Browsing by Author "Aurilio, Gaetano"

Now showing 1 - 6 of 6
  • Thumbnail Image
    Item
    Androgen Receptor Signaling Pathway in Prostate Cancer: From Genetics to Clinical Applications
    (MDPI, 2020-12) Aurilio, Gaetano; Cimadamore, Alessia; Mazzucchelli, Roberta; Lopez-Beltran, Antonio; Verri, Elena; Scarpelli, Marina; Massari, Francesco; Cheng, Liang; Santoni, Matteo; Montironi, Rodolfo; Pathology and Laboratory Medicine, School of Medicine
    Around 80–90% of prostate cancer (PCa) cases are dependent on androgens at initial diagnosis; hence, androgen ablation therapy directed toward a reduction in serum androgens and the inhibition of androgen receptor (AR) is generally the first therapy adopted. However, the patient’s response to androgen ablation therapy is variable, and 20–30% of PCa cases become castration resistant (CRPCa). Several mechanisms can guide treatment resistance to anti-AR molecules. In this regard, AR-dependent and -independent resistance mechanisms can be distinguished within the AR pathway. In this article, we investigate the multitude of AR signaling aspects, encompassing the biological structure of AR, current AR-targeted therapies, mechanisms driving resistance to AR, and AR crosstalk with other pathways, in an attempt to provide a comprehensive review for the PCa research community. We also summarize the new anti-AR drugs approved in non-metastatic castration-resistant PCa, in the castration-sensitive setting, and combination therapies with other drugs.
  • Thumbnail Image
    Item
    Key Role of Obesity in Genitourinary Tumors with Emphasis on Urothelial and Prostate Cancers
    (MDPI, 2019-08-22) Santoni, Matteo; Cimadamore, Alessia; Massari, Francesco; Piva, Francesco; Aurilio, Gaetano; Martignetti, Angelo; Scarpelli, Marina; Di Nunno, Vincenzo; Gatto, Lidia; Battelli, Nicola; Cheng, Liang; Lopez-Beltran, Antonio; Montironi, Rodolfo; Pathology and Laboratory Medicine, School of Medicine
    Background: In human populations, a certain amount of data correlate obesity/body mass index (BMI) with urothelial cancer (UC) and prostate cancer (PCa) occurrence, however this is not fully elucidated at all stages of disease. In an attempt to shed light on uncertain areas in such field, in the present review we illustrate the main molecular mechanisms linking obesity and cancer, focusing on the correlation between obesity and tumor risk, disease progression and response to chemo- and immunotherapy in patients with UC and the predictive/prognostic role of obesity in PCa patients treated with the currently available therapeutic approaches. Methods: We did a large-scale literature search on existing scientific websites focusing on keywords "obesity", "body mass index (BMI)", "urothelial cancer", "prostate cancer", "docetaxel", "cabazitaxel", "abiraterone acetate", "enzalutamide", and "radium223". Results: Many adipocytes-induced molecules support tumor proliferation through activation of various cellular pathways. The available evidence in the postoperative setting do the role of BMI in oncological outcomes prediction still not completely clear. Likewise, in metastatic UC patients controversial results link the role of obesity/BMI with clinical outcomes of tumor response to chemotherapy. Adipose stromal cells recruitment, induced by PCa cells, from white adipose tissue to the tumor sites inducing cell invasiveness was associated with poor survival. Conflicting data, although more oriented towards a better survival outcome, resulted in obese patients treated with docetaxel. In PCa cell-lines a certain cabazitaxel chemo resistance adipose stromal cells (ASC)-mediated was demonstrated. In metastatic castration-resistant PCa patients with high BMI (>25 kg/m2) receiving abiraterone acetate there were significant worse survival outcomes, while in enzalutamide patients BMI did not affect survival outcome. In radium 223 patients higher BMI significantly correlated with favorable overall survival. Conclusions: The main focus of this review was to understand the interplay between obesity/BMI and UC/PCa. Several pathogenic cellular pathways exploring the issue are discussed, opening the way to challenging tailored treatments on the basis of BMI. Improving the knowledge of molecular connections between obesity and UC and PCa could favor the development of new therapies likely reducing chemo- and immunotherapy drug resistance.
  • Thumbnail Image
    Item
    Morphologic, Molecular and Clinical Features of Aggressive Variant Prostate Cancer
    (MDPI, 2020-05) Montironi, Rodolfo; Cimadamore, Alessia; Lopez-Beltran, Antonio; Scarpelli, Marina; Aurilio, Gaetano; Santoni, Matteo; Massari, Francesco; Cheng, Liang; Pathology and Laboratory Medicine, School of Medicine
    The term aggressive variant prostate cancer (AVPCa) refers to androgen receptor (AR)-independent anaplastic forms of prostate cancer (PCa), clinically characterized by a rapidly progressive disease course. This involves hormone refractoriness and metastasis in visceral sites. Morphologically, AVPCa is made up of solid sheets of cells devoid of pleomorphism, with round and enlarged nuclei with prominent nucleoli and slightly basophilic cytoplasm. The cells do not show the typical architectural features of prostatic adenocarcinoma and mimic the undifferentiated carcinoma of other organs and locations. The final diagnosis is based on the immunohistochemical expression of markers usually seen in the prostate, such as prostate-specific membrane antigen (PSMA). A subset of AVPCa can also express neuroendocrine (NE) markers such as chromogranin A, synaptophysin and CD56. This letter subset represents an intermediate part of the spectrum of NE tumors which ranges from small cell to large cell carcinoma. All such tumors can develop following potent androgen receptor pathway inhibition. This means that castration-resistant prostate cancer (CRPCa) transdifferentiates and becomes a treatment-related NE PCa in a clonally divergent manner. The tumors that do not show NE differentiation might harbor somatic and/or germline alterations in the DNA repair pathway. The identification of these subtypes has direct clinical relevance with regard to the potential benefit of platinum-based chemotherapy, poly (ADP-ribose) polymerase inhibitors and likely further therapies.
  • Thumbnail Image
    Item
    Narrative review: update on immunotherapy and pathological features in patients with bladder cancer
    (AME Publishing, 2021-03) Aurilio, Gaetano; Cimadamore, Alessia; Lopez-Beltran, Antonio; Scarpelli, Marina; Massari, Francesco; Verri, Elena; Cheng, Liang; Santoni, Matteo; Montironi, Rodolfo; Pathology and Laboratory Medicine, School of Medicine
    Over the last few years efficacy of immunotherapy using immune checkpoint inhibitors (ICI) has been investigated in patients with bladder cancer (BC) at all stages. The present article aims to assess new therapeutic options with emerging agents in BC patients, shedding light on ICI-based treatments encompassing all disease stages, from non-muscle invasive (NMIBC) to muscle-invasive (MIBC) BC, concluding with metastatic MIBC. In bacillus Calmette-Guerin (BCG) unresponsive patients with carcinoma in situ, pembrolizumab has been recently approved. In the neoadjuvant setting, results from two clinical trials seem to identify pathological and genomic features of highly responsive tumors. Squamous cells and lymphoepithelioma/like histotypes, programmed cell-death ligand 1 (PD-L1) expression and high levels of activate T cells have been associated with higher response rate. In the metastatic setting, only 30% of patient may respond to ICI. A panel of biomarkers for patient selection is an actual need since the correlation between response and PD-L1 expression seem inconsistent across clinical trials, with some exceptions. Molecular characterization of BC, tumor mutation burden and immune-gene expression profiling might introduce new molecular biomarkers, hopefully transferable into the clinical-pathological practice.
  • Thumbnail Image
    Item
    New Frontiers in Prostate Cancer Treatment: Are We Ready for Drug Combinations with Novel Agents?
    (MDPI, 2020-06-22) Aurilio, Gaetano; Cimadamore, Alessia; Santoni, Matteo; Nolè, Franco; Scarpelli, Marina; Massari, Francesco; Lopez-Beltran, Antonio; Cheng, Liang; Montironi, Rodolfo; Pathology and Laboratory Medicine, School of Medicine
    Medical treatment for metastatic castration-resistant prostate cancer (mCRPC) patients has progressively been evolving from a nonspecific clinical approach to genomics-oriented therapies. The scientific community is in fact increasingly focusing on developing DNA damage repair (DDR) defect-driven novel molecules, both as single-agent therapy and in combined treatment strategies. Accordingly, research is under way into combined drug therapies targeting different pathways, e.g. androgen receptor signaling (ARS) and poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) enzymes, immune checkpoint (IC) and PARP, IC, and ARS, and prostate-specific membrane antigen (PSMA). In an attempt to formulate evolving treatment paradigms in mCRPC patients, here we selected clinical research into patients undergoing therapies with emerging molecules, with particular emphasis towards PARP-, IC-, and PSMA-inhibitors. In order to focus on those molecules and drug combinations most likely to be translated into routine clinical care in the near future, we selected only those clinical studies currently recruiting patients. A PubMed search focusing on the keywords “prostate cancer”, “metastatic castration-resistant prostate cancer”, “DDR pathways”, “ARS inhibitors”, “PARP inhibitors”, “IC inhibitors”, “PSMA-targeting agents”, and “drug combinations” was performed.
  • Thumbnail Image
    Item
    The Role of Obesity in Renal Cell Carcinoma Patients: Clinical-Pathological Implications
    (MDPI, 2019-11-13) Aurilio, Gaetano; Piva, Francesco; Santoni, Matteo; Cimadamore, Alessia; Sorgentoni, Giulia; Lopez-Beltran, Antonio; Cheng, Liang; Battelli, Nicola; Nolè, Franco; Montironi, Rodolfo; Pathology and Laboratory Medicine, School of Medicine
    Obesity is a well-known risk factor for renal cell carcinoma (RCC) development. However, the RCC–obesity link has not been fully addressed when considering a comprehensive scenario starting from pathogenetic aspects through pathological issues up to the outcome of medical treatment. We therefore conducted an electronic PubMed search using keywords “obesity”, “body mass index”, “overweight”, “renal cell carcinoma/kidney cancer”, “medical treatment”, “targeted therapy”, and “immunotherapy/immune checkpoint inhibitors”. The selected data supported a crosstalk between adipose tissue (adipocytes and other white adipose tissue cells) and cancer cells inducing several signaling pathways that finally stimulated angiogenesis, survival, and cellular proliferation. Accurate sampling of renal sinus fat correlated with a prognostic value. Retrospective clinical evidence in metastatic RCC patients with higher body mass index (BMI) and treated with targeted therapies and/or immune checkpoint inhibitors showed advantageous survival outcomes. Therefore, obesity may influence the course of RCC patients, although the interplay between obesity/BMI and RCC warrants a large prospective confirmation. We are therefore still far from determining a clear role of obesity as a prognostic/predictive factor in metastatic RCC patients undergoing targeted therapy and immunotherapy.