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Targeted Therapies for Prostate Cancer Tutorial

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Introduction

This is a split screen image. Shown on the left is a close-up of a surgeon's gloved hands using forceps during surgery, and on the right is a patient receiving radiation therapy. The screen text reads: Prostate Cancer.

While prostate cancer is commonly treated first with surgery or radiation, sometimes a different strategy is appropriate.

An approach called targeted therapies may be the treatment of choice when cancer recurs or when a patient's tumor can be controlled at an earlier stage by manipulating its growth signals.

Targeted therapies are possible because clinical researchers have identified several good molecular targets in the cancer cell. Some therapies are FDA-approved, and others are still being evaluated in clinical trials. Because cancer frequently involves alterations in multiple signaling pathways, clinical trials often test combinations of targeted therapies along with standard treatments.

This tutorial will show you a variety of targeted therapies that oncologists are using to treat prostate cancer including new hormone therapies, therapeutic vaccines, and new taxane combinations.

Hormone Therapy

In This Section:

 

Normal testosterone function and synthesis

Androgens are male sex hormones. The main androgen circulating in men's blood is testosterone. Testosterone is needed to develop and maintain male sex characteristics. About 85 to 90 percent is made by the testicles and about 10 to 15 percent is made by the adrenal glands and other body cells in healthy adult males.

Shown is an outline of a male body producing testosterone. Most of the testosterone is being produced by the testicles and a much smaller amount by the adrenal glands, which are located above the kidneys. Both the testicles and the adrenal glands are identified with labels.

Testosterone production begins when the hypothalamus in the brain detects low testosterone levels. In response, the hypothalamus releases luteinizing hormone-releasing hormone (LHRH), which is also called gonadotropin-releasing hormone (GnRH). LHRH travels to the pituitary gland, where it binds to LHRH receptors.

Shown is an outline of a front-facing male head. The hypothalamus in the brain is releasing LHRH molecules. LHRH is identified with a label.

The pituitary gland responds by releasing a hormone called luteinizing hormone (LH) that travels to the testicles and stimulates the production of testosterone. When an increase in testosterone is detected by the hypothalamus and the pituitary gland, the release of LHRH and LH stops. When testosterone levels drop again, the cycle begins anew.

Shown is an outline of a front-facing male body releasing LH from the pituitary gland in the brain, which is stimulating testosterone production in the testicles. LH is identified with a label.

Testosterone released into the blood from the testicles can easily enter a prostate cell, bind to receptor proteins in the cytoplasm and enter the cell's nucleus. This androgen receptor complex then binds to specific sequences of DNA to regulate the expression of numerous genes involved in cell growth.

Shown is a close-up view of a normal cell membrane, cytoplasm and nucleus with DNA. Testosterone bound to its androgen receptor complex is shown bound to DNA, and genes involved in cell growth are being expressed.

 

Targeting prostate hormones

Prostate cancer cells that grow in the presence of testosterone are called "androgen-dependent" and "androgen-sensitive." Androgen-dependent means "testosterone-dependent."

Shown on the left is an outline of a male body producing testosterone. On the right is an inset circle coming from the groin area showing a prostate tumor growing in the presence of testosterone. The screen text reads: Androgen-Dependent Prostate Cancer.

Prostate cancer cells that can still grow in the presence of very, very low levels of testosterone are called "castration-resistant" cancers. This type of prostate cancer can grow even when the testicles no longer supply the hormone. The cancer continues to thrive on the residual amount remaining in a patient's body. Other names for "castration-resistant" include androgen-independent, androgen-resistant or androgen-insensitive.

Shown on the left is an outline of a male body with an X over the testicles, indicating no testosterone production. On the right is an inset circle coming from the groin area showing a prostate tumor still growing in the presence of very, very low levels of testosterone.

The goal of hormone therapy in prostate cancer is to interfere with the androgen signaling that is critical to the growth of both androgen-dependent and castration-resistant cancer cells.

Shown on the left is an outline of a male body that is not producing testosterone. On the right are two inset circles. One circle is coming from the brain and one from a prostate cancer cell. Both circles have red Xs over them, indicating that the signaling for testosterone is interrupted.

Hormone therapy has many names. It is also called androgen deprivation therapy, hormonal ablation, androgen ablation, chemical castration, or surgical castration.

Interfering with the androgen signaling needed by prostate cancer to grow can be achieved in several ways. One approach uses agonists to suppress the pituitary gland's call for testosterone, prostate cancer's favorite androgen. These chemicals are called LHRH agonists.

Shown on the left is an outline of a male body with an X over the brain, indicating an interruption in androgen signaling from the pituitary gland. First bullet on the right reads: LHRH agonists.

Another technique uses antagonists to stop the production of testosterone in the testes and adrenal glands. These small molecule inhibitors are called LHRH antagonists.

Shown on the left is an outline of a male body with Xs over the adrenal glands and testicles, indicating an interruption in testosterone production from both sources. Second bullet on the right reads: LHRH antagonists.

A third therapy uses androgen receptor antagonists to inhibit the action of testosterone that has already been produced in androgen-dependent prostate cancer cells.

Shown on the left is an outline of a male body with an X over the prostate cancer, indicating an inhibition of testosterone's action on androgen-dependent prostate cancer cells. Third bullet on the right reads: Antiandrogens.

Finally, a new FDA-approved approach uses an androgen synthesis inhibitor to stop testosterone production from all sources in the patient's body. This is currently approved for men with castration-resistant prostate cancer.

Shown on the left is an outline of a male body with Xs over the adrenal glands, the prostate cancer, and the testicles, indicating an interruption in testosterone production from all sources. Fourth bullet on the right reads: Testosterone synthesis inhibitors (super-antiandrogens). A stamped overlay reads, FDA APPROVED.

We will review all four of these approaches in the next sections.

 

LHRH agonists

Binding of naturally occurring LHRH to its pituitary gland receptor initiates a cell signaling process that results in the release of LH, which in turn leads to testosterone production.

Shown is an outline of a front-facing male body releasing LH from the pituitary gland in the brain, which is stimulating testosterone production in the testicles.

An LHRH agonist is a chemical that mimics naturally occurring LHRH without being identical to it. LHRH agonists are similar enough to the naturally occurring LHRH to bind to the LHRH receptors and produce a physiologic effect. At the same time, they are dissimilar enough to have different binding affinities, and the agonists remain bound to the receptors for a longer time.

Shown in the foreground are 2 identical shapes of different colors. The purple shape on the left is labeled 'Naturally occurring LHRH,' and the orange shape on the right is labeled 'LHRH agonist.' Shown in the background is a close-up of a pituitary gland cell with LHRH receptors in the membrane.

As a result of the prolonged presence of the LHRH agonists and persistent release of LH, there is a sudden rise in testosterone. This spike in testosterone level is known as a "hormone flare."

Shown is an outline of a front-facing male body releasing LH from the pituitary gland in the brain, resulting in high levels of testosterone being produced from the testicles and adrenal glands. Screen text reads: Hormone Flare.

After several days, the LHRH receptors become desensitized and are down-regulated. LH production decreases and testosterone level drops to level seen with surgical removal of the testicles.

Shown is an outline of a front-facing male body no longer releasing LH from the pituitary gland in the brain, resulting in low levels of testosterone in the body.

 

LHRH antagonists

Binding of naturally occurring LHRH to its pituitary gland receptor initiates a cell signaling process that results in the release of LH, which in turn leads to testosterone production.

Shown is an outline of a front-facing male body releasing LH from the pituitary gland in the brain, which is stimulating testosterone production in the testicles.

An LHRH antagonist is similar in structure to naturally occurring LHRH and competes with it for binding to the LHRH receptors.

This is a split screen image. Shown on both halves of the screen is a close-up of LHRH receptors in pituitary gland cells. Bound to the LHRH receptor on the left is a structure labeled 'Naturally occurring LHRH,' and bound to the LHRH receptor on the right is a slightly different structure labeled 'LHRH antagonist.'

Instead of promoting testosterone production, LHRH antagonists are small molecule inhibitors that interfere with the production of testosterone in the testes and adrenal glands.

They do this by preventing naturally occurring LHRH from binding to their receptors.

LHRH receptors with bound LHRH antagonists do not stimulate the release of LH. As a result of this interruption in the release of LH, the testicles stop producing testosterone and the body's androgen levels drop.

In contrast to LHRH agonists, LHRH antagonists do not cause a "hormone flare" because they do not have the same physiologic effect as LHRH.

Shown on the left is an outline of a male body with Xs over the brain and testicles, indicating an interruption in the release of LH that stops testosterone production. On the right is an inset circle coming from the head showing an LHRH antagonist persistently bound to an LHRH receptor. Screen text reads: In contrast to LHRH agonists, LHRH antagonists do not cause a 'hormone flare.'

 

Antiandrogens

Testosterone binds to androgen receptor proteins in the cytoplasm of prostate cells and enters the cell nucleus. This androgen receptor complex then binds to specific sequences of DNA to regulate the expression of numerous genes involved in cell growth.

Shown is a close-up view of a normal cell membrane, cytoplasm and nucleus with DNA. Testosterone bound to its androgen receptor complex is shown bound to DNA, and genes involved in cell growth are being expressed.

Antiandrogens approved for cancer treatment target and inhibit this androgen action within androgen-dependent prostate cells. Antiandrogens are effectively androgen receptor antagonists.

When antiandrogens bind to androgen receptors within the prostate cancer cells, testosterone is unable to bind to its receptors and, in turn, is unable to stimulate cell growth to the same extent. This slows down the growth of prostate cancer.

Shown is a close-up view of a cancer cell membrane, cytoplasm, and nucleus with DNA. Antiandrogens in the cytoplasm are bound to the androgen receptors, blocking testosterone from binding. There is no expression of the genes involved in cell growth.

Antiandrogens are usually given before treatment with, or in combination with, an LHRH agonist.

More Information:

Antiandrogens

Examples of antiandrogens include Casodex (bicalutamide), Nilandron (nilutamide), and Eulexin (flutamide). These drugs are taken orally.

Antiandrogens are usually given before treatment with, or in combination with, an LHRH agonist.

 

Androgen synthesis inhibitors (super-antiandrogens)

An androgen synthesis inhibitor is a very recent addition to the treatment arsenal for prostate cancer. This new agent is an improvement to existing hormone therapies because it can drop testosterone levels in a man's body lower than can be achieved by any other known treatment. For this reason, it is being nicknamed a super-antiandrogen.

Shown is the hand of a health care provider handing two white tablets to a seated male patient. The on-screen title reads 'Androgen synthesis inhibitors.' First bullet reads: Drop testosterone levels lower than any other known treatment. Second bullet reads: Nicknamed super-antiandrogen.

Castration-resistant prostate cancer is hard to treat because it may grow in the presence of very low levels of testosterone. In these cases, an androgen synthesis inhibitor may be a better treatment option. An androgen synthesis inhibitor, or super-antiandrogen, can lower testosterone levels even more than was previously possible. It is FDA-approved to treat men diagnosed with castration-resistant prostate cancer.

Shown on the left is an outline of a male body with prostate cancer that is producing very low levels of testosterone. On the right is an inset circle coming from the groin area showing a prostate tumor growing in the presence of very low levels of testosterone.

Zytiga™ (abiraterone acetate) is a new androgen synthesis inhibitor. It blocks the synthesis of testosterone from all three locations: the testes, the adrenal glands, and prostate cancer cells themselves.

Shown is an outline of a male body with the pituitary gland signaling for testosterone production. There are Xs over the adrenal glands, the prostate cancer, and the testicles, indicating that Zytiga interrupts testosterone production from all three sources.

Zytiga™ works by blocking the action of an enzyme called CYP17. This enzyme plays a central role in allowing the body to produce testosterone from cholesterol.

Shown is a close up of the cytoplasm and endoplasmic reticulum of a cell. The CYP17 enzyme is on the endoplasmic reticulum and is labeled. Cholesterol, testosterone, and Zytiga are in the cytoplasm and are labeled. Shown is Zytiga approaching the CYP17 enzyme where it binds and subsequently blocks a step in the production of testosterone from cholesterol.

This new targeted therapy is FDA-approved for use in castration-resistant prostate cancer that has previously been treated with docetaxel.

Self Test

Questions

  1. Where does signaling for more testosterone production begin?
    1. In the pituitary gland
    2. In the testes
    3. In the hypothalamus
    4. In the prostate cancer cell

  2. Where does testosterone go once released from a man's testicles?
    1. Into the nucleus of his prostate cells
    2. Into the cytoplasm of his prostate cells
    3. Into the nucleus of prostate cancer cells
    4. All of the above

  3. Which of these are hormone therapy strategies in prostate cancer to deprive testosterone-dependent cancer cells of androgenic stimulation?
    1. Target and suppress the pituitary gland's call for testosterone
    2. Target and inhibit production of testosterone in the testicles and adrenal glands
    3. Target and inhibit androgen action in androgen-dependent prostate cells
    4. All of the above

  4. When a patient's prostate cancer continues to grow even after testosterone has been inhibited, the cancer is called castration-resistant. What other way can this condition be described?
    1. Androgen-independent
    2. Androgen-resistant
    3. Androgen-insensitive
    4. All of the above

  5. Which best describes the binding affinity of LHRH agonists to LHRH receptors on a man's pituitary cells?
    1. In the pituitary gland
    2. They remain bound for a shorter time than normal LHRH
    3. They remain bound for a longer time than LHRH
    4. In the prostate cancer cell

  6. When LHRH antagonists bind to the LHRH receptors and prevent naturally occurring LHRH from doing so, what effects does this have?
    1. There is an increase in the release of LH
    2. The testicles stop producing testosterone
    3. The androgen levels drop
    4. There is a "hormone flare"
    5. Both B and C

  7. How do antiandrogens slow the growth of prostate cancer cells?
    1. They slow testosterone binding to its receptor, which inhibits cell growth
    2. They stop the production of testosterone
    3. They prevent testosterone from signaling the hypothalamus
    4. They bind to testosterone directly so testosterone can't bind to other receptors

  8. A new drug named abiraterone acetate is called a super-antiandrogen because it blocks testosterone in which of these locations?
    1. In the testes
    2. In the adrenal glands
    3. In prostate cancer cells
    4. All of the above

Answers

  1. Correct answer to Question 1: c
    1. In the pituitary gland. Although the pituitary gland is involved in the signaling pathway, signaling for more testosterone production begins when the hypothalamus in the brain detects low testosterone levels.
    2. In the testes. The signaling for more testosterone production begins when the hypothalamus in the brain detects low testosterone levels.
    3. In the hypothalamus. The signaling for more testosterone production begins when the hypothalamus in the brain detects low testosterone levels.
    4. In the prostate cancer cell. The signaling begins when the hypothalamus in the brain detects low testosterone levels.

  2. Correct answer to Question 2: d
    1. Into the nucleus of his prostate cells. There is a better answer.
    2. Into the cytoplasm of his prostate cells. There is a better answer.
    3. Into the nucleus of prostate cancer cells. There is a better answer.
    4. All of the above. Testosterone released into the blood from the testicles can easily enter prostate cells (cancerous and noncancerous), bind to receptor proteins in the cytoplasm, and enter the cell nucleus.

  3. Correct answer to Question 3: d
    1. Target and suppress the pituitary gland's call for testosterone. There is a better answer.
    2. Target and inhibit production of testosterone in the testicles and adrenal glands. There is a better answer.
    3. Target and inhibit androgen action in androgen-dependent prostate cells. There is a better answer.
    4. All of the above. The goal of hormone therapy in prostate cancer is to interfere with the androgen signaling that is critical to the growth of testosterone-dependent cancer cells. Interfering with the androgen signaling can be achieved in several ways.

  4. Correct answer to Question 4: d
    1. Androgen-independent. There is a better answer.
    2. Androgen-resistant. There is a better answer.
    3. Androgen-insensitive. There is a better answer.
    4. All of the above. Correct.

  5. Correct answer to Question 5: c
    1. In the pituitary gland. The answer is C. LHRH agonists are similar enough to bind to LHRH receptors and produce a physiological effect, but they are dissimilar enough to remain bound for a longer time than naturally occurs.
    2. They remain bound for a shorter time than normal LHRH. The answer is C. LHRH agonists are similar enough to bind to LHRH receptors and produce a physiological effect, but they are dissimilar enough to remain bound for a longer time than naturally occurs.
    3. They remain bound for a longer time than LHRH. LHRH agonists are similar enough to bind to LHRH receptors and produce a physiological effect, but they are dissimilar enough to remain bound for a longer time than naturally occurs.
    4. In the prostate cancer cell. The answer is C. LHRH agonists are similar enough to bind to LHRH receptors and produce a physiological effect, but they are dissimilar enough to remain bound for a longer time than naturally occurs.

  6. Correct answer to Question 6: e
    1. There is an increase in the release of LH. The answer is E (both B and C). When LHRH antagonists are given, there is a decrease in the release of LH. The testicles then stop producing testosterone, androgen levels drop, and there is no "hormone flare."
    2. The testicles stop producing testosterone. Partially correct. The answer is E (both B and C). When LHRH antagonists are given, there is a decrease in the release of LH. The testicles then stop producing testosterone, androgen levels drop, and there is no "hormone flare."
    3. The androgen levels drop. Partially correct. The answer is E (both B and C). When LHRH antagonists are given, there is a decrease in the release of LH. The testicles then stop producing testosterone, androgen levels drop, and there is no "hormone flare."
    4. There is a "hormone flare". The answer is E (both B and C). When LHRH antagonists are given, there is a decrease in the release of LH. The testicles then stop producing testosterone, androgen levels drop, and there is no "hormone flare."
    5. Both B and C. When LHRH antagonists are given, there is a decrease in the release of LH. The testicles then stop producing testosterone, androgen levels drop, and there is no "hormone flare."

  7. Correct answer to Question 7: a
    1. They slow testosterone binding to its receptor, which inhibits cell growth. Antiandrogens bind to androgen receptors within prostate cancer cells, leaving fewer sites available for testosterone binding. As a result, the androgen receptor complex is unable to stimulate cell growth to the same extent.
    2. They stop the production of testosterone. The answer is A. Antiandrogens bind to androgen receptors within prostate cancer cells, leaving fewer sites available for testosterone binding. As a result, the androgen receptor complex is unable to stimulate cell growth to the same extent.
    3. They prevent testosterone from signaling the hypothalamus. The answer is A. Antiandrogens bind to androgen receptors within prostate cancer cells, leaving fewer sites available for testosterone binding. As a result, the androgen receptor complex is unable to stimulate cell growth to the same extent.
    4. They bind to testosterone directly so testosterone can't bind to other receptors. The answer is A. Antiandrogens bind to androgen receptors within prostate cancer cells, leaving fewer sites available for testosterone binding. As a result, the androgen receptor complex is unable to stimulate cell growth to the same extent.

  8. Correct answer to Question 8: d
    1. In the testes. There is a better answer.
    2. In the adrenal glands. There is a better answer.
    3. In prostate cancer cells. There is a better answer.
    4. All of the above. Correct.

Therapeutic Vaccines

In This Section:

 

Harnessing the power of the immune system

Although the immune system is programmed to defend the body against invaders such as bacteria or viruses, its ability to fight cancer is limited because it doesn't usually recognize cancer cells as foreign. In fact, some cancers actively suppress the body's immune response.

Shown on the left is an outline of a male body with prostate cancer. On the right is an inset circle coming from the groin area showing a layer of pink normal cells with an embedded mass of green cancer cells. Antibodies do not recognize the prostate cancer cells as foreign, so they do not attract the blue immune cells that could cause the cancer cells to die. Screen text reads: Some cancers actively suppress the body's immune response.

However, prostate cancer cells do differ from normal cells in some important ways. These differences can be used to harness the immune system's power to destroy cancer cells specifically. For example, proteins made by the cells, called antigens, may be more or less abundant on prostate cancer cells when compared to their normal counterparts.

Shown on the left is a green cell labeled Cancerous Prostate Cell with many yellow antigens on its surface. On the right is a pink cell labeled Normal Prostate Cell with far fewer yellow antigens on its surface. The yellow antigens are also labeled.

Therapeutic vaccines combine the body's general immune response, just like one toward a bacterial or viral infection, with an attack on specific prostate cancer antigens.

Shown are three activated immune cells attacking a green cancer cell. The cancer cell is carrying yellow antigens on its surface and the immune cells recognize the antigens as foreign. The immune cell is also parenthetically labeled as a 'Killer T Cell.'

Another challenge in prostate cancer immunotherapy has been the need to generate large numbers of killer T cells that can specifically recognize, target, and kill prostate cancer cells.

One technique to increase the number of killer T cells harnesses an immune cell called the dendritic cell, or antigen presenting cell, to make a prostate cancer vaccine.

Shown is a labeled dendritic cell with multiple waving arms that extend outward.

The blood of the cancer patient is collected and enriched to increase the population of dendritic cells. These cells are then grown in the laboratory in the presence of a protein or part of a protein that is present in or on the patient's tumor cells.

Shown are several dendritic cells. A protein labeled 'Tumor Cell Protein,' also called an antigen, is shown among the dendritic cells.

The patient's dendritic cells digest the protein and transport tiny pieces of it to the cell surface. When the dendritic cells are put back into the patient, they signal certain populations of killer T cells to destroy all cells with the telltale protein, including cancer cells.

Shown is a dendritic cell that has processed the tumor cell protein and is presenting pieces of the protein on its extended arms. One killer T cell is shown touching an arm of the dendritic cell. All three killer T cells have been activated by the dendritic cell to recognize the tumor cell protein as foreign.

 

Provenge® (sipuleucel-T)

Provenge® (generic drug name sipuleucel-T) is the only cancer therapeutic vaccine that has been approved by the FDA to date. It is approved for use in men with metastatic prostate cancer that does not respond to hormone therapy.

Provenge® uses prostatic acid phosphatase, or PAP, as the key antigen. PAP is highly expressed in nearly all prostate cancers and is largely restricted to prostate cells.

Shown in the background is an image of the head and shoulders of a male patient in a hospital bed. Screen title reads: Provenge®. First bullet reads: The only cancer therapeutic vaccine that has been approved by the FDA to date. Second bullet reads: Approved for use in men with metastatic prostate cancer that does not respond to hormone therapy. Third bullet reads: Uses PAP as the key antigen.

Provenge® is prepared by harvesting the patient's blood and enriching for specialized immune cells, called antigen presenting cells, from that blood.

The antigen presenting cells are then exposed to a recombinant antigen consisting of PAP and granulocyte macrophage colony stimulating factor (GM-CSF).

The role of GM-CSF is to prolong the body's general immune response. The role of PAP is to trigger a specific immune response.

Shown is an immune cell called an antigen presenting cell, or dendritic cell. The dendritic cell is approaching a recombinant antigen consisting of a yellow prostatic acid phosphatase (PAP) and a pale pink granulocyte macrophage colony stimulating factor (GM-CSF). The screen title reads: Provenge® Therapeutic Vaccine. Text across the bottom of the screen reads: The role of PAP is to trigger a specific immune response.

The patient's antigen presenting cells digest the antigen and transport tiny pieces of it to the cell surface. Antigen presenting cells that have taken up and processed the PAP–GM–CSF antigen are then infused back into the patient where they stimulate a specific immune response.

Shown is a dendritic cell, or antigen presenting cell, that has digested the recombinant GM-CSF antigen. The dendritic cell is presenting pieces of the antigen on its arms to an immune cell. The immune cell has been activated to recognize the antigen as foreign.

The infused cellular product can activate large numbers of killer T cells that destroy cells expressing the PAP antigen, primarily prostate cancer cells.

Shown on the left is an outline of a male body with a lymphatic system and prostate cancer. A vaccine has been administered and targeted therapy molecules are circulating through the lymphatic system. On the right is an inset circle coming from the groin area showing a layer of pink normal cells with an embedded mass of green prostate cancer cells. The activated blue immune cells recognize the antigens on cancer cells and destroy some of the cells. The dead cancer cells are colored black.

Self Test

Questions

  1. How do therapeutic vaccines work to attack cancer?
    1. They mount a general immune response.
    2. They promote a specific immune response to the cancer cell's antigens.
    3. They make antibodies against the cancer.
    4. Both A and B.

Answers

  1. Correct answer to Question 1:
    1. They mount a general immune response. There is a better answer.
    2. They promote a specific immune response to the cancer cell's antigens. There is a better answer.
    3. They make antibodies against the cancer. Incorrect. The answer is D (both A and B).
    4. Both A and B. Correct.

Taxane combination therapies

In This Section:

 

Normal apoptosis

Control of normal cell growth involves a process called apoptosis, or programmed cell death. In adults, the number of body cells is kept relatively constant. Stressed, diseased, malfunctioning or irreversibly damaged cells, as well as cells that need to be removed routinely as part of normal body maintenance or development, are all removed by apoptosis.

Shown is a layer of pink normal cells. One of the cells is fragmented into small vesicles, indicating that it has undergone apoptosis. Screen text reads: Apoptosis is programmed cell death.

Cells supervise their own destruction through a controlled and highly regulated series of steps.

The apoptotic cell shrinks & rounds up. It then condenses its DNA and cuts it into fragments. Finally, the cell breaks into small vesicles that can be easily engulfed by immune cells.

Shown is layer of pink normal cells. In the center of the image there is a close-up of a cell that has fragmented into small vesicles, indicating that it has undergone cell death or apoptosis.

 

Targeting tubulin & Bcl-2 to trigger apoptosis

The goal of targeted therapies that promote apoptosis is to tip the balance for cancer cells in favor of cell death. Taxotere® (generic drug name docetaxel) is a chemotherapy drug that promotes apoptosis in various ways.

Shown is a layer of pink normal cells with an embedded mass of green cancer cells. Several of the cancer cells have fragmented into small gray vesicles, indicating that they have undergone apoptosis. Screen text reads: The goal of therapies that promote apoptosis is to tip the balance toward cell death.

In normal cell division, or mitosis, structures called microtubules play an essential role in ensuring that each progeny cell receives a complete copy of DNA. In this process, microtubules assemble and disassemble in an orchestrated way.

Shown is a close-up of a cell during cell division, or mitosis. Inside the two hemispheres of the dividing cell are microtubule structures radiating like the spokes of a wheel from opposing poles. The microtubules are ready to move the cell's DNA to opposing poles in an orchestrated way. In the background is a layer of pink cells. Screen text reads: Mitosis (cell division) in normal cells.

Taxotere® binds to the protein tubulin, which is the building block of microtubules, and promotes microtubule formation. It also blocks microtubule disassembly, thereby "freezing" the structures. This results in the inhibition of mitosis in cells and eventually triggers apoptosis.

Shown is a close-up of a dividing cancer cell in the presence of Taxotere. Inside the two hemispheres of the dividing cell are microtubule structures radiating like the spokes of a wheel from opposing poles. Taxotere has frozen the microtubule structures, inhibiting cell division. In the background is a layer of green cancer cells.

Shown is a close-up of a cancer cell in the presence of Taxotere with frozen microtubule structures. The inhibition of cell division has caused the cell to self-destruct. In the background is a layer of green cancer cells.

In addition to interfering with normal tubulin function, Taxotere® inactivates the pro-survival protein Bcl-2. This inactivation allows cell death, or apoptosis, to occur.

 

Taxane combination therapy triggers apoptosis

Taxotere® in combination with prednisone is approved by the FDA for the treatment of patients with metastatic castration-resistant prostate cancer.

Metastatic castration-resistant prostate cancer is cancer that has spread throughout the body, beyond the prostate alone, and continues to grow, even when testosterone is inhibited.

Shown in the background is a magnification of actual prostate cancer cells stained purple. Screen title reads: Metastatic castration-resistant prostate cancer. First bullet reads: Is cancer that has spread throughout the body. Second bullet reads: Continues to grow even when testosterone is inhibited.

The "best" chemotherapy for a patient with metastatic castration-resistant prostate cancer combines treatment with taxanes and prednisone. Clinical trials showed that this combination improved both survival and the length of time a patient remained disease-free when compared with the previous therapy, which combined mitoxantrone and prednisone.

Shown is an image of the head and shoulders of a male patient in a hospital bed. Screen text reads: The 'best' chemotherapy for a patient with metastatic castration-resistant prostate cancer combines treatment with taxanes and prednisone.

The taxanes that are used in this setting are Taxotere® and Jevtana (generic drug name cabazitaxel). Jevtana is a new microtubule inhibitor specifically approved for the treatment of prostate cancer in patients who were previously treated with a docetaxel-containing treatment regimen.

Shown is a close-up of a dividing cancer cell in the presence of Taxotere. Inside the two hemispheres of the dividing cell are microtubule structures radiating like the spokes of a wheel from opposing poles. Taxotere has frozen the microtubule structures, inhibiting cell division. In the background is a layer of green cancer cells. Screen text reads: Jevtana® is a new microtubule inhibitor specifically approved for the treatment of prostate cancer.

Self Test

Questions

  1. How does docetaxel target prostate cancer?
    1. This drug blocks the microtubules from forming in mitosis.
    2. This drug blocks the microtubules from disassembling in mitosis.
    3. This drug inactivates the pro-survival protein called Bcl-2.
    4. Both B and C.

Answers

  1. How does docetaxel target prostate cancer?
    1. This drug blocks the microtubules from forming in mitosis. Incorrect.The answer is D (both B and C).
    2. This drug blocks the microtubules from disassembling in mitosis. There is a better answer.
    3. This drug inactivates the pro-survival protein called Bcl-2. There is a better answer.
    4. Both B and C. Correct.

New Approaches Under Investigation in Clinical Trials

In This Section:

 

Targeting angiogenesis in prostate cancer

Researchers running clinical trials are finding new ways to target prostate cancer. These experimental approaches have not yet been approved by the FDA, so clinical trials may be the only opportunity for patients to access them at present.

Shown is an image of two clinical researchers in a laboratory. Screen text reads: Clinical trials may be the only opportunity for patients to access new treatments.

Blocking angiogenesis, although still investigational, is another viable strategy for cancer therapy. Targeted therapies such as Avastin (generic drug name bevacizumab), Revlimid (generic drug name lenalidomide), and Thalomid (generic drug name thalidomide) interfere with specific molecules involved in angiogenesis, interrupting the essential blood supply to prostate tumors.

Shown is the edge of a blood vessel running across the top of the screen. The rest of the screen is filled with a layer of pink normal cells and a cluster of green cells labeled 'Prostate Cancer'. Branching off from the main blood vessel is an auxiliary blood vessel labeled 'Angiogenesis.' The auxiliary blood vessel is providing the blood supply essential for the survival of the cancer cell cluster. Screen text reads: Blocking angiogenesis is another viable strategy for cancer therapy.

Also under investigation is Celebrex (generic drug name celecoxib), which may stop the growth of tumor cells by blocking some necessary enzymes and by blocking blood flow to the tumor.

Shown is the edge of a blood vessel running across the top of the screen. The rest of the screen is filled with a layer of pink normal cells and a cluster of green cells labeled 'Prostate Cancer'. A red X labeled 'Angiogenesis' indicates that the formation of blood vessels is blocked. As a result, several of the cancer cells have fragmented into small gray vesicles, indicating that they have undergone apoptosis. Title on the left side of the screen reads: Targeted therapies under investigation. The bulleted list reads: Avastin, Revlimid, Thalomid, Celebrex.

 

Testing a Poxvirus therapeutic vaccine

Researchers running clinical trials are finding new ways to target prostate cancer. These experimental approaches have not yet been approved by the FDA, so clinical trials may be the only opportunity for patients to access them at present.

Shown are two healthcare providers looking at images on a computer screen. Screen text reads: Clinical trials may be the only opportunity for patients to access them at present.

A cancer vaccine, Prostvac™ (generic drug name PSA-TRICOM), made with two forms of Poxvirus that do not cause disease in humans, is being tested in Phase II and Phase III clinical trials as treatment for castration-resistant prostate cancer.

Shown is a group of cancer patients labeled 'Volunteer Cancer Patients.' The screen title reads: Prostvac™ is being tested in phase II and phase III clinical trials as treatment for castration-resistant prostate cancer. Boxes at the bottom of the screen read 'Phase II' and 'Phase III.'

Prostvac™ contains recombinant viruses that have been altered in the laboratory to express prostate-specific antigen, or PSA, a protein found mainly in prostate cells.

Shown are illustrations of several Poxviruses. Screen text reads: Prostvac™ contains recombinant viruses that have been altered in the laboratory to express prostate-specific antigen, or PSA, a protein found mainly in prostate cells.

The recombinant virus infects cells at the injection site, causing them to express PSA.

Shown is a close-up of a man's upper left chest, shoulder, and arm. A silhouette of the circulatory system is shown within the body. A syringe injecting a Poxvirus therapeutic vaccine into the arm results in an area of infection that triggers an immune response.

This PSA is then taken up and processed by antigen-presenting cells, including dendritic cells, which present antigens to killer T cells. The killer T cells respond by destroying cells that express PSA.

Shown is a dendritic cell that has processed the PSA antigen and is presenting pieces of it to a killer T cell. The killer T cell now recognizes PSA as a foreign protein.

Shown are three killer T cells activated to recognize PSA as foreign. The killer T cells are shown surrounding a cancer cell that expresses PSA, and the cancer cell is being destroyed. The cancer cell, its PSA antigen, and the killer T cells are all labeled.

More Information:

Prostvac

A Phase I study of PROSTVAC ™ and Ipilimumab (anti-CTLA4 antibody) demonstrated the utility of this approach.

 

Testing ways to regulate the immune response of therapeutic vaccines

Adding specific cytokines or antibodies to regulate the action of therapeutic vaccines is being tested in clinical trials.

Sometimes it is important to heighten the reactivity of a cancer vaccine. Interleukin 15 (Il-15) is a cytokine that is being tested in combination with other experimental treatments to do this. This molecule can further activate natural killer cells and T cells without activating the regulatory immune cells that normally signal for an immune response to draw to a close.

Shown on the left is an outline of a male body with a lymphatic system and prostate cancer. A therapeutic vaccine carrying the cytokine Interleukin 15 has been administered. On the right is an inset circle coming from the groin area showing a layer of pink normal cells with an embedded mass of green cancer cells. Three activated killer T cells are shown recognizing the cancer cells as foreign. Screen title is: Cytokines. Text at the bottom of the screen is 'Interleukin 15 can further activate natural killer cells and T cells.'

Other times it is necessary to extend the length of time that a vaccine can target cancer cells. Clinical researchers do this by adding anti-CTLA4 antibody to protocols. Anti-CTLA4 slows down the regulatory immune cells that usually signal for the immune response to end.

Shown on the left is an outline of a male body with a lymphatic system and prostate cancer. A therapeutic vaccine carrying anti-CTLA4 antibody has been administered. On the right is an inset circle coming from the groin area showing a layer of pink normal cells with an embedded mass of black, dying cancer cells. Two immune cells are shown destroying the cancer cells. Screen title is: Antibodies. Text across the bottom of the screen is: Anti-CTLA4 slows down the immune response to allow the vaccine time to work.

Self Test

Questions

  1. What are some other experimental targeted approaches being investigated for their potential as future prostate cancer treatments?
    1. Agents that disrupt the blood supply to the prostate cancer.
    2. Recombinant viruses that increase the PSA signal so killer cells can attack the cancer.
    3. Cytokines or antibodies to prolong the immune response once it starts.
    4. All of the above.

Answers

  1. How does docetaxel target prostate cancer?
    1. Agents that disrupt the blood supply to the prostate cancer. There is a better answer.
    2. Recombinant viruses that increase the PSA signal so killer cells can attack the cancer. There is a better answer.
    3. Cytokines or antibodies to prolong the immune response once it starts. There is a better answer.
    4. All of the above. Correct.

Risks of Targeted Therapies

In This Section:

 

Overview

This tutorial has explained the evidence-based design of targeted therapies and has shown the benefits of taking a more precise aim at specific prostate cancer pathways and processes. However, like all new cancer treatments, targeted therapies are not without risks.

 

Hormone therapy risks

Hormone therapy may shrink or slow the growth of your cancer, but, unless it is used in combination with another therapy, it will not eliminate the cancer. Side effects of hormone therapy can include hot flashes, growth of breast tissue, weight gain, and impotence.

Shown on the left is an outline of a male body producing testosterone. On the right is an inset circle coming from the groin area showing a prostate tumor growing in the presence of testosterone. The screen text reads: Hormone therapy may shrink or slow the growth of your cancer, but, unless it is used in combination with another therapy, it will not eliminate the cancer.

And LHRH agonists may increase a man's risk of diabetes and certain cardiovascular diseases.

 

Therapeutic vaccine risks

Almost all of the patients who received the therapeutic vaccine Provenge® had some type of side effect; however, most of these were mild and transient. Common adverse reactions reported included chills, fatigue, fever, back pain, nausea, joint ache, and headache. About one-fourth of patients receiving Provenge® had serious adverse reactions, including stroke and some acute infusion reactions.

Shown on the right is an outline of a male body with a lymphatic system. A therapeutic vaccine has been administered. Screen title reads: Common adverse reactions. The bulleted list reads: Chills, fatigue, fever, back pain, nausea, joint ache, headache.

 

Taxane risks

Blood-related side effects seen in prostate cancer patients treated with taxanes include a decrease in the number of red blood cells (anemia), a decrease in the number of specialized infection-fighting white blood cells (neutropenia), a decrease in the number of white blood cells (leukopenia), and a low level of platelets in the blood (thrombocytopenia).

Other side effects seen include diarrhea, fatigue, nausea, vomiting, constipation, weakness (asthenia), and possible renal failure.

Shown are two healthcare providers talking to a male patient in a hospital setting. Screen text reads: Taxanes.

 

Other risks

The most common adverse reactions reported for the super-antiandrogen Zytiga were joint swelling or discomfort, low potassium level in the blood, fluid retention, muscle discomfort, hot flush, diarrhea, urinary tract infection, cough, high blood pressure, arrhythmia, frequent urination, urination at night, digestive problems and upper respiratory tract infection.

In addition, new types of drug resistance can develop in patients given targeted therapies. Sometimes resistance to therapy occurs because the target itself mutates, so the new therapy is unable to interact with its target as it did earlier.

Shown is a close-up of the membrane, cytoplasm and nucleus of a cancer cell. There are multiple receptors in the cell membrane. One of the receptors has a red starburst. A close-up view of this receptor is shown and is labeled 'Mutation.' Screen text reads: Drug Resistance in Targeted Therapies.

Other times, the resistance is indirect, in that the tumor finds a new pathway to achieve tumor growth in spite of the presence of a targeted therapy that is successfully blocking its assigned target.

Clinicians do not know whether using targeted therapies in combination with one another to treat prostate cancer will trigger new side effects. They do not know how long treatments should continue, nor do they know what combinations of targeted therapies will be most effective.

They also do not know if prostate cancer cells can establish alternate survival pathways and continue their growth even when a targeted therapy successfully destroys its target.

The clinical trials currently under way are trying to answer these questions, and others, as they arise.

Self Test

Questions

  1. What questions about targeted therapies for prostate cancer still remain unanswered and are being investigated in clinical research?
    1. Clinicians do not know how long treatments should continue.
    2. Clinicians do not know what combinations of targeted therapies will be most effective.
    3. Clinicians do not know whether combination therapies will trigger new side effects.
    4. All of the above.

Answers

  1. How does docetaxel target prostate cancer?
    1. Clinicians do not know how long treatments should continue. There is a better answer.
    2. Clinicians do not know what combinations of targeted therapies will be most effective. There is a better answer.
    3. Clinicians do not know whether combination therapies will trigger new side effects. There is a better answer.
    4. All of the above. Correct.

Summary & Conclusions

In This Section:

 

FDA-Approved targeted therapies

Several targeted therapies have already been approved by the FDA for treatment of prostate cancer, and the number will likely increase as research continues to take place.

Shown are two healthcare professionals in a hospital. Screen text overlay reads: More targeted therapies will be approved as research continues to take place.

Visit the FDA and NCI Web sites for additional information about clinical trials.

Shown are web pages from the FDA and the National Cancer Institute. The caption contains the two web site addresses: www.fda.gov and www.cancer.gov.

 

About clinical trials

Clinical researchers are finding ways to use targeted therapies to effectively treat cancer. Since dozens of these new, innovative targeted therapies have not yet been approved by the FDA, clinical trials may be the only opportunity for patients to access them at present. Unfortunately, only 3 percent of adults with cancer choose this route and enroll in clinical trials.

A recent study indicated that 65 percent of patients would have been receptive to clinical trial enrollment if they had been made aware of the option at the time of initial diagnosis.

Eighty-seven percent would consider participating in a clinical trial if their initial treatment failed.

Physicians have the responsibility to talk to their patients about clinical trials and help them identify appropriate trials if the patients are interested.

 

Finding clinical trials

To do your own search for clinical trials, visit the Clinical Trials section of the National Cancer Institute's website at http://www.cancer.gov/clinicaltrials.

Shown is a picture of the National Cancer Institute's website. Screen caption reads: National Cancer Institute's clinical trials website www.cancer.gov/clinicaltrials.

The NCI Web site has information about clinical trials that are sponsored by the National Cancer Institute, pharmaceutical companies, medical centers, and other groups from around the world.

Shown In the background is a picture of the NCI Clinical Trials Web site. Screen text overlay reads: Contains information about clinical trials that are sponsored by the NCI and other groups around the world.

There are targeted therapies for prostate cancer in all phases of clinical study. Many of these targeted therapies target the cellular processes discussed in this tutorial.

 

Additional resources

Additional information about cancer clinical trials can be found at http://bethesdatrials.cancer.gov/, which will help a patient find cancer trials at the NIH Clinical Center in Bethesda, Maryland.

Shown in the background is a picture of the Clinical Trials at NCI Web site. Screen text overlay reads: http://bethesdatrials.cancer.gov

For answers to additional questions about cancer, visit the National Cancer Institute's Cancer Information Service Web page at http://www.cancer.gov/aboutnci/cis.

This Web page includes a link for accessing LiveHelp, a live, online service that provides information about cancer, including information about ongoing clinical trials.

Shown is a picture of the NCI Cancer Information Service website. Screen text overlay reads: http://www.cancer.gov/aboutnci/cis

The public also may contact the Cancer Information Service at 1-800-4-CANCER.