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Advances in Synthetic Lethality for Personalized Cancer Treatments
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Advances in Synthetic Lethality for Personalized Cancer Treatments

A special issue of Journal of Personalized Medicine (ISSN 2075-4426).

Deadline for manuscript submissions: closed (20 August 2022) | Viewed by 7560

Special Issue Editors

Dr. Giorgio Malpeli

E-Mail Website
Guest Editor
Department of Human Sciences and Promotion of Quality of Life, Università Telematica San Raffaele Roma, 00166 Rome, Italy
Interests: stem cells; epigenetic mechanisms; noncoding RNAs; cancer stem cells
Special Issues, Collections and Topics in MDPI journals
Dr. Maria Bencivenga

E-Mail Website
Guest Editor
Department of Surgery, Dentistry, Paediatrics and Gynaecology, University of Verona, 37129 Verona, Italy
Interests: gastric cancer; poorly cohesive carcinoma; signet ring cell; surgical oncology; minimally invasive surgery; multimodal therapies; molecular subtypes

Special Issue Information

Dear Colleagues, 

The transformation from a normal cell to a cancer cell is the result of the concerted action of multilevel changes in cell organization. Despite many recent advances in precision medicine, it remains difficult to restore the activity of a damaged tumor suppressor gene, replace an inadequately expressed protein, or inhibit an oncogene in a given cancer type.

The concept of synthetic lethality describes the interaction between two genes such that one functionally buffers against mutations in the other. Targeting a protein and its function that compensate for a change in the quality or quantity of proteins gained or lost can prove fatal for a cancer cell. Synthetic lethality, exploiting the complex relationships of the cellular universe, aims to overcome the current limitations and develop personalized treatments for the benefit of patients. Any oncogenic signaling pathway and compensatory coping mechanism acting in mutant cancer cells forms the basis for the synthetic lethal strategy.

One of the most significant challenges facing the development of precision medicine is the problem of managing and understanding clinical and genomic data. The genetic concept of synthetic lethality has been applied to the DNA damage response and clinically validated through the efficacy of poly (ADP-ribose) polymerase (PARP) inhibitors for the treatment of tumors in individuals with loss-of-function germline mutations in BRCA1 and BRCA2 genes. Further promising strategies involve the MAT2A/PRMT5/RIOK1 axis. Exploitation of CRISPR-Cas9 and shRNA technology has revealed a large number of synthetic lethal interactions involving epigenetic-related genes, such as those encoding the SWI/SNF complex, the PRC2 complex, SETD2, KMT2C, and MLL proteins.

In the highly correlated system of the cell, many pairs of codependent functions are expected to be active as cascading consequences of genetic and epigenetic oncogenic alterations. Application of the synthetic lethality paradigm raises the possibility of precisely targeting subgroups of tumors defined by a molecular alteration.

Synthetic lethality is an engine for the discovery of anticancer drug targets. The combination of high-throughput screening with CRISPR-Cas9 and shRNA technology, omics approaches, small molecule inhibitors, and functional assays has proven to be a promising research approach. Functional genomic screening based on the genetic concept of synthetic lethality provides a way to discover drug targets in all areas of cancer cure.

We invite authors to submit experimental articles aimed at studying mechanisms and identifying strategies for developing new molecular approaches in cancer targeting which are based on synthetic lethality. Contributions can involve any molecular mechanism in the fields of genetics, epigenetics, protein function, and cell metabolism in human or nonhuman models. Findings based on bioinformatic approaches are welcome.

We also call for studies to validate combinatorial cancer treatments resulting from the synthetic lethal approach.

We accept review articles that help researchers to clarify past results and propose ideas for new approaches and strategies.

Dr. Giorgio Malpeli
Dr. Maria Bencivenga
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. Journal of Personalized Medicine is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). 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

  • synthetic lethality
  • genetic interaction
  • functional genomics
  • drug resistance mechanisms
  • targeted therapy
  • combinatorial treatment
  • CRISPR/Cas9 screening
  • oncogene addiction
  • checkpoint inhibitor treatments
  • DNA repair inhibitors

Published Papers (3 papers)

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Research

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27 pages, 1026 KiB  
Article
Landscape of Druggable Molecular Pathways Downstream of Genomic CDH1/Cadherin-1 Alterations in Gastric Cancer
by Giorgio Malpeli, Stefano Barbi, Giulio Innamorati, Mariella Alloggio, Federica Filippini, Ilaria Decimo, Claudia Castelli, Roberto Perris and Maria Bencivenga
J. Pers. Med. 2022, 12(12), 2006; https://doi.org/10.3390/jpm12122006 - 3 Dec 2022
Cited by 3 | Viewed by 1609
Abstract
Loss of CDH1/Cadherin-1 is a common step towards the acquisition of an abnormal epithelial phenotype. In gastric cancer (GC), mutation and/or downregulation of CDH1/Cadherin-1 is recurrent in sporadic and hereditary diffuse GC type. To approach the molecular events downstream of CDH1/Cadherin-1 alterations and [...] Read more.
Loss of CDH1/Cadherin-1 is a common step towards the acquisition of an abnormal epithelial phenotype. In gastric cancer (GC), mutation and/or downregulation of CDH1/Cadherin-1 is recurrent in sporadic and hereditary diffuse GC type. To approach the molecular events downstream of CDH1/Cadherin-1 alterations and their relevance in gastric carcinogenesis, we queried public databases for genetic and DNA methylation data in search of molecular signatures with a still-uncertain role in the pathological mechanism of GC. In all GC subtypes, modulated genes correlating with CDH1/Cadherin-1 aberrations are associated with stem cell and epithelial-to-mesenchymal transition pathways. A higher level of genes upregulated in CDH1-mutated GC cases is associated with reduced overall survival. In the diffuse GC (DGC) subtype, genes downregulated in CDH1-mutated compared to cases with wild type CDH1/Cadherin-1 resulted in being strongly intertwined with the DREAM complex. The inverse correlation between hypermethylated CpGs and CDH1/Cadherin-1 transcription in diverse subtypes implies a common epigenetic program. We identified nonredundant protein-encoding isoforms of 22 genes among those differentially expressed in GC compared to normal stomach. These unique proteins represent potential agents involved in cell transformation and candidate therapeutic targets. Meanwhile, drug-induced and CDH1/Cadherin-1 mutation-related gene expression comparison predicts FIT, GR-127935 hydrochloride, amiodarone hydrochloride in GC and BRD-K55722623, BRD-K13169950, and AY 9944 in DGC as the most effective treatments, providing cues for the design of combined pharmacological treatments. By integrating genetic and epigenetic aspects with their expected functional outcome, we unveiled promising targets for combinatorial pharmacological treatments of GC. Full article
(This article belongs to the Special Issue Advances in Synthetic Lethality for Personalized Cancer Treatments)
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19 pages, 4555 KiB  
Article
Therapeutic Interaction of Apatinib and Chidamide in T-Cell Acute Lymphoblastic Leukemia through Interference with Mitochondria Associated Biogenesis and Intrinsic Apoptosis
by Mengya Zhong, Fusheng Lin, Yuelong Jiang, Guangchao Pan, Jinshui Tan, Hui Zhou, Qian Lai, Qinwei Chen, Manman Deng, Jie Zha and Bing Xu
J. Pers. Med. 2021, 11(10), 977; https://doi.org/10.3390/jpm11100977 - 29 Sep 2021
Cited by 3 | Viewed by 2225
Abstract
T-cell acute lymphoblastic leukemia (T-ALL) shows poor clinical outcome and has limited therapeutic options, indicating that new treatment approaches for this disease are urgently required. Our previous study demonstrated that apatinib, an orally selective VEGFR-2 antagonist, is highly effective in T-ALL. Additionally, chidamide, [...] Read more.
T-cell acute lymphoblastic leukemia (T-ALL) shows poor clinical outcome and has limited therapeutic options, indicating that new treatment approaches for this disease are urgently required. Our previous study demonstrated that apatinib, an orally selective VEGFR-2 antagonist, is highly effective in T-ALL. Additionally, chidamide, a histone deacetylase inhibitor, has proven to be cytotoxic against T-ALL in preclinical and clinical settings. However, whether the therapeutic interaction of apatinib and chidamide in T-ALL remains unknown. In this study, apatinib and chidamide acted additively to decrease cell viability and induce apoptosis in T-ALL in vitro. Notably, compared with apatinib or chidamide alone, the combinational regimen was more efficient in abrogating the leukemia burden in the spleen and bone marrow of T-ALL patient-derived xenograft (PDX) models. Mechanistically, the additive antileukemia effect of apatinib and chidamide was associated with suppression of mitochondrial respiration and downregulation of the abundance levels of several rate-limiting enzymes that are involved in the citric acid cycle and oxidative phosphorylation (OXPHOS). In addition, apatinib enhanced the antileukemia effect of chidamide on T-ALL via activation of the mitochondria-mediated apoptosis pathway and impediment of mitochondrial biogenesis. Taken together, the study provides a potential role for apatinib in combination with chidamide in the management of T-ALL and warrants further clinical evaluations of this combination in patients with T-ALL. Full article
(This article belongs to the Special Issue Advances in Synthetic Lethality for Personalized Cancer Treatments)
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Review

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10 pages, 880 KiB  
Review
Harnessing Synthetic Lethal Interactions for Personalized Medicine
by Grace S. Shieh
J. Pers. Med. 2022, 12(1), 98; https://doi.org/10.3390/jpm12010098 - 12 Jan 2022
Cited by 5 | Viewed by 2816
Abstract
Two genes are said to have synthetic lethal (SL) interactions if the simultaneous mutations in a cell lead to lethality, but each individual mutation does not. Targeting SL partners of mutated cancer genes can kill cancer cells but leave normal cells intact. The [...] Read more.
Two genes are said to have synthetic lethal (SL) interactions if the simultaneous mutations in a cell lead to lethality, but each individual mutation does not. Targeting SL partners of mutated cancer genes can kill cancer cells but leave normal cells intact. The applicability of translating this concept into clinics has been demonstrated by three drugs that have been approved by the FDA to target PARP for tumors bearing mutations in BRCA1/2. This article reviews applications of the SL concept to translational cancer medicine over the past five years. Topics are (1) exploiting the SL concept for drug combinations to circumvent tumor resistance, (2) using synthetic lethality to identify prognostic and predictive biomarkers, (3) applying SL interactions to stratify patients for targeted and immunotherapy, and (4) discussions on challenges and future directions. Full article
(This article belongs to the Special Issue Advances in Synthetic Lethality for Personalized Cancer Treatments)
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