Hormonal Agents in Localized and Advanced Prostate Cancer: Current Use and Future Perspectives.

Prostate cancer (PC) is generally a hormone-dependent tumor. Androgen deprivation therapy ( has been the standard of care in metastatic disease for more than 80 years. Subsequent studies have highlighted the efficacy of ADT even in earlier disease settings such as in localized disease or in the case of biochemical recurrence (BCR). Improved knowledge of PC biology and ADT resistance mechanisms have led to the development of novel generation androgen receptor pathway inhibitors (ARPI). Initially used only in patients who became resistant to ADT, ARPI have subsequently shown to be effective when used in patients with metastatic hormone-naive disease and in recent years their effectiveness has also been evaluated in localized disease and in case of BCR. The objective of this review is to describe the current role of agents interfering with the androgen receptor in different stages of PC and to point out future perspectives.

On the interplay between lipids and asymmetric dynamics of an NBS degenerate ABC transporter.

Multidrug resistance-associated proteins are ABC C-family exporters. They are crucial in pharmacology as they transport various substrates across membranes. However, the role of the degenerate nucleotide-binding site (NBS) remains unclear likewise the interplay with the surrounding lipid environment. Here, we propose a dynamic and structural overview of MRP1 from ca. 110 µs molecular dynamics simulations. ATP binding to NBS1 is likely maintained along several transport cycles. Asymmetric NBD behaviour is ensured by lower signal transduction from NBD1 to the rest of the protein owing to the absence of ball-and-socket conformation between NBD1 and coupling helices. Even though surrounding lipids play an active role in the allosteric communication between the substrate-binding pocket and NBDs, our results suggest that lipid composition has a limited impact, mostly by affecting transport kinetics. We believe that our work can be extended to other degenerate NBS ABC proteins and provide hints for deciphering mechanistic differences among ABC transporters.

Computational and structural insights into the pre- and post-hydrolysis states of bovine multidrug resistance-associated protein 1.

ATP-binding cassette C-family drug membrane transporters play an important role in local pharmacokinetics, that is, drug concentration in cellular compartments. From the structural point of view, only the bovine ortholog of the multidrug resistance-associated protein 1 (bMRP1) has been resolved. We here used µs-scaled molecular dynamics simulations to investigate the structure and dynamics of the bovine multidrug resistance-associated protein 1 in pre- and post-hydrolysis functional states. The present work aims to examine the slight but likely relevant structural differences between pre- and post-hydrolysis states of outward-facing conformations as well as the interactions between the multidrug resistance-associated protein 1 and the surrounding lipid bilayer. Global conformational dynamics show unfavourable extracellular opening associated with nucleotide-binding domain dimerization indicating that the post-hydrolysis state adopts a close-cleft conformation rather than an outward-open conformation. Our present simulations also highlight persistent interactions with annular cholesterol molecules and the expected active role of lipid bilayer in the allosteric communication between distant domains of the transporter.

The Role of Germline Mutations in Thoracic Malignancies: Between Myth and Reality.

Considering the established contribution of environmental factors to the development of thoracic malignancies, the inherited susceptibility of these tumors has rarely been explored. However, the recent introduction of next-generation sequencing-based tumor molecular profiling in the real-word setting enabled us to deeply characterize the genomic background of patients with lung cancer with or without smoking-related history, increasing the likelihood of detecting germline mutations with potential prevention and treatment implications. Pathogenic germline variants have been detected in 2% to 3% of patients with NSCLC undergoing next-generation sequencing analysis, whereas the proportion of germline mutations associated with the development of pleural mesothelioma widely varies across different studies, ranging between 5% and 10%. This review provides an updated summary of emerging evidence about germline mutations in thoracic malignancies, focusing on pathogenetic mechanisms, clinical features, therapeutic implications, and screening recommendations for high-risk individuals.

How to Improve the Quality of Life of Patients with Prostate Cancer Treated with Hormone Therapy?

Prostate cancer (PC) is a hormone-sensitive tumor. Androgen deprivation therapy (ADT) is the cornerstone of systemic therapy for patients with intermediate or high-risk localized, recurrent, and metastatic prostate cancer. Although generally well tolerated, ADT can lead to short- and long-term adverse events that can worsen the quality of life of patients with PC. In the last decade, the introduction of novel generation androgen receptor pathway inhibitors (ARPI) has resulted in an improvement in the prognosis of patients with metastatic PC when used in combination with ADT. The use of ARPI in increasingly early stages of the disease determines a longer exposure of patients to these treatments. Although ARPIs are normally well-tolerated drugs, they generally cause an increase in toxicity compared to ADT alone, being able to worsen some adverse events already induced by ADT or leading to the development of specific side effects. Although there are no specific treatments for all the adverse events induced by hormonal therapies, it is essential to know the possible toxicities induced by the different treatments and to start procedures to prevent and/or recognize and consequently treat them early in order to not compromise the quality of life of the patients with PC. The aim of this review is to describe the adverse events induced by hormonal therapies. We will first describe the side effects induced by both ADT and ARPI and then the specific adverse events of the different ARPIs. Furthermore, we will try to highlight the possible therapeutic options to prevent or mitigate the toxicity induced by hormone therapies in order to improve the quality of life of the patients with PC.

Metastatic Urothelial Carcinoma: Have We Take the Road to the Personalized Medicine?

Urothelial cancer is a lethal malignancy characterized by a wide diffusion in Western countries due to a larger exposure to known risk factors, such as aromatic amines, tobacco smoke and benzene [...].

Bevacizumab-induced hypertension as a predictor of clinical outcome in metastatic colorectal cancer: An individual patient data-based pooled analysis of two randomized studies and a systematic review of the literature.

BACKGROUND: Retrospective series suggest that bevacizumab-induced hypertension (HTN) is a prognostic and potentially predictive biomarker of efficacy of the antiangiogenic drug in the upfront treatment of metastatic colorectal cancer (mCRC) patients. The immortal-time bias and the effect of pre-existing HTN might affect these findings. We conducted a pooled, post hoc analysis of 2 prospective randomized trials of chemotherapy plus bevacizumab in mCRC, and performed a systematic review of the available literature focusing on how the immortal-time bias was taken into account and how pre-existing HTN potentially requiring the use of antihypertensive drugs was managed. METHODS: The pooled-analysis included patients enrolled in the phase III TRIBE and TRIBE-2 studies that compared upfront FOLFOXIRI + bevacizumab to FOLFIRI or FOLFOX + bevacizumab, respectively. Association between HTN and survival outcomes was assessed by incorporating a time-dependent Cox regression model to consider the time-dependency of the probability of HTN onset during the treatment. The systematic review was conducted according to PRISMA guidelines. RESULTS: The systematic review retrieved 14 eligible and highly heterogeneous studies. A positive prognostic impact of bevacizumab-induced HTN was reported in the 58% of the analyses reporting Progression Free Survival (PFS) and in the 54% of the analyses reporting Overall Survival (OS) data. Immortal-time bias was incorporated in 4 studies (28%). In TRIBE and TRIBE-2 study populations (N = 1175), patients experiencing ≥ G2 HTN during first-line bevacizumab administration showed longer PFS (median: 14.7 versus 10.3 months, p < 0.001) and OS (median: 31.7 versus 24.2 months, p < 0.001). The association with OS retained statistical significance after correction for time-dependency (p = 0.003) and was confirmed in the multivariable model including HTN as a time-dependent variable (p = 0.02). Moreover, in patients with pre-existing HTN, no difference in terms of PFS and OS was observed compared with the subgroup of patients who never experienced ≥G2 HTN (HR 1.01, p = 0.86 and HR 1.02, p = 0.78 respectively. CONCLUSIONS: Bevacizumab-induced HTN during the first-line treatment of mCRC is an independent prognostic factor, also adopting a time-dependency correction. Toxicity should be interpreted as a time-dependent variable when exploring its association with clinical outcome.