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7.4
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Cancers
Special Issues
Cancer Targets for Personalized Therapy
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Cancer Targets for Personalized Therapy

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (31 July 2021) | Viewed by 28772

Special Issue Editors

Dr. Raffaele Di Francia

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Guest Editor
Scientific directorate ITALIAN ASSOCIATION OF PHARMACOGENOMICS AND MOLECULAR DIAGNOSTICS (IAPharmagen), via Martiri della Resistenza 61, 60125 Ancona Italy.
Interests: pharmacogenomics; personalized medicine; molecular diagnostics in the cancer field
Dr. Giancarlo Di Blasio

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Guest Editor
Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Via L. De Crecchio 7, 80138 Napoli, Italy.
Interests: pharmacogenomics; personalized medicine; molecular diagnostics in the cancer field

Special Issue Information

Summary: Currently, to plan personalized anticancer therapy, the detection and quantification of novel biomarkers and molecular targets remains a matter of great importance. Recent novel techniques, including in cancer mutational analysis, pharmacogenomics, proteomics, and metabolomics, have given rise to new efforts in performing pathological, biochemical, molecular, and immunological research to study the mechanisms of carcinogenesis, with the final aim of finding the cancer molecular targets which could be applied in clinical practice. This Special Issue aims to present the most recent studies related to the detection of old and novel biomarkers and molecular targets in various cancers. The research could consider different aspects, including A) genetic alterations in cancer, B) diagnosis using novel molecular methods, C) cancer molecular targets, E) in vitro and in vivo pharmacogenomics models for the prevention of toxic and adverse events, F) cancer metabolic and proteomic signatures and altered pathways, G) immunologic biomarkers in cancer immunotherapy, and H) clinical and preclinical studies in drug–nutrient interactions.

Dr. Raffaele Di Francia
Dr. Giancarlo Di Blasio
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. Cancers is an international peer-reviewed open access semimonthly 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 2900 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

  • pharmacogenomics
  • nutrigenomics
  • cancer
  • lymphoma biomarkers
  • target therapy
  • molecular detection methods
  • complementary and alternative medicine

Published Papers (9 papers)

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Research

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15 pages, 2091 KiB  
Article
Development and Validation of Targeted Gene Sequencing Panel Based Companion Diagnostic for Korean Patients with Solid Tumors
by Byung-Joo Min, Woo Seung Lee, Myung-Eui Seo, Kye-Hwa Lee, Seung-Yong Jeong, Ja-Lok Ku, Yeul Hong Kim, Sang-Won Shin and Ju Han Kim
Cancers 2021, 13(20), 5112; https://doi.org/10.3390/cancers13205112 - 12 Oct 2021
Viewed by 2013
Abstract
Recently, several panels using two representative targeting methods have been developed but they do not reflect racial specificity, especially for Asians. We have developed and analytically validated the Korean Pan-cancer Companion Diagnostic (CDX) Panel to apply targeted anticancer drugs to Korean patients based [...] Read more.
Recently, several panels using two representative targeting methods have been developed but they do not reflect racial specificity, especially for Asians. We have developed and analytically validated the Korean Pan-cancer Companion Diagnostic (CDX) Panel to apply targeted anticancer drugs to Korean patients based on the molecular characteristics of tumors using tumor samples without matched patient normal samples. The panel included 31 genes with reported single nucleotide variants, 9 genes with reported copy number variations, and 15 genes with predictive responses to targeted drugs under clinical testing, enabling the panel to be analyzed for the targets of 30 targeted anticancer drugs. It is cost-effective and optimized for cancer type-specific therapy in Korean cancer patients across solid cancer types while minimizing the limitations of existing approaches. In addition, the optimized filtering protocol for somatic variants from tumor-only samples enables researchers to use this panel without matched normal samples. To verify the panel, 241 frozen tumor tissues and 71 formalin-fixed paraffin-embedded (FFPE) samples from several institutes were registered. This gene screening method is expected to reduce test turnaround time and cost, making it a balanced approach to investigate solid cancer-related gene regions. Full article
(This article belongs to the Special Issue Cancer Targets for Personalized Therapy)
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12 pages, 4368 KiB  
Article
Enhanced Antitumor Effect of Trastuzumab and Duligotuzumab or Ipatasertib Combination in HER-2 Positive Gastric Cancer Cells
by Maria Maddalena Laterza, Vincenza Ciaramella, Bianca Arianna Facchini, Elisena Franzese, Carmela Liguori, Stefano De Falco, Paola Coppola, Luca Pompella, Giuseppe Tirino, Massimiliano Berretta, Liliana Montella, Gaetano Facchini, Fortunato Ciardiello and Ferdinando de Vita
Cancers 2021, 13(10), 2339; https://doi.org/10.3390/cancers13102339 - 12 May 2021
Cited by 4 | Viewed by 2255
Abstract
The anti-HER2 monoclonal antibody trastuzumab is a key drug for the treatment of HER2-positive gastric cancer (GC); however, its activity is often limited by the onset of resistance and mechanisms of resistance are still poorly understood. Several targeted agents showed synergistic activity by [...] Read more.
The anti-HER2 monoclonal antibody trastuzumab is a key drug for the treatment of HER2-positive gastric cancer (GC); however, its activity is often limited by the onset of resistance and mechanisms of resistance are still poorly understood. Several targeted agents showed synergistic activity by concomitant use with trastuzumab in vitro and are under clinical investigation. The aim of this study was to assess the antitumor activity of duligotuzumab, an anti HER3/EGFR antibody or ipatasertib, an AKT inhibitor, combined with trastuzumab in a panel of HER2-positive human gastric cancer cells (GCC), and the efficacy of such combinations in HER2-resistant cells. We have assessed the efficacy of duligotuzumab or ipatasertib and trastuzumab in combination, analyzing proliferation, migration and apoptosis and downstream intracellular signaling in vitro on human HER2-positive GCC (NCI-N87, OE33, OE19) and in negative HER2 GCC (MKN28). We observed a reduction of proliferation, migration and apoptotic rate in HER2-positive OE33, OE19 and N87 cell lines with the combination of duligotuzumab or ipatasertib plus trastuzumab. In particular, in OE33 and OE19 cell lines, the same combined treatment inhibited the activation of proteins downstream of HER2, HER3, AKT and MAPK pathways. Targeting both HER2 and HER3, or HER2 and AKT, results in an improved antitumor effect on HER2-positive GCC. Full article
(This article belongs to the Special Issue Cancer Targets for Personalized Therapy)
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14 pages, 4559 KiB  
Article
Genomic Correlates of DNA Damage in Breast Cancer Subtypes
by Esther Cabañas Morafraile, Javier Pérez-Peña, Jesús Fuentes-Antrás, Aránzazu Manzano, Pedro Pérez-Segura, Atanasio Pandiella, Eva M. Galán-Moya and Alberto Ocaña
Cancers 2021, 13(9), 2117; https://doi.org/10.3390/cancers13092117 - 27 Apr 2021
Cited by 3 | Viewed by 2468
Abstract
Among the described druggable vulnerabilities, acting on the DNA repair mechanism has gained momentum, with the approval of PARP inhibitors in several indications, including breast cancer. However, beyond the mere presence of BRCA1/BRCA2 mutations, the identification of additional biomarkers that would help to [...] Read more.
Among the described druggable vulnerabilities, acting on the DNA repair mechanism has gained momentum, with the approval of PARP inhibitors in several indications, including breast cancer. However, beyond the mere presence of BRCA1/BRCA2 mutations, the identification of additional biomarkers that would help to select tumors with an extreme dependence on DNA repair machinery would help to stratify therapeutic decisions. Gene set enrichment analyses (GSEA) using public datasets evaluating expression values between normal breast tissue and breast cancer identified a set of upregulated genes. Genes included in different pathways, such as ATM/ATR, BARD1, and Fanconi Anemia, which are involved in the DNA damage response, were selected and confirmed using molecular alterations data contained at cBioportal. Nineteen genes from these gene sets were identified to be amplified and upregulated in breast cancer but only five of them NBN, PRKDC, RFWD2, UBE2T, and YWHAZ meet criteria in all breast cancer molecular subtypes. Correlation of the selected genes with prognosis (relapse free survival, RFS, and overall survival, OS) was performed using the KM Plotter Online Tool. In last place, we selected the best signature of genes within this process whose upregulation can be indicative of a more aggressive phenotype and linked with worse outcome. In summary, we identify genomic correlates within DNA damage pathway associated with prognosis in breast cancer. Full article
(This article belongs to the Special Issue Cancer Targets for Personalized Therapy)
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18 pages, 759 KiB  
Article
Association of Polygenetic Risk Scores Related to Cell Differentiation and Inflammation with Thyroid Cancer Risk and Genetic Interaction with Dietary Intake
by Sang Shin Song, ShaoKai Huang and Sunmin Park
Cancers 2021, 13(7), 1510; https://doi.org/10.3390/cancers13071510 - 25 Mar 2021
Cited by 8 | Viewed by 2537
Abstract
The incidence of thyroid cancer continues to increase steadily, and this increasing incidence cannot be attributed solely to the overdiagnosis of microcarcinoma or technical advancements in detection methods and may also depend on environmental and genetic factors. However, the impacts and interactions of [...] Read more.
The incidence of thyroid cancer continues to increase steadily, and this increasing incidence cannot be attributed solely to the overdiagnosis of microcarcinoma or technical advancements in detection methods and may also depend on environmental and genetic factors. However, the impacts and interactions of genetic and environmental factors remain controversial, and they may differ in Eastern and Western countries. The study’s purpose was to identify single nucleotide polymorphisms of genes related to cell differentiation and inflammation to influence thyroid cancer incidence and determine interactions with lifestyles in a large city hospital-based cohort. Genetic variants were selected by genome-wide association study with thyroid cancer participants (case; n = 495) and controls without cancers (n = 56,439). SNPs having gene–gene interactions were selected by generalized multifactor dimensionality reduction. Polygenic risk scores (PRSs) were generated by summing the number of selected SNP risk alleles. PRSs of the best model included 6 SNPs, that is, DIRC3_rs6759952, GAP43_rs13059137, NRG1_rs7834206, PROM1_rs72616195, LRP1B_rs1369535, and LOC100507065_rs11175834. Participants with a high-PRS had a higher thyroid cancer risk by 3.9-fold than those with a low-PRS. The following variables were related to an increased thyroid cancer risk; female (OR = 4.21), high white blood cell count (OR = 4.03), and high energy (OR = 7.00), low alcohol (OR = 4.11), and high seaweed (OR = 4.02) intakes. These variables also interacted with PRS to influence thyroid cancer risk. Meat/noodle diet patterns interacted with PRSs to increase thyroid cancer risk (p = 0.0023). In conclusion, women with a high-PRS associated with cell differentiation and inflammation were at an elevated thyroid cancer risk. Daily energy, seaweeds, and alcohol intake interacted with PRS for thyroid cancer risk. These results could be applied to personalized nutrition plans to reduce the risk of thyroid cancer. Full article
(This article belongs to the Special Issue Cancer Targets for Personalized Therapy)
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25 pages, 2498 KiB  
Article
Mutant Kras as a Biomarker Plays a Favorable Role in FL118-Induced Apoptosis, Reactive Oxygen Species (ROS) Production and Modulation of Survivin, Mcl-1 and XIAP in Human Bladder Cancer
by Sreevidya Santha, Xiang Ling, Ieman A. M. Aljahdali, Sailee S. Rasam, Xue Wang, Jianqun Liao, Jue Wang, Christos Fountzilas, Qingyong Li, Jun Qu and Fengzhi Li
Cancers 2020, 12(11), 3413; https://doi.org/10.3390/cancers12113413 - 18 Nov 2020
Cited by 12 | Viewed by 2752
Abstract
Tumor heterogeneity in key gene mutations in bladder cancer (BC) is a major hurdle for the development of effective treatments. Using molecular, cellular, proteomics and animal models, we demonstrated that FL118, an innovative small molecule, is highly effective at killing T24 and UMUC3 [...] Read more.
Tumor heterogeneity in key gene mutations in bladder cancer (BC) is a major hurdle for the development of effective treatments. Using molecular, cellular, proteomics and animal models, we demonstrated that FL118, an innovative small molecule, is highly effective at killing T24 and UMUC3 high-grade BC cells, which have Hras and Kras mutations, respectively. In contrast, HT1376 BC cells with wild-type Ras are insensitive to FL118. This concept was further demonstrated in additional BC and colorectal cancer cells with mutant Kras versus those with wild-type Kras. FL118 strongly induced PARP cleavage (apoptosis hallmark) and inhibited survivin, XIAP and/or Mcl-1 in both T24 and UMUC3 cells, but not in the HT1376 cells. Silencing mutant Kras reduced both FL118-induced PARP cleavage and downregulation of survivin, XIAP and Mcl-1 in UMUC3 cells, suggesting mutant Kras is required for FL118 to exhibit higher anticancer efficacy. FL118 increased reactive oxygen species (ROS) production in T24 and UMUC3 cells, but not in HT1376 cells. Silencing mutant Kras in UMUC3 cells reduced FL118-mediated ROS generation. Proteomics analysis revealed that a profound and opposing Kras-relevant signaling protein is changed in UMUC3 cells and not in HT1376 cells. Consistently, in vivo studies indicated that UMUC3 tumors are highly sensitive to FL118 treatment, while HT1376 tumors are highly resistant to this agent. Silencing mutant Kras in UMUC3 cell-derived tumors decreases UMUC3 tumor sensitivity to FL118 treatment. Together, our studies revealed that mutant Kras is a favorable biomarker for FL118 targeted treatment. Full article
(This article belongs to the Special Issue Cancer Targets for Personalized Therapy)
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20 pages, 3149 KiB  
Article
Saponin-Rich Extracts and Their Acid Hydrolysates Differentially Target Colorectal Cancer Metabolism in the Frame of Precision Nutrition
by Marta Gómez de Cedrón, Joaquín Navarro del Hierro, Marina Reguero, Sonia Wagner, Adrián Bouzas, Adriana Quijada-Freire, Guillermo Reglero, Diana Martín and Ana Ramírez de Molina
Cancers 2020, 12(11), 3399; https://doi.org/10.3390/cancers12113399 - 17 Nov 2020
Cited by 6 | Viewed by 2645
Abstract
Saponins or their aglycone form, sapogenin, have recently gained interest as bioactive agents due to their biological activities, their antitumoral effects being among them. Metabolic reprogramming has been recognized as a hallmark of cancer and, together with the increased aerobic glycolysis and glutaminolysis, [...] Read more.
Saponins or their aglycone form, sapogenin, have recently gained interest as bioactive agents due to their biological activities, their antitumoral effects being among them. Metabolic reprogramming has been recognized as a hallmark of cancer and, together with the increased aerobic glycolysis and glutaminolysis, the altered lipid metabolism is considered crucial to support cancer initiation and progression. The purpose of this study was to assess and compare the inhibitory effects on colorectal cancer cell lines of saponin-rich extracts from fenugreek and quinoa (FE and QE, respectively) and their hydrolyzed extracts as sapogenin-rich extracts (HFE and HQE, respectively). By mean of the latest technology in the analysis of cell bioenergetics, we demonstrate that FE and HFE diminished mitochondrial oxidative phosphorylation and aerobic glycolysis; meanwhile, quinoa extracts did not show relevant activities. Distinct molecular mechanisms were identified for fenugreek: FE inhibited the expression of TYMS1 and TK1, synergizing with the chemotherapeutic drug 5-fluorouracil (5-FU); meanwhile, HFE inhibited lipid metabolism targets, leading to diminished intracellular lipid content. The relevance of considering the coexisting compounds of the extracts or their hydrolysis transformation as innovative strategies to augment the therapeutic potential of the extracts, and the specific subgroup of patients where each extract would be more beneficial, are discussed in the frame of precision nutrition. Full article
(This article belongs to the Special Issue Cancer Targets for Personalized Therapy)
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20 pages, 6006 KiB  
Article
p53 Loss Mediates Hypersensitivity to ETS Transcription Factor Inhibition Based on PARylation-Mediated Cell Death Induction
by Carina Dinhof, Christine Pirker, Philipp Kroiss, Dominik Kirchhofer, Lisa Gabler, Johannes Gojo, Daniela Lötsch-Gojo, Mirjana Stojanovic, Gerald Timelthaler, Franziska Ferk, Siegfried Knasmüller, Johannes Reisecker, Sabine Spiegl-Kreinecker, Peter Birner, Matthias Preusser and Walter Berger
Cancers 2020, 12(11), 3205; https://doi.org/10.3390/cancers12113205 - 30 Oct 2020
Cited by 8 | Viewed by 3031
Abstract
The small-molecule E26 transformation-specific (ETS) factor inhibitor YK-4-279 was developed for therapy of ETS/EWS fusion-driven Ewing’s sarcoma. Here we aimed to identify molecular factors underlying YK-4-279 responsiveness in ETS fusion-negative cancers. Cell viability screenings that deletion of P53 induced hypersensitization against YK-4-279 especially [...] Read more.
The small-molecule E26 transformation-specific (ETS) factor inhibitor YK-4-279 was developed for therapy of ETS/EWS fusion-driven Ewing’s sarcoma. Here we aimed to identify molecular factors underlying YK-4-279 responsiveness in ETS fusion-negative cancers. Cell viability screenings that deletion of P53 induced hypersensitization against YK-4-279 especially in the BRAFV600E-mutated colon cancer model RKO. This effect was comparably minor in the BRAF wild-type HCT116 colon cancer model. Out of all ETS transcription factor family members, especially ETS1 overexpression at mRNA and protein level was induced by deletion of P53 specifically under BRAF-mutated conditions. Exposure to YK-4-279 reverted ETS1 upregulation induced by P53 knock-out in RKO cells. Despite upregulation of p53 by YK-4-279 itself in RKOp53 wild-type cells, YK-4-279-mediated hyperphosphorylation of histone histone H2A.x was distinctly more pronounced in the P53 knock-out background. YK-4-279-induced cell death in RKOp53-knock-out cells involved hyperPARylation of PARP1, translocation of the apoptosis-inducible factor AIF into nuclei, and induction of mitochondrial membrane depolarization, all hallmarks of parthanatos. Accordingly, pharmacological PARP as well as BRAFV600E inhibition showed antagonistic activity with YK-4-279 especially in the P53 knock-out background. Taken together, we identified ETS factor inhibition as a promising strategy for the treatment of notoriously therapy-resistant p53-null solid tumours with activating MAPK mutations. Full article
(This article belongs to the Special Issue Cancer Targets for Personalized Therapy)
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Review

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32 pages, 2434 KiB  
Review
Toward a Personalized Therapy in Soft-Tissue Sarcomas: State of the Art and Future Directions
by Liliana Montella, Lucia Altucci, Federica Sarno, Carlo Buonerba, Stefano De Simone, Bianca Arianna Facchini, Elisena Franzese, Ferdinando De Vita, Salvatore Tafuto, Massimiliano Berretta and Gaetano Facchini
Cancers 2021, 13(10), 2359; https://doi.org/10.3390/cancers13102359 - 13 May 2021
Cited by 6 | Viewed by 3145
Abstract
Soft-tissue sarcomas are rare tumors characterized by pathogenetic, morphological, and clinical intrinsic variability. Median survival of patients with advanced tumors are usually chemo- and radio-resistant, and standard treatments yield low response rates and poor survival results. The identification of defined genomic alterations in [...] Read more.
Soft-tissue sarcomas are rare tumors characterized by pathogenetic, morphological, and clinical intrinsic variability. Median survival of patients with advanced tumors are usually chemo- and radio-resistant, and standard treatments yield low response rates and poor survival results. The identification of defined genomic alterations in sarcoma could represent the premise for targeted treatments. Summarizing, soft-tissue sarcomas can be differentiated into histotypes with reciprocal chromosomal translocations, with defined oncogenic mutations and complex karyotypes. If the latter are improbably approached with targeted treatments, many suggest that innovative therapies interfering with the identified fusion oncoproteins and altered pathways could be potentially resolutive. In most cases, the characteristic genetic signature is discouragingly defined as “undruggable”, which poses a challenge for the development of novel pharmacological approaches. In this review, a summary of genomic alterations recognized in most common soft-tissue sarcoma is reported together with current and future therapeutic opportunities. Full article
(This article belongs to the Special Issue Cancer Targets for Personalized Therapy)
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36 pages, 924 KiB  
Review
Response and Toxicity to Cytarabine Therapy in Leukemia and Lymphoma: From Dose Puzzle to Pharmacogenomic Biomarkers
by Raffaele Di Francia, Stefania Crisci, Angela De Monaco, Concetta Cafiero, Agnese Re, Giancarla Iaccarino, Rosaria De Filippi, Ferdinando Frigeri, Gaetano Corazzelli, Alessandra Micera and Antonio Pinto
Cancers 2021, 13(5), 966; https://doi.org/10.3390/cancers13050966 - 25 Feb 2021
Cited by 47 | Viewed by 6908
Abstract
Cytarabine is a pyrimidine nucleoside analog, commonly used in multiagent chemotherapy regimens for the treatment of leukemia and lymphoma, as well as for neoplastic meningitis. Ara-C-based chemotherapy regimens can induce a suboptimal clinical outcome in a fraction of patients. Several studies suggest that [...] Read more.
Cytarabine is a pyrimidine nucleoside analog, commonly used in multiagent chemotherapy regimens for the treatment of leukemia and lymphoma, as well as for neoplastic meningitis. Ara-C-based chemotherapy regimens can induce a suboptimal clinical outcome in a fraction of patients. Several studies suggest that the individual variability in clinical response to Leukemia & Lymphoma treatments among patients, underlying either Ara-C mechanism resistance or toxicity, appears to be associated with the intracellular accumulation and retention of Ara-CTP due to genetic variants related to metabolic enzymes. Herein, we reported (a) the latest Pharmacogenomics biomarkers associated with the response to cytarabine and (b) the new drug formulations with optimized pharmacokinetics. The purpose of this review is to provide readers with detailed and comprehensive information on the effects of Ara-C-based therapies, from biological to clinical practice, maintaining high the interest of both researcher and clinical hematologist. This review could help clinicians in predicting the response to cytarabine-based treatments. Full article
(This article belongs to the Special Issue Cancer Targets for Personalized Therapy)
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