitive to PARP inhibitors (i.e., more likely to undergo growth arrest and apoptosis) than cells with normal BRCA1 or BRCA2. This is most likely because the combination of inhibition of PARP and loss of BRCA1 or BRCA2 function results in inactivation of two major forms of DNA repair, making it more difficult for cells to maintain the integrity of their genome and leaving them more vulnerable to apoptosis.
    2. False - Correct.
      There is no evidence that BRCA-mutation-associated tumors have increased expression of PARP. However, it appears that cancer cells with BRCA1 or BRCA2 mutations are more sensitive to PARP inhibitors (i.e., more likely to undergo growth arrest and apoptosis) than cells with normal BRCA1 or BRCA2. This is most likely because the combination of inhibition of PARP and loss of BRCA1 or BRCA2 function results in inactivation of two major forms of DNA repair, making it more difficult for cells to maintain the integrity of their genome and leaving them more vulnerable to apoptosis.

Inhibiting the PI3K/Akt/mTOR Signaling Pathway

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 breast. 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.

PI3-kinase is an enzyme that phosphorylates certain components of the cell membrane. Once these components become phosphorylated, they bind to a protein called Akt. Akt then becomes phosphorylated and activated. This triggers activation of several downstream signaling pathways, which increase 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.'

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.

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.

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'

mTOR can also increase the activity of Akt, thus enhancing the other downstream effects of this protein.

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.

 

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.

Activation of the mTOR pathway is associated with poor prognosis in many cancers, including breast cancer, and is linked to resistance to many types of therapy.

 

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. This complex binds to and inhibits mTOR. Inhibition of mTOR with rapamycin has been found to slow cancer cell proliferation.

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 breast cancer. Many of these trials are using mTOR inhibitors in combination with standard therapies or other targeted therapies, such as a monoclonal antibody against HER2.

A group of green female 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.

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

mTOR

Several drugs that target mTOR and its signaling partners are being tested in clinical studies.

 Research NameCommon NameTrade NameDrug Type
mTOR inhibitors Rapamycin (also called sirolimus)Rapamune®Small molecule
 CCI-779TemsirolimusTorisel®Small molecule
 RAD-001EverolimusCertican®Small molecule
Akt inhibitorsKRX-0401Perifosinen/aSmall molecule
PI3-kinase inhibitorsBGT226n/an/aSmall molecule
 BEZ235n/an/aSmall molecule

For more information on types of targeted therapies, see Understanding Targeted Therapies: An Overview at http://www.cancer.gov/cancertopics/understandingcancer/targetedtherapies.

 

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.

Summary and Conclusions

In This Section:

Finding the Right Combinations

Most targeted therapies being developed for breast cancer are being used and tested in combination with standard therapies. Since multiple signaling pathways are often disrupted in cancer cells, many clinical trials are also testing combinations of targeted therapies. It is hoped that targeting multiple pathways might reduce the development of drug-resistant tumor cells.

A breast cancer patient is shown with a health care professional.

Some trials are testing the angiogenesis inhibitor Avastin® (bevacizumab) in combination with Herceptin® (trastuzumab). This multipronged approach should keep breast cancer cells from signaling through HER2 and also prevent the tumor from recruiting new blood vessels.

In the background, a layer of normal cells is shown with a mass of green cancer cells in the center. A blood vessel is running across the top of the screen. One call-out bubble, labeled 'Avastin,' shows a close-up view of an endothelial (blood vessel) cell. Receptors on the surface of the cell are unable to interact with a growth factor because of the presence of an antibody that is bound to the growth factor. A second call-out bubble, labeled 'Herceptin,' shows a cross-section of a cancer cell.

Temsirolimus, an mTOR inhibitor, is being tested in combination with IMC-A12, a monoclonal antibody against IGF receptor. Using both of these strategies to shut down the cancer cell's growth signaling may decrease the likelihood of resistance to therapy and increase the likelihood of killing the tumor cell.

In the background, a layer of normal cells is shown with a mass of green cancer cells in the center. One call-out bubble, labeled 'IMC-A12,' shows a close-up of a cancer cell with a purple antibody interacting with a pair of cell surface receptors. A gray (inactive) intracellular signaling pathway is visible. A second call-out bubble, labeled 'Temsirolimus,' shows a close-up of a cancer cell with Akt, mTOR, and drug-bound FKBP12 visible.

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.

Accessing Targeted Therapies for Breast Cancer

Several targeted therapies have already been approved by the FDA for treatment of breast cancer or reduction of risk of breast cancer. For a list of these drugs and their approved uses, click on the Additional Information link at the bottom of the screen.

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

Two health care professionals are shown in a hospital.

More Information

Approved Targeted Drugs for Breast Cancer

Targeted therapies that are approved by the FDA for the treatment of breast cancer or for reducing risk of breast cancer for those at high risk include the following:

Tamoxifen (Nolvadex®, Soltamox®)

  • Mechanism: selective estrogen receptor modulator; antiestrogenic in breast tissue
  • Indications: treatment of metastatic breast cancer; treatment of axillary lymph node-positive or -negative breast cancer following surgery and radiation therapy, and of ductal carcinoma in situ (DCIS), which is a pre-invasive lesion, following surgery and radiation therapy; reduction of risk for women at high risk for breast cancer

Raloxifene (Evista®)

  • Mechanism: selective estrogen receptor modulator; antiestrogenic in breast tissue
  • Indications: treatment and prevention of osteoporosis in postmenopausal women; reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis; reduction in risk of invasive breast cancer in postmenopausal women at increased risk for invasive breast cancer

Toremifene (Fareston®)

  • Mechanism: selective estrogen receptor modulator; antiestrogenic in breast tissue
  • Indications: treatment of advanced breast cancer in postmenopausal women

Fulvestrant (Faslodex®)

  • Mechanism: estrogen receptor antagonist
  • Indications: treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy

Anastrozole (Arimidex®)

  • Mechanism: aromatase inhibitor
  • Indications: adjuvant treatment of hormone receptor-positive early breast cancer in postmenopausal women; first-line treatment of hormone receptor-positive or -unknown locally advanced or metastatic breast cancer in postmenopausal women; treatment of advanced breast cancer in postmenopausal women with disease progression following tamoxifen therapy

Exemestane (Aromasin®)

  • Mechanism: aromatase inhibitor
  • Indications: adjuvant treatment of ER-positive early breast cancer in postmenopausal women who have received 2 to 3 years of tamoxifen and are switched to exemestane for completion of a total of 5 consecutive years of adjuvant anti-hormone therapy; treatment of advanced breast cancer in postmenopausal women whose disease has progressed following tamoxifen therapy

Letrozole (Femara®)

  • Mechanism: aromatase inhibitor
  • Indications: adjuvant treatment of hormone receptor-positive early breast cancer in postmenopausal women; extended adjuvant treatment of early breast cancer in postmenopausal women who have received 5 years of adjuvant tamoxifen therapy; first-line treatment of hormone receptor-positive or hormone receptor-unknown locally advanced or metastatic breast cancer in postmenopausal women

Trastuzumab (Herceptin®)

  • Mechanism: anti-HER2 monoclonal antibody, prevents HER2-mediated signaling and activates antibody-dependent cellular cytotoxicity
  • Indications: as part of a treatment regimen containing doxorubicin, cyclophosphamide, and paclitaxel for the adjuvant treatment of HER2-overexpressing breast cancer; as a single agent for the adjuvant treatment of HER2-overexpressing axillary lymph node-negative (ER/PR-negative or with one high-risk feature) or node-positive breast cancer following multimodality anthracycline-based therapy; in combination with paclitaxel for treatment of HER2-overexpressing metastatic breast cancer; as a single agent for treatment of HER2-overexpressing breast cancer in patients who have received one or more chemotherapy regimens for metastatic disease

Lapatinib (Tykerb®)

  • Mechanism: inhibitor of the kinase domain of EGFR and HER2
  • Indications: in combination with capecitabine for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 and who have received prior therapy including an anthracycline, a taxane, and trastuzumab

Bevacizumab (Avastin®)

  • Mechanism: monoclonal antibody that inhibits VEGF
  • Indications: in combination with paclitaxel for treatment of patients who have not received chemotherapy for metastatic HER2-negative breast cancer

For more information on types of targeted therapies, see Understanding Targeted Therapies: An Overview at http://www.cancer.gov/cancertopics/understandingcancer/targetedtherapies.

Finding Clinical Trials

Targeted therapies for breast cancer are in all phases of clinical study. There are a number of ways to find clinical trials.

The National Cancer Institute's (NCI) Web site contains information about cancer clinical trials sponsored by NCI, pharmaceutical companies, medical centers, and other groups from around the world.  To access this information, please visit http://www.cancer.gov/clinicaltrials on the Internet.

For information about cancer clinical trials being conducted at the National Institutes of Health Clinical Center, please visit http://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.  To access this site, please visit http://www.clinicaltrials.gov.

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 NCI's Web site, http://www.cancer.gov on the Internet.