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Novel Therapeutic Targets in Cancers
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Novel Therapeutic Targets in Cancers

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 2023) | Viewed by 41257

Special Issue Editors

Dr. Elena Levantini

E-Mail Website
Guest Editor
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA
Interests: NSCLC; murine models; therapeutic targeting; BMI1; scRNAseq; transcription factors; KRAS; EGFR; miRNA
Special Issues, Collections and Topics in MDPI journals
Dr. Daniela Sanchez Bassères

E-Mail Website
Guest Editor
Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, 05508-000 São Paulo, Brazil
Interests: NSCLC; PDAC; non-coding RNAs; cancer stem cells; metastasis; therapeutic targets; KRAS

Special Issue Information

Dear Colleagues, 

We are proposing a special issue on “Novel Therapeutic Targets in Cancer”.

In the last decades we have developed novel precision-oncology protocols that are starting to be adopted in routine clinical practice. However, despite major advances, the dream of converting solid tumors into a chronic disease is still unfulfilled, and long-term remission eludes us.

Starting from preclinical models (cell lines, organoids, murine models) we can identify oncogenic pathways, mechanisms of resistance, and novel avenues to inhibit tumor growth and metastatic spread, that will eventually enter the clinical trial portfolios. Novel technologies, such as those able to pinpoint the contribuition of tumor heterogeneity to transformation and tumor dissemination, as well as tumor evolution during drug response and recurrence, will revolutionize cancer treatment by expanding the therapeutic arsenal at our disposal. State-of-the-art precision medicine protocols require convergence of multiple interdisciplinary contributions including identification of single cell specific genetic and epigenetic alterations, discovery of diagnostic and prognostic biomarkers, implementation of efficient and specific diagnostic tools, design of genomic editing protocols, planning of well-designed therapeutic strategies that take into consideration the best sequential options to delay/prevent development of recurrence. This Special Issue welcomes original investigations as well as concise review manuscripts from experts in these relevant research fields.

The topics of interest for our Special Issue include but are not limited to:

  1. Solid tumor heterogeneity
  2. Targeted-therapy, including target identification and validation
  3. Immune-modulation
  4. RNA-based therapy
  5. Epigenetic therapy
  6. Combination therapy, considering also sequential treatments and drug holidays
  7. Cancer stem cell targeting
  8. Recurrence mechanisms
  9. Tumor evolution as defined by high-resolution transcriptomics
  10. Preclinical modeling of the heterogeneous tumor milieux

Please note: manuscripts consisting solely of bioinformatics or computational analysis of public genomic or transcriptomic databases which are not accompanied by validation (independent cohort or biological validation in vitro or in vivo) are out of scope for this section.

Dr. Elena Levantini
Dr. Daniela Sanchez Bassères
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

  • targeted therapy
  • precision-oncology
  • immune-modulation
  • cancer stem cell targeting
  • RNA-based therapy

Published Papers (16 papers)

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Editorial

Jump to: Research, Review

6 pages, 197 KiB  
Editorial
Novel Therapeutic Targets in Cancers
by Elena Levantini
Int. J. Mol. Sci. 2023, 24(19), 14660; https://doi.org/10.3390/ijms241914660 - 28 Sep 2023
Cited by 1 | Viewed by 1016
Abstract
Cancer cells can arise in any organ of the body, and their cells of origin vary depending on the tissue type [...] Full article
(This article belongs to the Special Issue Novel Therapeutic Targets in Cancers)

Research

Jump to: Editorial, Review

17 pages, 2411 KiB  
Article
The Males Absent on the First (MOF) Mediated Acetylation Alters the Protein Stability and Transcriptional Activity of YY1 in HCT116 Cells
by Tingting Wu, Bingxin Zhao, Chengyu Cai, Yuyang Chen, Yujuan Miao, Jinmeng Chu, Yi Sui, Fuqiang Li, Wenqi Chen, Yong Cai, Fei Wang and Jingji Jin
Int. J. Mol. Sci. 2023, 24(10), 8719; https://doi.org/10.3390/ijms24108719 - 13 May 2023
Cited by 1 | Viewed by 1454
Abstract
Yin Yang 1 (YY1) is a well-known transcription factor that controls the expression of many genes and plays an important role in the occurrence and development of various cancers. We previously found that the human males absent on the first (MOF)-containing histone acetyltransferase [...] Read more.
Yin Yang 1 (YY1) is a well-known transcription factor that controls the expression of many genes and plays an important role in the occurrence and development of various cancers. We previously found that the human males absent on the first (MOF)-containing histone acetyltransferase (HAT) complex may be involved in regulating YY1 transcriptional activity; however, the precise interaction between MOF-HAT and YY1, as well as whether the acetylation activity of MOF impacts the function of YY1, has not been reported. Here, we present evidence that the MOF-containing male-specific lethal (MSL) HAT complex regulates YY1 stability and transcriptional activity in an acetylation-dependent manner. First, the MOF/MSL HAT complex was bound to and acetylated YY1, and this acetylation further promoted the ubiquitin–proteasome degradation pathway of YY1. The MOF-mediated degradation of YY1 was mainly related to the 146–270 amino acid residues of YY1. Further research clarified that acetylation-mediated ubiquitin degradation of YY1 mainly occurred through lysine 183. A mutation at the YY1K183 site was sufficient to alter the expression level of p53-mediated downstream target genes, such as CDKN1A (encoding p21), and it also suppressed the transactivation of YY1 on CDC6. Furthermore, a YY1K183R mutant and MOF remarkably antagonized the clone-forming ability of HCT116 and SW480 cells facilitated by YY1, suggesting that the acetylation–ubiquitin mode of YY1 plays an important role in tumor cell proliferation. These data may provide new strategies for the development of therapeutic drugs for tumors with high expression of YY1. Full article
(This article belongs to the Special Issue Novel Therapeutic Targets in Cancers)
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17 pages, 2863 KiB  
Article
A Novel Anti-CD44 Variant 3 Monoclonal Antibody C44Mab-6 Was Established for Multiple Applications
by Hiroyuki Suzuki, Kaishi Kitamura, Nohara Goto, Kenichiro Ishikawa, Tsunenori Ouchida, Tomohiro Tanaka, Mika K. Kaneko and Yukinari Kato
Int. J. Mol. Sci. 2023, 24(9), 8411; https://doi.org/10.3390/ijms24098411 - 7 May 2023
Cited by 5 | Viewed by 2013
Abstract
Cluster of differentiation 44 (CD44) promotes tumor progression through the recruitment of growth factors and the acquisition of stemness, invasiveness, and drug resistance. CD44 has multiple isoforms including CD44 standard (CD44s) and CD44 variants (CD44v), which have common and unique functions in tumor [...] Read more.
Cluster of differentiation 44 (CD44) promotes tumor progression through the recruitment of growth factors and the acquisition of stemness, invasiveness, and drug resistance. CD44 has multiple isoforms including CD44 standard (CD44s) and CD44 variants (CD44v), which have common and unique functions in tumor development. Therefore, elucidating the function of each CD44 isoform in a tumor is essential for the establishment of CD44-targeting tumor therapy. We have established various anti-CD44s and anti-CD44v monoclonal antibodies (mAbs) through the immunization of CD44v3–10-overexpressed cells. In this study, we established C44Mab-6 (IgG1, kappa), which recognized the CD44 variant 3-encoded region (CD44v3), as determined via an enzyme-linked immunosorbent assay. C44Mab-6 reacted with CD44v3–10-overexpressed Chinese hamster ovary (CHO)-K1 cells (CHO/CD44v3–10) or some cancer cell lines (COLO205 and HSC-3) via flow cytometry. The apparent KD of C44Mab-6 for CHO/CD44v3–10, COLO205, and HSC-3 was 1.5 × 10−9 M, 6.3 × 10−9 M, and 1.9 × 10−9 M, respectively. C44Mab-6 could detect the CD44v3–10 in Western blotting and stained the formalin-fixed paraffin-embedded tumor sections in immunohistochemistry. These results indicate that C44Mab-6 is useful for detecting CD44v3 in various experiments and is expected for the application of tumor diagnosis and therapy. Full article
(This article belongs to the Special Issue Novel Therapeutic Targets in Cancers)
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17 pages, 2837 KiB  
Article
MYCN Amplification, along with Wild-Type RB1 Expression, Enhances CDK4/6 Inhibitors’ Efficacy in Neuroblastoma Cells
by Piergiuseppe De Rosa, Federica Severi, Suleman Khan Zadran, Marco Russo, Sara Aloisi, Alberto Rigamonti, Giovanni Capranico, Giorgio Milazzo and Giovanni Perini
Int. J. Mol. Sci. 2023, 24(6), 5408; https://doi.org/10.3390/ijms24065408 - 12 Mar 2023
Cited by 1 | Viewed by 2349
Abstract
Neuroblastoma (NB) is one of the primary causes of death for pediatric malignancies. Given the high heterogeneity in NB’s mutation landscape, optimizing individualized therapies is still challenging. In the context of genomic alterations, MYCN amplification is the most correlated event with poor outcomes. [...] Read more.
Neuroblastoma (NB) is one of the primary causes of death for pediatric malignancies. Given the high heterogeneity in NB’s mutation landscape, optimizing individualized therapies is still challenging. In the context of genomic alterations, MYCN amplification is the most correlated event with poor outcomes. MYCN is involved in the regulation of several cellular mechanisms, including cell cycle. Thus, studying the influence of MYCN overexpression in the G1/S transition checkpoint of the cell cycle may unveil novel druggable targets for the development of personalized therapeutical approaches. Here, we show that high expression of E2F3 and MYCN correlate with poor prognosis in NB despite the RB1 mRNA levels. Moreover, we demonstrate through luciferase reporter assays that MYCN bypasses RB function by incrementing E2F3-responsive promoter activity. We showed that MYCN overexpression leads to RB inactivation by inducing RB hyperphosphorylation during the G1 phase through cell cycle synchronization experiments. Moreover, we generated two MYCN-amplified NB cell lines conditionally knockdown (cKD) for the RB1 gene through a CRISPRi approach. Indeed, RB KD did not affect cell proliferation, whereas cell proliferation was strongly influenced when a non-phosphorylatable RB mutant was expressed. This finding revealed the dispensable role of RB in regulating MYCN-amplified NB’s cell cycle. The described genetic interaction between MYCN and RB1 provides the rationale for using cyclin/CDK complexes inhibitors in NBs carrying MYCN amplification and relatively high levels of RB1 expression. Full article
(This article belongs to the Special Issue Novel Therapeutic Targets in Cancers)
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15 pages, 1926 KiB  
Article
Hyperpolarized 13C-Pyruvate to Assess Response to Anti-PD1 Immune Checkpoint Inhibition in YUMMER 1.7 Melanoma Xenografts
by Chantale Farah, Marie-Aline Neveu, Caroline Bouzin, Zorica Knezevic, Bernard Gallez, Eleonora Leucci, Jean-François Baurain, Lionel Mignion and Bénédicte F. Jordan
Int. J. Mol. Sci. 2023, 24(3), 2499; https://doi.org/10.3390/ijms24032499 - 28 Jan 2023
Cited by 2 | Viewed by 1913
Abstract
There is currently no consensus to determine which advanced melanoma patients will benefit from immunotherapy, highlighting the critical need to identify early-response biomarkers to immune checkpoint inhibitors. The aim of this work was to evaluate in vivo metabolic spectroscopy using hyperpolarized (HP) 13 [...] Read more.
There is currently no consensus to determine which advanced melanoma patients will benefit from immunotherapy, highlighting the critical need to identify early-response biomarkers to immune checkpoint inhibitors. The aim of this work was to evaluate in vivo metabolic spectroscopy using hyperpolarized (HP) 13C-pyruvate and 13C-glucose to assess early response to anti-PD1 therapy in the YUMMER1.7 syngeneic melanoma model. The xenografts showed a significant tumor growth delay when treated with two cycles of an anti-PD1 antibody compared to an isotype control antibody. 13C-MRS was performed in vivo after the injection of hyperpolarized 13C-pyruvate, at baseline and after one cycle of immunotherapy, to evaluate early dynamic changes in 13C-pyruvate–13C-lactate exchange. Furthermore, ex vivo 13C-MRS metabolic tracing experiments were performed after U-13C-glucose injection following one cycle of immunotherapy. A significant decrease in the ratio of HP 13C-lactate to 13C-pyruvate was observed in vivo in comparison with the isotype control group, while there was a lack of change in the levels of 13C lactate and 13C alanine issued from 13C glucose infusion, following ex vivo assessment on resected tumors. Thus, these results suggest that hyperpolarized 13C-pyruvate could be used to assess early response to immune checkpoint inhibitors in melanoma patients. Full article
(This article belongs to the Special Issue Novel Therapeutic Targets in Cancers)
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19 pages, 5117 KiB  
Article
Tumor Suppressor miRNA-503 Inhibits Cell Invasion in Head and Neck Cancer through the Wnt Signaling Pathway via the WNT3A/MMP Molecular Axis
by Shang-Ju Tang, Kang-Hsing Fan, Guo-Rung You, Shiang-Fu Huang, Chung-Jan Kang, Yi-Fang Huang, Yu-Chen Huang, Joseph Tung-Chieh Chang and Ann-Joy Cheng
Int. J. Mol. Sci. 2022, 23(24), 15900; https://doi.org/10.3390/ijms232415900 - 14 Dec 2022
Cited by 7 | Viewed by 1825
Abstract
Head and neck cancer (HNC) is the fifth most common cancer worldwide, and its incidence and death rates have been consistently high throughout the past decades. MicroRNAs (miRNAs) have recently gained significant attention because of their role in the regulation of a variety [...] Read more.
Head and neck cancer (HNC) is the fifth most common cancer worldwide, and its incidence and death rates have been consistently high throughout the past decades. MicroRNAs (miRNAs) have recently gained significant attention because of their role in the regulation of a variety of biological processes via post-transcriptional silencing mechanisms. Previously, we determined a specific profile of miRNAs associated with HNC using a miRNA microarray analysis. Of the 23 miRNAs with highly altered expression in HNC cells, miR-503 was the most significantly downregulated miRNA. In this study, we confirmed that miR-503 acts as a tumor suppressor, as our results showed decreased levels of miR-503 in cancer cells and patients with HNC. We further characterized the role of miR-503 in the malignant functions of HNC. Although there was a minimal effect on cell growth, miR-503 was found to inhibit cellular invasion significantly. Algorithm-based studies identified multiple potential target genes and pathways associated with oncogenic mechanisms. The candidate target gene, WNT3A, was confirmed to be downregulated by miR-503 at both the mRNA and protein levels and validated by a reporter assay. Furthermore, miR-503 modulated multiple invasion-associated genes, including matrix metalloproteinases (MMPs), through the Wnt downstream signaling pathway. Overall, this study demonstrates that miR-503 suppresses HNC malignancy by inhibiting cell invasion through the Wnt signaling pathway via the WNT3A/MMP molecular axis. The modulation of miR-503 may be a novel therapeutic approach to intervene in cancer invasion. Full article
(This article belongs to the Special Issue Novel Therapeutic Targets in Cancers)
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13 pages, 2400 KiB  
Article
MiR-223 Exclusively Impairs In Vitro Tumor Growth through IGF1R Modulation in Rhabdomyosarcoma of Adolescents and Young Adults
by Michela Casanova, Francesca Pontis, Patrizia Ghidotti, Ilaria Petraroia, Lara Veronica Venturini, Luca Bergamaschi, Stefano Chiaravalli, Loris De Cecco, Maura Massimino, Gabriella Sozzi, Andrea Ferrari, Orazio Fortunato and Patrizia Gasparini
Int. J. Mol. Sci. 2022, 23(22), 13989; https://doi.org/10.3390/ijms232213989 - 13 Nov 2022
Cited by 4 | Viewed by 1489
Abstract
Adolescents and young adults (AYA) with rhabdomyosarcoma (RMS) form a subgroup of patients whose optimal clinical management and best possible access to care remain a challenge and whose survival rates lag behind that of children diagnosed with histologically similar tumors. A better understanding [...] Read more.
Adolescents and young adults (AYA) with rhabdomyosarcoma (RMS) form a subgroup of patients whose optimal clinical management and best possible access to care remain a challenge and whose survival rates lag behind that of children diagnosed with histologically similar tumors. A better understanding of tumor biology that differentiates children (PEDS-) from AYA-RMS could provide critical information and drive new initiatives to improve their final outcome. We investigated the functional role of miRNAs implicated in AYA-RMS development, as they have the potential to lead to discovery of new targets pathways for a more tailored treatment in these age groups of young RMS patients. MiR-223 and miR-486 were observed de-regulated in nine RMS tissues compared to their normal counterparts, yet only miR-223 replacement impaired proliferation and aggressiveness of AYA-RMS cell lines, while inducing apoptosis and determining cell cycle arrest. Interestingly, IGF1R resulted in the direct target of miR-223 in AYA-RMS cells, as demonstrated by IGF1R silencing. Our results highlight an exclusive functional role of miR-223 in AYA-RMS development and aggressiveness. Full article
(This article belongs to the Special Issue Novel Therapeutic Targets in Cancers)
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19 pages, 2659 KiB  
Article
Establishment of In Vitro and In Vivo Anticolorectal Cancer Efficacy of Lithocholic Acid-Based Imidazolium Salts
by Diana Sawicka, Agnieszka Hryniewicka, Sylwia Gohal, Anna Sadowska, Anna Pryczynicz, Katarzyna Guzińska-Ustymowicz, Emilia Sokołowska, Jacek W. Morzycki and Halina Car
Int. J. Mol. Sci. 2022, 23(13), 7019; https://doi.org/10.3390/ijms23137019 - 24 Jun 2022
Cited by 4 | Viewed by 2387
Abstract
Imidazolium salts (IMSs) are the subject of many studies showing their anticancer activities. In this research, a series of novel imidazolium salts substituted with lithocholic acid (LCA) and alkyl chains of various lengths (S1–S10) were evaluated against colon cancer [...] Read more.
Imidazolium salts (IMSs) are the subject of many studies showing their anticancer activities. In this research, a series of novel imidazolium salts substituted with lithocholic acid (LCA) and alkyl chains of various lengths (S1–S10) were evaluated against colon cancer cells. A significant reduction in the viability and metabolic activity was obtained in vitro for DLD-1 and HT-29 cell lines when treated with tested salts. The results showed that the activities of tested agents are directly related to the alkyl chain length, where S6–S8 compounds were the most cytotoxic against the DLD-1 line and S4–S10 against HT-29. The research performed on the xenograft model of mice demonstrated a lower tendency of tumor growth in the group receiving compound S6, compared with the group receiving 5-fluorouracil (5-FU). Obtained results indicate the activity of S6 in the induction of apoptosis and necrosis in induced colorectal cancer. LCA-based imidazolium salts may be candidates for chemotherapeutic agents against colorectal cancer. Full article
(This article belongs to the Special Issue Novel Therapeutic Targets in Cancers)
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Review

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20 pages, 2519 KiB  
Review
Targeting IGF2BP3 in Cancer
by Xin Liu, Jiayu Chen, Wenliang Chen, Yangtao Xu, Yang Shen and Ximing Xu
Int. J. Mol. Sci. 2023, 24(11), 9423; https://doi.org/10.3390/ijms24119423 - 29 May 2023
Cited by 5 | Viewed by 2465
Abstract
RNA-binding proteins (RBPs) can regulate multiple pathways by binding to RNAs, playing a variety of functions, such as localization, stability, and immunity. In recent years, with the development of technology, researchers have discovered that RBPs play a key role in the N6-methyladenosine (m6A) [...] Read more.
RNA-binding proteins (RBPs) can regulate multiple pathways by binding to RNAs, playing a variety of functions, such as localization, stability, and immunity. In recent years, with the development of technology, researchers have discovered that RBPs play a key role in the N6-methyladenosine (m6A) modification process. M6A methylation is the most abundant form of RNA modification in eukaryotes, which is defined as methylation on the sixth N atom of adenine in RNA. Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) is one of the components of m6A binding proteins, which plays an important role in decoding m6A marks and performing various biological functions. IGF2BP3 is abnormally expressed in many human cancers, often associated with poor prognosis. Here, we summarize the physiological role of IGF2BP3 in organisms and describe its role and mechanism in tumors. These data suggest that IGF2BP3 may be a valuable therapeutic target and prognostic marker in the future. Full article
(This article belongs to the Special Issue Novel Therapeutic Targets in Cancers)
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22 pages, 2107 KiB  
Review
CAR T Cell Therapy: A Versatile Living Drug
by Rodrigo C. De Marco, Hector J. Monzo and Päivi M. Ojala
Int. J. Mol. Sci. 2023, 24(7), 6300; https://doi.org/10.3390/ijms24076300 - 27 Mar 2023
Cited by 16 | Viewed by 7444
Abstract
After seeing a dramatic increase in the development and use of immunotherapy and precision medicine over the past few decades, oncological care now embraces the start of the adoptive cell therapy (ACT) era. This impulse towards a new treatment paradigm has been led [...] Read more.
After seeing a dramatic increase in the development and use of immunotherapy and precision medicine over the past few decades, oncological care now embraces the start of the adoptive cell therapy (ACT) era. This impulse towards a new treatment paradigm has been led by chimeric antigen receptor (CAR) T cells, the only type of ACT medicinal product to be commercialized so far. Brought about by an ever-growing understanding of cellular engineering, CAR T cells are T lymphocytes genetically modified with an appropriate DNA construct, which endows them with expression of a CAR, a fusion protein between a ligand-specific recognition domain, often an antibody-like structure, and the activating signaling domain of the T cell receptor. Through this genetic enhancement, CAR T cells are engineered from a cancer patient’s own lymphocytes to better target and kill their cancer cells, and the current amassed data on clinical outcomes point to a stream of bright developments in the near future. Herein, from concept design and present-day manufacturing techniques to pressing hurdles and bright discoveries around the corner, we review and thoroughly describe the state of the art in CAR T cell therapy. Full article
(This article belongs to the Special Issue Novel Therapeutic Targets in Cancers)
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26 pages, 2717 KiB  
Review
Promising Strategy of mPTP Modulation in Cancer Therapy: An Emerging Progress and Future Insight
by Mohammad Waseem and Bi-Dar Wang
Int. J. Mol. Sci. 2023, 24(6), 5564; https://doi.org/10.3390/ijms24065564 - 14 Mar 2023
Cited by 13 | Viewed by 2407
Abstract
Cancer has been progressively a major global health concern. With this developing global concern, cancer determent is one of the most significant public health challenges of this era. To date, the scientific community undoubtedly highlights mitochondrial dysfunction as a hallmark of cancer cells. [...] Read more.
Cancer has been progressively a major global health concern. With this developing global concern, cancer determent is one of the most significant public health challenges of this era. To date, the scientific community undoubtedly highlights mitochondrial dysfunction as a hallmark of cancer cells. Permeabilization of the mitochondrial membranes has been implicated as the most considerable footprint in apoptosis-mediated cancer cell death. Under the condition of mitochondrial calcium overload, exclusively mediated by oxidative stress, an opening of a nonspecific channel with a well-defined diameter in mitochondrial membrane allows free exchange between the mitochondrial matrix and the extra mitochondrial cytosol of solutes and proteins up to 1.5 kDa. Such a channel/nonspecific pore is recognized as the mitochondrial permeability transition pore (mPTP). mPTP has been established for regulating apoptosis-mediated cancer cell death. It has been evident that mPTP is critically linked with the glycolytic enzyme hexokinase II to defend cellular death and reduce cytochrome c release. However, elevated mitochondrial Ca2+ loading, oxidative stress, and mitochondrial depolarization are critical factors leading to mPTP opening/activation. Although the exact mechanism underlying mPTP-mediated cell death remains elusive, mPTP-mediated apoptosis machinery has been considered as an important clamp and plays a critical role in the pathogenesis of several types of cancers. In this review, we focus on structure and regulation of the mPTP complex-mediated apoptosis mechanisms and follow with a comprehensive discussion addressing the development of novel mPTP-targeting drugs/molecules in cancer treatment. Full article
(This article belongs to the Special Issue Novel Therapeutic Targets in Cancers)
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20 pages, 8426 KiB  
Review
Overcoming Acquired Drug Resistance to Cancer Therapies through Targeted STAT3 Inhibition
by Sunanda Singh, Hector J. Gomez, Shreya Thakkar, Samara P. Singh and Ashutosh S. Parihar
Int. J. Mol. Sci. 2023, 24(5), 4722; https://doi.org/10.3390/ijms24054722 - 1 Mar 2023
Cited by 8 | Viewed by 2581
Abstract
Anti-neoplastic agents for cancer treatment utilize many different mechanisms of action and, when combined, can result in potent inhibition of cancer growth. Combination therapies can result in long-term, durable remission or even cure; however, too many times, these anti-neoplastic agents lose their efficacy [...] Read more.
Anti-neoplastic agents for cancer treatment utilize many different mechanisms of action and, when combined, can result in potent inhibition of cancer growth. Combination therapies can result in long-term, durable remission or even cure; however, too many times, these anti-neoplastic agents lose their efficacy due to the development of acquired drug resistance (ADR). In this review, we evaluate the scientific and medical literature that elucidate STAT3-mediated mechanisms of resistance to cancer therapeutics. Herein, we have found that at least 24 different anti-neoplastic agents—standard toxic chemotherapeutic agents, targeted kinase inhibitors, anti-hormonal agents, and monoclonal antibodies—that utilize the STAT3 signaling pathway as one mechanism of developing therapeutic resistance. Targeting STAT3, in combination with existing anti-neoplastic agents, may prove to be a successful therapeutic strategy to either prevent or even overcome ADR to standard and novel cancer therapies. Full article
(This article belongs to the Special Issue Novel Therapeutic Targets in Cancers)
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17 pages, 1117 KiB  
Review
Quiescent Cancer Cells—A Potential Therapeutic Target to Overcome Tumor Resistance and Relapse
by Emma Lindell, Lei Zhong and Xiaonan Zhang
Int. J. Mol. Sci. 2023, 24(4), 3762; https://doi.org/10.3390/ijms24043762 - 13 Feb 2023
Cited by 9 | Viewed by 3042
Abstract
Quiescent cancer cells (QCCs) are nonproliferating cells arrested in the G0 phase, characterized by ki67low and p27high. QCCs avoid most chemotherapies, and some treatments could further lead to a higher proportion of QCCs in tumors. QCCs are also associated with [...] Read more.
Quiescent cancer cells (QCCs) are nonproliferating cells arrested in the G0 phase, characterized by ki67low and p27high. QCCs avoid most chemotherapies, and some treatments could further lead to a higher proportion of QCCs in tumors. QCCs are also associated with cancer recurrence since they can re-enter a proliferative state when conditions are favorable. As QCCs lead to drug resistance and tumor recurrence, there is a great need to understand the characteristics of QCCs, decipher the mechanisms that regulate the proliferative–quiescent transition in cancer cells, and develop new strategies to eliminate QCCs residing in solid tumors. In this review, we discussed the mechanisms of QCC-induced drug resistance and tumor recurrence. We also discussed therapeutic strategies to overcome resistance and relapse by targeting QCCs, including (i) identifying reactive quiescent cancer cells and removing them via cell-cycle-dependent anticancer reagents; (ii) modulating the quiescence-to-proliferation switch; and (iii) eliminating QCCs by targeting their unique features. It is believed that the simultaneous co-targeting of proliferating and quiescent cancer cells may ultimately lead to the development of more effective therapeutic strategies for the treatment of solid tumors. Full article
(This article belongs to the Special Issue Novel Therapeutic Targets in Cancers)
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21 pages, 1264 KiB  
Review
Therapeutic Implications of the Drug Resistance Conferred by Extracellular Vesicles Derived from Triple-Negative Breast Cancer Cells
by Yong Weon Yi
Int. J. Mol. Sci. 2023, 24(4), 3704; https://doi.org/10.3390/ijms24043704 - 12 Feb 2023
Cited by 7 | Viewed by 2033
Abstract
Anticancer drug resistance is a significant impediment in current cancer treatment. Extracellular vesicles (EVs) derived from cancer cells were recently acknowledged as a critical mechanism of drug resistance, tumor progression, and metastasis. EVs are enveloped vesicles comprising a lipid bilayer that transfers various [...] Read more.
Anticancer drug resistance is a significant impediment in current cancer treatment. Extracellular vesicles (EVs) derived from cancer cells were recently acknowledged as a critical mechanism of drug resistance, tumor progression, and metastasis. EVs are enveloped vesicles comprising a lipid bilayer that transfers various cargo, including proteins, nucleic acids, lipids, and metabolites, from an originating cell to a recipient cell. Investigating the mechanisms whereby EVs confer drug resistance is still in the early stages. In this review, I analyze the roles of EVs derived from triple-negative breast cancer cells (TNBC-EVs) in anticancer drug resistance and discuss strategies to overcome TNBC-EV-mediated drug resistance. Full article
(This article belongs to the Special Issue Novel Therapeutic Targets in Cancers)
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21 pages, 3084 KiB  
Review
CARs and Drugs: Pharmacological Ways of Boosting CAR-T-Cell Therapy
by Dennis Christoph Harrer, Jan Dörrie and Niels Schaft
Int. J. Mol. Sci. 2023, 24(3), 2342; https://doi.org/10.3390/ijms24032342 - 25 Jan 2023
Cited by 5 | Viewed by 2900
Abstract
The development of chimeric antigen receptor T cells (CAR-T cells) has marked a new era in cancer immunotherapy. Based on a multitude of durable complete remissions in patients with hematological malignancies, FDA and EMA approval was issued to several CAR products targeting lymphoid [...] Read more.
The development of chimeric antigen receptor T cells (CAR-T cells) has marked a new era in cancer immunotherapy. Based on a multitude of durable complete remissions in patients with hematological malignancies, FDA and EMA approval was issued to several CAR products targeting lymphoid leukemias and lymphomas. Nevertheless, about 50% of patients treated with these approved CAR products experience relapse or refractory disease necessitating salvage strategies. Moreover, in the vast majority of patients suffering from solid tumors, CAR-T-cell infusions could not induce durable complete remissions so far. Crucial obstacles to CAR-T-cell therapy resulting in a priori CAR-T-cell refractory disease or relapse after initially successful CAR-T-cell therapy encompass antigen shutdown and CAR-T-cell dysfunctionality. Antigen shutdown predominately rationalizes disease relapse in hematological malignancies, and CAR-T-cell dysfunctionality is characterized by insufficient CAR-T-cell proliferation and cytotoxicity frequently observed in patients with solid tumors. Thus, strategies to surmount those obstacles are being developed with high urgency. In this review, we want to highlight different approaches to combine CAR-T cells with drugs, such as small molecules and antibodies, to pharmacologically boost CAR-T-cell therapy. In particular, we discuss how certain drugs may help to counteract antigen shutdown and CAR-T-cell dysfunctionality in both hematological malignancies and solid tumors. Full article
(This article belongs to the Special Issue Novel Therapeutic Targets in Cancers)
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Review
Therapeutic Perspectives of HIV-Associated Chemokine Receptor (CCR5 and CXCR4) Antagonists in Carcinomas
by Wilfredo Alejandro González-Arriagada, Isaac E. García, René Martínez-Flores, Sebastián Morales-Pison and Ricardo D. Coletta
Int. J. Mol. Sci. 2023, 24(1), 478; https://doi.org/10.3390/ijms24010478 - 28 Dec 2022
Cited by 4 | Viewed by 2052
Abstract
The interaction between malignant cells and the tumor microenvironment is critical for tumor progression, and the chemokine ligand/receptor axes play a crucial role in this process. The CXCR4/CXCL12 and CCR5/CCL5 axes, both related to HIV, have been associated with the early (epithelial–mesenchymal transition [...] Read more.
The interaction between malignant cells and the tumor microenvironment is critical for tumor progression, and the chemokine ligand/receptor axes play a crucial role in this process. The CXCR4/CXCL12 and CCR5/CCL5 axes, both related to HIV, have been associated with the early (epithelial–mesenchymal transition and invasion) and late events (migration and metastasis) of cancer progression. In addition, these axes can also modulate the immune response against tumors. Thus, antagonists against the receptors of these axes have been proposed in cancer therapy. Although preclinical studies have shown promising results, clinical trials are needed to include these drugs in the oncological treatment protocols. New alternatives for these antagonists, such as dual CXCR4/CCR5 antagonists or combined therapy in association with immunotherapy, need to be studied in cancer therapy. Full article
(This article belongs to the Special Issue Novel Therapeutic Targets in Cancers)
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