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Pharmacotherapy for Prostate Cancer: The Role of Hormonal Treatment

Prolactin in Breast and Prostate Cancer: Molecular and Genetic Perspectives

Abstract: Prostate and breast cancers affect millions of men and women, respectively. Advanced forms of the disease, which can no longer be controlled by hormonal disruption or chemotherapy, have very limited treatment options. Consequently, there is a major benefit to identify new targets for therapy in both types of cancer. The prolactin (PRL) signaling cascade, by virtue of its importance to the pathology of both diseases, has emerged as a potential treatment target. To date, several methods for antagonizing the PRL receptor (PRLR) and its signaling pathways have been developed which include protein-based and small molecule antagonists. However, a better understanding of the genetic and molecular characteristics of the PRL cascade is needed for the successful therapeutic application of antagonists. At the level of genetics, it is necessary to determine the functional significance of non-synonymous single nucleotide polymorphisms of the PRLR and their association with disease prevalence and severity. At the molecular level, a comprehensive knowledge of interactions of the PRL signaling pathway with other oncogenic molecules is warranted so as to identify beneficial combinatorial strategies. This review discusses multiple features of the PRL signaling cascade and how they can be exploited in the search for effective therapies for patients with breast and prostate cancers. ... Read more

Developing an Effective Gene Therapy for Prostate Cancer: New Technologies with Potential to Translate from the Laboratory into the Clinic

Abstract: Prostate cancer is the second leading cause of cancer-related deaths in men in the U.S. At present, no single or combination therapy has shown efficacy in decreasing disease progression in patients with metastatic disease. A potentially viable approach for treating late-stage prostate cancer is gene therapy. Adenoviruses (Ad) are the most commonly used mode of gene delivery, but progress using this vector has been hampered by concerns over the safety and practicality of viruses including conditionally replicating Ads (CRAds), particularly for intravenous delivery, and the inefficiency of non-viral transfection techniques. Major challenges for effective gene therapy using Ads are the limited infectivity of regular Ad serotype 5 (Ad5) and the inability to specifically deliver the therapeutic directly into diseased tissue without trapping in the liver or elimination by the immune system. The shortcoming in using Ad5 is mostly attributed to a reduction in Coxsackie-adenovirus receptors (CAR) on the surface of cancer cells, which can be mitigated by generating tropism-modified Ads permitting CAR-independent infection of tumor cells. The limitations of systemic gene delivery can now be overcome by using a novel targeted-delivery approach such as ultrasound (US) contrast agents (microbubbles) to deliver effective therapeutic reagents, Ads, or recombinant proteins, combined with ultrasound-targeted microbubble destruction (UTMD), to develop a site-specific therapy in immune competent transgenic mouse models. These unique strategies for enhancing the efficacy of gene therapy provide a direct path to translation from the laboratory into the clinic for developing an effective gene therapy of prostate cancer. ... Read more

Alternative Approaches to Prevent Androgen Action in Prostate Cancer: Are We There Yet?

Abstract: Prostate cancer (CaP) is the most frequently diagnosed cancer and the second leading cause of cancer deaths in men in the U.S. CaP deaths are due to failure of androgen deprivation therapy (ADT). ADT is the standard of care for non-organ confined CaP and inhibits action of androgen receptor (AR), which is necessary for the growth of CaP. ADT blocks AR activity by preventing either production of its ligands or interaction between AR and its ligands. Following an initial remission, almost all patients experience CaP recurrence during ADT. Remarkably, CaP that reemerges remains dependent on AR. This recognition has led to the recent development of novel treatment strategies that focus on alternative means to target ligand production and availability for AR. These therapies induce remission and offer moderate survival benefits but none are curative while all are associated with significant side effects. We propose that an alternative tactic to achieve the beneficial effects of ADT could be explored by targeting a different step in the AR signaling cascade, namely the biological consequences of AR activation. Insights in molecular regulation of AR function and genome-wide AR action could be used to develop therapeutic interventions that focus on eliminating only distinct AR-dependent biological processes responsible for aggressive CaP cell behavior. Such selective forms of ADT could be used alone or in combination with existing therapies to improve CaP therapeutic outcome in a stage-specific and personalized manner. ... Read more

Mitochondria, Prostate Cancer, and Biopsy Sampling Error

Abstract: Mitochondria and their associated genome are emerging as sophisticated indicators of prostate cancer (PCa) biology. Alterations in the mitochondrial genome (mtgenome) have been implicated in cell proliferation, metastatic behavior, androgen independence, as a signal for apoptosis, and as a predictor of biochemical recurrence. Somatic mutation patterns in complete mtgenomes are associated with prostate specific antigen levels (PSA) in PCa patients and a large-scale mtgenome deletion (3.4kb) is consistent with a prostate "cancerization" field effect. This review will focus on the biological characteristics of mitochondria and their direct clinical application to PCa. Mitochondrial science is currently influencing clinical PCa diagnostics and the rapid progress in this area indicates future, break-through contributions in the general field of oncology. ... Read more

Polyphenols Inhibit Indoleamine 3,5-Dioxygenase-1 Enzymatic Activity -- A Role of Immunomodulation in Chemoprevention

Abstract: Metastasis is one of the cancer hallmarks described by Hanahan and Weinberg. Emerging evidence shows that it requires interplays between cancer cells and micro-environmental biofactors. Indoleamine 3,5-dioxygenase-1 (IDO-1) produced by cancer, local lymph nodes, and satellite cells have been demonstrated as one of the biofactors. Aberrant IDO-1 activity has partially contributed to immunosuppressive environment by repressing T lymphocyte and natural killer cell activities, and activating regulatory T cells (Treg, CD4+CD25+). Clinical investigations further show a negative correlation between the enzyme activity and prognosis in patients with various cancer types. The findings suggest a possible role of IDO-1 inhibitor in restoring host anti-tumor immunity and attenuating cancer metastasis. Data from preclinical and phase I/II clinical studies with IDO-1 inhibitors support this hypothesis. Polyphenols as antioxidants are shown to exhibit anticancer activities. However, the underlying mechanism has not been entirely characterized. We recently found that certain flavone molecules profoundly inhibit the enzymatic activity of IDO-1 but not mRNA expression in human neuronal stem cells (hNSC) confirmed by cell-based assay and qRT-PCR. To further the investigation, we studied additional anti-cancer phytochemicals including chalcone, flavonol, isoflavone, and diterpene. Here we summarize the results and show that the inhibitory sensitivity depends on the molecular structure in the following order: apigenin > wogonin > chrysin > biacalein ~ genistein > quercetin. Curcumin and isoliquiritigenin (a chalcone) exhibited toxicity to hNSCs. Although oridonin (a diterpene) showed a null toxicity toward hNSCs, it repressed the enzymatic function only marginally in contrast to its potent cytotoxicity in various cancer cell lines. While the mode of action of the enzyme-polyphenol complex awaits to be investigated, the sensitivity of enzyme inhibition was compared to the anti-proliferative activities toward three cancer cell lines. The IC50s obtained from both sets of the experiments indicate that they are in the vicinity of micromolar concentration with the enzyme inhibition slightly more active. These results suggest that attenuation of immune suppression via inhibition of IDO-1 enzyme activity may be one of the important mechanisms of polyphenols in chemoprevention or combinatorial cancer therapy. ... Read more

Drug Profile: Plenaxis

Other Names: abarelix.

Maker: Praecis Pharmaceuticals.

Disease Treated: Men with advanced prostate cancer who refuse surgical castration and yet for whom treatment with gonadotropin-releasing hormone (GnRH) agonist is not appropriate.

Approval Status: Approved by the U.S. FDA on November 25, 2003.

Chemical/Biological Nature: PLENAXIS is a synthetic decapeptide, consisting of both natural and artificial amino acids, of 1,416 daltons. It is supplied as a sterile powder which, when mixed with a 0.9% sodium chloride solution, becomes a depot suspension ready for intramuscular injections.

Administration: The single-dose vial of PLENAXIS contains 113 mg of anhydrous peptide and is ... Read more

Focal Therapy for Prostate Cancer: Opportunities and Uncertainties

Abstract: Prostate cancer is the most common cancer and the second most common cause of cancer-related death in men. Screening with prostate specific antigen (PSA) has led to a clinical and pathological stage migration such that currently most men diagnosed with prostate cancer have clinically localized disease potentially offering opportunity for curative intervention. On the other hand, the benefit of radical therapy in terms of reducing overall mortality in PSA-screened populations has been controversial with concerns being raised about over-diagnosis and over-treatment. Treatment of prostate cancer is associated with risk and complications that negatively affect the quality of life of men with localized disease. Recently, a new treatment paradigm has been proposed which is called focal therapy, defined as an individualized treatment by which only known disease is targeted and ablated while preserving normal tissue. This review will attempt to describe the opportunities and uncertainties behind this proposed paradigm shift. ... Read more

Stereotactic Body Radiation Therapy (SBRT) for Genitourinary Malignancies

Abstract: Stereotactic body radiation therapy (SBRT) is a novel treatment modality in radiation oncology that delivers a very high dose of radiation to the tumor target with high precision using single or a small number of fractions. SBRT is the result of technological advances in patient/tumor immobilization, image guidance, and treatment planning and delivery. This modality is safe and effective in both early stage primary cancer and oligometastases. Compared to the use of stereotactic radiosurgery for other tumor sites, SBRT is slow to be adopted in the management of genitourinary malignancies. There are now emerging data that show the safety and efficacy of this treatment modality in genitourinary (GU) malignancies especially in prostate cancer and renal cell carcinoma. Preclinical data, clinical experience, and challenges are reviewed and discussed. ... Read more

GM-CSF-Secreting Vaccines for Solid Tumors: Moving Forward

Abstract: Cancer vaccines consisting of intact tumor cells genetically modified to secrete the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) have undergone extensive preclinical development. These vaccines induce the massive accumulation of dendritic cells at the intradermal injection site, which engulf, process, and present tumor antigens to activate tumor-specific T cells. Early phase clinical testing demonstrated promising evidence of safety and bioactivity, although initial phase III clinical trials were unsuccessful. Together, the preclinical and clinical data argue for the continued clinical development of these vaccines, integrating them with standard and novel cancer therapeutics that enhance vaccine activity by overcoming immune tolerance and suppression, and/or augmenting co-stimulatory pathways of T cell activation. ... Read more

Prostate Specific Membrane Antigen -- A Target for Imaging and Therapy with Radionuclides

Abstract: Prostate cancer continues to represent a major health problem, and yet there is no effective treatment available for advanced metastatic disease. Thus, there is an urgent need for the development of more effective treatment modalities that could improve the outcome. Because prostate specific membrane antigen (PSMA), a transmembrane protein, is expressed by virtually all prostate cancers, and its expression is further increased in poorly differentiated, metastatic, and hormone-refractory carcinomas, it is a very attractive target. Molecules targeting PSMA can be labelled with radionuclides to become both diagnostic and/or therapeutic agents. The use of PSMA binding agents, labelled with diagnostic and therapeutic radio-isotopes, opens up the potential for a new era of personalized management of metastatic prostate cancer. ... Read more

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