Tagged: Oncotarget

Synergistic Effects of Drug Combinations Targeting AML Cells

In this new study, researchers investigated a promising new approach to acute myeloid leukemia (AML) therapy by combining multiple drugs to enhance cytotoxic effects on AML cells.

Acute myeloid leukemia (AML) is a cancer characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells. ABT199, also known as venetoclax, is a targeted therapy that inhibits the BCL-2 protein, which is often overexpressed in AML cells and contributes to their survival. By blocking this protein, venetoclax can trigger apoptosis, or programmed cell death, in cancer cells. Thiotepa, a DNA alkylating agent, has been used in conditioning regimens for hematopoietic stem cell transplantation (HSCT) but its combination with ABT199/venetoclax has not been thoroughly explored, until now.

In a new study, researchers Benigno C. Valdez, Bin Yuan, David Murray, Jeremy L. Ramdial, Uday Popat, Yago Nieto, and Borje S. Andersson from The University of Texas MD Anderson Cancer Center and the University of Alberta investigated a promising new approach to AML therapy by combining multiple drugs to enhance cytotoxic effects on AML cells. On March 14, 2024, their new research paper was published in Oncotarget’s Volume 15, entitled, “ABT199/venetoclax synergism with thiotepa enhances the cytotoxicity of fludarabine, cladribine and busulfan in AML cells.”

“The results may provide relevant information for the design of clinical trials using these drugs to circumvent recognized drug-resistance mechanisms when used as part of pre-transplant conditioning regimens for AML patients undergoing allogenic HSCT.”

The Study

In this study, the researchers demonstrated a notable synergistic effect between ABT199/venetoclax and thiotepa, significantly amplifying cytotoxicity against AML cells. This effect was further magnified when these drugs were combined with fludarabine, cladribine, and busulfan, well-established chemotherapeutic agents renowned for their efficacy in AML treatment.

One pivotal discovery of the research lies in elucidating the molecular mechanism behind this heightened cytotoxicity. The combined drug regimen led to increased cleavage of Caspase 3, PARP1, and HSP90, recognized markers of apoptosis, indicative of a robust activation of the cell death pathway. Additionally, heightened Annexin V positivity, an indicator of early apoptosis stages, was observed, suggesting the effective initiation of cell death in AML cells.

The investigation also shed light on an augmented DNA damage response, evidenced by elevated levels of γ-H2AX, P-CHK1 (S317), P-CHK2 (S19), and P-SMC1 (S957). These markers imply that the drug combination not only induces apoptosis but also contributes to the accumulation of DNA damage in AML cells, further fostering their demise.

Another significant outcome was the activation of stress signaling pathways, reflected in increased levels of P-SAPK/JNK (T183/Y185) and decreased P-PI3Kp85 (Y458). These alterations indicate cellular stress induced by drug treatment, potentially heightening sensitivity to the cytotoxic effects of the combination therapy.

Furthermore, the study addressed the pressing issue of drug resistance, commonly encountered in AML treatment. The five-drug combination notably decreased the levels of BCL-2, BCL-xL, and MCL-1, proteins associated with resistance to venetoclax, suggesting potential efficacy in overcoming resistance and improving treatment outcomes for AML patients. Various AML cell lines, including those with P53-negative and FLT3-ITD-positive mutations associated with poor prognosis, were subjected to the drug combination.

Results & Conclusion

The results exhibited promising activity of the combination therapy against these challenging cell lines. Moreover, extending the findings to clinical relevance, the drug combination was tested on leukemia patient-derived cell samples, revealing enhanced activation of apoptosis, which hints at potential effectiveness in a clinical setting and provides a basis for future clinical trials.

The implications of this research are profound, offering a novel strategy for conditioning regimens in AML patients undergoing HSCT. Combining ABT199/venetoclax and thiotepa with fludarabine, cladribine, and busulfan presents a promising approach for eradicating AML cells and preparing patients for stem cell transplantation. In conclusion, the study signifies a significant advancement in combating AML. The synergistic effects observed in combining ABT199/venetoclax with thiotepa and other chemotherapeutic agents pave the way for enhancing treatment regimens. This research sets the stage for future clinical trials and the potential development of more effective therapies for AML patients.

“The results provide a rationale for clinical trials using these two- and five-drug combinations as part of a conditioning regimen for AML patients undergoing HSCT.”

Click here to read the full research paper in Oncotarget.

Oncotarget is an open-access, peer-reviewed journal that has published primarily oncology-focused research papers since 2010. These papers are available to readers (at no cost and free of subscription barriers) in a continuous publishing format at Oncotarget.com

Oncotarget is indexed and archived by PubMed/Medline, PubMed Central, Scopus, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science).

Click here to subscribe to Oncotarget publication updates.

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Identifying Biomarkers for Predicting Paclitaxel Response

In this research perspective, researchers discuss causal and correlative approaches to identify potential biomarkers for predicting paclitaxel response.

Cancer therapy has come a long way from its one-size-fits-all beginning to the awakening era of personalized medicine. This change has been largely driven by the discovery of biomarkers. Biomarkers can help refine patient selection for specific therapies. A blend of causal and correlative approaches is needed to elucidate the full potential of biomarkers in cancer research. This fusion of methodologies allows for a comprehensive exploration of biomarker efficacy, leading to more accurate predictions of drug response.

In a new paper, researchers Alberto Moscona-Nissan, Karl J. Habashy, Victor A. Arrieta, Adam M. Sonabend, and Crismita Dmello from the Universidad Panamericana School of Medicine, Northwestern University and Universidad Nacional Autónoma de México discuss causal and correlative approaches to identify potential biomarkers for predicting response to paclitaxel — a commonly used chemotherapeutic agent. On February 8, 2024, their research perspective was published in Oncotarget’s Volume 15, entitled, “Combining causal and correlative approaches to discover biomarkers of response to paclitaxel.”

“[…] studying the combination of non-overlapping biomarkers’ expression, in addition to clinical and sociodemographic data could generate predictive models for paclitaxel susceptibility.”

Combining Causal and Correlative Approaches

Paclitaxel is a mainstay of treatment for various cancers, including breast, pancreatic, ovarian, and non-small cell lung carcinomas. However, the benefit derived from paclitaxel treatment varies across patients, and a significant proportion does not receive therapeutic benefit and experiences unnecessary toxicity. The variability in response to paclitaxel underscores the need for predictive biomarkers. Predictive biomarkers of response to paclitaxel can lead to improved treatment efficacy, less unnecessary toxicity, and potentially better health outcomes.

In a recent study, researchers used a whole-genome CRISPR/Cas9 knockout to identify genes that influence paclitaxel susceptibility in gliomas. They identified 51 genes that have implications in pathways such as NFkB, toll-like receptor, and MAPK signaling, transcriptional misregulation, and apoptosis. The team also identified the signal sequence receptor 3 (SSR3) gene as a predictive biomarker for paclitaxel susceptibility.

The SSR3 gene encodes the gamma subunit of the signal sequence receptor (SSR) complex, a glycosylated membrane receptor located at the endoplasmic reticulum (ER). This complex is involved in protein translocation across the ER membrane. In the study, it was found that higher SSR3 expression correlated with increased paclitaxel susceptibility in cancer cell lines. SSR3 knockout cells showed decreased susceptibility to paclitaxel, while cells overexpressing SSR3 had increased susceptibility.

The study also revealed a link between SSR3 and the unfolded protein response (UPR) pathway, which reduces the amount of unfolded proteins in the cell under stressful conditions. A positive correlation was found between SSR3 expression and IRE1a levels in glioma PDX cells. IRE1a is a serine/threonine kinase that is involved in the UPR pathway and has been implicated in various disorders.

Conclusions & Future Directions

A significant challenge in the treatment of glioblastoma is the blood-brain barrier which limits the efficacy of paclitaxel. However, innovative strategies like convection-enhanced delivery, biodegradable wafers, peptide-drug conjugates, and low-intensity pulsed ultrasound administered with microbubbles are being developed to overcome this barrier.

The researchers also wrote in their research perspective that, after identifying a potential predictive biomarker in a training cohort of patients, it is vital to validate the finding in an independent cohort. The correlation between patients’ overall survival and SSR3 expression is currently being studied in a phase 2 trial at Northwestern University. Based on the outcomes of these validations, the predictive models can be further refined by incorporating other non-overlapping histologic and molecular biomarkers along with patient demographics. The discovery of predictive biomarkers for paclitaxel response, such as SSR3, promises to significantly impact cancer treatment. 

“Precision and personalized medicine can lead to a transition from a stochastic treatment response into predictable scenarios. Further identification of predictive biomarkers, validation, and study of combinations as predictive models is critical to generate a greater impact that can be translated to the bedside of patients.”

Click here to read the full research paper in Oncotarget.

Oncotarget is an open-access, peer-reviewed journal that has published primarily oncology-focused research papers since 2010. These papers are available to readers (at no cost and free of subscription barriers) in a continuous publishing format at Oncotarget.com

Oncotarget is indexed and archived by PubMed/Medline, PubMed Central, Scopus, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science).

Click here to subscribe to Oncotarget publication updates.

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Antitumor Effects of Sacituzumab Govitecan Plus Platinum-Based Chemotherapy

In this study, researchers investigated the antitumor effects of Sacituzumab govitecan in combination with platinum-based chemotherapy.

The relentless search for effective cancer therapies has led to numerous breakthroughs in drug discovery and development. Advancements have emerged in recent years through the promising avenue of combination therapy, where two or more drugs are used synergistically to enhance their collective therapeutic effect. This strategy has shown significant potential in overcoming drug resistance, reducing side effects, and improving patient survival rates.

In a new study, researchers Thomas M. Cardillo, Maria B. Zalath, Roberto Arrojo, Robert M. Sharkey, Serengulam V. Govindan, Chien-Hsing Chang, and David M. Goldenberg from Gilead Sciences and the Center for Molecular Medicine and Immunology demonstrated the significant antitumor effects of Sacituzumab govitecan, an anti-Trop-2-SN-38 antibody-drug conjugate, in combination with platinum-based chemotherapy. On February 22, 2024, their research paper was published in Oncotarget, entitled, “Sacituzumab govitecan plus platinum-based chemotherapy mediates significant antitumor effects in triple-negative breast, urinary bladder, and small-cell lung carcinomas.”

Sacituzumab Govitecan & Platinum-Based Chemotherapy

Sacituzumab govitecan is an innovative drug that has gained prominence in recent years due to its unique mechanism of action and remarkable antitumor effects. It is an antibody-drug conjugate composed of an anti-Trop-2-directed antibody linked with the topoisomerase I inhibitory drug, SN-38, via a proprietary hydrolysable linker. Trop-2 is a transmembrane glycoprotein that is highly expressed in various solid tumors, making it an attractive target for cancer therapy. SN-38, the active metabolite of the chemotherapy drug irinotecan, is a potent topoisomerase I inhibitor that triggers DNA damage and apoptosis in cancer cells.

Platinum-based chemotherapy, primarily cisplatin and carboplatin, is a cornerstone of cancer treatment. These drugs work by interfering with DNA replication in cancer cells, leading to cell death. However, their use is often limited by drug resistance and toxic side effects.

“Using multiple drugs to treat cancer may allow for direct activity against multiple targets simultaneously or may indirectly affect the same target through different mechanisms of action [16].”

The Study

The combination of Sacituzumab govitecan and platinum-based chemotherapy has the potential to overcome these limitations. In the current study, the researchers found this combination to produce significant antitumor effects in various cancer models, including triple-negative breast, urinary bladder, and small-cell lung carcinomas. They found that the combination treatment resulted in additive growth inhibitory effects in vitro. The combination led to significant down-regulation of anti-apoptotic proteins and up-regulation of pro-apoptotic proteins, suggesting a shift towards pro-apoptotic signaling.

The in vivo efficacy of the combination therapy was further confirmed in mice bearing human tumor xenografts. The combination of Sacituzumab govitecan and carboplatin or cisplatin resulted in significant tumor regressions in all tested models. Importantly, the combination therapy was well tolerated by the animals, indicating a favorable safety profile.

Conclusions

The findings from this study represent a significant leap forward in the field of chemotherapy combination therapy drug discovery. The team provided strong evidence to support the clinical investigation of Sacituzumab govitecan in combination with platinum-based chemotherapy for the treatment of various solid tumors. Future studies should investigate the optimal dosing and sequencing of this combination therapy to maximize its efficacy and minimize potential toxicities. Additionally, the exploration of potential biomarkers could help identify patients who are most likely to benefit from this combination therapy.

In summary, the combination of Sacituzumab govitecan (SG) and platinum-based chemotherapy holds great promise as a potent antitumor therapy. It represents a novel approach that could potentially revolutionize the treatment of various solid tumors and improve patient outcomes.

“Importantly, these data demonstrate significantly greater antitumor effects of SG plus carboplatin or cisplatin in tumor-bearing mice than monotherapies, and that they were well tolerated by the animals. Based on these results, SG plus platinum-based chemotherapeutics merit clinical investigation.”

Click here to read the full research paper in Oncotarget.

Oncotarget is an open-access, peer-reviewed journal that has published primarily oncology-focused research papers since 2010. These papers are available to readers (at no cost and free of subscription barriers) in a continuous publishing format at Oncotarget.com

Oncotarget is indexed and archived by PubMed/Medline, PubMed Central, Scopus, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science).

Click here to subscribe to Oncotarget publication updates.

For media inquiries, please contact media@impactjournals.com.

Raw Areca Nut Betel Quid Consumption and Esophageal Cancer

In this new study, researchers provide valuable insights into raw areca nut betel quid consumption and esophageal cancer.


Betel quid chewing, a traditional custom widely practiced in South Asia, Southeast Asia, the Asia-Pacific region, and East Africa for centuries, involves the consumption of raw areca nut mixed with slaked lime and wrapped in a betel leaf. This habit is particularly popular in certain regions, including Northeast India, where the areca nut is raw, wet, and consumed unprocessed. The act of chewing and swallowing this mixture leads to the release of alkaloids, polyphenols, and tannins. However, the consumption of raw areca nut betel quid has been strongly associated with the development of oral, esophageal, and gastric cancers, and has adverse consequences on oral health. Several studies have shown a significant relationship between periodontitis and betel quid chewing habits in many countries, including India.

In this context, esophageal cancer is a devastating disease that affects millions of people around the world. Recent research has shed light on the role of the Mad2 gene in the development and progression of esophageal cancer, a disease strongly associated with the consumption of raw areca nut betel quid. In a new study, researchers Chongtham Sovachandra Singh, Nabamita Boruah, Atanu Banerjee, Sillarine Kurkalang, Pooja Swargiary, Hughbert Dakhar, and Anupam Chatterjee from The Assam Royal Global University, University of Pennsylvania, LN Mithila University, University of Chicago Medicine, Nazareth Hospital, Laitumkhrah, and North-Eastern Hill University provide valuable insights into the molecular mechanisms underlying Mad2 gene deregulation in esophageal cancer. On February 5, 2024, their new research paper was published in Oncotarget’s Volume 15, entitled, “Differential expression of Mad2 gene is consequential to the patterns of histone H3 post-translational modifications in its promoter region in human esophageal cancer samples.”

Understanding the Mad2 Gene & Raw Areca Nut Betel Quid Consumption

The Mad2 gene, also known as the Mitotic Arrest Deficient 2 gene, plays a crucial role in regulating the spindle assembly checkpoint (SAC) during cell division. The SAC is responsible for ensuring the accurate distribution of chromosomes between daughter cells, preventing the formation of aneuploid cells. Aneuploidy, characterized by an abnormal number of chromosomes, is a hallmark of cancer and can drive tumor development and progression.

Building on this understanding, the researchers in this study turned their attention to the impact of raw areca nut betel quid consumption on Mad2 gene expression in esophageal cancer. They analyzed 131 esophageal cancer biopsies and peripheral blood samples from patients with a history of raw areca nut betel quid consumption. Using quantitative real-time PCR (qRT-PCR) and immunohistochemistry (IHC), they assessed the expression of the Mad2 gene. The results revealed that 41% of the samples overexpressed Mad2, while 50% showed downregulation.

To delve deeper into the underlying mechanisms of Mad2 gene deregulation, the researchers examined the patterns of histone H3 post-translational modifications in the promoter region of the Mad2 gene. Histone proteins, which play a crucial role in regulating gene expression by modulating the accessibility of DNA to the transcriptional machinery, were the focus of this part of the study. They specifically looked at modifications, including histone methylation (H3K4me3, H3K9me3) and histone acetylation (H3K9ac, H3K27ac), which are known to affect gene expression.

In order to assess the recruitment of these histone modifications in the Mad2 gene promoter region, Chromatin immunoprecipitation (ChIP) assays were performed on esophageal tumor tissues and adjacent normal tissues. The results revealed a significant decrease in H3K4me3 and H3K9ac levels in tumor tissues where Mad2 was underexpressed, while an increase in these modifications was observed in tumor tissues with Mad2 overexpression. Interestingly, repressive histone modifications such as H3K9me3 and H3K27me3 showed the opposite pattern.

Finally, the researchers conducted a loss of heterozygosity (LOH) analysis on a panel of 99 esophageal cancer tissues using microsatellite markers mapped to chromosome 4q, where the Mad2 gene is located. This analysis revealed deletions in at least one marker in 62% of the samples with a history of raw areca nut betel quid consumption. The most frequent deletion was observed in the 4q27 region, which is in close proximity to the Mad2 gene, providing further insight into the potential mechanisms of Mad2 deregulation in esophageal cancer.

Conclusions

The study provides valuable insights into the molecular mechanisms underlying Mad2 gene deregulation in esophageal cancer. The disruption of the 4q27 region, coupled with altered histone modifications, plays a crucial role in reducing Mad2 expression in raw areca nut-induced esophageal carcinogenesis. Mad2 gene expression levels can serve as a clinical biomarker for identifying patients with chromosomal abnormalities.

Further research is needed to fully understand the role of the Rb-E2F1 circuit in Mad2 gene deregulation and the implications for esophageal cancer prognosis. Investigating the potential therapeutic targeting of Mad2 and its downstream signaling pathways may lead to more effective treatments for esophageal cancer patients.

The differential expression of the Mad2 gene in esophageal cancer and its association with histone H3 post-translational modifications has implications for esophageal carcinogenesis. Understanding these mechanisms may pave the way for the development of novel diagnostic and therapeutic strategies for esophageal cancer patients.

Click here to read the full research paper in Oncotarget.

Oncotarget is an open-access, peer-reviewed journal that has published primarily oncology-focused research papers since 2010. These papers are available to readers (at no cost and free of subscription barriers) in a continuous publishing format at Oncotarget.com. Oncotarget is indexed/archived on MEDLINE / PMC / PubMed.

Click here to subscribe to Oncotarget publication updates.

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Oncotarget’s Top 10 Papers Published in 2023 (Crossref Data)

Crossref is a non-profit organization that logs and updates citations for scientific publications. Each month, Crossref identifies a list of the most popular Oncotarget papers based on the number of times a DOI is successfully resolved. 

Below are Crossref’s Top 10 Oncotarget DOIs published in 2023.


#10: Everolimus downregulates STAT3/HIF-1α/VEGF pathway to inhibit angiogenesis and lymphangiogenesis in TP53 mutant head and neck squamous cell carcinoma (HNSCC)

DOI: https://doi.org/10.18632/oncotarget.28355 

Authors: Md Maksudul Alam, Janmaris Marin Fermin, Mark Knackstedt, Mackenzie J. Noonan, Taylor Powell, Landon Goodreau, Emily K. Daniel, Xiaohua Rong, Tara Moore-Medlin, Alok R. Khandelwal, and Cherie-Ann O. Nathan

Institution: LSU-Health Sciences Center  

Quote: “[…] we sought to investigate the mechanism for everolimus-induced inhibition of TP53 HNSCC.”


#9: Novel inflammation-combined prognostic index to predict survival outcomes in patients with gastric cancer

DOI: https://doi.org/10.18632/oncotarget.28353 

Authors: Noriyuki Hirahara, Takeshi Matsubara, Shunsuke Kaji, Hikota Hayashi, Yohei Sasaki, Koki Kawakami, Ryoji Hyakudomi, Tetsu Yamamoto, and Yoshitsugu Tajima

Institutions: Shimane University Faculty of Medicine and Matsue Red Cross Hospital

Quote: “In this study, the ICPI [inflammation-combined prognostic index] was devised as a novel predictive index of prognosis, and its usefulness was clarified.”


#8: Crosstalk between triple negative breast cancer and microenvironment

DOI: https://doi.org/10.18632/oncotarget.28397 

Authors: Karly Smrekar, Artem Belyakov and Kideok Jin

Institution: Albany College of Pharmacy and Health Science 

Quote: “[…] the study of immunotherapy for treating triple negative breast cancer might still be at its early stages of development but is full of future promise.”


#7: Systemic AL amyloidosis: current approach and future direction

DOI: https://doi.org/10.18632/oncotarget.28415 

Authors: Maroun Bou Zerdan, Lewis Nasr, Farhan Khalid, Sabine Allam, Youssef Bouferraa, Saba Batool, Muhammad Tayyeb, Shubham Adroja, Mahinbanu Mammadii, Faiz Anwer, Shahzad Raza, and Chakra P. Chaulagain

Institutions: SUNY Upstate Medical University, University of Texas MD Anderson Cancer Center, Monmouth Medical Center, University of Balamand, Cleveland Clinic Ohio, UnityPoint Methodist, Houston Methodist Cancer Center, and Cleveland Clinic Florida

Quote: “AL amyloidosis is a fatal disease and systemic therapy is required to prevent deposition of amyloid in other organs and prevent progressive organ failure.”


#6: Deciphering the mechanisms of action of progesterone in breast cancer

DOI: https://doi.org/10.18632/oncotarget.28455 

Authors: Gaurav Chakravorty, Suhail Ahmad, Mukul S. Godbole, Sudeep Gupta, Rajendra A. Badwe, and Amit Dutt

Institutions: Tata Memorial Centre, Homi Bhabha National Institute and MIT World Peace University 

Quote: “The mechanisms underlying the observed effects of progesterone on breast cancer outcomes are unclear.”


#5: Targeting cellular respiration as a therapeutic strategy in glioblastoma

DOI: https://doi.org/10.18632/oncotarget.28424 

Authors: Enyuan Shang, Trang Thi Thu Nguyen, Mike-Andrew Westhoff, Georg Karpel-Massler, and Markus D. Siegelin

Institutions: Columbia University Medical Center, City University of New York and Ulm University Medical Center 

Quote: “Here, we provide a brief overview of the status quo of targeting mitochondrial energy metabolism in glioblastoma and highlight a novel combination therapy.”


#4: Selective protection of normal cells from chemotherapy, while killing drug-resistant cancer cells

DOI: https://doi.org/10.18632/oncotarget.28382 

Author: Mikhail V. Blagosklonny, M.D., Ph.D. 

Institution: Roswell Park Comprehensive Cancer Center 

Quote: “Selective protection of normal cells may transform therapy of cancer.”


#3: The immunoregulatory protein CD200 as a potentially lucrative yet elusive target for cancer therapy

DOI: https://doi.org/10.18632/oncotarget.28354 

Authors: Anqi Shao and David M. Owens

Institution: Columbia University Irving Medical Center

Quote: “CD200 expression is reported across most cancer types […]” 


#2: Genomic landscape of metastatic breast cancer (MBC) patients with methylthioadenosine phosphorylase (MTAP) loss

DOI: https://doi.org/10.18632/oncotarget.28376 

Authors: Maroun Bou Zerdan, Prashanth Ashok Kumar, Elio Haroun, Nimisha Srivastava, Jeffrey Ross, and Abirami Sivapiragasam

Institutions: SUNY Upstate Medical University and Foundation Medicine, Inc. 

Quote: “In breast cancer, MTAP downregulation activates ornithine decarboxylase (ODC) which in turn leads to formation of putrescine which promotes tumor migration, invasion and angiogenesis.”


#1: Using cancer proteomics data to identify gene candidates for therapeutic targeting

DOI: https://doi.org/10.18632/oncotarget.28420 

Authors: Diana Monsivais, Sydney E. Parks, Darshan S. Chandrashekar, Sooryanarayana Varambally, and Chad J. Creighton

Institutions: Baylor College of Medicine and University of Alabama at Birmingham 

Quote: “[…] we consider some public molecular resources, including proteomics datasets, that may be leveraged to help identify gene candidates for therapeutic targeting in cancer.”

Click here to read the latest papers published by Oncotarget.

Oncotarget is an open-access, peer-reviewed journal that has published primarily oncology-focused research papers since 2010. These papers are available to readers (at no cost and free of subscription barriers) in a continuous publishing format at Oncotarget.com. Oncotarget is indexed/archived on MEDLINE / PMC / PubMed.

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New Drug May Boost Effectiveness of Glioblastoma Treatment

In a new study, researchers investigated the activity of gartisertib, a potent ATR inhibitor, alone and in combination with standard therapy in multiple glioblastoma cell lines.

Glioblastoma is a type of brain cancer that is very aggressive and difficult to treat. The current standard treatment involves surgery, radiation therapy, and chemotherapy with a drug called temozolomide (TMZ). However, many glioblastoma cells can resist the DNA-damaging effects of TMZ and radiation by activating a mechanism called the DNA damage response (DDR). This mechanism, while beneficial in normal cells, is detrimental to cancer therapy because it allows cancer cells to repair damage and continue to grow and divide. There is a need to counteract this mechanism in glioblastoma cancer cells.

In a new study, researchers Mathew Lozinski, Nikola A. Bowden, Moira C. Graves, Michael Fay, Bryan W. Day, Brett W. Stringer, and Paul A. Tooney from University of Newcastle, Hunter Medical Research Institute, GenesisCare, QIMR Berghofer Medical Research Institute, and Griffith University found that a drug called gartisertib may overcome this resistance by inhibiting a key protein involved in the DDR, called ataxia-telangiectasia and Rad3-Related protein (ATR). On January 16, 2024, the researchers published their new research paper in Oncotarget’s Volume 15, entitled, “ATR inhibition using gartisertib enhances cell death and synergises with temozolomide and radiation in patient-derived glioblastoma cell lines.”

“Here, we investigated the activity of gartisertib, a potent ATR inhibitor, alone and in combination with TMZ and/or RT in 12 patient-derived glioblastoma cell lines.”

The Study

In this study, the team tested the effects of gartisertib alone and in combination with TMZ and radiation in 12 patient-derived glioblastoma cell lines. They found that gartisertib alone reduced the viability of glioblastoma cells, and that the sensitivity was associated with the frequency of DDR mutations and the expression of genes involved in the G2 phase of the cell cycle (the phase where cells prepare for division and check for DNA damage). The researchers also found that gartisertib enhanced the cell death induced by TMZ and radiation, and that the combination was more synergistic than TMZ and radiation alone. 

Interestingly, gartisertib was more effective in glioblastoma cells that had unmethylated MGMT promoters and were resistant to TMZ and radiation. (MGMT is a gene that encodes an enzyme that can reverse the damage caused by TMZ, and its promoter is a region that controls its expression. Methylation is a chemical modification that can silence genes, so unmethylated MGMT promoters mean higher MGMT expression and more resistance to TMZ.) The researchers also analyzed the gene expression changes in glioblastoma cells treated with gartisertib, and found that the drug upregulated pathways related to the innate immune system. The researchers speculated that gartisertib may trigger an immune response against glioblastoma cells, which could enhance the anti-tumor effects of the drug.

“We showed that gartisertib alone potently reduced the cell viability of glioblastoma cell lines, where sensitivity was associated with the frequency of DDR mutations and higher expression of the G2 cell cycle pathway. ATR inhibition significantly enhanced cell death in combination with TMZ and RT and was shown to have higher synergy than TMZ+RT treatment. MGMT promoter unmethylated and TMZ+RT resistant glioblastoma cells were also more sensitive to gartisertib. Analysis of gene expression from gartisertib treated glioblastoma cells identified the upregulation of innate immune-related pathways.”

Conclusion

The study is the first to demonstrate the activity of gartisertib in patient-derived glioblastoma cell lines, and it provides evidence that ATR inhibition may be a promising strategy to improve the outcomes of glioblastoma patients. Gartisertib is a potent and selective inhibitor of ATR that has been tested in a phase 1 clinical trial for patients with advanced solid tumors. The researchers suggest that further studies are needed to evaluate the safety and efficacy of gartisertib in combination with TMZ and radiation in glioblastoma patients, and to explore the potential role of the immune system in mediating the anti-tumor effects of the drug.

“In conclusion, this study identifies gartisertib as a potent ATRi within patient-derived glioblastoma cell lines. […] Further investigation of the concept of ATR inhibition for treatment of brain tumours, especially in vivo with brain penetrant compounds, is needed to validate these findings. Lastly, ATR inhibition alters the gene expression of innate immune and inflammatory signalling pathways within glioblastoma cells, which requires additional validation and investigation as a strategy to provoke an immunomodulatory response.”

Click here to read the full research paper in Oncotarget.

Oncotarget is an open-access, peer-reviewed journal that has published primarily oncology-focused research papers since 2010. These papers are available to readers (at no cost and free of subscription barriers) in a continuous publishing format at Oncotarget.com. Oncotarget is indexed/archived on MEDLINE / PMC / PubMed.

Click here to subscribe to Oncotarget publication updates.

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Melatonin in Cancer Therapy: Lessons From 50 Years of Research

In a new research perspective, researchers discuss melatonin’s effects on cancer and the key importance of the timing of administration.

Melatonin in Cancer Therapy: Lessons From 50 Years of Research

In the realm of cancer research, the potential of melatonin as an anti-cancer agent has garnered significant attention. Over the past 50 years, numerous studies have been conducted to investigate the effects of melatonin on tumor growth and development in mice. These studies have provided valuable insights into the complex relationship between melatonin and carcinogenesis.

In a new research perspective, researchers Vladimir N. Anisimov and Alexey G. Golubev from N.N. Petrov National Medical Research Center of Oncology wrote about the history of studies of melatonin effects on cancer in mice. Their paper was published in Oncotarget on December 12, 2023, entitled, “Melatonin and carcinogenesis in mice: the 50th anniversary of relationships.”

Early Discoveries and Controversies

In 1973, Vladimir N. Anisimov and his coauthors made a groundbreaking discovery by demonstrating the inhibitory effect of melatonin on transplantable mammary tumors in mice. This pivotal study laid the foundation for subsequent investigations into the potential anti-cancer properties of melatonin. However, early studies encountered controversies regarding the consistency of melatonin’s effects on in vivo cancer models. The lack of consistency in these studies prompted further exploration of the factors influencing melatonin’s efficacy.

Importance of Timing in Melatonin Administration

One of the crucial findings in melatonin research is the significant impact of timing in melatonin administration. Bartsch and Bartsch demonstrated that the effects of melatonin on cancer in mice depend on the time of treatment. The administration of melatonin in the morning stimulated tumor growth, while late afternoon administration inhibited it. This observation highlighted the importance of considering animal conditions and the systemic effects of melatonin when evaluating its anti-cancer properties. These systemic effects may not be evident in cell cultures or ex vivo explants.

Murine Models for Melatonin and Cancer Studies

Murine models have played a pivotal role in elucidating the effects of melatonin on various types of cancer. These models have provided valuable insights into the potential utility of melatonin in oncology. Some of the notable murine models include mice grafted with murine tumors, chemically induced tumors, spontaneous carcinogenesis in mice, transgenic HER2/neu oncogene-bearing mice, and nude mice grafted with human prostate tumors. These models have allowed researchers to evaluate not only the effects of melatonin on cancer development but also its impact on the efficacy and side effects of anticancer therapies.

Melatonin’s Effects on Spontaneous Tumor Incidence

One intriguing finding in murine studies is the effect of melatonin on spontaneous tumor incidence. Anisimov et al. showed that lifelong treatment of mice with melatonin decreased the incidence of spontaneous tumors, particularly mammary carcinomas, but only at a low concentration of melatonin in drinking water. Interestingly, this effect was not observed at a high melatonin concentration. These findings suggest that the dose of melatonin may play a crucial role in its anti-cancer effects.

Melatonin’s Role in Potentiating Cytotoxic Therapy

Another area of interest in melatonin research is its potential to enhance the efficacy of cytotoxic therapy against tumors. Panchenko et al. demonstrated that the timing of melatonin administration relative to cytotoxic drug administration significantly influenced its potentiating effect on cytotoxic therapy in HER2/neu transgenic mice. This finding highlights the importance of optimizing the timing of melatonin administration in combination with other cancer treatments.

Melatonin’s Protective Effects on Side Effects

Beyond its direct anti-cancer effects, melatonin has shown promise in alleviating the side effects of cytotoxic drugs and radiation therapy. Several murine models have demonstrated the ability of melatonin to mitigate the side effects associated with these treatments. For example, melatonin was shown to alleviate the depression syndrome in mice treated with the alkylating agent temozolomide used in brain cancer therapy. Additionally, melatonin has been found to protect against ovarian follicle depletion caused by cisplatin, a commonly used chemotherapy drug. These findings suggest that melatonin may have a broader role in cancer treatment by reducing the adverse effects of traditional therapies.

Melatonin’s Effects on Metastasis and Epithelial-Mesenchymal Transition

Metastasis is a significant challenge in cancer treatment, and melatonin has shown promise in inhibiting metastatic spread. In nude mice grafted with human gastric cancer, melatonin was found to suppress lung metastases development by inhibiting the epithelial-to-mesenchymal transition (EMT). The inhibition of EMT by melatonin has also been observed in other murine models, highlighting its potential as an anti-metastatic agent. Given the crucial role of EMT in primary cancer and metastasis development, these findings have significant implications for oncology research.

Melatonin and Inflammation

Chronic inflammation is increasingly recognized as a contributing factor in cancer development and progression. Melatonin has been found to modulate inflammatory processes in murine models. In a murine model of low-grade inflammation, melatonin inhibited EMT), suggesting a potential role in suppressing cancer-related inflammation. While the direct anti-inflammatory effects of melatonin require further investigation, these findings shed light on the multifaceted mechanisms through which melatonin may exert its anti-cancer effects.

Clinical Applications and Promising Results

The employment of melatonin in clinical settings beyond its established fields does not require licensing, making it more readily accessible for testing novel applications in cancer treatment. Promising clinical results have already been reported, such as increased overall survival in prostate cancer patients with poor prognosis after combined hormone radiation treatment. These findings highlight the potential translational impact of murine studies and underscore the importance of continued research to fully understand the clinical implications of melatonin in cancer therapy.

Conclusion

Over the past 50 years, murine models have provided valuable insights into the relationship between melatonin and carcinogenesis. These studies have shed light on the importance of timing in melatonin administration, its effects on tumor incidence and metastasis, as well as its role in potentiating cytotoxic therapy and mitigating side effects. While the precise mechanisms underlying melatonin’s anti-cancer effects require further exploration, the promising results observed in both preclinical and clinical studies warrant continued investigation. As researchers continue to unravel the complexities of melatonin’s interactions with cancer, new opportunities for therapeutic interventions may emerge, offering hope for improved cancer treatment outcomes.

“The […] main lesson being that the systemic in vivo effects of melatonin on animals may overwhelm the in vitro effects found using tissue explants or cell cultures. In particular, the timing of melatonin administration is of crucial importance for using the drug, which is freely available over [the] counter and thus needs no licensing for its applications in oncology.”

Click here to read the full research perspective in Oncotarget.

Oncotarget is an open-access, peer-reviewed journal that has published primarily oncology-focused research papers since 2010. These papers are available to readers (at no cost and free of subscription barriers) in a continuous publishing format at Oncotarget.com. Oncotarget is indexed/archived on MEDLINE / PMC / PubMed.

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Can Mechanisms of Hair Loss Shed Light on Cancer and Aging?

In a 2023 study, researchers investigated hair loss and their findings may lead to a better understanding of tissue homeostasis, initiation of cancer and the aging process.

Hair follicles are dynamic structures that undergo cyclic phases of growth, regression and quiescence. The growth phase, known as anagen, lasts for several years, followed by a short regression phase called catagen. During catagen, most cells within the follicle undergo programmed cell death, but a small population of stem cells remains viable to replenish the follicle during the subsequent growth phase. Understanding the mechanisms involved in hair follicle regression is not only important for elucidating normal tissue homeostasis but also for studying pathological conditions such as cancer and aging.

In a recent study, researchers Bradley D. Keister, Kailin R. Mesa and Krastan B. Blagoev from the National Science Foundation, The Jane Coffin Childs Memorial Fund for Medical Research, Yale School of Medicine, Johns Hopkins University, Bulgarian Academy of Sciences, and Sorbonne Université shed light on the role of apoptotic cells in hair follicle regression and cell death. Their research paper was published in Oncotarget on October 19, 2023, entitled, “Apoptotic cells may drive cell death in hair follicles during their regression cycle.”

“Here, we use a quantitative analysis of the length of hair follicles during their regression cycle.”

The Role of Apoptotic Cells in Hair Follicle Regression

In this study, researchers suggest that apoptotic cells play a crucial role in driving cell death during hair follicle regression. Intravital microscopy in live mice revealed that the elimination of epithelial cells involves supra-basal cell differentiation and basal cell apoptosis, which are influenced by the synergistic action of TGF-β (transforming growth factor) and mesenchymal-epithelial interactions. The study also demonstrated that the basal epithelial cells are not internally committed to death, and the mesenchymal dermal papilla (DP) is essential in inducing apoptosis.

While the exact mechanism leading to the propagation of apoptosis towards the regenerative stem cell population remains unclear, the researchers proposed a quantitative analysis of the length of hair follicles during their regression cycle. The data obtained from this analysis suggested a propagation mechanism driven by apoptotic cells inducing apoptosis in their neighboring cells. Interestingly, the study found that apoptosis slows down as it approaches the stem cells at the end of the follicle, indicating the presence of a pro-survival signal released by these stem cells.

“In this paper we introduced a mathematical model of the hair follicle regression cycle that postulates that the regression is initiated by the dermal papilla, but that this signal affects only the cells adjacent to it.”

Hair Follicle Regression & Stem Cell Niches

To understand the dynamics of hair follicle regression, it is essential to consider the concept of stem cell niches. Adult stem cells, along with their supporting cells, form these niches, which maintain the functionality of renewable tissues in various organs. Stem cell niches have been identified in organs such as the colon, breast, skin, hair follicles, and bone marrow. Each organ has a distinct stem cell niche architecture, which can influence the rate of aging and susceptibility to cancer.

The study by Keister et al. highlights the importance of stem cell niches in hair follicle regression. The mesenchymal DP cells, located at the bottom of the follicle, were implicated in the initiation of regression through the release of a pro-apoptotic signal, possibly associated with TGF-β. While the DP cells are necessary for the initiation of regression, they are not required for the completion of the regression phase. This suggests that other mechanisms, in addition to the DP signal, contribute to the observed apoptotic propagation.

Quantitative Analysis of Hair Follicle Regression

The team conducted a quantitative analysis of hair follicle length during catagen to gain insights into the dynamics of regression. The study measured the length of hair follicles at two time points separated by 12 hours using intravital microscopy. The data revealed that shorter hair follicles regress at a slower rate compared to longer follicles. This observation suggests that the apoptotic propagation slows down as the dying cells approach the regenerative stem cell pool.

To explain the observed data, the researchers proposed a quantitative model in which apoptotic cells release a local signal that primes neighboring cells for apoptosis. Simultaneously, the stem cells release a pro-survival signal, creating a spatial gradient. This model is consistent with the experimentally measured distribution of follicle lengths and the deceleration of hair follicle regression. The simulations of the model demonstrated that the propagation of apoptosis along the follicle becomes slower and eventually stops when it reaches the stem cells.

The Power Law Distribution of Follicle Lengths

In addition to the quantitative analysis, the researchers investigated the distribution of follicle lengths during catagen. They found that the data obtained from the experiments were consistent with a power law distribution. (Note: The power law refers to the relationship between two quantities, stating that a relative change in one leads to a relative change in the other.) While the power law distribution was observed in the model, it is important to note that the biological lengths of the follicles make it challenging to have high confidence in this distribution. However, the model generated a power law probability distribution function, providing further support for its validity.

Implications & Future Directions

This research paper presents a comprehensive understanding of the role of apoptotic cells in hair follicle regression. The proposed model, which involves the interplay between apoptotic cells and stem cells, provides insights into the dynamics of regression and the maintenance of stem cell niches. Further research is needed to validate the model and explore the potential application to other stem cell niches in different organs.

The findings of this study have implications for the understanding of tissue homeostasis, initiation of cancer and the aging process. By unraveling the mechanisms behind hair follicle regression, researchers can gain valuable insights into the regulation of cell death and renewal in various tissues. This knowledge can potentially lead to advancements in regenerative medicine and the development of targeted therapies for conditions related to abnormal cell death and tissue regeneration.

“In conclusion, hair follicle regression may be governed by cell-cell induced programmed cell death, which slows down as the stem cell compartment is approached and does not affect the stem cell compartment from which the growth phase is initiated. […]. The generalization of the model to different geometries and topologies of different stem cell niches, as well as to the details of their stem cell renewal kinetics can address problems related [to] disease states like cancer and aging.”

Click here to read the full research paper in Oncotarget.

Oncotarget is an open-access, peer-reviewed journal that has published primarily oncology-focused research papers since 2010. These papers are available to readers (at no cost and free of subscription barriers) in a continuous publishing format at Oncotarget.com. Oncotarget is indexed/archived on MEDLINE / PMC / PubMed.

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Whole-Genome Doubling and Aneuploidy in Human Cancer

In a new editorial paper, researchers from Tel Aviv University discuss a recent study exploring how whole-genome doubling shapes the aneuploidy landscape of human cancers.

Whole-genome doubling (WGD) and aneuploidy are two common genomic alterations that occur in human cancers. WGD is a macro-evolutionary event that results in the duplication of the entire genome, while aneuploidy is a micro-evolutionary event that results in the gain or loss of individual chromosomes or chromosome arms. Both WGD and aneuploidy can have profound effects on cellular physiology, gene expression and genome stability, and are associated with tumor initiation, progression and drug resistance.

However, the relationship between WGD and aneuploidy is complex and context-dependent. In a new editorial paper, researchers Kavya Prasad and Uri Ben-David from Tel Aviv University discuss a recent study exploring how WGD shapes the aneuploidy landscape of human cancers. Their editorial was published in Oncotarget on April 26, 2023, and entitled, “A balancing act: how whole-genome doubling and aneuploidy interact in human cancer.”

“It is known that tumors that have undergone WGD are more permissive to aneuploidy, but whether WGD also affects aneuploidy patterns has remained an open question.”

The Study

The researchers analyzed 5,586 clinical tumor samples that had not undergone WGD (WGD-) and 3,435 tumors that had (WGD+) from The Cancer Genome Atlas (TCGA), across 22 tumor types. They found that WGD+ tumors were characterized by more promiscuous aneuploidy patterns, in line with increased aneuploidy tolerance. The relative prevalence of recurrent aneuploidies decreased in WGD+ tumors, suggesting that WGD+ tumors are more tolerant to aneuploidy than WGD- tumors. 

The genetic interactions between chromosome arms differed between WGD- and WGD+ tumors, resulting in different co-occurrence and mutual exclusivity patterns. The proportion of whole-chromosome aneuploidy was significantly higher in WGD+ tumors than in WGD- tumors, indicating that different mechanisms of aneuploidy formation are dominant in WGD- and WGD+ tumors. The authors proposed that whole-chromosome missegregation is more prevalent in WGD+ tumors due to increased centrosome amplification and multipolar mitoses.

To validate their findings from the clinical tumor analysis, the authors used human cancer cell lines that reproduced the WGD/aneuploidy interactions observed in vivo. They also induced WGD in human colon cancer cell lines by treating them with a microtubule-stabilizing drug, and followed the evolution of aneuploidy in the isogenic WGD+/WGD- cells under standard or selective conditions. These experiments confirmed that WGD alters the aneuploidy landscape of human cancer cells, and revealed a causal link between WGD and altered aneuploidy patterns.

“We note that these experiments were not powered to assess the associations between specific aneuploidies, which remain to be experimentally validated in future studies.”

Conclusions & Future Studies

In their editorial, the researchers note that their study prompts questions about how different tetraploidization methods affect aneuploidy landscapes. They used cytokinesis failure for cell lines, but processes like cell fusion could impact aneuploidy differently. Further research should explore how selection pressures shape karyotype evolution, considering factors beyond tissue type. Analyzing intra-chromosomal arm-level vs. whole-chromosomal aneuploidies may identify cancer-driving chromosome arms. Overall, this study provides novel insights into how WGD and aneuploidy interact in human cancer, and how this interaction affects tumor evolution. The authors suggest that the interaction between WGD and aneuploidy is a major contributor to tumor heterogeneity, adaptation, and drug resistance, and that targeting this interaction could be a promising therapeutic strategy.

“In summary, our recent study shows that WGD contributes to aneuploidy formation in human tumors in both qualitative and quantitative ways. Hence, we propose that the WGD status of the tumor should be taken into account when examining the tumorigenic role of individual aneuploidies or aneuploidy patterns. In general, WGD should be considered in the study of aneuploidy landscapes in human cancers.”

Click here to read the full editorial in Oncotarget.

Oncotarget is an open-access, peer-reviewed journal that has published primarily oncology-focused research papers since 2010. These papers are available to readers (at no cost and free of subscription barriers) in a continuous publishing format at Oncotarget.com. Oncotarget is indexed/archived on MEDLINE / PMC / PubMed.

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Novel GEM Model Unveils PLK1’s Role in Tumorigenesis

In a new editorial, researchers discuss a study using their team’s new genetically engineered mouse (GEM) model to assess PLK1 as a driver of oncogenic transformation.

Figure 1: The role of PLK1 in tumorigenesis and cancer heterogeneity. GEM Model

On the bright side, polo-like kinase 1 (PLK1) is considered a master regulator of the ever-important cell cycle. On the dark side, PLK1 expression (at both the mRNA and protein level) has shown to be upregulated in tumor cells, suggesting that PLK1 may also contribute to tumorigenesis. Despite this direct association, researchers studying the role of PLK1 in cancer have encountered a problem: a lack of appropriate animal models for experimentation.

“Even though studies have suggested that PLK1 contributes to tumorigenesis, the ability of PLK1 to drive oncogenic transformation on its own in vivo was still questionable due to a lack of sophisticated animal models for experimentation [18, 19].”

This problem may have been solved in 2021. In a new editorial paper, researchers Lilia Gheghiani and Zheng Fu from Virginia Commonwealth University discuss a recent study using their team’s new genetically engineered mouse (GEM) model to assess the ability of PLK1 to be a sole driver of oncogenic transformation in vivo. Their editorial was published in Oncotarget’s Volume 14 on June 27, 2023, and entitled, “The dark side of PLK1: Implications for cancer and genomic instability.”

PLK1 in Tumorigenesis

“To address this important scientific question, we generated a new genetically engineered mouse (GEM) model using the CAGGS (cytomegalovirus (CMV) early enhancer/chicken β-actin) promoter to drive exogenous PLK1 expression, allowing its ubiquitous and robust gene expression in transgenic mice [20].”

In an effort to determine if PLK1 overexpression causes tumors, the researchers created a new GEM mouse model that expresses high levels of PLK1. These high levels caused various types of spontaneous tumors. The increased PLK1 levels caused defects in cell division and resulted in abnormal numbers of centrosomes and compromised cell cycle checkpoints. This allowed for the accumulation of chromosomal instability, leading to abnormal numbers of chromosomes and tumor formation. In human cancers, higher PLK1 expression was associated with an increase in genome-wide copy number alterations. Their study provides evidence that abnormal PLK1 expression can trigger chromosomal instability and tumor formation, suggesting potential therapeutic opportunities for cancers with chromosomal instability.

“In summary, this study provides a novel GEM model that recapitulates the increased PLK1 expression observed in many human cancers and demonstrates that PLK1 overexpression drives spontaneous tumor formation in multiples organs in mouse, revealing the dark side of PLK1 as a potent proto-oncogene.”

Conclusions

In conclusion, the limitations of previous studies on PLK1 and its role in cancer have been partially addressed by the development of the new GEM model created by these researchers. This model allowed the team to examine PLK1’s ability to drive oncogenic transformation in vivo. Their study demonstrates that overexpression of PLK1 leads to the formation of spontaneous tumors in multiple organs, highlighting the dark side of PLK1 as a potent proto-oncogene. The findings of this study provide valuable insights into the role of PLK1 in tumorigenesis and suggest potential therapeutic opportunities for cancers associated with chromosomal instability. This breakthrough in animal models opens up new avenues for further research in understanding the mechanisms underlying PLK1-related tumorigenesis and developing targeted therapies to combat cancer.

“Alternative therapeutic strategies, such as co-delivery systems using nanoparticles or combination therapies, are under development in order to enhance the efficacy of PLK1 inhibition [2528]. With expanding discoveries of PLK1 function and mechanisms of action, we hope that PLK1-targeted therapies will soon join the frontlines in the fight against cancer.”

Click here to read the full editorial paper in Oncotarget.

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Oncotarget is an open-access, peer-reviewed journal that has published primarily oncology-focused research papers since 2010. These papers are available to readers (at no cost and free of subscription barriers) in a continuous publishing format at Oncotarget.com. Oncotarget is indexed/archived on MEDLINE / PMC / PubMed.

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