Finding the place of histone deacetylase inhibitors in prostate cancer therapy

Histone deacetylase inhibitors (HDACIs) are showing promise as therapeutic agents for hematological malignancies and solid tumors. In the case of prostate cancer, HDACIs are effective at inhibiting proliferation and inducing apoptosis in a range of in vitro and in vivo experimental models. Recent studies have revealed that the actions of HDACIs in prostate cancer cells extend beyond regulation of histone acetylation and affect proteins involved in maintaining cellular homeostasis and tumor progression, including the androgen receptor, p21(WAF1) and VEGF. The broad spectrum of HDACI targets has allowed rational design of combinations with other therapeutic agents to target multiple pathways involved in prostate cancer progression, including angiogenesis and androgen signaling. In particular, synergistic inhibition of prostate cancer cell growth has been demonstrated using HDACIs in combination with radio- and chemo-therapy, Apo2L/TRAIL, angiogenesis inhibitors, heat-shock protein 90 inhibitors and androgen receptor antagonists. This review examines the current understanding of the actions of HDACIs in prostate cancer cells, both in a laboratory and a clinical context and discusses the potential utility of combination strategies for the treatment of prostate cancer.     

The hurdle of antiandrogen drug resistance: drug design strategies

Introduction: Prostate cancer is the second most common cancer death in men after lung cancer, due to distant metastases. While distant prostate cancer is typically castrate resistant, it is not necessarily androgen independent. For this reason, a review of the literature regarding the pathways involved in androgen signaling and therapeutic regimens to treat distant metastases is beneficial to increasing the survival rate of prostate cancer patients.

Areas covered: In this article, the author reviews the literature from the past decade covering metastatic hormone refractory prostate cancer with the aim to examine and identify pathways, therapeutic targets and current therapies for treating castrate-resistant disease. As this area is lacking, the author aims to provide the reader with knowledge of the molecular consequences of castrate resistant prostate cancer, the current treatment paradigms and future directions.

Expert opinion: While there have been advances in the treatment of castrate resistant prostate cancer, only minimal advances have been made in overall survival rate. Due to aberrant mutations and activation in the androgen receptor gene, and the complexity of cell signaling within prostate cancer, the androgen receptor should remain a main target for drug discovery efforts. This author believes that designing compounds that will reduce the activation of the androgen receptor may hold the key to a cure in the future.     

Src kinase inhibitors: an emerging therapeutic treatment option for prostate cancer

Importance of the field: Once prostate cancer becomes castration-resistant, bone metastases are a significant problem and treatment options are limited. As a result, there is a need for more effective therapies that have antitumor and anti-bone metastatic effects. Because Src and Src-family kinases (SFKs) are involved in multiple signaling pathways central to prostate cancer development, progression, and metastasis, in addition to normal and pathologic osteoclast activities, Src inhibition represents a valid therapeutic strategy for investigation.

Areas covered in this review: Here, current treatment options for advanced prostate cancer, the preclinical rationale behind using Src inhibitors, emerging data from clinical trials of Src inhibitors in prostate cancer, and future therapeutic directions are described. Data published in peer-reviewed journals within the last 20 years or presented at recent European or American Society of Clinical Oncology conferences have been reviewed.

What the reader will gain: Readers will gain an insight into the development of therapeutic Src inhibitors, including dasatinib and saracatinib; an understanding of their effects on prostate cancer cells and the bone microenvironment; and emerging clinical data.

Take home message: Src is implicated in prostate cancer progression and metastasis, therefore treatment with Src inhibitors warrants further investigation.     

Emerging drugs for prostate cancer

Prostate cancer mortality usually occurs as a result of castrate resistant disease. Many approaches are currently being evaluated to improve the treatment of this condition. These include drugs that induce androgen deprivation, that is, LHRH antagonists; more active or less toxic chemotherapy agents; immunologic approaches, including passive and active immunization; drugs that target the androgen receptor and/or androgen synthesis; drugs that target specific pathways, including tyrosine kinase inhibitors, angiogenesis inhibitors, endothelin antagonists and matrix metalloproteinase inhibitors; and antioxidants and cell cycle inhibitors. Many of these agents seem promising. The rationale, biologic activity and therapeutic results of these emerging drugs are reviewed.     

Angiogenesis inhibitors in the treatment of prostate cancer

Importance of the field: Prostate carcinoma is the most common non-cutaneous malignancy in U.S. men. The efficacy of docetaxel and prednisone in metastatic castrate-resistant prostate cancer (mCRPC) has been shown to improve overall survival; however, its effect is not durable, highlighting the need for new therapies.

Areas covered in this review: We will review the development of some of the leading compounds with direct and indirect antiangiogenic activity in prostate cancer including antibodies to VEGF and its receptors, small-molecule inhibitors of downstream signaling, immunomodulatory drugs with antiangiogenic activity, and compounds thought to directly inhibit or destroy vascular endothelial cells.

What the reader will gain: The reader will gain a basic understanding of the role of angiogenesis in prostate cancer growth and metastasis. Current and potential targets of angiogenesis and their corresponding drugs under development for prostate cancer are discussed.

Take home message: There are now multiple early-phase clinical trials of antiangiogenic agents alone or in combination in prostate cancer. Several of these agents are now in Phase III development. Combined therapy with two antiangiogenic compounds may improve the activity of either compound alone. Multiple targets in the angiogenesis pathway continue to be elucidated and should remain an active area of investigation for the treatment of prostate cancer.     

Targeting TGF-β in prostate cancer: therapeutic possibilities during tumor progression

Background: TGF-β regulates prostate growth by inhibiting epithelial cell proliferation and inducing apoptosis through eliciting a dynamic signaling pathway. In metastatic prostate cancer, however, TGF-β serves as a tumor promoter. TGF-β engages Smad-dependent and Smad-independent mechanisms to exert its action. During prostate tumorigenesis, prostate cells exhibit loss or mutation of TGF-β transmembrane receptors. Increased production of TGF-β causes immunosuppression, extracellular matrix degradation, epithelia to mesenchymal transition and angiogenesis that promotes tumor cell invasion and metastasis. Objective: The molecular basis for effective therapeutic targeting of TGF-β must be directed towards the double-edge-sword nature of the cytokine: Inhibiting the TGF-β tumor promoter capabilities in advanced metastatic prostate cancer, although retaining the growth-inhibitory abilities exhibited in early stages of prostate tumorigenesis. Results/conclusion: The current understanding of the therapeutic possibilities of targeting TGF-β signaling during prostate tumor progression is built on preclinical studies. Studies targeting TGF-β signaling pathway for the treatment of several human malignancies include the use of neutralizing antibodies, antisense oligonucelotides and small molecule inhibitors of kinase activity of the receptor complex. This review focuses on exploiting the therapeutic potential of targeting TGF-β signaling in the context of its contribution to prostate cancer initiation and progression to metastasis.     

Focus on deacetylation for therapeutic benefit

Preclinical studies have demonstrated that several genes silenced in cancer cells can be re-expressed in their fully functional state by epigenetic modifiers such as DNA methyltransferase inhibitors and histone deacetylase inhibitors (HDACIs). While gene re-expression may be a reason for the success of HDACIs in preclinical and clinical studies, it is not the only factor. HDACIs display pleiotropic effects, including inhibition of cell cycle progression, differentiation, apoptosis and anti-proliferative effects. In addition, many studies have indicated that combining HDACIs with other agents results in an enhanced anti-proliferative effect. Structure-activity relationship studies of HDACIs with their substrates, histone deacetylases, have enabled design and synthesis of improved HDACIs. Due to their activity and perceived low toxicity, HDACIs have gained popularity as agents for clinical investigation. This review focuses on the cellular and biological effects of HDACIs, either alone or in combination with other agents. A brief summary on completed and ongoing cancer clinical trials is provided.     

Selective genetic analysis of myoma pseudocapsule and potential biological impact on uterine fibroid medical therapy

Introduction: Tumor-associated angiogenesis is one of the essential hallmarks underlying cancer development and metastasis. Anti-angiogenic agents accordingly aim to restrain cancer progression by blocking the formation of new vessels, improving the delivery of chemotherapeutic agents to the tumor site and reducing the shedding of metastatic cells into the circulation. This review article addresses some key issues in the use of angiogenesis inhibitors in cancer.

Areas covered: The authors review the complex interactions between cell signaling pathways involved in tumor angiogenesis, and focus in particular on the molecular mechanisms that may induce resistance to angiogenesis inhibitors. They will also discuss some novel therapeutic strategies evolving within anti-angiogenic therapy such as the targeting of VEGFR-3, endothelial integrins and hepatocyte growth factor-MET signaling.

Expert opinion: Although anti-angiogenic therapy is targeted at the non-malignant part of the tumor, the intricate network of growth promoting signaling pathways and in particular the redundancy when single pathways are targeted in endothelial cells represents a major therapeutic obstacle. A key challenge will be to develop more efficient inhibitors, combined with an individualized approach based on each tumor's own endothelial signaling profile. Furthermore, reliable biomarkers which pinpoint those patients that will benefit from anti-angiogenic therapy need to be identified.     

The role of HGF/c-Met signaling in prostate cancer progression and c-Met inhibitors in clinical trials

Introduction: An increasing number of basic, translational and clinical studies demonstrate the importance of the protein tyrosine kinase receptor, c-Met, in the progression of prostate cancer. c-Met is overexpressed in primary prostate cancers, further increased in expression in bone metastases and is associated with the development of castrate-resistant disease. Because of its importance as a target, c-Met inhibitors have reached clinical trial for advanced, castrate-resistant prostate cancer.

Areas covered: In this review, altered expression of c-Met and hepatocyte growth factor in prostate tumors and the microenvironment and how they contribute to growth and invasion of prostate cancer cells is described. Next, preclinical studies providing the support for use of c-Met inhibitors are discussed. Finally, early promising results from c-Met inhibitors in clinical trial, and future prospects for c-Met inhibitors in the treatment of advanced stage prostate cancer, are discussed.

Expert opinion: An emerging theme in treating metastatic prostate cancer is the requirement to target both the epithelial and stromal compartments. Results from clinical trials suggest that inhibitors of c-Met that block stromal-mediated c-Met activation in prostate tumors may be important therapeutic agents in at least a subset of patients with metastatic prostate cancer. However, as many of the inhibitors have multiple targets, the efficacy of targeting c-Met alone remains to be determined.     

Zibotentan for the treatment of castrate-resistant prostate cancer

Importance of the field: Patients with prostate cancer who have progression of their disease while on androgen deprivation therapy have limited therapeutic options. Docetaxel is currently the only agent that increases overall survival in patients with metastatic, castration-resistant prostate cancer; additional agents are needed.

Areas covered in this review: This review will describe the importance of endothelin-1 (ET-1) for growth of prostate cancer cells, development of bone metastases, and pain responses; the preclinical data for zibotentan, a specific inhibitor of the ET_A receptor; and the clinical development of atrasentan, a first-generation ET receptor inhibitor, and zibotentan, a more selective inhibitor of the ET_A receptor.

What the reader will gain: Readers will understand the importance of ET-1 as a novel pathway to target for patients with castration-resistant prostate cancer due to its association with prostate cancer growth, metastases to bone, and pain. Readers will learn about the preclinical and clinical development of zibotentan, including the promising Phase II results that have resulted in an extensive Phase III clinical trials program.

Take home message: Modulating the activity of ET-1 through the ET_A receptor is a novel target for treating patients with metastatic, castration-resistant prostate cancer. There are currently three ongoing Phase III trials with zibotentan, a selective ET_A inhibitor, to determine the effect of this agent on overall survival in these patients.     

作用于雄激素受体不同结合位点的前列腺癌治疗药物的研究进展

前列腺癌是最常见的男性泌尿生殖系统的恶性肿瘤。雄激素受体在前列腺癌的发生、发展中起着重要作用。目前,所有治疗前列腺癌的药物(包括第一代的氟他胺、比卡鲁胺、尼鲁米特和第二代的恩扎鲁胺)都与雄激素受体的配体结合口袋结合,并且这些药物有着相似的分子结构,这可能引起药物之间的交叉耐药。为了避免耐药性的产生,研究者们致力于发现雄激素受体上新的药物结合位点。除雄激素受体配体结合位点外,主要对作用于氮端结合位点上的第一活性功能区(AF1)、第二活性功能区(AF2)、AF2附近的第三结合功能区(BF3)和DNA结合位点(DBD)的药物进行综述。     

New therapies for castrate-resistant prostate cancer

Introduction: Prostate cancer is the second leading cause of cancer death in men in the USA, and most of these deaths will occur as a result of castrate-resistant prostate cancer (CRPC) that has progressed despite androgen deprivation therapy. There has been better understanding of castration resistance and molecular mechanisms of prostate cancer progression recently, leading to new treatment strategies.

Areas covered: This review focuses on emerging and new therapies for castrate-resistant prostate cancer, including hormonal therapy, immunotherapy and cytotoxic agents.

Expert opinion: New treatment strategies have been developed in recent years and, with improved understanding of advanced CRPC, additional targeted treatments are expected in the near future. Further cost effectiveness research of these treatments is warranted before dissemination of these promising agents.     

Anti-epidermal growth factor receptor drugs in cancer therapy

The epidermal growth factor receptor is a cell membrane growth factor receptor that plays a key role in cancer development and progression. Epidermal growth factor receptor-activated signalling pathways control cell proliferation, apoptosis, angiogenesis and metastatic spread in the majority of human epithelial cancers. Targeting the epidermal growth factor receptor represents a valuable molecular approach to cancer therapy. Promising strategies in clinical development include monoclonal antibodies which block ligand binding and small molecule inhibitors of the tyrosine kinase enzymatic activity which prevent epidermal growth factor receptor autophosphorylation and propagation of downstream intracellular signals. Several anti-epidermal growth factor receptor agents are in clinical development for cancer therapy. Among these, IMC-225 (cetuximab), a chimeric human-mouse monoclonal IgG1 antibody, OSI-774 (Tarceva^?) and ZD1839 (Iressa^?), two small molecule epidermal growth factor receptor-selective tyrosine kinase inhibitors, are currently in Phase II and III development as single agents or in combination with conventional therapies, such as radiotherapy or chemotherapy. Results from Phase I – II trials in advanced cancer demonstrate that these drugs have an acceptable tolerability and an interesting clinical activity in patients with a variety of tumour types.     

Implications of Bcl-2 and its interplay with other molecules and signaling pathways in prostate cancer progression

Introduction: Among several genetic alterations involved in the progression of prostate cancer, B cell lymphoma gene number 2 (BCL-2) is an important target molecule in the progression of androgen-independent prostate cancer (AIPC) after androgen ablation or castration. Nevertheless, the molecular mechanism of BCL-2 in prostate cancer progression remains elusive and controversial. In the current review, we discuss the critical role of BCL-2 in the carcinogenesis of prostate cancer with experimental evidences on the BCL-2 molecular networks in AIPC and androgen-dependent prostate cancer (ADPC) and subsequently suggest perspective research targeting BCL-2.

Areas covered: This review focused on the molecular implications of BCL-2 in association with other molecules and signaling pathways involved in the progression and carcinogenesis of prostate cancer.

Expert opinion: BCL-2 plays a pivotal role in the progression of AIPC than in ADPC since androgen represses BCL-2. BCL-2 acts as a pro-survival molecule in association with androgen-related signaling in the progression of ADPC, while BCL-2 upregulation, PTEN loss, PI3K/AKT phosphorylation and receptor tyrosine kinase (RTK) activation are primarily involved in AIPC. To identify more effective prostate cancer therapy, further mechanistic studies are required with BCL-2 inhibitors in AIPC and ADPC, considering a multi-target therapy against BCL-2 and its related signaling.     

SRC family nonreceptor tyrosine kinases as molecular targets for cancer therapy

The Src family of kinases has nine known members, all of which are nonreceptor tyrosine kinases involved in signal transduction in both normal and cancer cells. Interest in these kinases has increased recently because of the development, initial clinical success, and low toxicity of pharmacologic inhibitors. c-Src is the best-studied member of the Src family and the one most often implicated in cancer progression. c-Src has multiple substrates that lead to diverse biologic effects, including changes in proliferation, motility, invasion, survival, and angiogenesis. c-Src has been most extensively studied in colon cancer where correlative and direct experimental evidence has shown that it mediates several aspects of cancer cell progression. c-Src has a similar role in multiple tumor types, including pancreatic cancer, breast cancer, lung cancer, head and neck squamous cell carcinoma, and prostate cancer. Several inhibitors of the Src family kinases are in clinical development; three are currently being studied in clinical trials. Initial data from these trials suggest that these agents are well tolerated. Future clinical development of these inhibitors will include trials in patients with solid tumors and of combination therapy.     

Current status and future prospects for anti-angiogenic therapies in cancer

Background: Angiogenesis is essential for tumour growth and development and since the pioneering work of Judah Folkman several anti-angiogenic strategies have now been successfully employed. Objective: This article aims to present a detailed review of current knowledge of the main pathways involved in angiogenesis, the strategies employed for inhibition and the current status of angiogenesis inhibitors in therapeutic use. Methods: A systematic review of the literature was undertaken including angiogenesis in cancer and angiogenesis inhibitors in pre-clinical and clinical trials. Conclusion: While angiogenic inhibitors are now in clinical use, their limited benefits mean we must urgently develop strategies to improve the efficacy of this approach.     

Novel therapeutic strategy for breast cancer: mammalian target of rapamycin inhibition

Background: Mammalian target of rapamycin (mTOR) plays a central role in regulating cellular protein synthesis. Dysregulation of mTOR signaling pathway is strongly associated with tumorigenesis, angiogenesis, tumor progression and drug resistance. Inhibition of mTOR might not only promote cell cycle arrest, but also sensitize resistant cancer cells to chemotherapeutic and other targeted agents. Objective: To review and summarize the mechanism of mTOR on regulation of protein synthesis and latest clinical data, and to discuss the novel therapeutic strategy for the use of mTOR inhibitors in the treatment of breast cancer. Methods: A review of published literatures and conference abstracts obtained from MEDLINE, American Society of Clinical Oncology Meeting and San Antonio Breast Cancer Symposia proceedings for results of previous preclinical and latest clinical studies of mTOR inhibition in breast cancer was performed. Conclusions: mTOR inhibitors seemed to be potentially useful for the treatment of breast cancer with acceptable safety profile. The challenge remains the identification of suitable candidates with different phenotypes. More structured studies incorporating molecular, clinical and translational research need to be initiated. Future research on mTOR inhibitors for breast cancer should focus on the evaluation of optimal schedule, patient selection and combination strategies to maximize the use of this new class of targeted agents.     

Cholesterol as a Potential Target for Castration-Resistant Prostate Cancer

Advanced prostate cancer (CaP) is often treated with androgen deprivation therapy (ADT). Despite high initial success rates of this therapy, recurrence of the cancer in a castration-resistant (CRPC) form is inevitable. It has been demonstrated that, despite the low levels of circulating androgens resulting from ADT, intratumoral androgen levels remain high and androgen receptor activation persists. Recently, it was discovered that de novo androgen synthesis is occurring within the tumor cells themselves, thus providing a potential mechanism for the high endogenous concentrations. A common upstream precursor in this steroidogenic pathway is cholesterol. For many decades, the breakdown of cholesterol homeostasis in cancer has been the focus of research, but this was largely to elucidate its involvement in maintaining membrane integrity and cell signaling. De novo steroidogenesis has provided a new avenue for cholesterol research and reinforces the importance of understanding the mechanisms that lead to the alterations in cholesterol regulation in the progression to CRPC. The findings to date suggest that cholesterol homeostasis is altered to support de novo androgen synthesis and appear to facilitate disease progression. We further propose that a better understanding of the link between cholesterol and de novo androgen synthesis in CaP progression may provide opportunities for novel therapeutic intervention, namely via eliminating sources of the precursor cholesterol. This review summarizes the implications of cholesterol dysregulation in CaP and particularly in the post-ADT castration-resistant state, as well as the potential implementation of novel therapies targeting these cholesterol sources.     

Manipulation of the nerve growth factor network in prostate cancer

Autocrine and paracrine events regulated by nerve growth factor (NGF) and relevant receptors (low- and high affinity; p75 neurotrophin receptor [p75(NTR)] and TrkA, respectively) seem to play a significant role in prostate carcinogenesis. Studies reveal that p75(NTR) is both a tumor suppressor of growth and a metastasis suppressor of human prostate cancer cells. Furthermore, p75(NTR) is progressively lost during prostate carcinogenesis. An imbalance between p75(NTR) and tropomyosin receptor kinase A (TrkA)-mediated signals may be involved in the progression of prostate cancer through increased proliferation and reduced apoptosis. The antiproliferative and apoptotic effects of GnRH analogs in prostate cancer cells may be mediated by altering the TrkA:p75(NTR) NGF receptor ratio. Administration of NGF induces a reversion of the androgen-independent/androgen receptor-negative prostate cancer cell lines to a less malignant phenotype. Finally, Trk inhibition is a novel, attractive and rational approach for prostate cancer therapy. This review unravels the NGF 'circuitry' in prostate cancinogenesis for relevant pharmacologic manipulation to lead to the development of novel therapeutic agents.