Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 9, Issue 10, 2009

Prostate cancer is the leading non-cutaneous cancer among American men. While most prostate cancers are diagnosed in the early stages and are potentially curable, a subset of men will experience biochemical relapse or manifest with metastatic disease. Treatment of metastatic prostate cancer continues to be an area of increased unmet need. As such, novel therapeutic agents are being developed. Up until recently, hormonal therapy has been the cornerstone of treatment for metastatic prostate cancer. Results from cytotoxic chemotherapy had been disappointing until the advent of taxane use, making docetaxel and prednisone the standard first line of treatment for metastatic castrationresistant prostate cancer today. However, limited therapy exists after disease progression from the use of taxanes. Several promising fields of investigation and agents are currently in development, including angiogenic/tyrosine kinase inhibitors, androgen receptor manipulation, immunologic/vaccine strategies, prostate cancer stem cells, bone-targeting agents, and novel cytotoxic compounds, provide interesting insights into molecular targets and rational drug design. In this issue, Lee and Aragon-Ching provide background on the use of cytotoxic chemotherapy as the foundation for treatment of metastatic castration-resistant prostate cancer, with alternative second-line chemotherapeutic agents and promising novel cytotoxics in development. Madan and Dahut provide data on the rationale for using angiogenic inhibitors and promising agents in development for targeting the prototype, vascular endothelial growth factor and other ligands. Similarly, thalidomide and its analogues have been utilized in the treatment of prostate cancer. Sissung et al. provide provocative data on the mechanism of action, metabolites, and novel analogues in preclinical and clinical development. Metastatic prostate cancer frequently involves bone. Mohammad, et al. detail the bone microenvironment, animal models of bone metastases, along with the development of bone-targeted therapies that are critical to the treatment of prostate cancer. The most expansive area of molecular targeting in oncology has been the development of a plethora of tyrosine kinase inhibitors. Limvorasak and Posadas provide a comprehensive review of preclinical and clinical evaluation of tyrosine kinase inhibitors for prostate cancer. Androgen receptor signaling also proves to be an important pathway of treating prostate cancer both in the pre- and post-chemotherapy setting, and Sharifi provides insights into the mechanisms of resistance to hormonal therapies, along with strategies and investigational agents for overcoming it. Various immunotherapeutic strategies and exciting results from mature clinical data are presented by Arlen and Gulley, with the conclusion that immunotherapy's time has finally come. A major advance in cancer biology has been the identification cancer stem cells as a minor component of the tumor but a critical subset that is resistant to chemotherapy. Crea, et al. describe the identification and biology of prostate cancer stem cells and discuss investigational agents that specifically target this important population of tumor cells. We hope that the readers of this thematic issue will find these concise reviews of relevant anti-cancer drugs in development with a special focus on cytotoxic agents, hormonal therapies, immunotherapies, antiangiogenesis agents, thalidomide analogs, bone targeting agents, kinase inhibitors and stem cell targeting agents, used in the treatment of prostate cancer, valuable and useful, for the research and treatment of men with prostate cancer.

Prostate cancer is the most common non-cutaneous cancer among men in the United States. Most will be diagnosed at an early stage, but a significant number will still develop metastatic castration resistant disease. Docetaxel has demonstrated improved quality of life and overall survival in metastatic castration-resistant prostate cancer but virtually all patients will ultimately become refractory to taxane therapy. Second-line options are limited and new effective chemotherapeutic agents or combinations are needed in this setting. This review will focus on cytotoxic compounds in clinical investigation either in combination with taxanes in the first or second-line setting and other novel compounds, such as platinums and microtubule-targeting agents that are in active clinical investigation.

Prostate cancer is a major cause of cancer-related death in men. Prostate cancer is an androgen-responsive tumor and the treatment of advanced prostate cancer involves hormonal therapy. First-line treatment for advanced prostate cancer is androgen deprivation therapy (ADT), usually with agents that suppress gonadotropins through a pituitary mechanism. Gonadotropin-releasing hormone agonists and antagonists both suppress gonadal release of testosterone, although their activity profiles vary. ADT down-regulates androgen receptor (AR) transcriptional activity in the tumor but the response in metastatic disease is transient and tumors eventually progress as castration-resistant prostate cancer (CRPC). Although serum testosterone concentrations decline dramatically with ADT, CRPC growth remains largely dependent on AR activity. Secondary hormonal therapies are then often employed to further dampen AR-driven transcription. These secondary hormonal therapies either further deplete adrenal or intratumoral androgen synthesis, or directly and competitively antagonize AR. New hormonal agents with both of these mechanisms are in clinical trials and show promising activity in patients with CRPC. Abiraterone acetate is an inhibitor of CYP17, which is an enzyme required for the synthesis of all androgens and estrogens. MDV3100 is an AR antagonist that has a higher affinity for AR than any other AR antagonist in clinic use. In phase I and phase II clinical trials, both agents have significant activity. These agents and the promise of the development of others provide hope that more effective hormonal therapies may soon be offered to patients, which will improve clinical outcomes.

The use of vaccines as a potential therapeutic modality for the treatment of cancer has been extensively studied. Recent advances include identification and characterization of tumor-associated antigens, novel vaccine delivery systems, and the combination of vaccines with immune stimulants and other therapeutic modalities. Immunotherapy as a modality for treatment of prostate cancer has received significant attention. There are several characteristics of prostate cancer that make it an ideal target for immunotherapy. Prostate cancer's relative indolence allows sufficient time to generate immune responses, which may take weeks or months to mount. In addition, prostate cancer-associated antigens direct the immune response to prostate cancer cells, thus sparing normal vital tissue. This review focuses on promising new vaccines and novel perspectives in the treatment of prostate cancer.

Thalidomide is emerging as a potentially important therapeutic option in the treatment of metastatic prostate cancer. Although the mechanism of action of this agent remains elusive in malignancies of the prostate, recent data has indicated that thalidomide may play a role in inflammation, immunomodulation, and anti-angiogenesis. Lenalidomide (CC-5013), a thalidomide analogue with improved activity and safety profile in certain disease contexts, is in the early stages of development in prostate cancer. This review will provide the current status of the history, mechanism, metabolism, and clinical use of thalidomide in metastatic prostate cancer. It will also describe the mechanism and clinical use of lenalidomide as it pertains to malignancies of the prostate.

For many men, prostate cancer is an indolent disease that, even without definitive therapy, may have no impact on their quality of life or overall survival. However for those men who are either diagnosed with or eventually develop metastatic disease, prostate cancer is a painful and universally fatal disease. Testosterone-lowering hormonal therapy may control the disease for some time, but patients eventually develop resistance and progress clinically. At this point, only docetaxel has been shown to improve survival, so clearly additional therapeutic options are needed. Angiogenesis inhibition is an active area of clinical research in prostate cancer. Without angiogenesis, tumors have insufficient nutrients and oxygen to grow larger than a few millimeters and are potentially less likely to metastasize. In prostate cancer in particular, angiogenesis plays a significant role in tumor proliferation, and markers of angiogenesis appear to have prognostic significance. Several different compounds have been developed to inhibit angiogenesis, including monoclonal antibodies, multitargeted kinase inhibitors, and fusion proteins. In addition, more traditional agents may also have an impact on angiogenesis. Trials studying antiangiogenic agents have been conducted in localized and advanced prostate cancer. There are several large, ongoing phase III trials in metastatic castration-resistant prostate cancer. The findings of these and future studies will ultimately determine the role of angiogenesis inhibitors in the treatment of prostate cancer.

Bone is the most common site for metastasis of advanced prostate cancers. Once housed in the skeleton, tumors are incurable and cause protracted morbidity, and bone metastases may contribute to mortality through unknown mechanisms. Bone provides a unique microenvironment whose local interactions with tumor cells offer novel targets for therapeutic interventions. Many standard cancer treatments cause bone loss, which may aggravate skeletal metastases, although this is preventable with approved agents. Improved bonetargeted treatments can decrease the serious skeletal morbidities associated with metastatic prostate cancer and may in the future improve overall survival. The development of such treatments requires preclinical evaluation in animal models of prostate cancer growth in bone.

Prostate cancer is a significant public health problem around the world. Once a patient has disease that is no longer addressable by local means, the cancer is considered incurable. Therapeutic goals at this point include not only extension of survival but also alteration of the natural history which may otherwise lead to significant pain and morbidity from the disease process- all related to metastases. While effective systemic therapies do currently exist, their roles are considered limited for many patients. Given the overwhelming incidence and annual mortality figures related to prostate cancer, there continues to be an urgent need for therapeutic advances. Protein kinases have emerged as “druggable” therapeutic targets as they control a multitude of basic cellular activities, including growth, survival, proliferation, differentiation and apoptosis. Several of these kinases have oncogenic properties as in the setting of malignancy they may be overactive and/or dysregulated leading to the excessive proliferation and motility typical of cancer cells. Small molecule inhibitors have shown efficacy in several tumor models and are actively being studied in prostate cancer. This review summarizes historical and contemporary studies evaluating kinase inhibitors in the treatment of prostate cancer.

Cancer stem cells are the sub-population of cells present within tumors responsible for tumorigenesis. These cells have unique biological properties including self-renewal and the ability to differentiate. Furthermore, it is thought that these cells are more resistant to conventional chemotherapy and, as a result, are responsible for patient relapse. We will discuss the identification of prostate cancer stem cells, their unique properties and how these cells may be targeted for more efficacious therapies.

Improvement in the outcome of cancer patients who are refractory to currently available treatments relies on the development of target-directed therapies. One group of molecular targets with potential clinical relevance is a set of protein tyrosine kinases encoded mostly by proto-oncogenes and that are frequently deregulated in cancer. Glycogen synthase kinase 3β (GSK3β), a serine/threonine protein kinase, has emerged as a therapeutic target for common chronic diseases including type 2 diabetes mellitus, neurodegenerative disorders, inflammation and osteoporosis. This is based on its currently known functions and primary pathologic causalities. GSK3β has well characterized roles in the regulation of gene transcription and in oncogenic signaling. We have shown that deregulated GSK3β promotes gastrointestinal, pancreatic and liver cancers and glioblastomas. Furthermore, we have demonstrated that inhibition of GSK3β attenuates cancer cells survival and proliferation, induces cell senescence and apoptosis and sensitizes tumor cells to chemotherapeutic agents and ionizing radiation. This has led us to propose GSK3β as a potential therapeutic target in cancer. The anti-tumor effects of GSK3β inhibition are mediated by changes in the expression and phosphorylation of molecules critical to the regulation of cell cycling, proliferation and apoptosis and underlie the pathological role for GSK3β in cancer. Investigation of the mechanisms responsible for deregulation of GSK3β and the consequent downstream pathologic effects in cancer cells has shed light on the molecular pathways leading to tumorigenesis. This will allow exploration of novel therapeutic strategies for cancer that target aberrant GSK3β.

Lymphoid malignancies may affect the eye either as primary intraocular lymphomas (PIOL), or by secondary involvement of a nodal lymphoma. PIOL is a subtype of primary central nervous system (CNS) lymphoma and in up to 98% of the cases are non- Hodgkin's B cell lymphomas. PIOL may occur in isolation, without involvement of the CNS. They may affect both the vitreous and the retina, while secondary invasion predominantly affects the uvea. Both forms frequently masquerade as intraocular inflammation or uveitis. Systemic chemotherapy, alone or in combination with radiotherapy has been used in the past for the treatment of PIOL. Methotrexate and rituximab are immunomodulatory agents used in the treatment of cancer and autoimmune diseases. Recent reports have shown the intraocular safety and efficacy of both of these agents for the treatment of PIOL.