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New Wave of Cancer Therapeutics: Challenges and Opportunities
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New Wave of Cancer Therapeutics: Challenges and Opportunities

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (20 April 2025) | Viewed by 9781

Special Issue Editor

Dr. Moon Jong Kim

E-Mail Website
Guest Editor
1. Department of Life Science, Gachon University, Seongnam, Republic of Korea
2. Gachon Advanced Institute for Health Sciences & Technology (GAIHST), Gachon University, Incheon, Republic of Korea
3. Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Republic of Korea
Interests: Wnt signaling; cancer stem cell; metastasis; cancer niche; tumor microenvironment; immune microenvironment; targeted therapy; combination therapy; immunotherapy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Given the recent blockbuster success of the Herceptin-derived antibody-drug conjugates (ADCs) Kadcyla and Enhertu, in cancer therapy, numerous biomedical groups are enthusiastically moving forward to develop the next cancer therapeutics that combine new techniques. For the past decade, new cancer-targeting technologies, such as antibody–drug conjugates (ADCs), PROTACs, molecular glue, biphasic antibodies, and antisense oligonucleotides (ASOs), have seen continuous development and explosive growth. Furthermore, accumulating knowledge based on cancer niches, metabolism, and combination therapy has continuously provided updates on the promising preclinical results in the cancer field.

I am convinced that this new wave of cutting-edge cancer therapeutics could provide a fourth or fifth generation of cancer treatments beyond the third-generation cancer treatments created by immunotherapy a decade ago.

Following the current revolutionary trends in cancer research, this Special Issue aims to compile the latest advances in basic and translational cancer research at the molecular level and therapeutic applications.

Experts in the field are invited and welcome to submit original research articles and reviews that cover a wide range of topics of recent cancer therapeutics, including promising molecular targets, advanced combination strategies, and new targeting strategies against cancer niches/metabolism. We also encourage submissions associated with the molecular mechanism underlying cancer progression, metastasis, and drug resistance. Revisiting research on existing therapeutic targets in combination with recently developed technologies such as drug conjugates (ADCs), PROTACs, molecular glue, biphasic antibodies, and antisense oligonucleotides (ASOs) is also welcomed.

Your contributions are eagerly awaited. We look forward to the insights and advancements you will bring to the field of cancer therapeutics.

Dr. Moon Jong Kim
Guest Editor

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

  • new therapeutic targets in cancers
  • advanced combination therapy strategies
  • advanced strategies for targeting cancer metabolism
  • advanced strategies for targeting the tumor microenvironment
  • antibody–drug conjugates (ADCs)
  • biphasic antibody
  • PROTAC (proteolysis-targeting chimera)
  • molecular glue
  • anti-sense oligonucleotides (ASOs)

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Published Papers (5 papers)

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Research

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23 pages, 4232 KiB  
Article
MYC Overexpression Enhances Sensitivity to MEK Inhibition in Head and Neck Squamous Cell Carcinoma
by Cuicui Yang, Xiaowu Pang, Shaolei Teng, Shamel Wilson, Xinbin Gu and Guiqin Xie
Int. J. Mol. Sci. 2025, 26(2), 588; https://doi.org/10.3390/ijms26020588 - 12 Jan 2025
Viewed by 914
Abstract
MEK inhibitors, such as trametinib, have shown therapeutic potential in head and neck squamous cell carcinoma (HNSCC). However, the factors influencing cancer cell sensitivity and resistance to MEK inhibition remain poorly understood. In our study, we observed that MEK inhibition significantly reduced the [...] Read more.
MEK inhibitors, such as trametinib, have shown therapeutic potential in head and neck squamous cell carcinoma (HNSCC). However, the factors influencing cancer cell sensitivity and resistance to MEK inhibition remain poorly understood. In our study, we observed that MEK inhibition significantly reduced the expression of MYC, a transcription factor critical for the therapeutic response. MYC overexpression markedly enhanced the sensitivity of HNSCC cells to trametinib, as evidenced by delayed wound healing and reduced colony formation. Cell cycle analysis revealed that trametinib induced a G1 phase arrest, whereas MYC overexpression accelerated cell cycle progression, with a reduced induction of p27 and p21 and diminished decreases in E2F1 and phospho-Ser2/5 levels. Flow cytometry and protein analyses demonstrated that MYC overexpression amplified trametinib-induced apoptosis and DNA damage, as evidenced by elevated levels of pro-apoptotic markers (p53, cleaved PARP, and BIM) and γH2AX. In vivo xenograft models confirmed these findings, showing increased sensitivity to trametinib in MYC-overexpressing tumors. Moreover, MEK inhibition increased autophagy in HNSCC cells, a factor critical for therapeutic resistance. Inhibiting trametinib-induced autophagy further enhanced apoptotic cell death. These findings suggest that MYC expression and autophagy play crucial roles in HNSCC’s response to MEK inhibition. Combining trametinib with autophagy inhibition may improve therapeutic outcomes in HNSCC. Full article
(This article belongs to the Special Issue New Wave of Cancer Therapeutics: Challenges and Opportunities)
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19 pages, 9839 KiB  
Article
Expression of Lumican and Osteopontin in Perivascular Areas of the Glioblastoma Peritumoral Niche and Its Value for Prognosis
by María Dolores Salinas, Pablo Rodriguez, Gonzalo Rubio and Rut Valdor
Int. J. Mol. Sci. 2025, 26(1), 192; https://doi.org/10.3390/ijms26010192 - 29 Dec 2024
Viewed by 1044
Abstract
Glioblastoma (GB) is one of the most aggressive and treatment-resistant cancers due to its complex tumor microenvironment (TME). We previously showed that GB progression is dependent on the aberrant induction of chaperone-mediated autophagy (CMA) in pericytes (PCs), which promotes TME immunosuppression through the [...] Read more.
Glioblastoma (GB) is one of the most aggressive and treatment-resistant cancers due to its complex tumor microenvironment (TME). We previously showed that GB progression is dependent on the aberrant induction of chaperone-mediated autophagy (CMA) in pericytes (PCs), which promotes TME immunosuppression through the PC secretome. The secretion of extracellular matrix (ECM) proteins with anti-tumor (Lumican) and pro-tumoral (Osteopontin, OPN) properties was shown to be dependent on the regulation of GB-induced CMA in PCs. As biomarkers are rarely studied in TME, in this work, we aimed to validate Lumican and OPN as prognostic markers in the perivascular areas of the peritumoral niche of a cohort of GB patients. Previously, we had validated their expression in GB xenografted mice presenting GB infiltration (OPN) or GB elimination (Lumican) dependent on competent or deficient CMA PCs, respectively. Then, patient sample classification by GB infiltration into the peritumoral brain parenchyma was related to GB-induced CMA in microvasculature PCs, analyzing the expression of the lysosomal receptor, LAMP-2A. Our results revealed a correlation between GB-induced CMA activity in peritumoral PCs and GB patients’ outcomes, identifying three degrees of severity. The perivascular expression of both immune activation markers, Iba1 and CD68, was related to CMA-dependent PC immune function and determined as useful for efficient GB prognosis. Lumican expression was identified in perivascular areas of patients with less severe outcome and partially co-localizing with PCs presenting low CMA activity, while OPN was primarily found in perivascular areas of patients with poor outcome and partially co-localizing with PCs presenting high CMA activity. Importantly, we found sex differences in the incidence of middle-aged patients, being significantly higher in men but with worse prognosis in women. Our results confirmed that Lumican and OPN in perivascular areas of the GB peritumoral niche are effective predictive biomarkers for evaluating prognosis and monitoring possible therapeutic immune responses dependent on PCs in tumor progression. Full article
(This article belongs to the Special Issue New Wave of Cancer Therapeutics: Challenges and Opportunities)
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17 pages, 3273 KiB  
Article
A Novel Glycoengineered Humanized Antibody Targeting DLK1 Exhibits Potent Anti-Tumor Activity in DLK1-Expressing Liver Cancer Cell Xenograft Models
by Koji Nakamura, Kota Takahashi, Izumi Sakaguchi, Takumi Satoh, Lingyi Zhang, Hiroyuki Yanai and Yukihito Tsukumo
Int. J. Mol. Sci. 2024, 25(24), 13627; https://doi.org/10.3390/ijms252413627 - 19 Dec 2024
Viewed by 1290
Abstract
Delta-like 1 homolog (DLK1), a non-canonical Notch ligand, is highly expressed in various malignant tumors, especially in hepatocellular carcinoma (HCC). CBA-1205 is an afucosylated humanized antibody against DLK1 with enhanced antibody-dependent cellular cytotoxicity (ADCC). The binding characteristics of CBA-1205 were analyzed by enzyme-linked [...] Read more.
Delta-like 1 homolog (DLK1), a non-canonical Notch ligand, is highly expressed in various malignant tumors, especially in hepatocellular carcinoma (HCC). CBA-1205 is an afucosylated humanized antibody against DLK1 with enhanced antibody-dependent cellular cytotoxicity (ADCC). The binding characteristics of CBA-1205 were analyzed by enzyme-linked immunosorbent assay and fluorescence-activated cell sorting assay. The ADCC activity of CBA-1205 was assessed. The anti-tumor efficacy of CBA-1205 was evaluated in xenograft mouse models, and toxicity and toxicokinetic profiles of CBA-1205 were evaluated in cynomolgus monkeys. CBA-1205 selectively bound to DLK1 among the Notch ligands and only to monkey and human DLK1. The binding epitope was between epidermal growth factor-like domains 1 and 2 of DLK1, which are not involved in any known physiological functions. The ADCC activity of CBA-1205 was confirmed using human peripheral blood mononuclear cells as effector cells. CBA-1205 as a single agent and in combination with lenvatinib demonstrated long-lasting anti-tumor efficacy, including tumor regression, in two liver cancer xenograft models. The toxicity and toxicokinetic profiles of CBA-1205 in cynomolgus monkeys were favorable. These findings suggest that CBA-1205 has the potential to be a useful therapeutic option for drug treatment in HCC. A phase 1 study is ongoing in patients with advanced cancers (jRCT2080225288, NCT06636435). Full article
(This article belongs to the Special Issue New Wave of Cancer Therapeutics: Challenges and Opportunities)
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Review

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20 pages, 2977 KiB  
Review
Emerging Role of the DREAM Complex in Cancer and Therapeutic Opportunities
by Ye-Jin Hwang and Moon Jong Kim
Int. J. Mol. Sci. 2025, 26(1), 322; https://doi.org/10.3390/ijms26010322 - 1 Jan 2025
Viewed by 1556
Abstract
The DREAM (dimerization partner, RB-like, E2F, and multi-vulval class B) complex is an evolutionarily conserved transcriptional repression complex that coordinates nearly one thousand target genes, primarily associated with the cell cycle processes. The formation of the DREAM complex consequently inhibits cell cycle progression [...] Read more.
The DREAM (dimerization partner, RB-like, E2F, and multi-vulval class B) complex is an evolutionarily conserved transcriptional repression complex that coordinates nearly one thousand target genes, primarily associated with the cell cycle processes. The formation of the DREAM complex consequently inhibits cell cycle progression and induces cellular quiescence. Given its unique role in cell cycle control, the DREAM complex has gained significant interest across various physiological and pathological contexts, particularly in conditions marked by dysregulated cell cycles, such as cancer. However, the specific cancer types most significantly affected by alterations in the DREAM complex are yet to be determined. Moreover, the possibility of restoring or pharmacologically targeting the DREAM complex as a therapeutic intervention against cancer remains a relatively unexplored area of research and is currently under active investigation. In this review, we provide an overview of the latest advances in understanding the DREAM complex, focusing on its role in cancer. We also explore strategies for targeting the DREAM complex as a potential approach for cancer therapeutics. Advances in understanding the precise role of the DREAM complex in cancer, combined with ongoing efforts to develop targeted therapies, may pave the way for new options in cancer therapy. Full article
(This article belongs to the Special Issue New Wave of Cancer Therapeutics: Challenges and Opportunities)
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29 pages, 3451 KiB  
Review
Antibody–Drug Conjugates—Evolution and Perspectives
by Adriana Aurelia Chis, Carmen Maximiliana Dobrea, Anca Maria Arseniu, Adina Frum, Luca-Liviu Rus, Gabriela Cormos, Cecilia Georgescu, Claudiu Morgovan, Anca Butuca, Felicia Gabriela Gligor and Andreea Loredana Vonica-Tincu
Int. J. Mol. Sci. 2024, 25(13), 6969; https://doi.org/10.3390/ijms25136969 - 26 Jun 2024
Cited by 5 | Viewed by 3954
Abstract
Antineoplastic therapy is one of the main research themes of this century. Modern approaches have been implemented to target and heighten the effect of cytostatic drugs on tumors and diminish their general/unspecific toxicity. In this context, antibody–drug conjugates (ADCs) represent a promising and [...] Read more.
Antineoplastic therapy is one of the main research themes of this century. Modern approaches have been implemented to target and heighten the effect of cytostatic drugs on tumors and diminish their general/unspecific toxicity. In this context, antibody–drug conjugates (ADCs) represent a promising and successful strategy. The aim of this review was to assess different aspects regarding ADCs. They were presented from a chemical and a pharmacological perspective and aspects like structure, conjugation and development particularities alongside effects, clinical trials, safety issues and perspectives and challenges for future use of these drugs were discussed. Representative examples include but are not limited to the following main structural components of ADCs: monoclonal antibodies (trastuzumab, brentuximab), linkers (pH-sensitive, reduction-sensitive, peptide-based, phosphate-based, and others), and payloads (doxorubicin, emtansine, ravtansine, calicheamicin). Regarding pharmacotherapy success, the high effectiveness expectation associated with ADC treatment is supported by the large number of ongoing clinical trials. Major aspects such as development strategies are first discussed, advantages and disadvantages, safety and efficacy, offering a retrospective insight on the subject. The second part of the review is prospective, focusing on various plans to overcome the previously identified difficulties. Full article
(This article belongs to the Special Issue New Wave of Cancer Therapeutics: Challenges and Opportunities)
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