From gut dysbiosis to altered brain function and mental illness: mechanisms and pathways

The human body hosts an enormous abundance and diversity of microbes, which perform a range of essential and beneficial functions. Our appreciation of the importance of these microbial communities to many aspects of human physiology has grown dramatically in recent years. We know, for example, that animals raised in a germ-free environment exhibit substantially altered immune and metabolic function, while the disruption of commensal microbiota in humans is associated with the development of a growing number of diseases. Evidence is now emerging that, through interactions with the gut-brain axis, the bidirectional communication system between the central nervous system and the gastrointestinal tract, the gut microbiome can also influence neural development, cognition and behaviour, with recent evidence that changes in behaviour alter gut microbiota composition, while modifications of the microbiome can induce depressive-like behaviours. Although an association between enteropathy and certain psychiatric conditions has long been recognized, it now appears that gut microbes represent direct mediators of psychopathology. Here, we examine roles of gut microbiome in shaping brain development and neurological function, and the mechanisms by which it can contribute to mental illness. Further, we discuss how the insight provided by this new and exciting field of research can inform care and provide a basis for the design of novel, microbiota-targeted, therapies.GB Rogers, DJ Keating, RL Young, M-L Wong, J Licinio, and S Wesseling

Clinical Implications of Hedgehog Pathway Signaling in Prostate Cancer

Activity in the Hedgehog pathway, which regulates GLI-mediated transcription, is important in organogenesis and stem cell regulation in self-renewing organs, but is pathologically elevated in many human malignancies. Mutations leading to constitutive activation of the pathway have been implicated in medulloblastoma and basal cell carcinoma, and inhibition of the pathway has demonstrated clinical responses leading to the approval of the Smoothened inhibitor, vismodegib, for the treatment of advanced basal cell carcinoma. Aberrant Hedgehog pathway signaling has also been noted in prostate cancer with evidence suggesting that it may render prostate epithelial cells tumorigenic, drive the epithelial-to-mesenchymal transition, and contribute towards the development of castration-resistance through autocrine and paracrine signaling within the tumor microenvironment and cross-talk with the androgen pathway. In addition, there are emerging clinical data suggesting that inhibition of the Hedgehog pathway may be effective in the treatment of recurrent and metastatic prostate cancer. Here we will review these data and highlight areas of active clinical research as they relate to Hedgehog pathway inhibition in prostate cancer

Castration-resistant prostate cancer: latest evidence and therapeutic implications

Medical oncologists who treat men with castration-resistant prostate cancer (CRPC) have seen an abundance of new agents approved by the United States Food and Drug Administration in the last decade for a disease that was previously difficult to treat after becoming resistant to androgen-deprivation therapy. Advances in understanding of the mechanisms of castration-resistance and prostate cancer progression have highlighted several pathways and targets that appear promising to better treat CRPC. As the majority of CRPC appears to continue to rely on the androgen receptor for growth and progression, several of these agents directly or indirectly target the androgen receptor. A novel microtubule-targeted agent, cabazitaxel, has demonstrated an overall survival benefit following progression on docetaxel. Other agents target tumor immunogenicity and immune checkpoint pathways to attempt to harness the host immune system. The recently approved radiopharmaceutical, radium-223 dichloride, has demonstrated impressive results in patients with extensive bony metastases with minimal toxicity. Lastly, further understanding of the pathways underlying CRPC progression has led to late-phase clinical trials with the novel agents: custirsen, tasquinimod and cabozantinib. This article reviews the approved therapies for CRPC, the agents currently in late-phase clinical trials, and notable early-phase trials of novel therapies and their combinations, with particular attention to trials incorporating novel biomarkers and intermediate endpoints to better identify those men who may or may not benefit from specific therapies

Characterization of outcomes in patients with metastatic non-small cell lung cancer treated with programmed cell death protein 1 inhibitors past RECIST version 1.1–defined disease progression in clinical trials

Based on anecdotal cases of clinically important decreases in tumor size following initial evidence of disease progression when treating patients with anti-PD-1 therapies, investigators have conducted clinical trials in patients with metastatic non-small lung cancer (mNSCLC) receiving anti–PD-1 therapy allowing for treatment past RECIST-defined disease progression (TPP). We describe the findings of a pooled analysis of three clinical trials submitted to the US Food and Drug administration (FDA) where treatment of patients with mNSCLC permitted TPP in terms of reduction in the sum of target lesions following initial RECIST-defined progression. We identified patients who received TPP and the characteristics and post-TPP change in tumor burden. All patients had advanced or mNSCLC and had previously received a platinum-based doublet regimen. In total, 535 patients were treated with anti–PD-1 therapy in three clinical trials of which 121 patients (23%) received TPP. Among all 535 patients treated with anti–PD-1 therapy, the partial response (PR) rate (≥30% reduction in the size of target lesions compared to baseline) following TPP was 1.9% (10 of 535) or 8.3% (10 of 121) in the TPP subgroup. Patients who responded to TPP were more likely to have responded to the initial course of anti–PD-1 therapy, prior to progression. The subgroup of patients who received TPP appeared to have similar baseline characteristics and response to initial treatment compared to the overall population. This suggests that a treatment strategy that includes TPP may not benefit the overall population. The risks of TPP should be weighed against the low likelihood of a PR and the potential for changing to a different therapy with a higher likelihood of benefit

FDA Approval Summary: Nivolumab for the Treatment of Metastatic Non‐Small Cell Lung Cancer With Progression On or After Platinum‐Based Chemotherapy

On October 9, 2015, the U.S. Food and Drug Administration expanded the nivolumab metastatic non-small cell lung cancer (NSCLC) indication to include patients with nonsquamous NSCLC after a 3.25-month review timeline. Approval was based on demonstration of an improvement in overall survival (OS) in an international, multicenter, open-label, randomized trial comparing nivolumab to docetaxel in patients with metastatic nonsquamous NSCLC with progression on or after platinum-based chemotherapy. The CheckMate 057 trial enrolled 582 patients who were randomized (1:1) to receive nivolumab or docetaxel. Nivolumab demonstrated improved OS compared with docetaxel at the prespecified interim analysis with a hazard ratio (HR) of 0.73 (p = .0015), and a median OS of 12.2 months (95% CI: 9.7–15.0 months) in patients treated with nivolumab compared with 9.4 months (95% CI: 8.0–10.7 months) in patients treated with docetaxel. A statistically significant improvement in objective response rate (ORR) was also observed, with an ORR of 19% (95% CI: 15%–24%) in the nivolumab arm and 12% (95% CI: 9%–17%) in the docetaxel arm. The median duration of response was 17 months in the nivolumab arm and 6 months in the docetaxel arm. Progression-free survival was not statistically different between arms. A prespecified retrospective subgroup analysis suggested that patients with programmed cell death ligand 1-negative tumors treated with nivolumab had similar OS to those treated with docetaxel. The toxicity profile of nivolumab was consistent with the known immune-mediated adverse event profile except for 1 case of grade 5 limbic encephalitis, which led to a postmarketing requirement study to better characterize immune-mediated encephalitis. IMPLICATIONS FOR PRACTICE: Based on the results from the CheckMate 057 clinical trial, nivolumab represents a new treatment option for patients requiring second-line treatment for metastatic non-small cell lung cancer. The role of nivolumab in patients with sensitizing epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) alterations is less clear. Until dedicated studies are performed to better characterize the role and sequence of programmed cell death 1 (PD-1) therapy, patients with EGFR or ALK alterations should have progressed on appropriate targeted therapy before initiating PD-1 inhibitor therapy. Some patients whose tumors lack programmed cell death ligand 1 (PD-L1) expression also appear to have durable responses. The U.S. Food and Drug Administration granted approval to Dako’s PD-L1 test, PD-L1 IHC 28-8 pharmDx, which the applicant claimed as a nonessential complementary diagnostic for nivolumab use