Immunotherapy in Prostate Cancer: Teaching an Old Dog New Tricks

Immunotherapy is rapidly transforming cancer care across a range of tumor types. Although Sipuleucel-T represented the first successful vaccine for the treatment of established cancer, other immunotherapeutic approaches for prostate cancer such as checkpoint inhibitors have been relatively disappointing to date. However, significant promise is on the horizon as there is a wide array trials evaluating immunotherapy in prostate cancer patients. These include both immune checkpoint inhibitors and antigen-specific approaches including vaccines, antibody-drug conjugates, and antitumor antibodies. Furthermore, a better understanding of the key mechanisms that promote the immunosuppressive microenvironment of prostate cancer is emerging. These insights may eventually make it possible to determine which patients will benefit from immunotherapy. This review will discuss the successes and failures of immunotherapy in prostate cancer. We will also present key lessons learned from completed trials and highlight important ongoing studies.     

New Approaches for the Prevention of Bone Metastases in Patients with Prostate Cancer

Bone metastases are the most frequent complication of advanced prostate cancer and are responsible for the vast majority of disease-related morbidity and mortality. With the extensive number of predictive models for patients with prostate cancer, we can now determine to some degree which patients are at highest risk for progression to metastatic bone disease and therefore might benefit from earlier or more aggressive therapy. Combining this with our better understanding of the molecular biology underlying the progression to bone metastasis, we are able to identify more specific targets or pathways to approach therapeutically to prevent or delay the development of metastatic bone disease. General strategies for the prevention of bone metastases include bone-targeting approaches, antimetastatic therapies, and purely antineoplastic agents. Bisphosphonates comprise the most studied and effective of the bone-targeted agents and now have relatively sound clinical data supporting their role not only in the treatment of bone metastases, but also in the secondary prevention and, in some cases, primary prevention, of new skeletal complications. Their ease of administration and relatively low short- and long-term toxicities make them ideal for potential treatment earlier in the disease process as well. Radioisotopes have been studied and used for decades for the treatment of painful bone metastases but only recently have data accumulated demonstrating their efficacy in the prevention of new metastases. The endothelin receptor antagonist, atrasentan, has recently been shown to delay the progression of systemic disease and potentially improve survival in patients with prostate cancer. It appears to do so, at least in part, by bone-targeting mechanisms. Antimetastatic strategies are also promising for the prevention of bone metastases and include matrix metalloproteinase inhibitors, gene therapy, and other novel approaches, such as inhibiting tyrosine kinases or NFκB and immunomodulation of prostate stem cell antigens. Utilizing standard hormonal or cytotoxic therapies in the adjuvant setting has also been studied extensively and in certain groups of patients may provide meaningful clinical benefit in preventing or delaying systemic progression, including bone metastases. Finally, as we learn more about molecular synergies with various agents, combinations of these approaches with each other or with more traditional hormonal or chemotherapy agents may be even more effective in the prevention of bone metastases in patients with prostate cancer.     

激素难治性前列腺癌治疗进展

激素难治性前列腺癌(HRPC)患者的治疗已成为一个极具挑战性的课题，近年仍然发展了许多治疗方法可供选择，包括二线内分泌治疗、细胞毒药物化疗、维生素D及其类似物骨化=三醇、反应停、Epothilones、以骨为靶向的治疗、内皮素受体拮抗剂以及其它一些新的治疗方法，如金属蛋白酶抑制剂、基因治疗、肿瘤疫苗等。     

Parenteral Estrogens for Prostate Cancer: Can a New Route of Administration Overcome Old Toxicities?

Androgen deprivation therapy (ADT) is the mainstay of management of advanced-stage prostate cancer and recently has been shown to improve survival when administered in earlier stages of the disease. The oncologic benefits of ADT might be partially offset, however, by a reduction in quality of life because of adverse effects. In addition to the well-recognized adverse consequences of ADT, recent evidence suggests that ADT is associated with dyslipidemia, impaired glucose metabolism, adverse body compositional changes, and osteoporosis. Therefore, there is a pressing need to develop less toxic forms of ADT. A novel approach to this problem is the use of estrogen to induce androgen suppression. Whereas oral estrogen therapy is known to be associated with thromboembolic complications, studies of parenteral estrogen in men with prostate cancer suggest that the use of parenteral estrogen achieves target androgen suppression, does not adversely affect prothrombotic protein levels, and is not associated with adverse metabolic, skeletal, and body compositional changes when compared with conventional ADT. Herein, we review the data for parenteral estrogen use in prostate cancer, the antineoplastic mechanisms of action of estrogen in prostate cancer, the potential advantages of parenteral estrogen compared with conventional ADT, and the remaining barriers in the use of parenteral estrogen in prostate cancer.     

激素抵抗型前列腺癌新的治疗方法

激素抵抗型前列腺癌是临床治疗上的重点和难点，目前的治疗方法包括化疗、放疗、核素内照射以及双磷酸盐等疗效均不满意，文章综述了近年来激素抵抗型前列腺癌新的治疗方法。     

激素抵抗型前列腺癌新的治疗方法

激素抵抗型前列腺癌是临床治疗上的重点和难点，目前的治疗方法包括化疗、放疗、核素内照射以及双磷酸盐等疗效均不满意，文章综述了近年来激素抵抗型前列腺癌新的治疗方法。     

Peptide Growth Factors and Prostate Cancer: New Models, New Opportunities

Prostate cancer is the leading form of newly diagnosed cancer cases in men in the United States. However, the molecular mechanisms contributing to the initiation, progression and ultimate development of metastatic and androgen independent disease are poorly understood. This is due in part to the difficulty in obtaining clinical samples representing early disease and the lack of animal models that recapitulate the full spectrum of the clinical disease. To this end we have developed and characterized the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) animal model that expresses the oncogene SV40 T antigen specifically in the epithelium of the prostate. TRAMP develops spontaneous autochthonous prostate cancer compelte with distant site metastasis and can progress to androgen independent disease. Changes in the fibroblast growth factor (FGF) axis and the insulin-like growth factor (IGF) axis have been examined during prostate cancer progression utilizing the TRAMP model and these data generally support observations reproted in the clinical disease. Moreover, we report novel changes in the FGF axis and IGF axis utilizing TRAMP. Thus, TRAMP can be used as a potent tool in understanding the mechanism of prostate cancer initiation and progression.     

Department of Defense Prostate Cancer Clinical Trials Consortium: A New Instrument for Prostate Cancer Clinical Research

Background

In 2005, the US Department of Defense, through the US Army Medical Research and Materiel Command, Office of the Congressionally Directed Medical Research Programs, created a funding mechanism to form a clinical trials consortium to conduct phase I and II studies in prostate cancer. This is the first report of the Prostate Cancer Clinical Trials Consortium (PCCTC).

Patients and Methods

The Department of Defense award supports a consortium of 10 prostate cancer research centers. Memorial Sloan-Kettering Cancer Center was awarded the Coordinating Center grant for the consortium and charged with creating an infrastructure to conduct early-phase multicenter clinical trials. Each participating center was required to introduce ≤1 clinical trial per year and maintain accrual of a minimum of 35 patients per year.

Results

The PCCTC was launched in 2006 and now encompasses 10 leading prostate cancer research centers. Fifty-one trials have been opened, and 1386 patients have been accrued at member sites. Members share an online clinical trial management system for protocol tracking, electronic data capture, and data storage. A legal framework has been instituted, and standard operating procedures, an administrative structure, editorial support, centralized budgeting, and mechanisms for scientific review are established.

Conclusion

The PCCTC fulfills a congressional directive to create a clinical trials instrument dedicated to early-phase prostate cancer studies. The member institutions have built an administrative, informatics, legal, financial, statistical, and scientific infrastructure to support this endeavor. Clinical trials are open and accruing in excess of federally mandated goals.     

New Approaches for Hormone-Receptor Positive Metastatic Breast Cancer

Overcoming endocrine resistance remains critical to further enhancing the benefit of existing endocrine therapies in estrogen receptor (ER) positive metastatic breast cancer. Preclinical research has significantly improved our understanding of molecular mechanisms associated with endocrine resistance. In turn, clinical research is focusing on designing trials that combine endocrine therapies with targeted inhibitors of specific signalling pathways that have been implicated in endocrine resistance. To date, first line studies have largely been disappointing, with many phase III trials failing to demonstrate a significant delay in endocrine resistance by the addition of a given targeted therapy. In contrast, the more successful trials have been performed in selected populations with acquired endocrine resistance. Numerous therapeutic agents are currently being tested in combination with endocrine therapies based on varying levels of preclinical data to support their use. In this review we provide the most recent advances in ER+ breast cancer, giving emphasis to recently concluded or ongoing trials with the potential to change current clinical practice.     

Metastatic Prostate Cancer

The treatment of metastatic prostate cancer is based upon the principle that prostate cancer growth is stimulated by androgens. Androgen ablation therapy is an effective treatment for metastatic prostate cancer. The timing of initiation of androgen ablation and the role of combined androgen blockade have been investigated. The utilization of intermittent androgen suppression offers the potential for improved quality of life. Intermittent therapy for metastatic disease is being compared with continuous therapy in an ongoing cooperative group trial. Recent studies have defined the evolving role of cytotoxic chemotherapy in hormone-refractory disease.     

Hormone-refractory Prostate Cancer

Opinion statement For more than five decades, the preferred treatment for advanced prostate cancer has been suppression of androgen production by medical or surgical castration. However, all patients treated with androgen deprivation eventually develop resistant disease as manifested by increasing prostate-specific antigen levels, progressive disease on imaging studies, and ultimately worsening symptoms. The treatment of patients with hormone-refractory prostate cancer (HRPC), once thought to represent a relatively futile endeavor, has changed significantly in the past several years with the development of new therapeutics. One of the most important new treatment strategies involves secondary hormonal manipulation after the failure of primary androgen depri-vation; this approach is predicated on the recognition that HRPC is a heterogenous disease. Some patients may respond to alternative hormonal interventions despite the presence of castrate levels of testosterone. Furthermore, the application of chemother-apeutic regimens has provided viable treatment options for patients with HRPC.     

Advanced Prostate Cancer

Prostate cancer is the second leading cause of cancer death in men. Screening and advances in the treatment of localized disease may help reduce the burden of this disease. Unfortunately, despite progress in these areas, a significant number of men continue to present with advanced disease or to develop advanced disease at some time after treatment for their local disease. The treatment of advanced or metastatic prostate cancer is systemic therapy. The mainstay of systemic therapy for prostate cancer has been hormonal therapy for many years. Orchiectomy and estrogens were the initial hormonal therapies used. Over the past several years a number of agents have been shown to produce similar rates of disease control with improved tolerability profiles. The luteinizing hormone releasing hormone (LHRH) agonists are the most frequently used hormonal agents in prostate cancer. Antiandrogens have also been used as single agents, or in combination with LHRH agonists. Soon LHRH antagonists may come into clinical practice. When hormone therapy fails to control this disease, chemotherapy is the next line of treatment. Over the past several years, several newer chemotherapy agents have renewed enthusiasm for this avenue of treatment in prostate cancer. Novel agents utilizing a variety of recently identified mechanisms of action are likely to become clinically relevant in the treatment of prostate cancer over the next few years. This review seeks to address the major issues relating to the pharmacological treatment of advanced prostate cancer.