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January 2009 Volume 3 #1
 True Grit: Facing advanced PCa Hormone resistant PCa: News Osteoporosis and prostate cancer Fort McKay: A sharing tradition |
Treating hormone resistant prostate cancer: Current responses to the challenge  There is an old adage among prostate cancer survivors: "Early detection is the only cure." Men say this because, once prostate cancer has spread beyond the prostate, once it has metastasized, it can only be controlled---not cured. Fortunately, hormonal therapy, while not a cure, can lead to the long-term remission of advanced prostate cancer and enable men to enjoy an excellent quality of life.Hormonal therapy is treatment that stops the production of male hormones, such as testosterone, or that blocks the effects of these hormones. It works because male hormones, also called androgens, stimulate prostate cancer cell growth. So limiting or controlling androgens checks prostate cancer progression. But there is a problem. With time, prostate cancer cells may learn to grow even when androgens like testosterone are curtailed. The cancer no longer responds to hormonal therapy as it did initially, and we say that the cancer is hormone resistant, meaning that it is resistant to hormone deprivation therapy. When metastatic prostate cancer reaches this stage, no therapy has been shown to be an effective cure. But researchers are working hard to discover better ways of treating men with hormone resistant prostate cancer. Here are some of the promising areas of research: Androgens, Again Doctors now know that men whose cancers have developed a resistance to conventional hormone therapy can often be treated successfully using different methods of hormone deprivation. Many of the drugs used in this "second line" hormone therapy are antiandrogens, which block the effects of male hormones at the prostate tissue level. These include bicalutamide, flutamide, and nilutamide, all of which can be used in "first line" hormone therapy as well. Low dose corticosteroids, such as prednisone and dexamethasone, can also be part of second line hormone therapy. These drugs work by diminishing adrenal androgen production. Other drugs work to prevent steroidogenesis---the synthesis of steroid hormones (e.g., androgens). Ketoconazole and abiraterone acetate have this effect. The antifungal drug ketoconazole has been in use since the 1970s to treat a broad spectrum of fungi. As the drug became widely used as an antifungal agent, physicians noticed that a small number of male patients taking it developed enlarged breasts, and this observation led to the discovery of the drug's ability to inhibit the production of an enzyme necessary for the synthesis of androgens. Ketoconazole, while effective for some men with hormone resistant prostate cancer, can cause significant nausea, vomiting, rash, and fatigue in others. So researchers set out to find other agents that interfere with enzymes necessary in hormone synthesis. Dr. Johann de Bono and his colleagues developed and began testing one such drug, abiraterone acetate. The drug targets an enzyme called CYP17, which plays a key role in androgen synthesis throughout the body. Results from the phase I clinical trial of abiraterone were published in the October 2008 issue of the Journal of Clinical Oncology, and researchers concluded that "abiraterone acetate is safe and has significant antitumor activity" in men with hormone resistant prostate cancer. (See an abstract of this article.) An important principle behind the development of these "second line" hormone treatments, then, is that hormone resistant prostate cancer commonly remains hormone driven and can respond to hormone deprivation. This is something that Dr. Charles Sawyer of Memorial Sloan-Kettering has believed for a while. "Until 5 years or so ago," remarks Dr. Joel Nelson, chair of the department of urology at the University of Pittsburgh, "we had started to think that hormone therapy did not work [for hormone resistant prostate cancer]. All along, a number of researchers, including Charles Sawyers, said: 'No, we need better hormone therapy.'" Dr. Sawyers has been instrumental in the development of this "better hormone therapy" for men whose cancer has become resistant to hormone deprivation. MDV3100 is one result of his efforts. It is a selective androgen receptor modulator, which means that it works by inhibiting the activity of the androgen receptors in prostate cancer cells. These androgen receptors are proteins that enable male hormones to interact with cells. And hormone resistant prostate cancer cells seem to over-express (produce more than the normal amount of) androgen receptors. Consequently, interfering with the action of androgen receptors may result in a reduction in prostate cancer cell proliferation and, correspondingly, a reduction in prostate-specific antigen (PSA) level. A phase 1 clinical trial is due to report soon. Targeting Other Cell Growth Mechanisms Some researchers are investigating how to treat hormone resistant prostate cancer by disrupting other cell signalling or cellular growth processes, ones not directly related to androgens. An interesting area of study involves the tumour suppressor gene PTEN, which is frequently mutated or "lost" in advanced prostate cancer. PTEN regulates a critical cell signalling pathway involving the versatile proteins Akt, which inhibits programmed cell death (apoptosis), and mTOR, which regulates cell growth. Researchers have discovered that a drug called rapamycin, an antibiotic developed to prevent the rejection of organ and bone marrow transplants, inhibits these proteins. Two rapamycin analogues (drugs that are structurally similar to rapamycin) are currently being tested in clinical trials: everolimus and temsirolimus. (Click here to see a 2008 article on these two mTOR inhibitors). Immune-Based Strategies Encouraging the body's own immune system to fight prostate cancer has always seemed an attractive option. But, as you can imagine, this system is complex, involving many checks and balances that allow cells to recognize the body's own constituent parts as self and to avoid an immune response against the body's own healthy cells and tissues. Key players in the body's immune response are the dendritic cells, which reside in the lymph nodes. In their immature state, these cells sample their environment, checking for "danger" signals. When they discover trouble, they transform into mature cells capable of initiating an immune response. This maturation is accompanied by the display of an antigen on the cell's surface, in a form that can be recognized by T cells---cells that can generate immune responses tailored to a specific danger or pathogen and "remember" each pathogen encountered, so they are able to fight it effectively again. These remembered battles are the basis for the effectiveness of vaccines. Research into immune-based treatments for men with hormone resistant prostate cancer focuses either on stimulating specific immune responses or on "turning off" particular factors that check these responses. One idea for stimulating an immune response to prostate cancer was to administer activated dendritic cells loaded up with tumour antigens as targets as well as granulocyte macrophage colony-stimulating factor (GM-CSF), which supports the survival, expansion, and differentiation of dendritic cells. This approach led to the development of the vaccine sipuleucel-T (ProvengeŽ), which contains mature dendritic cells that present the antigen prostatic acid phosphatase (PAP), an enzyme produced by the prostate and found in high levels in metastasized prostate cancer. In October 2008, interim data from phase III of the IMPACT trail designed to assess the safety and efficacy of Provenge® reported a 20 per cent reduction in the risk of death among those who received the vaccine rather than the placebo. The final results should be ready in the spring of 2009. (Get more information on this clinical trial.) While the vaccine Provenge® modifies a man's own antigen-presenting cells so that they can initiate an immune response against his tumour, another approach uses a vaccine that is not patient specific. GVAX® is comprised of cells derived from two prostate cancer cell lines, one from a man with early-stage, metastatic prostate cancer that is still sensitive to hormones and the other from a man with more advanced, metastatic, hormone resistant prostate cancer. The hope was that the vaccine would stimulate both a broad immune response by introducing many antigens and a strong immune response by using cells that are not as weak or as compromised as those of a man with advanced hormone resistant prostate cancer. Although GVAX® immunotherapy reached phase III clinical trials, Cell Genesys, the company creating the vaccine, placed its further development on hold in October 2008 after an analysis indicated that the trial VITAL-1 had less than a 30 per cent chance of meeting its predefined endpoint of an improvement in survival. Another area of immunotherapy research involves CTLA-4 (cytotoxic t-lymphocyte antigen 4), which acts as a check for T cells, thereby controlling immune responses. The idea is that CTLA-4 may hold back T cells from fighting off prostate cancer, allowing cancerous cells to multiply unchecked. So, by blocking CTLA-4, researchers hope to unleash the immune system. "CTLA-4 blockade works by removing the brakes on the immune system. Our results show that enhancing immune responses in prostate cancer patients can lead to clinical responses," said Dr. Lawrence Fong, a researcher at University of California, San Francisco. In prostate cancer, ipilimumab (MDX-010), an anti-CTLA-4 monoclonal antibody, is being tested as both a single-agent therapy and in combination approaches using radiation, chemotherapy, or other immunotherapy agents. (For current clinical trials of MDX-010, click here.) Bone Directed Therapy Another approach to hormone resistant prostate cancer involves delaying the progression of metastatic disease in the bone. In men with advanced prostate cancer that has metastasized to the bone, osteoblasts, the cells responsible for bone formation, show high levels of endothelin-1 (ET-1) receptors, which researchers think are involved in several aspects of prostate cancer progression as well as in new bone formation. Atrasentan, a substance that blocks ET-1 receptors, is being studied in a phase III trial to see how docetaxel, prednisone, and atrasentan work compared to docetaxel and prednisone as a treatment for men who have advanced, hormone resistant prostate cancer with bone metastases. Another drug, denosumab, is being studied for its potential to delay bone metastases and inhibit and treat bone destruction. This summer, researchers reported that denosumab improved bone mineral density significantly and reduced fractures in men undergoing androgen deprivation therapy (ADT) for non-metastatic prostate cancer. Denosumab works by targeting the RANK ligand, a signalling molecule that bonds to osteoclasts (the cells that break down bone). A phase III trial comparing denosumab to a placebo as a treatment to prolong bone metastasis-free survival in men with hormone resistant prostate cancer is underway and should report in 2010. Chemotherapy Combinations Currently, the standard treatment for men with hormone resistant, metastatic prostate cancer is the chemotherapy drug docetaxel (TaxotereŽ). This drug, made from the needles of the European yew tree, is a proven chemotherapy drug, which is known to extend the life of men with advanced prostate cancer. (See the CPCN article "TaxotereŽ: Encouraging news for men with metastatic prostate cancer. ") But survival benefits are modest with docetaxel (about 2 to 3 months) and the duration of the drug's effect is short (about 6 months). Consequently, researchers are looking at combining the drug with other therapies and potentially effective anti-cancer agents. Two of these are bevacizumab, which inhibits tumour growth by blocking the formation of new blood cells, and DN-101, an investigational drug that contains high amounts of calcitriol. Calcitriol is the biologically active form of vitamin D, and lab experiments have associated higher levels of it with anti-cancer effects. ASCENT (the Androgen Independent Prostate Cancer Study of Calcitriol Enhancing Taxotere) reported in January 2008 that "DN-101 treatment was associated with improved survival" and "did not increase the toxicity of weekly docetaxel." More research is necessary to confirm improved survival. (See this report in the Journal of Clinical Oncology.) Bevacizumab, which blocks the activity of a protein called vascular endothelial growth factor (VEGF), is being studied in combination with docetaxel and prednisone. Many cancers use VEGF to help form the new blood vessels they need for continued growth, and high levels of VEGF in the blood and urine of patients with hormone resistant prostate cancer have been found to indicate a reduced likelihood of survival. "This phase III trial will answer the question of whether adding bevacizumab to docetaxel and prednisone actually does improve survival over the current standard of care," says Dr. William K. Kelly, the principal investigator. (Click for more information on this clinical trial.) All of us at CPCN applaud these research efforts and look forward to the day when medical advances go even further to improve and extend the lives of men battling hormone resistant prostate cancer. |
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