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Molecular Research on Hereditary Cancer Syndromes
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Molecular Research on Hereditary Cancer Syndromes

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (30 June 2021) | Viewed by 4575

Special Issue Editors

Assoc. Prof. Yoland C. Antill

E-Mail Website
Guest Editor
1. Cabrini Health, Malvern, Australia
2. Peninsula Health, Frankston, Australia
3. Monash University, VIC, Australia
Interests: hereditary breast cancer; hereditary gynaecological cancers (endometrial and ovarian)
Assoc. Prof. Paul James

E-Mail Website
Guest Editor
Parkville Familial Cancer Centre, Peter MacCallum Cancer Centre and Royal Melbourne Hospitals, Parkville, Australia
Interests: familial genetic disorders (cancer, cardiac, neurological); genetic testing

Special Issue Information

Dear colleagues,

Hereditary cancer syndromes represent a small proportion of all cancer risk, but their impact on cancer management and cancer-risk management is significant. Technologies have evolved to enable more frequent testing with a rapid turnaround and at lower costs than ever before. The impact of understanding whether a tumour has occurred in the setting of a germline mutation has significant impacts at multiple levels for both the individual and their families. Understanding tumorigenesis on the molecular level has enabled the development of target therapeutic options, such as parp inhibitors in the setting of germline BRCA pathogenic variants or immune checkpoint inhibitors in mismatch-repair-deficient tumours. The provision of cascade testing enables preventative or screening measures to be implemented to reduce the burden of risk.

Assoc. Prof. Yoland C. Antill
Assoc. Prof. Paul James
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • hereditary cancer syndromes
  • emerging genes
  • targeted therapeutics
  • cancer-risk management
  • molecular sequencing
  • circulating tumour DNA

Published Papers (1 paper)

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Research

16 pages, 3872 KiB  
Article
Combined Gemcitabine and Immune-Checkpoint Inhibition Conquers Anti-PD-L1 Resistance in Low-Immunogenic Mismatch Repair-Deficient Tumors
by Inken Salewski, Julia Henne, Leonie Engster, Bjoern Schneider, Heiko Lemcke, Anna Skorska, Peggy Berlin, Larissa Henze, Christian Junghanss and Claudia Maletzki
Int. J. Mol. Sci. 2021, 22(11), 5990; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115990 - 01 Jun 2021
Cited by 11 | Viewed by 4178
Abstract
Tumors arising in the context of Lynch Syndrome or constitutional mismatch repair deficiency are hypermutated and have a good response towards immune-checkpoint inhibitors (ICIs), including α-PD-L1 antibodies. However, in most cases, resistance mechanisms evolve. To improve outcomes and prevent resistance development, combination approaches [...] Read more.
Tumors arising in the context of Lynch Syndrome or constitutional mismatch repair deficiency are hypermutated and have a good response towards immune-checkpoint inhibitors (ICIs), including α-PD-L1 antibodies. However, in most cases, resistance mechanisms evolve. To improve outcomes and prevent resistance development, combination approaches are warranted. Herein, we applied a combined regimen with an α-PD-L1 antibody and gemcitabine in a preclinical tumor model to activate endogenous antitumor immune responses. Mlh1−/− mice with established gastrointestinal tumors received the α-PD-L1 antibody (clone 6E11; 2.5 mg/kg bw, i.v., q2wx3) and gemcitabine (100 mg/kg bw, i.p., q4wx3) in mono- or combination therapy. Survival and tumor growth were recorded. Immunological changes in the blood were routinely examined via multi-color flow cytometry and complemented by ex vivo frameshift mutation analysis to identify alterations in Mlh1−/−-tumor-associated target genes. The combined therapy of α-PD-L1 and gemcitabine prolonged median overall survival of Mlh1−/− mice from four weeks in the untreated control group to 12 weeks, accompanied by therapy-induced tumor growth inhibition, as measured by [18F]-FDG PET/CT. Plasma cytokine levels of IL13, TNFα, and MIP1β were increased and also higher than in mice receiving either monotherapy. Circulating splenic and intratumoral myeloid-derived suppressor cells (MDSCs), as well as M2 macrophages, were markedly reduced. Besides, residual tumor specimens from combi-treated mice had increased numbers of infiltrating cytotoxic T-cells. Frameshift mutations in APC, Tmem60, and Casc3 were no longer detectable upon treatment, likely because of the successful eradication of single mutated cell clones. By contrast, novel mutations appeared. Collectively, we herein confirm the safe application of combined chemo-immunotherapy by long-term tumor growth control to prevent the development of resistance mechanisms. Full article
(This article belongs to the Special Issue Molecular Research on Hereditary Cancer Syndromes)
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