Pseudoprogression with subsequent complete response and severe thrombocytopenia to checkpoint inhibitor immunotherapy in a patient with advanced mucosal melanoma of the sinonasal cavity

In this case report, we describe a patient with an inoperable mucosal melanoma of the sinonasal cavity who achieved an ongoing complete response to combined immunotherapy with ipilimumab and nivolumab after initial pseudoprogression. Despite massive enlargement of the tumor 9 weeks after treatment initiation, we decided to continue with checkpoint inhibitor immunotherapy because of lacking potent therapeutic alternatives and the possibility of pseudoprogression. In the computed tomography scan 3 months later, the tumor was no longer detectable. To date, the patient is still in remission. However, she developed severe immune-related thrombocytopenia and neutropenia that are rarely encountered with checkpoint inhibitor immunotherapy. Thrombocytopenia did not respond to corticosteroids, but rapidly improved after the administration of single-dose intravenous immunoglobulin. This exceptional case highlights the effectiveness of combined immunotherapy with ipilimumab and nivolumab in mucosal melanoma, the phenomenon of pseudoprogression, as well as the rare event of immune-related hematological side effects. Correspondence to Magdalena Philipp, MD, Department of Dermatology, Venerology and Allergology, Medical University Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria Tel: +43 512 5048 2839; fax: +43 512 5042 2990;e-mail: magdalena.philipp@i-med.ac.at Received March 14, 2018 Accepted June 8, 2018 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

https://ift.tt/2lz3PNP

Reversal of docetaxel resistance in prostate cancer by Notch signaling inhibition

Acquired docetaxel (Doc) resistance in hormone-refractory prostate cancer (HRPC) remains an ongoing clinical challenge, resulting in failed chemotherapy and tumor recurrence. However, the mechanism of Doc-resistance development in prostate cancer cells is still unclear. Here, we observed a subpopulation of prostate cancer cells, in both Doc-resistant cell lines and the tumors of patients with HRPC, which show stem cell markers and greater tumorigenic potential. Those stem-like prostate cancer cells show high expression of ABCB1, which encodes multidrug resistance-related protein P-glycoprotein, leading to the Doc-resistance in prostate cancer. Moreover, we found that Notch signaling pathway activation in Doc-resistant cell lines and tumor tissues of patients with HRPC correlated with tumorigenicity and the development of Doc resistance. Here, we revealed that a combination of Doc and a Notch signaling inhibitor overcomes Doc resistance and increases the survival of mice with Doc-resistant xenografts. Therefore, targeting the Notch signaling pathway may be a promising strategy to overcome the Doc-resistant cancer in the clinic. *Shi Qiu, Linghui Deng, and Yige Bao contributed equally to the writing of this article. Correspondence to Qiang Wei, MD, Department of Urology, Institute of Urology, West China Hospital of Sichuan University, No. 37, Guoxue Alley, Chengdu, Sichuan 610041, People's Republic of China Tel: +86 189 806 01425; fax: +86 288 558 2944; e-mail: weiqiang163163@163.com or Correspondence to Lu Yang, MD, Department of Urology, Institute of Urology, West China Hospital of Sichuan University, No. 37, Guoxue Alley, Chengdu, Sichuan 610041, People's Republic of China Tel: +86 135 412 35213; fax: +86 288 558 2944; e-mail: wycleflue@163.com Received January 22, 2018 Accepted May 17, 2018 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

https://ift.tt/2yLWUKO

Ginsenoside Rg1 impairs homologous recombination repair by targeting CtBP-interacting protein and sensitizes hepatoblastoma cells to DNA damage

The ginsenoside Rg1, the primary pharmacologically active ingredient of the traditional Chinese herb ginseng, is widely used in the clinical treatment of diseases of the immune and nervous systems. Recent studies have shown that it also has an antitumor effect. In this study, we explored the effects of Rg1 on hepatoblastoma (HB) and its underlying mechanisms. We demonstrated that Rg1 significantly inhibited HB cell growth both in vivo and in vitro. Mechanistic studies revealed that Rg1 impaired homologous recombination and triggered double-strand breaks in HB cells by directly targeting CtBP-interacting protein (CtIP), a key double-strand break repair factor, which is highly expressed in HB tissues. Moreover, we also demonstrated that Rg1 sensitized HB cells to DNA-damaging agents both in vitro and in vivo. In conclusion, our data not only demonstrate the potential clinical application of Rg1 as a novel chemotherapeutic candidate but also offer a mechanism-based therapeutic option by which DNA-damaging agents can be used in combination with Rg1 to target HB. *Ni Zhen and Lei Jin contributed equally to the writing of this article. Correspondence to Xiaorong Ni, PhD, Department of Gynecology, Shanghai Municipal Hospital of Traditional Chinese Medicine of Shanghai, University of Traditional Chinese Medicine, No. 274 Zhijiang Middle Road, Jingan District, 200071 Shanghai, People's Republic of China Tel: +86 216 258 8203; fax: +86 215 663 9828; e-mail: xiaorongni_stcmh00@163.com or Correspondence to Min Xu, PhD, Department of Surgery, Shanghai Children's Medical Center of Shanghai Jiaotong University School of Medicine, No. 1678 Dongfang Road, Pudong District, 200127 Shanghai, People's Republic of China Tel: +86 213 862 6161; fax: +86 215 089 1405; e-mail: xuminmed@163.com Received September 6, 2017 Accepted April 23, 2018 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

https://ift.tt/2lBZbPm

Early Drug Development in the era of Immuno-Oncology: are we ready to face the challenges?

Abstract

The classical development of drugs has progressively faded away, and we are currently in an era of seamless drug-development, where first-inhuman trials include unusually big expansion cohorts in the search for early signs of activity and rapid regulatory approval. The fierce competition between different pharmaceutical companies and the hype for immune combinations obliges us to question the current way in which we are evaluating these drugs. In this review, we discuss critical issues and caveats in immunotherapy development. A particular emphasis is put on the limitations of pre-clinical toxicology studies, where both murine models and cynomolgus monkeys have underpredicted toxicity in humans. Moreover, relevant issues surrounding dose determination during phase 1 trials, such as dose-escalation methods or flat vs. body-weight dosing, are discussed. A proposal of how to face these different challenges is offered, in order to achieve maximum efficacy with minimum toxicity for our patients.

https://ift.tt/2yJ5J7R

Comprehensive molecular classification of localized prostate adenocarcinoma reveals a tumour subtype predictive of a non-aggressive disease

Abstract

Background

Management of localized prostate cancer is a major clinical challenge since most of these cancers won't evolve but a majority of patients will still undergo a life-changing radical surgery. Molecular studies have shown that prostate cancer can be classified according to their genomic alterations but none of the published prostate cancer molecular classifications could identify a subtype corresponding to non-evolutive tumours.

Materials and methods

Multi-omics molecular profiling was performed on post-radical prostatectomy material from a cohort of 130 patients with localized prostate cancer. We used unsupervised classification techniques to build a comprehensive classification of prostate tumours based on three molecular levels: DNA copy number, DNA methylation, and mRNA expression. Merged data from our cohort and The Cancer Genome Atlas (TCGA) cohort were used to characterize the resulting tumour subtypes. We measured subtype-associated risks of biochemical relapse using Cox regression models and survival data from five cohorts including the two aforementioned.

Results

We describe three prostate cancer molecular subtypes associated with specific molecular characteristics and different clinical outcomes. Particularly, one subtype was strongly associated with the absence of biochemical recurrence. We validated this finding on 746 samples from five distinct cohorts (P = 3.41 x 10⁻⁸, N = 746 tumour samples), and showed that our subtyping approach outperformed the most popular prognostic molecular signatures to accurately identify a subset of patients with a non-evolutive disease. We provide a set of 36 transcriptomic biomarkers to robustly identify this subtype of non-evolutive cases whose prevalence was estimated to 22% of all localized prostate cancer tumours.

Conclusion

At least 20% of patients with localized prostate cancer can be accurately predicted to have a non-evolutive disease on the basis of their molecular subtype. Those patients should not undergo immediate surgery and rather be placed under active surveillance.

https://ift.tt/2tvO6nc

Tumor Cell-Intrinsic Factors Underlie Heterogeneity of Immune Cell Infiltration and Response to Immunotherapy

Using a library of pancreatic cancer cell clones, Li et al. identify heterogeneous and multifactorial pathways regulating tumor-cell-intrinsic mechanisms that dictate the immune microenvironment and thereby responses to immunotherapy. This tumor clone library provides a tool for identifying new targets responsible for thwarting responses to immunotherapy in resistant tumors.

https://ift.tt/2KjuM6j

Iron Drives T Helper Cell Pathogenicity by Promoting RNA-Binding Protein PCBP1-Mediated Proinflammatory Cytokine Production

Iron accumulation is observed in the brain of patients with neuroinflammatory diseases, yet its functional significance is poorly understood. Wang et al. demonstrate that iron promotes T cell pathogenicity by protecting RNA-binding protein PCBP1 from proteolysis, thereby promoting PCBP1-mediated stabilization of GM-CSF mRNA. These findings indicate that iron homeostasis can be targeted to suppress pathogenic T cells for treatment of neuroinflammatory diseases.

https://ift.tt/2MoOHhl