323,180 research outputs found
Efficacy of signal transduction inhibition in advanced prostate cancer
No full textThe overall survival of patients with metastatic Castration-resistant Prostate Cancer (CRPC) is discouraging low (Attar et al., Clin Cancer Res 15:3251-3255, 2009). CRPC exhibit tremendous heterogeneity and complexity, reflecting the dysregulation of multiple patterns, mutations, and pathways, combined in a different manner in each patient. Of course, the impact of this heterogeneity on outcome and response to therapy is tremendous. It is therefore an urgent need to identify the multiple cellular pathways cooperatively promoting progression of the single cases of CRPC for successfully therapeutically target them. Several molecular pathways have been implicated in prostate cancer progression from localized androgen-sensitive disease to lethal CRPC. In this article, we will review some of the recent findings on signal transduction studies performed to identify novel targets and alternative chances of therapeutic intervention for advanced prostate cancer
Resistance to castration - Resistance to drugs
No full textUp to 70 % of newly diagnosed patients with advanced prostate cancer (PCa) will progress to castration-resistant prostate cancer (CRPC) and, in most cases (from 50 to 70 %), will develop hematogenous bone metastasis. Once PCa cells spread to the skeleton, cancer-related death becomes inevitable, with a death burden of more than 28,000 cases in 2012, in the United States (Semenas et al, Curr Drug Target, 13(10):1308-1323, 2012). To date, therapeutic regimens are unable to revert this fatal progression (Semenas et al, Curr Drug Target, 13(10):1308-1323, 2012). Thus, PCa bone metastatic prostate cancer still represents a major clinical challenge. Prostate cancer biology is tightly linked to AR, which regulates epithelial proliferation and suppresses apoptosis both in normal and in cancer prostate tissue, and is involved in the progression of the disease toward a castration-resistant state (Hodgson et al, World J Urol, 30(3):279-285, 2012). Our knowledge of the molecular mechanisms, responsible for the acquired resistance to ADT in prostate cancer, has exponentially progressed during the last years. For instance, we have recently learnt that it may be associated with the occurrence of AR splicing variants (Hu et al. 2011). Surgical castration has shown to induce regression of advanced disease 40-years before the cloning of androgen receptor (AR) (Huggins et al, Arch Surg, 43:209-223, 1941; Lubahn et al, Science, 240:327-330, 1988). Since then, hormonal therapy was held over as the main available therapeutic option for aggressive prostate cancers. In the last decade, however, chemotherapy was introduced to targeting the epithelium of metastatic, hormone-resistant prostate cancer (Pinto et al, Tumour Biol, 33(2):421-426, 2012; Hodgson et al, World J Urol, 30(3):279-285, 2012). The cytotoxic conventional drug Docetaxel was approved by the Food and Drug Administration in 2004, and still represents the standard first-line treatment for patients with castration-resistant prostate cancer (CRPC) (Sartor et al, Oncologist, 16(11):1487-1497, 2011). It produces sensible palliative effects on bone-metastasis-related symptoms, but prolongs only modestly the survival of patients (Hodgson et al, World J Urol, 30(3):279-285, 2012; Tannock et al, N Engl J Med, 351:1502-1512, 2004; Petrylak et al, N Engl J Med, 351:1513-1520, 2004). Docetaxel acts mainly by inducing apoptosis of target epithelial cells. The common intrinsic defects of mCRPC in apoptosis pathways, such as BCL-2 overexpression and/or phosphatase and tensin homolog (PTEN) loss (Mathew, Dipaola, J Urol, 178:S36-S41, 2007; Galsky, Vogelzang, Ann Oncol, 21:2135-2144, 2010), may constitute the rationale of the unsatisfactory rate of cure attributable to this drug (Srigley et al, Histopathology, 60(1):153-165, 2012). In recent years, similar effects on survival have been demonstrated also for several other chemotherapeutic agents, such as mitoxantrone, etoposide, cisplatinum, vinblastine-estramustine and taclitaxel. Following progression after treatment with docetaxel, new cabazitaxel (XRP6258)-prednisone treatment regimens have led to a significantly longer overall survival, and other novel agents are currently being evaluated, including the cell-based immunotherapy sipuleucel-T, the androgen biosynthesis inhibitors abiraterone acetate and MDV3100, the chemotherapic Cabazitaxel, as well as the radionuclide alpharadin/Radium 223 (bone microenvironment targeting agents) (Sartor et al, Oncologist, 16(11):1487-1497, 2011; Liu et al, Front Endocrinol (Lausanne), 3:72, 2012; Antonarakis, Armstrong, Prostate Cancer Prostatic Dis, 14(3):206-218, 2011). To date, they seem to offer a survival advantage to patients, and look promising to improve the prognosis of metastatic CRPC. However, the real clinical benefit of these systemic therapies remains still transient, probably due also to the well-known clonal heterogeneity of advanced prostate cancers, and the overall survival of patients that holds frustratingly steady. The high cost of these therapies and the increasing complexity of clinical decision making, further underscore the need to multiply the efforts to develop more potent chemotherapy agents and/or novel AR/inhibitors agents that may better overcome resistance mechanisms to existing therapies (Liu et al, Front Endocrinol (Lausanne), 2012; Hodgson et al, World J Urol, 30(3):279-285, 2012; Armstrong, George, Urol Oncol, 26:430-437, 2008; Schrijvers et al, Adv Ther, 27:285-296, 2010). Several recently developed drug candidates, directed against the metastatic cancer microenvironments or niches, show promising results in this direction (Hodgson et al, World J Urol, 30(3):279-285, 2012). The efficacy of the standard-of-care therapeutic intervention directed to mCRPC will be greatly improved by our increasing understanding of molecular mechanisms of the acquired resistance to ADT and chemotherapy, which is expected to provide valuable insights also to new unfailing biomarkers of resistance, therapeutic response and disease progression of prostate cancer, allowing us to personalize the therapy for the single patients with mCRPC (Liu et al, Front Endocrinol (Lausanne), 3:72, 2012; Antonarakis and Armstrong, Prostate Cancer Prostatic Dis, 14(3):206-218, 2011). The knowledge of the molecular mechanisms underpinning prostate cancer progression is changing dramatically our therapeutic approach to its advanced, metastasizing phase, opening up the chance to design and develop novel agents targeting the multiple pathways responsible for the lethal cancer phenotype, in a more efficient and safer manner (Corcoran and Gleave, Histopathology, 60(1): 216-231, 2012)
Crossroads of signaling pathways
No full textAs studies on PC progression continue to uncover a growing number of crosstalks and co-occurrences of mutations and epigenetic alterations, new drugs are getting approved bringing significant changes in the treatment paradigm of these tumors. This chapter recapitulates the best known examples of molecular interactions potentially targetable to achieve these therapeutic evolutionary changes, to allow a better control of PC which, in 2012 alone, has still killed more than 28,000 men, in USA (Siegel et al, CA Cancer J Clin, 62:10-29, 2012; El-Amm, Aragon-Ching, Ther Adv Med Oncol, 5(1):25-40, 2013
Molecular determinants of cancer-related inflammation
No full textTumor cells communicate with the cells of their microenvironment via a series of molecular and cellular interactions to aid their progression to a malignant state and ultimately their metastatic spread. Of the cells in the microenvironment with a key role in cancer development, tumor associated macrophages (TAMs) are among the most notable. Tumor cells release a range of chemokines, cytokines and growth factors to attract macrophages, and these in turn release numerous factors (e.g. VEGF, MMP-9 and EGF) that are implicated in invasion-promoting processes such as tumor cell growth, flicking of the angiogenic switch and immunosuppression (Rogers and Holen, J Transl Med 9:177, 2011
Counteracting hypoxia in radio-resistant metastatic lesions
No full textThe identification of hypoxia-regulated genes and proteins, has provided the basis for the generation of new hypoxia-targeted drugs, conceived to re-oxygenate hypoxic tumor areas. In patients with advanced metastasizing prostate cancer (PC), these kinds of drugs are expected to optimize the effect of radiotherapy, reducing also its side effects. Immunohistochemistry, DNA, proteomic and, tissue array profiling, are increasingly providing us with exciting data, that could lead to the formulation of pre-treatment multimarker tests able to identify the individualized tumor response profiles to radiotherapy, basing on the specific cancer tissue hypoxia pattern and degree (Bussink et al., Radiother Oncol 67:3-15, 2003). As an example, the recent discovery of the role of microRNA in PC tumor genesis points towards (Kulshreshtha et al., Cell Cycle 6(12):1426-1431, 2007) the, Inactivation of miRs affected by hypoxia as a promising synergistic therapeutic strategy for the radiotherapy-refractory subset of metastatic PC (Kulshreshtha et al., Cell Death Differ 15:667-671, 2008). This chapter aims to give an outlook of the main hot-topics concerning the new trends of hypoxia-targeted molecular therapies for advanced metastasizing prostate cancer
Targeting tumor angiogenesis
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Prostate Cancer: Shifting from Morphology to Biology
1 July 2013, Pages 221-231
Targeting tumor angiogenesis (Book Chapter)
Staibano, S.a , Ascierto, P.A.b
a Department of Advanced Biomedical Sciences, Faculty of Medicine and Surgery, University of Naples Federico II, via S. Pansini, n.5, Naples, Italy
b Unit of Melanoma, Cancer Immunotherapy and Innovative Therapy, Department of Melanoma, National Institute of Tumors Fondazione G. Pascale, Via Mariano Semmola 1, Naples, Italy
View references (66)
Abstract
Four decades after the seminal work of Judah Folkman, in 1971, cancer therapies based on the suppression of neo-angiogenesis (Folkman, N Engl J Med 285:1182-1186, 1971) are becoming a reality (Verheul et al., Clin Cancer Res 14(11):3589-3597, 2008). The shift toward the up-regulation of pro-angiogenic factors secretion from both tumor and stroma, results from the interplay between endothelial cell activation, proliferation, extracellular matrix degradation, migration, canalization. It leads to the generation of a chaotic vascular vessels network in prostate cancer tissue (Ahmed and Bicknell, Method Mol Biol 467:3-24, 2009), which can be detected also by modern imaging techniques based on magnetic resonance, ultrasound, and nuclear imaging through targeting of key angiogenic factors (Russo et al., BJU Int 110(11 Pt C):E794-E808, 2012). This hopefully will lead to further improvements in prostate cancer diagnosis and staging. Preclinical evidence indicates that angiogenesis inhibitors can improve the efficacy of conventional cytotoxic agents mainly by normalizing tumor blood flow, thus improving drug delivery. Although significant biological activity of most vascular growth factors-interfering agents is demonstrated in preclinical models, single-agent activity is almost universally poor (Aragon-Ching et al., J Oncol 2010:361836, 2010). Due to the redundancy within the signalling pathways that promote angiogenesis, combining anti-angiogenic agents with different mechanisms of action seems likely to significatively potentiate their therapeutic efficacy (Corcoran and Gleave 2012; Ellis and Hicklin, Nat Rev Cancer 8:579-591, 2008; Verheul et al., Cancer Chemother Pharmacol 60:29-39, 200
Metastatic dissemination
No full textIn spite of recent developments in diagnosis, staging and treatment, most patients with advanced prostate cancer will ultimately progress from androgen-sensitive to an irreversible castration-resistant disease. These androgen-independent cancers frequently give rise to widespread metastasis, dramatically reducing the median survival of patients (Tannock et al, N Engl J Med, 351(15):1502-1512, 2004) and accounting for more than 32, 000 deaths/year in USA (Jemal et al, CA Cancer J Clin, 60:277-300, 2010), which correspond to over 90 % of PC related mortality (Man, Gardner, Int J Biol Sci, 4(4):246-258, 2008). It is a common belief that cancer metastasis result from a multi-stage nonrandom process characterized by intricate interactions between cancer cells and the host microenvironment, leading to the detachment of cancer cells from their tissue of origin, their dissemination through the bloodstream and to invasion of the target metastatic site (Patel et al, Future Oncol, 7(11):1285-1297, 2011). Metastasis represents yet one of the most enigmatic aspects of prostate cancer pathogenesis, in which a cascade of proteolytic enzymes, inflammatory cytokines, growth factors, activated oncogenes, oxidative stress and hypoxia linked proteins and adhesion molecules, orchestrate a continuous loop that enable migrating cancer cells detached from the primary tumor bulk, to survive and proliferate in an adverse remote body microenvironment. In this chapter, we discuss the nature and alterations of the signaling pathways involved in the development of prostate cancer metastasis, reporting the current status of knowledge on the changes occurring either in prostate cancer cells and in tumor-associated stromal tissue, with particular emphasis to the process of epithelial-mesenchymal transition (phenotypic plasticity) and to the role of cancer stem cells in prostate cancer progression and metastasis. We will highlight, also, the emerging data concerning new therapeutic targets for treatment of metastatic prostate cancer that, while deserving further inquiry, look very promising to improve our chances to successful approach the advanced disease or, even, primarily reduce the risk of metastasis from castration-resistant prostate cancer (Vashisht, Bagler, PLoS One, 7(11):e49401, 2012
Synthetic lethality: Molecular co-targeting to restore the DNA repair mechanisms in prostate cancer cells
No full textResistance to anticancer radiation treatment has a strong negative impact upon morbidity and mortality related to prostate cancer (Liu et al., Radiother Oncol 88(2):258-268, 2008). This justifies the great interest in the advancing efforts toward the design of new molecularly-targeted agents which could improve the therapeutic ratio for aggressive prostate cancers via tumor radio-sensitization (Fan et al., Cancer Res 64(23):8526-8533, 2004). Tumor progression of prostate cancer is associated, as in most of human malignancies, with the sequential loss of function of genes that normally protect against DNA damage. Malignant prostate cells respond to both endogenous and exogenous DNA damage through complex signaling responses. Due to a specific genetic background, or in an acquired manner during tumor progression, PC cell clones show defect in either DNA single-strand break (SSB) and/or double-strand break (DSB) repair, and/or base damage repair (Stewart et al., Biochem Pharmacol 81(2):203-210, 2011), DSBs are the principal responsible for cell killing due to ionizing radiation (Ward 1988). A defective DNA double-strand break repair increases genetic instability of PC cells, could be considered as part of their mutator phenotype (Tyson et al., Prostate 67:1601-1613, 2007). During the last decades, it has emerged the concept of synthetic lethality (Chalmers et al., Semin Radiat Oncol 20(4):274-281, 2010). This concept derives from the observation that the use of a single inhibitor of a DNA repair enzyme leads to the selective killing of tumor cells, bearing a second DNA repair defect (Bryant et al., Nature 434(7035):913-917, 2005; Jones and Plummer, Br J Radiol 81(Spec No 1):S2-S5, 2008; Fong et al., N Engl J Med 361:123-134, 2009). To this end, PARP inhibitors are the well-known class of drugs that have recently been proposed to reach synthetic lethality in DNA repair-defective, radio-resistant prostate tumors. This chapter aims to provide a framework for understanding the recent therapeutic trends designed to overcome radioresistance in prostate cancer via synthetic lethality, we review what it is actually known about the structures and functions of the members of the PARP family of enzymes, outlining a series of open questions that should be addressed in the short time to better guide the development (and the safe clinical use) of PARP inhibitors as new anticancer agents for prostate cancer (Cybulski et al., Cancer Res 64:1215-1219, 2004; Stewart et al., Biochem Pharmacol 81(2):203-210, 2011
Non-Hodgkin's lymphoma in systemic sclerosis: case and literature review.
No full textThe occurrence of non-Hodgkin's lymphoma in systemic sclerosis is an uncommon event. In our scleroderma cohort, a case of primary gastric B-cell lymphoma was diagnosed in 2007. The patient was a 45-year-old woman suffering from late systemic sclerosis sine scleroderma in whom non-Hodgkin's lymphoma presented with progressive weight loss, later with gastrointestinal symptoms. Subsequently, we retrospectively analyzed the charts of 251 systemic sclerosis patients consecutively admitted to our Unit from 2000 to 2008 to search for other non-Hodgkin's lymphoma cases (prevalence, 0.49%). Then we performed a Pubmed search for "systemic sclerosis & non-Hodgkin's lymphoma," limited to the English language. Twenty detailed cases of such an association were found, pointing out the following: non-Hodgkin's lymphoma seems to be associated to old age, female sex, diffuse cutaneous subset and early disease; B-cell lymphoma subtypes are the majority; the interval between systemic sclerosis and lymphoma onset is usually short; systemic sclerosis could present as a paraneoplastic syndrome in some cases. We concluded that, although rare, the association of systemic sclerosis and non-Hodgkin's lymphoma may not be coincidental and the clinician should be aware of the risk for lymphoproliferative disorders in scleroderma patients. This is the first description of non-Hodgkin's lymphoma in systemic sclerosis sine scleroderma. The insidious onset of gastric lymphomas, mimicking the most common features of gastrointestinal involvement in systemic sclerosis is underlined
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