Targeted Therapy for Prostate Cancer

Overview

A targeted therapy is one that is designed to treat only the cancer cells and minimize damage to normal, healthy cells. Cancer treatments that “target” cancer cells may offer the advantage of reduced treatment-related side effects and improved outcomes.

Conventional cancer treatments, such as chemotherapy and radiation therapy, cannot distinguish between cancer cells and healthy cells. Consequently, healthy cells are commonly damaged in the process of treating the cancer, which results in side effects. Chemotherapy damages rapidly dividing cells, a hallmark trait of cancer cells. In the process, healthy cells that are also rapidly dividing, such as blood cells and the cells lining the mouth and GI tract are also damaged. Radiation therapy kills some healthy cells that are in the path of the radiation or near the cancer being treated. Newer radiation therapy techniques can reduce, but not eliminate this damage. Treatment-related damage to healthy cells leads to complications of treatment, or side effects. These side effects may be severe, reducing a patient’s quality of life, compromising their ability to receive their full, prescribed treatment, and sometimes, limiting their chance for an optimal outcome from treatment.

Advances in science and technology have led to the development of several different types of targeted therapies, which target cancer through different mechanisms. Currently, there are no targeted therapies approved for the treatment of prostate cancer. However, clinical studies show promising results with a selective endothelin A receptor antagonist (SERA™) called atrasentan (Xinlay®), and the FDA is in the process of determining whether atrasentan will be approved for the treatment of relapsed or recurrent prostate cancer.

A receptor antagonist is a substance that prevents the binding between proteins in cells (called receptors) and substances in the blood. This “receptor binding” is a normal activity in the body that is responsible for initiating many biological processes.  Endothelins are peptides produced by the body that are comprised of 21 amino acids, the building blocks of protein. The binding of endothelins with endothelin receptor A, located on the surface of some cells, is known to constrict blood vessels, stimulate cell growth, and increase cell survival.

The interaction between endothelins and the endothelin receptor A plays a role in the progression of many cancers.[1] Prostate cancer cells produce high levels of endothelins and have an unusually high number of endothelin receptors expressed on their cell surface, especially advanced prostate cancers.  As a result, the endothelin receptor is over-stimulated, increasing growth and survival of the cancer cells.  The use of a selective endothelin A receptor antagonist (SERA™) to block endothelins from binding with the endothelin receptor A may slow or stop these effects.

Atrasentan (Xinlay™): Atrasentan is a SERA™ that appears to delay cancer progression in patients with bone metastases.

A phase III clinical trial of atrasentan involved 809 patients with metastatic prostate cancer that had become resistant to hormonal therapy.[2] Patients received atrasentan or placebo (inactive substitute) and the two groups were compared for clinical and x-ray indications of cancer progression and change from baseline in bio-markers of progression, including prostate specific antigen (PSA), bone alkaline phosphatase (BAP), and total alkaline phosphatase (ALP). Alkaline phosphatase is an enzyme that is involved in bone formation and other processes. Blood levels of alkaline phosphatase are increased in patients with bone metastases.

Atrasentan significantly delayed cancer progression in patients with bone metastases,[3] but not in the overall group of patients involved in this trial. Results also suggest that atrasentan appears to delay progression of bone metastases, as it was shown to delay BAP progression.  Compared to patients that received placebo, patients treated with atrasentan experienced a 2-fold longer period (a total of 505 days, 251 days more than placebo) before measures of their BAP increased 50% or more from the low point (nadir).

Researchers have also determined that treatment with atrasentan provided a small improved quality of life over placebo.[4] Quality of life was evaluated using two questionnaires that measure symptoms related to prostate cancer, including pain, fatigue, weight loss, and urinary problems.  Higher scores indicate better quality of life and fewer symptoms.  The questionnaires were filled out before and after treatment. Scores for the patients treated with placebo went down more between baseline (initial) measurement and post-treatment, indicating a greater reduction in quality of life and increase in symptoms, compared to patients treated with atrasentan. The benefit with atrasentan was most apparent with patients who had cancer that had spread (metastasized) only to bone.

Researchers continue to investigate different types of targeted therapies for the treatment of prostate and other cancer.  Some of these include:

Anti-angiogenic drugs starve the cancer cells of blood that they need to survive and grow.

Monoclonal antibodies can locate cancer cells in the body by recognizing proteins that are more abundant in cancer cells than normal cells, called receptors. The monoclonal antibody may then cause its anti-cancer effect by blocking the receptor from binding with substances in the blood. Treatments that block receptors may also be called “receptor antagonists”.

Radioactive monoclonal antibodies are comprised of a radioactive substance attached to a monoclonal antibody, the latter of which acts as a homing device, and the radioactive substance kills the targeted cell.

Tyrosine kinase inhibitors interact with the enzyme (protein) tyrosine, which is active in a complex signaling system that is used by some cancers as a survival mechanism to allow them to grow out of control. The drug Gleevec® (imitinib mesylate) is an example of this type of targeted therapy that inhibits a mutated form of tyrosine kinase and stops the abundant growth of cancerous white blood cells in chronic myeloid leukemia.

Vaccines are synthetic substances that are made from a patient’s own cancer cells and stimulate the body to recognize and attack cancer cells,

[4] Yount S, Cella D, Mulani P, et al. Impact of atrasentan on prostate-specific outcomes with hormone refractory prostate cancer patients. Journal of Clinical Oncology, 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition);22(14S), Abstract #4582.

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