Macrophage Inflammatory Protein-1&alpha: An Inhibitor of Clonogenic Epidermal Keratinocyte Proliferation

Chemokines display a wide range of diverse functions and MIP-1alpha is no exception. It is not only a potent inflammatory molecule but also an inhibitor of primitive haemopoietic cell proliferation. The studies described in this thesis focus on the activity of MIP-1alpha on keratinocyte proliferation. These experiments have shown that a pure form of MIP-1alpha, derived from COS 7 cells by transient transfection, inhibits the proliferation of clonogenic human epidermal keratinocytes in vitro. This activity is fully reversible by specific anti- MIP-1alpha polyclonal antibodies. Despite this, the pure bacterial recombinant preparation of MIP-1alpha is largely inactive. In order to investigate this discrepancy, studies analysing the difference between these two MIP-1alpha preparations have been carried out. These studies suggest that the activation of the keratinocyte inhibitory function of MIP-1alpha results through a subtle structural modification which may involve the truncation of the amino-terminal amino acids. The potential role of MIP-1alpha in epithelial tissues in vivo is also discussed

Chromatin to Clinic: The Molecular Rationale for PARP1 Inhibitor Function.

Poly(ADP-ribose) polymerase 1 (PARP1) inhibitors were recently shown to have potential clinical impact in a number of disease settings, particularly as related to cancer therapy, treatment for cardiovascular dysfunction, and suppression of inflammation. The molecular basis for PARP1 inhibitor function is complex, and appears to depend on the dual roles of PARP1 in DNA damage repair and transcriptional regulation. Here, the mechanisms by which PARP-1 inhibitors elicit clinical response are discussed, and strategies for translating the preclinical elucidation of PARP-1 function into advances in disease management are reviewed

Statin and metformin use and outcomes in patients with castration-resistant prostate cancer treated with enzalutamide: A meta-analysis of AFFIRM, PREVAIL and PROSPER

Castration-resistant prostate cancer; Metformin; Overall survivalCàncer de pròstata resistent a la castració; Metformina; Supervivència globalCáncer de próstata resistente a la castración; Metformina; Supervivencia globalBackground: Statins and metformin are commonly prescribed for patients, including those with prostate cancer. Preclinical and epidemiologic studies of each agent have suggested anti-cancer properties. Methods: Patient data from three randomised, double-blind, placebo-controlled, phase III studies evaluating enzalutamide (AFFIRM, PREVAIL and PROSPER) in patients with castration-resistant prostate cancer were included in this analysis. This post hoc, retrospective study examined the association of statin and metformin on radiographic progression-free survival (rPFS), metastasis-free survival (MFS), toxicity and overall survival (OS). After adjusting for available clinical prognostic variables, multivariate analyses were performed on pooled data from AFFIRM and PREVAIL, all three trials pooled, and each trial individually, to assess differential efficacy in these end-points associated with the baseline use of these medications. Results: In the multivariate analysis of the individual trials, OS and rPFS/MFS were not significantly influenced by statin or metformin use in AFFIRM or PROSPER. However, in PREVAIL, OS was significantly influenced by statin (hazard ratio [HR] 0.72; 95% confidence interval [CI] 0.59-0.89) and rPFS was significantly influenced by metformin (HR, 0.48; 95% CI 0.34-0.70). In pooled analyses, improved OS was significantly associated with statin use but not metformin use for AFFIRM+PREVAIL trials (HR 0.83; 95% CI 0.72-0.96) and AFFIRM+PREVAIL+PROSPER (HR 0.75; 95% CI 0.66-0.85). Conclusions: The association between statin or metformin use and rPFS, MFS and OS was inconsistent across three trials. Analyses of all three trials pooled and AFFIRM+PREVAIL pooled revealed that statin but not metformin use was significantly associated with a reduced risk of death in enzalutamide-treated patients. Additional prospective, controlled studies are warranted.This study was sponsored by Pfizer Inc. (New York, NY, USA) and Astellas Pharma, Inc. (Northbrook, IL, USA), the co-developers of enzalutamide. Medical writing and editorial support funded by the sponsors were provided by Stephanie Vadasz, PhD, and Dena McWain of Ashfield MedComms (an Ashfield Health company), Lauren Rainer, BSc, and Julie B. Stimmel, PhD, of Onyx (a Prime Global agency)

Management of Patients with Advanced Prostate Cancer. Part I: Intermediate-/High-risk and Locally Advanced Disease, Biochemical Relapse, and Side Effects of Hormonal Treatment: Report of the Advanced Prostate Cancer Consensus Conference 2022

Hormonal treatment; Prostate cancer; Side effectsTratamiento hormonal; Cáncer de próstata; Efectos secundariosTractament hormonal; Càncer de pròstata; Efectes secundarisBackground Innovations in imaging and molecular characterisation and the evolution of new therapies have improved outcomes in advanced prostate cancer. Nonetheless, we continue to lack high-level evidence on a variety of clinical topics that greatly impact daily practice. To supplement evidence-based guidelines, the 2022 Advanced Prostate Cancer Consensus Conference (APCCC 2022) surveyed experts about key dilemmas in clinical management. Objective To present consensus voting results for select questions from APCCC 2022. Design, setting, and participants Before the conference, a panel of 117 international prostate cancer experts used a modified Delphi process to develop 198 multiple-choice consensus questions on (1) intermediate- and high-risk and locally advanced prostate cancer, (2) biochemical recurrence after local treatment, (3) side effects from hormonal therapies, (4) metastatic hormone-sensitive prostate cancer, (5) nonmetastatic castration-resistant prostate cancer, (6) metastatic castration-resistant prostate cancer, and (7) oligometastatic and oligoprogressive prostate cancer. Before the conference, these questions were administered via a web-based survey to the 105 physician panel members (“panellists”) who directly engage in prostate cancer treatment decision-making. Herein, we present results for the 82 questions on topics 1–3. Outcome measurements and statistical analysis Consensus was defined as ≥75% agreement, with strong consensus defined as ≥90% agreement. Results and limitations The voting results reveal varying degrees of consensus, as is discussed in this article and shown in the detailed results in the Supplementary material. The findings reflect the opinions of an international panel of experts and did not incorporate a formal literature review and meta-analysis. Conclusions These voting results by a panel of international experts in advanced prostate cancer can help physicians and patients navigate controversial areas of clinical management for which high-level evidence is scant or conflicting. The findings can also help funders and policymakers prioritise areas for future research. Diagnostic and treatment decisions should always be individualised based on patient and cancer characteristics (disease extent and location, treatment history, comorbidities, and patient preferences) and should incorporate current and emerging clinical evidence, therapeutic guidelines, and logistic and economic factors. Enrolment in clinical trials is always strongly encouraged. Importantly, APCCC 2022 once again identified important gaps (areas of nonconsensus) that merit evaluation in specifically designed trials

A Phase I Study Investigating AZD8186, a Potent and Selective Inhibitor of PI3Kβ/δ, in Patients with Advanced Solid Tumors

Advanced Solid Tumors; PI3K beta/delta inhibitorTumores sólidos avanzados; Inhibidor de PI3K beta/deltaTumors sòlids avançats; Inhibidor de PI3K beta/deltaPurpose: To characterize safety and tolerability of the selective PI3Kβ inhibitor AZD8186, identify a recommended phase II dose (RP2D), and assess preliminary efficacy in combination with abiraterone acetate or vistusertib. Patients and Methods: This phase I open-label study included patients with advanced solid tumors, particularly prostate cancer, triple-negative breast cancer, and squamous non–small cell lung cancer. The study comprised four arms: (i) AZD8186 monotherapy dose finding; (ii) monotherapy dose expansion; (iii) AZD8186/abiraterone acetate (with prednisone); and (iv) AZD8186/vistusertib. The primary endpoints were safety, tolerability, and identification of the RP2D of AZD8186 monotherapy and in combination. Secondary endpoints included pharmacokinetics (PK), pharmacodynamics, and tumor and prostate-specific antigen (PSA) responses. Results: In total, 161 patients were enrolled. AZD8186 was well tolerated across all study arms, the most common adverse events being gastrointestinal symptoms. In the monotherapy dose-finding arm, four patients experienced dose-limiting toxicities (mainly rash). AZD8186 doses of 60-mg twice daily [BID; 5 days on, 2 days off (5:2)] and 120-mg BID (continuous and 5:2 dosing) were taken into subsequent arms. The PKs of AZD8186 were dose proportional, without interactions with abiraterone acetate or vistusertib, and target inhibition was observed in plasma and tumor tissue. Monotherapy and combination therapy showed preliminary evidence of limited antitumor activity by imaging and, in prostate cancer, PSA reduction. Conclusions: AZD8186 monotherapy had an acceptable safety and tolerability profile, and combination with abiraterone acetate/prednisone or vistusertib was also tolerated. There was preliminary evidence of antitumor activity, meriting further exploration of AZD8186 in subsequent studies in PI3Kβ pathway–dependent cancers.This study was sponsored by AstraZeneca. We thank the patients and their doctors and caregivers who participated in this study. We acknowledge support in Cambridge from Cancer Research UK, Experimental Cancer Medicine Center, NIHR Biomedical Research Center, and NIHR Cambridge Clinical Research Center. Research at the Christie NHS Foundation Trust was supported by the NIHR Manchester Clinical Research Facility and Manchester Experimental Cancer Medicine Center award. We also thank Martine Roudier (AstraZeneca) for providing analysis data of tumor tissue biopsies, and Wolfram Brugger and Caroline Kennedy (AstraZeneca, Cambridge, UK). Abiraterone acetate was kindly provided by Janssen. Medical writing and editorial assistance were provided by Bioscript Medical, Macclesfield, UK, and funded by AstraZeneca

Effects of metformin and statins on outcomes in men with castration-resistant metastatic prostate cancer: Secondary analysis of COU-AA-301 and COU-AA-302

Abiraterone acetate; Metastatic castration-resistant prostate cancer; MetforminAcetato de abiraterona; Cáncer de próstata metastásico resistente a la castración; MetforminaAcetat d'abiraterona; Càncer de pròstata resistent a la castració metastàtic; MetforminaBackground The associations of metformin and statins with overall survival (OS) and prostate specific antigen response rate (PSA-RR) in trials in metastatic castration-resistant prostate cancer remain unclear. Objective To determine whether metformin or statins ± abiraterone acetate plus prednisone/prednisolone (AAP) influence OS and PSA-RR. Design, setting and participant COU-AA-301 and COU-AA-302 patients were stratified by metformin and statin use. Cox proportional hazards models were used to estimate hazards ratio (HR) stratified by concomitant medications, and a random effects model was used to pool HR. We compared PSA-RR using Chi χ2 test. Results In COU-AA-301-AAP, metformin was associated with improved PSA-RR (41.1% versus 28.6%) but not prolonged OS. In COU-AA-301-placebo-P, there was no association between metformin and prolonged OS or PSA-RR. In COU-AA-302-AAP, metformin was associated with prolonged OS (adjHR 0.69, 95% CI 0.48–0.98) and improved PSA-RR (72.7% versus 60.0%). In COU-AA-302-P, metformin was associated with prolonged OS (adjHR 0.66, 95% CI 0.47–0.93). In pooled analysis, OS was prolonged among those treated with metformin (pooled HR 0.77, 95% CI 0.62–0.95).In COU-AA-301-AAP, statins were associated with an improved OS (adjHR 0.76, 95% CI 0.62–0.93), while there was no difference in COU-AA-301-P. There was no association with statins and OS in either COU-AA-302 groups. When pooling HR, OS was prolonged among those treated with statins (pooled HR 0.78, 95% CI 0.68–0.88). Conclusion Within the limitations of post-hoc sub-analyses, metformin and statins are associated with a prolonged OS and increased PSA-RR, particularly in combination with AAP