Blog | Page 2 of 12 | Mikhail Blagosklonny Oncotarget

Mikhail Blagosklonny Oncotarget

SARS-CoV-2 Spike Protein Disrupts p53 Tumor Suppressor Pathway

May 9, 2024

In this new study, researchers investigated the interplay between the SARS-CoV-2 spike protein and tumor suppressor gene p53.

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The profound impact of the COVID-19 pandemic, caused by the SARS-CoV-2 virus, has been felt across various domains, including the realm of cancer research and treatment. As scientists delve deeper into the intricate mechanisms of this viral pathogen, intriguing revelations have emerged regarding its potential influence on cellular processes pivotal to cancer development and progression.

In a new study, researchers Wafik S. El-Deiry and Shengliang Zhang from Brown University and Lifespan Health System shed light on the intricate interplay between the SARS-CoV-2 spike protein and the tumor suppressor p53, a key guardian of genomic integrity. On May 3, 2024, they published their new research paper in Oncotarget’s Volume 15, entitled, “Transfected SARS-CoV-2 spike DNA for mammalian cell expression inhibits p53 activation of p21(WAF1), TRAIL Death Receptor DR5 and MDM2 proteins in cancer cells and increases cancer cell viability after chemotherapy exposure.”

The Study

In this study, researchers El-Deiry and Zhang uncovered a hitherto unknown facet of the SARS-CoV-2 spike protein’s impact on cancer cells. Their findings, meticulously detailed in their research paper, have ignited a newfound curiosity within the scientific community.

To appreciate the significance of this discovery, one must first comprehend the critical function of the p53 protein, often referred to as the “guardian of the genome.” This multifaceted tumor suppressor plays a pivotal role in safeguarding cellular integrity by regulating various processes, including cell cycle arrest, DNA repair, and apoptosis (programmed cell death). When cells encounter stress or DNA damage, p53 is activated, triggering a cascade of events aimed at preserving genomic stability or eliminating compromised cells.

The study has unveiled a remarkable phenomenon: the SARS-CoV-2 spike protein appears to disrupt the intricate balance of the p53 pathway, potentially compromising its tumor-suppressive capabilities. Through a series of meticulously designed experiments, the researchers demonstrated that the presence of the SARS-CoV-2 spike protein in cancer cells interferes with the binding of p53 to its negative regulator, MDM2.

This disruption, in turn, impedes the activation of key downstream targets of p53, including the cell cycle regulator p21(WAF1), the apoptosis-inducing TRAIL Death Receptor DR5, and even MDM2 itself. Consequently, cancer cells expressing the SARS-CoV-2 spike protein exhibited a diminished response to chemotherapeutic agents, manifested by a reduced induction of these critical p53 targets and an increased cell viability following treatment.

Implications for Cancer Therapy

The ramifications of this discovery are far-reaching, particularly in the context of cancer treatment. Chemotherapy remains a cornerstone of cancer management, and its efficacy is heavily reliant on the proper functioning of cellular mechanisms that detect and respond to DNA damage. The p53 pathway plays a pivotal role in this intricate process, acting as a sentinel that triggers cell cycle arrest or apoptosis in response to genotoxic insults.

However, the findings of this study suggest that the presence of the SARS-CoV-2 spike protein may compromise these critical defense mechanisms, potentially rendering cancer cells more resistant to chemotherapeutic agents. This revelation raises concerns about the potential impact of SARS-CoV-2 infection or the administration of spike protein-based vaccines on the efficacy of cancer treatments, particularly in individuals undergoing chemotherapy.

Mechanistic Underpinnings

While the study has shed light on the disruption of the p53 pathway by the SARS-CoV-2 spike protein, the precise mechanisms underlying this phenomenon remain to be fully elucidated. Several intriguing questions arise:

What are the structural determinants that govern the interaction between the SARS-CoV-2 spike protein and components of the p53 pathway?
Could post-translational modifications of the spike protein or p53 itself influence their functional interplay?
How do different cellular contexts, such as varying expression levels of p53 regulators or the presence of specific mutations, modulate the observed effects?
Can this newfound knowledge be leveraged to develop strategies that mitigate the potential impact of SARS-CoV-2 on cancer treatment outcomes?

Addressing these questions will require a concerted effort from the scientific community, involving multidisciplinary collaborations and a diverse array of experimental approaches.

Expanding the Scope of Investigation

While the current study focused on the interaction between the SARS-CoV-2 spike protein and the p53 pathway, it is essential to broaden the scope of investigation to encompass other viral proteins and their potential impact on cellular processes relevant to cancer development and progression. The SARS-CoV-2 genome encodes a multitude of proteins, each with the potential to interact with various host factors and signaling cascades.

Exploring these interactions may unveil additional mechanisms by which SARS-CoV-2 infection could influence tumorigenesis, metastasis, or therapeutic responses. Additionally, investigating the effects of viral proteins on DNA damage sensing, repair mechanisms, and other cellular stress response pathways could yield invaluable insights into the intricate interplay between viral infections and cancer biology.

Implications Beyond COVID-19

The findings of this study have implications that extend beyond the realm of SARS-CoV-2 and COVID-19. They underscore the importance of thoroughly evaluating the potential consequences of viral proteins or antigens employed in vaccine development on critical host pathways, such as those involved in tumor suppression and DNA damage response.

As the scientific community continues to develop novel vaccines and therapeutic interventions, it is imperative to consider the potential impact of these interventions on cellular processes essential for maintaining genomic integrity and preventing malignant transformation. Comprehensive preclinical studies and rigorous safety assessments should be undertaken to ensure that the benefits of these interventions outweigh any potential risks, particularly for individuals with pre-existing conditions or those undergoing cancer treatment.

Collaborative Efforts & Future Directions

Unraveling the complexities of the SARS-CoV-2 spike protein’s interactions with the p53 pathway and other cellular processes will require a concerted effort from researchers across various disciplines. Interdisciplinary collaborations between virologists, cancer biologists, structural biologists, and computational scientists will be crucial in elucidating the mechanistic underpinnings of these interactions and their potential implications for cancer development and treatment.

Furthermore, it is essential to conduct long-term studies to assess the potential long-term consequences of SARS-CoV-2 infection or spike protein exposure on cancer incidence and progression. Such investigations could shed light on the potential risks associated with repeated exposure to viral proteins or antigens, as in the case of booster vaccinations.

A Call for Vigilance & Proactive Measures

The findings of this groundbreaking study serve as a clarion call for increased vigilance and proactive measures within the scientific community. As we continue to navigate the complexities of viral pandemics and develop innovative therapeutic interventions, it is imperative to remain cognizant of the potential unintended consequences on critical cellular pathways, such as those involved in tumor suppression and DNA damage response.

By fostering interdisciplinary collaborations, embracing rigorous scientific inquiry, and maintaining a commitment to thorough preclinical evaluation, we can ensure that our efforts to combat viral threats do not inadvertently compromise our ability to combat cancer and other life-threatening diseases.

The path forward is one of cautious optimism, where scientific discoveries illuminate potential risks while simultaneously paving the way for novel strategies to mitigate these risks and safeguard human health. It is through this delicate balance of exploration and prudence that we can continue to make strides in our fight against both viral and malignant diseases, ensuring a brighter and healthier future for all.

Click here to read the full research 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 and archived by PubMed/Medline, PubMed Central, Scopus, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science).

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Synergistic Effects of Drug Combinations Targeting AML Cells

April 11, 2024

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.

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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.

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Identifying Biomarkers for Predicting Paclitaxel Response

March 28, 2024

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

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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.

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Antitumor Effects of Sacituzumab Govitecan Plus Platinum-Based Chemotherapy

March 14, 2024

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.

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Raw Areca Nut Betel Quid Consumption and Esophageal Cancer

February 23, 2024

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

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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.

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

February 15, 2024

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.”

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Genetic Alterations in Thyroid Cancer: Resistance to BRAFi and Anaplastic Transformation

February 8, 2024

In this new research perspective, researchers discuss the role of genetic alterations in resistance to BRAF inhibition and anaplastic transformation in thyroid cancer.

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Thyroid cancer is a complex disease with various subtypes and clinical presentations. While some cases can be successfully treated with standard therapy, others present challenges due to resistance to treatment and the development of aggressive forms of the disease. In a new research perspective, researchers Mark Lee and Luc GT Morris from New York Presbyterian Hospital and Memorial Sloan Kettering Cancer Center discuss the recent research that has shed light on the role of genetic alterations in mediating both resistance to BRAF inhibition and anaplastic transformation in thyroid cancer. On January 24, 2024, their paper was published in Oncotarget, entitled, “Genetic alterations in thyroid cancer mediating both resistance to BRAF inhibition and anaplastic transformation.”

“An improved understanding of the molecular basis of thyroid cancer has led to the development of new targeted agents.”

Understanding Thyroid Cancer and its Molecular Landscape

Thyroid cancer is generally characterized by well-differentiated histology and a relatively indolent course. However, a subset of patients presents with more advanced disease or dedifferentiated histologies that are less responsive to standard therapy. These dedifferentiated subtypes include anaplastic thyroid cancers (ATC) and poorly differentiated thyroid cancers (PDTC), which are thought to arise from a process of microevolution from papillary thyroid cancers (PTC).

The mitogen-activated protein kinase (MAPK) pathway plays a crucial role in regulating cell proliferation and differentiation. Mutations in this pathway, particularly in the BRAF gene (specifically the V600E mutation), have been identified in a significant proportion of thyroid cancers. The BRAF V600E mutation leads to constitutive activation of the MAPK pathway, resulting in dedifferentiation and tumor progression.

BRAF Inhibition as a Therapeutic Approach

Given the role of the BRAF V600E mutation in thyroid cancer, targeted agents that inhibit BRAF have been explored as potential treatments. Sorafenib and lenvatinib were the first agents approved for use in thyroid cancer but have shown limited overall survival benefits. More recent agents, such as vemurafenib and dabrafenib, specifically target the V600E mutant oncoprotein and have demonstrated promising results in early trials.

However, despite initial responses, the long-term efficacy of BRAF inhibitors is limited due to the emergence of resistance mechanisms. Multiple compensatory pathways and mutations have been observed in thyroid carcinoma cells that mediate bypass of BRAF blockade, leading to disease progression. These mechanisms can be primary, already present in the tumor, or secondary, acquired over the course of treatment.

Genetic Alterations Associated with Resistance to BRAF Inhibition

Recent studies have identified specific genetic alterations that are associated with resistance to BRAF inhibitors and anaplastic transformation in thyroid cancer. One such alteration is the presence of mutations in the PI3K/AKT/mTOR pathway, particularly in the PIK3CA gene. These mutations paradoxically hyperactivate the ERK pathway when BRAF is inhibited, leading to decreased response to therapy].

Other genetic alterations associated with resistance include mutations in the MAPK/ERK pathway (such as MET amplifications, NF2, NRAS, and RASA1), the SWI/SNF chromatin remodeling complex (ARID2 and PBRM1), and the JAK/STAT pathway (JAK1). These alterations have been observed in tumors that dedifferentiate after treatment with BRAF inhibitors, suggesting their involvement in both resistance and anaplastic transformation.

Mechanisms of Anaplastic Transformation in Thyroid Cancer

Anaplastic transformation, the transition from well-differentiated to dedifferentiated thyroid cancer, is a rare but aggressive form of the disease. The mechanisms underlying anaplastic transformation are not fully understood but likely involve genetic and molecular changes that drive the loss of cellular differentiation.

Ultrastructural analyses have shown that well-differentiated thyroid carcinomas transforming into anaplastic thyroid cancers undergo changes in cellular architecture, including the loss of tight junctions, desmosomes, and cellular polarity. Molecular alterations associated with anaplastic transformation include aneuploidy, increased copy number alterations, and mutations affecting genes such as p53, bcl-2, cyclin D1, β-catenin, Met, c-myc, Nm23, and Ras.

Overlapping Mechanisms of Resistance and Anaplastic Transformation

Recent research has revealed a significant overlap between the genetic alterations associated with resistance to BRAF inhibitors and the development of anaplastic thyroid cancer. Studies have shown that tumors that dedifferentiate after BRAF inhibition are enriched in known genetic alterations that mediate resistance to BRAF blockade, including mutations in the PI3K/AKT/mTOR, MAPK/ERK, SWI/SNF chromatin remodeling complex, and JAK/STAT pathways.

These findings suggest that selective pressures exerted by BRAF inhibition can promote the outgrowth of subclones harboring these mutations, ultimately leading to anaplastic transformation. The complex and multifactorial nature of these compensatory mechanisms underscores the need for alternative treatment strategies to address resistance and improve long-term disease control.

Immune Microenvironment in Resistance and Anaplastic Transformation

The immune microenvironment of thyroid tumors has been a topic of active investigation, as it plays a crucial role in both tumor pathogenesis and drug resistance. While BRAF inhibitors are thought to increase anti-tumor immunity, they may also have competing effects, such as driving tumor infiltration by macrophages. Anaplastic thyroid cancer is associated with changes in the immune milieu, including increased infiltration by macrophages and fibroblasts.

The immunosuppressive microenvironment observed in resistance to BRAF inhibitors and anaplastic evolution suggests a potential role for combined targeted therapy with immunotherapy. Preclinical studies have shown that the combination of BRAF inhibitors with immune checkpoint inhibitors can enhance anti-tumor immune activity. Clinical trials evaluating the efficacy of combined BRAF blockade with immunomodulatory therapies are ongoing, with preliminary results showing promising anti-tumor effects.

Current Approaches and Future Directions

The current standard therapeutic approach for locally advanced, recurrent, metastatic, and dedifferentiated thyroid cancers involves surgical resection and adjuvant radioactive iodine therapy. However, in cases where surgery is not feasible or tumors are resistant to standard therapy, targeted agents have emerged as potential treatment options.

For patients with ATCs harboring the BRAF V600E mutation, neoadjuvant combination kinase inhibition with dabrafenib plus trametinib has shown promise . Other targeted agents, such as everolimus (MTOR inhibitor), crizotinib (MET inhibitor), and PI3K inhibitors, have demonstrated antitumor activity in preclinical and early clinical studies.

Combined BRAF blockade with immunotherapy is also being investigated as a potential treatment strategy. Early clinical trials have shown promising outcomes, with significant partial response rates and stable disease rates in advanced thyroid cancers. However, further studies with long-term follow-up are needed to evaluate the real-world effectiveness of these novel immunotherapies in combination with targeted therapy.

Conclusion

Genetic alterations play a crucial role in mediating both resistance to BRAF inhibition and anaplastic transformation in thyroid cancer. Understanding the mechanisms underlying these processes is essential for developing effective treatment strategies. Targeted therapies, such as BRAF inhibitors, have shown initial promise but are limited by the emergence of compensatory mechanisms.

The identification of specific genetic alterations associated with resistance and anaplastic transformation provides insights into potential therapeutic targets. Combined targeted therapy with immunomodulatory agents is being explored as a means to enhance anti-tumor immune activity and overcome resistance. Ongoing clinical trials will further elucidate the effectiveness of these novel treatment approaches and pave the way for personalized therapies for patients with thyroid cancer.

In conclusion, the study of genetic alterations in thyroid cancer has provided valuable insights into the development of resistance to targeted therapies and the progression to more aggressive forms of the disease. By understanding the underlying mechanisms and identifying potential therapeutic targets, researchers can work towards improved treatment strategies and better outcomes for patients with thyroid cancer.

“Dual-target therapies have been trialed but with continued limitations to long-term disease control. Thyroid tumor dedifferentiation and BRAF inhibitor resistance are also found to be associated with a transition to an immunosuppressed state. Early studies on combined targeted and immune-modulated therapy have demonstrated promising outcomes. Further clinical studies are needed to test real-world effectiveness of these novel immunotherapies with targeted therapy.”

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Oncotarget

New Drug May Boost Effectiveness of Glioblastoma Treatment

January 25, 2024

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.

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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.

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Mikhail Blagosklonny

Dr. Blagosklonny’s Battle With Cancer (Part 1)

January 22, 2024

“Diagnosed with numerous metastases of lung cancer in my brain in January 2023, I felt compelled to accomplish a mission.”

On January 3, 2024, Mikhail V. Blagosklonny M.D., Ph.D., from Roswell Park Comprehensive Cancer Center published a new brief report in Oncoscience (Volume 11), entitled, “My battle with cancer. Part 1.”

BUFFALO, NY- January 22, 2024 – On January 3, 2024, Mikhail V. Blagosklonny M.D., Ph.D., from Roswell Park Comprehensive Cancer Center published a new brief report in Oncoscience (Volume 11), entitled, “My battle with cancer. Part 1.”

“In January 2023, diagnosed with numerous metastases of lung cancer in my brain, I felt that I must accomplish a mission. If everything happens for a reason, my cancer, in particular, I must find out how metastatic cancer can be treated with curative intent. This is my mission now, and the reason I was ever born. In January 2023, I understood the meaning of life, of my life. I was born to write this article. In this article, I argue that monotherapy with targeted drugs, even when used in sequence, cannot cure metastatic cancer. However, preemptive combinations of targeted drugs may, in theory, cure incurable cancer. Also, I share insights on various topics, including rapamycin, an anti-aging drug that can delay but not prevent cancer, through my personal journey.”

Read the full paper: DOI: https://doi.org/10.18632/oncoscience.593

Correspondence to: Mikhail V. Blagosklonny

Emails: Blagosklonny@oncotarget.com, Blagosklonny@rapalogs.com

Keywords: lung cancer, brain metastases, capmatinib, resistance, MET

About Oncoscience:

Oncoscience is a peer-reviewed, open-access, traditional journal covering the rapidly growing field of cancer research, especially emergent topics not currently covered by other journals. This journal has a special mission: Freeing oncology from publication cost. It is free for the readers and the authors.

To learn more about Oncoscience, visit Oncoscience.us and connect with us on social media:

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Oncotarget

How Osteopontin Stimulates Mitochondrial Biogenesis and Cancer Metastasis

January 11, 2024

In this new study, researchers investigated the role of Osteopontin splice variants in cancer metastasis.

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Mitochondrial biogenesis, the process of increasing the size and number of mitochondria within cells, plays a crucial role in cancer metastasis. Metastasizing cells exhibit a unique metabolism that differs from the well-known Warburg effect observed in primary tumors. While primary tumors primarily rely on glycolysis for energy production, metastatic cells rely on oxidative phosphorylation and ATP generation for short-term energy needs. However, over longer time frames, mitochondrial biogenesis becomes a prominent feature in the success of metastasis.

In a new study, researchers Gulimirerouzi Fnu and Georg F. Weber from the University of Cincinnati’s James L. Winkle College of Pharmacy investigate the connection between short-term oxidative metabolism and long-term mitochondrial biogenesis in cancer metastasis. They hypothesized that Osteopontin splice variants, specifically Osteopontin-c, stimulate an increase in mitochondrial size through the activation of specific signaling mechanisms. On December 1, 2023, their new research paper was published in Oncotarget, entitled, “Osteopontin induces mitochondrial biogenesis in deadherent cancer cells.”

“Over longer time frames, mitochondrial biogenesis becomes a pronounced feature and aids metastatic success. It has not been known whether or how these two phenomena are connected. We hypothesized that Osteopontin splice variants, which synergize to increase ATP levels in deadherent cells, also increase the mitochondrial mass via the same signaling mechanisms.”

The Role of Osteopontin Variants in Mitochondrial Biogenesis

Deadhesion, the process of detaching cancer cells from the extracellular matrix, is known to induce metabolic reprogramming and promote cancer cell survival in circulation. Osteopontin (OPN), a cytokine produced by cancer cells, has been implicated in tumor progression and the development of metastases. It mediates tumor cell survival and expansion under deadherent conditions, making it an ideal candidate for studying the mechanisms behind mitochondrial biogenesis. The authors of the research paper focused on two Osteopontin splice variants, Osteopontin-a and Osteopontin-c, and their effects on mitochondrial biogenesis.

Through their experiments with breast tumor cells, the authors found that both Osteopontin-a and Osteopontin-c contribute to mitochondrial biogenesis in deadherent cells. However, Osteopontin-c was more effective in stimulating an increase in mitochondrial size compared to Osteopontin-a. The authors also observed that the autocrine effects of Osteopontin variants are critical for the survival and anchorage-independence of disseminating malignant cells.

The Role of CD44v and SLC7A11 in Osteopontin Signaling

To further elucidate the mechanism behind Osteopontin-induced mitochondrial biogenesis, the authors investigated the receptors involved in Osteopontin signaling. They focused on CD44, a cell surface receptor known to interact with Osteopontin, and its variant CD44v. The authors found that Osteopontin-induced mitochondrial biogenesis is mediated via the binding of Osteopontin to CD44v.

Additionally, the authors discovered that the chloride-dependent cystine-glutamate transporter SLC7A11 plays a crucial role in Osteopontin signaling. The upregulation and co-ligation of SLC7A11, along with CD44v, leads to the activation of PGC-1, a known inducer of mitochondrial biogenesis. Surprisingly, the authors found that peroxide, an important intermediate in this signaling cascade, acts upstream of PGC-1 and is likely produced as a consequence of SLC7A11 recruitment and activation.

In Vivo Implications and Therapeutic Targets

To validate the relevance of their findings in clinical settings, the authors analyzed gene expression profiles in breast cancer metastases and metastases from other types of cancers. They identified the master regulator of mitochondrial biogenesis, PPARG, as well as its downstream effectors NRF1 and BACH1, to be upregulated in various metastases. These findings suggest that the Osteopontin-induced activation of PGC-1 and subsequent mitochondrial biogenesis may play a crucial role in cancer metastasis.

The authors also conducted in vivo experiments using mouse models. They observed that suppression of the biogenesis-inducing mechanisms led to a reduction in disseminated tumor mass. These findings not only confirm the functional connection between short-term oxidative metabolism and long-term mitochondrial biogenesis in cancer metastasis but also provide potential mechanisms and targets for treating cancer metastasis.

Conclusion

This study provides valuable insights into the role of Osteopontin splice variants in regulating mitochondrial biogenesis in metastatic cancer cells. The researchers demonstrated that Osteopontin-c stimulates an increase in mitochondrial size through the activation of specific signaling mechanisms involving CD44v and SLC7A11. These findings have significant implications for understanding the metabolic adaptations of metastatic cancer cells and suggest potential targets for therapeutic interventions. Further research is needed to fully elucidate the intricate signaling pathways involved in Osteopontin-induced mitochondrial biogenesis and to explore the clinical applications of these findings in cancer treatment.

“This study confirms a functional connection between the short-term oxidative metabolism and the longer-term mitochondrial biogenesis in cancer metastasis – both are induced by Osteopontin-c. The results imply possible mechanisms and targets for treating cancer metastasis.”

Click here to read the full research paper in Oncotarget.

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