Tagged: summary

Oncotarget

Mapping the Hidden Structure of Glioma Research: What Are We Missing?

May 5, 2026

“Unlike previous studies that focused primarily on metrics such as the h-index, our approach identifies the limited but notable mention of social factors in glioma classification research, thereby highlighting a thematic gap.”

Glioma research has evolved rapidly over the past decade, driven by breakthroughs in molecular biology, imaging technologies, and computational tools. Today, clinicians can classify tumors with far greater precision than ever before, using genetic mutations, epigenetic markers, and advanced diagnostic frameworks. Yet, despite this progress, an important question remains: are we truly capturing the full picture of what shapes patient outcomes?

Traditionally, glioma classification has focused on what can be measured in the tumor itself—its histology, molecular profile, and biological behavior. While these factors are undeniably critical, they may not fully explain why patients with similar tumors can experience very different clinical trajectories. Increasingly, researchers are beginning to recognize that broader influences—particularly social and environmental factors—may also play a role. Understanding how these different layers of information connect is becoming an important challenge in neuro-oncology.

A review was published in Volume 17 of Oncotarget on March 31, 2026, titled “Bibliometric mapping of glioma classification research through main path, key route, and K-core analyses.” The study was led by first and corresponding author Kayode Ahmed from The University of Texas MD Anderson Cancer Center, in collaboration with Juan E. Núñez-Ríos from Universidad Panamericana. 

A Bird’s-Eye View of an Entire Field

Rather than focusing on a single experiment or dataset, the researchers analyzed the structure of glioma research itself. Using bibliometric and network-based approaches, they examined thousands of scientific publications to understand how knowledge in this field has developed over time.

By constructing a large citation network—comprising tens of thousands of articles and hundreds of thousands of connections—they were able to trace the intellectual pathways that have shaped modern glioma classification. Techniques such as main path analysis and key route analysis helped identify the most influential studies, while K-core analysis revealed tightly connected clusters of research activity.

What Drives Glioma Classification Today?

The findings confirm what many in the field might expect: glioma classification has been heavily shaped by advances in molecular and technological approaches.

DNA methylation profiling, genetic mutations, and imaging innovations have emerged as central pillars in modern classification systems. These tools have significantly improved diagnostic accuracy and helped refine prognostic models, enabling more personalized approaches to treatment.

At the same time, the network analysis highlights how interconnected these advances are. Progress in glioma research has not occurred in isolation, but through the convergence of multiple disciplines—molecular biology, bioinformatics, imaging science, and clinical oncology.

The Missing Piece: Social Factors

However, one of the most striking insights from the study is not what dominates the field—but what is largely absent.

Despite growing awareness that factors such as socioeconomic status, education, and access to healthcare can influence disease outcomes, these variables are rarely integrated into glioma classification research. Compared to molecular and imaging-based studies, the contribution of social determinants remains minimal.

This gap suggests that current classification systems, while biologically sophisticated, may still overlook important aspects of patient reality. As a result, they may fall short of fully explaining differences in treatment response and survival.

Why This Matters

This study shifts the conversation from what we know to how we know it. By mapping the structure of scientific research itself, the authors reveal both the strengths and blind spots of the field.

Glioma classification has become increasingly precise at the molecular level—but precision medicine may ultimately require a broader perspective. Integrating biological data with social and environmental context could lead to more comprehensive and clinically meaningful classification systems.

Looking Ahead

Moving forward, the challenge will be to bridge this gap. Incorporating social determinants into glioma research will not be straightforward, but it may be essential for developing more holistic models of disease.

Future studies may need to combine traditional biomedical approaches with data from public health, epidemiology, and social sciences. Such integration could improve not only how gliomas are classified, but also how patients are treated and supported.

Conclusion

By stepping back and examining the structure of glioma research as a whole, this study offers a fresh perspective on a rapidly evolving field. It highlights how far we have come in understanding the biology of gliomas—while also reminding us that important pieces of the puzzle may still be missing.

In the end, advancing glioma classification may depend not just on better technology, but on a more complete understanding of the patient behind the tumor.

Click here to read the full review published 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).

Click here to subscribe to Oncotarget publication updates.

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

Oncotarget

SCD1 Inhibition Strategy Shows Potent Synergy with Regorafenib and Metformin in Tumor Cell Killing

April 21, 2026

“Our data demonstrates that UM cells are killed by treatment with aramchol plus regorafenib plus metformin via enhanced autophagic flux and that this combination may have the potential to control UM tumors that have metastasized to the liver.”

Cancer has long been understood through a variety of biological frameworks, including genetic mutations, dysregulated signaling pathways, and uncontrolled cell proliferation. Yet, these models often capture the visible consequences of disease rather than the deeper metabolic dependencies that sustain tumor survival. Despite major advances in targeted therapies, a central challenge remains: what underlying mechanisms make cancer cells vulnerable to treatment, and how can these vulnerabilities be exploited more effectively? Increasing attention has shifted toward cellular metabolism—particularly lipid regulation and energy-sensing pathways such as AMPK—as critical determinants of tumor behavior. Scientists are now taking a closer look at how metabolism works together with stress responses like autophagy—and how this connection could be used to develop better cancer treatments.

A new research paper was published in Volume 17 of Oncotarget, titled “The SCD1 inhibitor aramchol interacts with regorafenib and metformin to kill tumor cells.” The study was led by first author Michael R. Booth and corresponding author Paul Dent from Virginia Commonwealth University, in collaboration with Laurence Booth and Jane L. Roberts from Virginia Commonwealth University and John M. Kirkwood from the University of Pittsburgh Cancer Institute.

Targeting Tumor Metabolism Through Lipid Enzymes

Cancer cells rely heavily on metabolic reprogramming to sustain growth and survival. One enzyme of growing interest is stearoyl-CoA desaturase 1 (SCD1), which regulates lipid metabolism and cellular redox balance. Aramchol, an SCD1 inhibitor originally developed for metabolic liver disease, is being investigated as a potential strategy for targeting tumor metabolism.

In this study, researchers explored how aramchol behaves in combination with two clinically relevant agents: regorafenib, a multi-kinase inhibitor, and metformin, a widely used anti-diabetic drug known to activate AMPK signaling.

A Three-Drug Combination with Enhanced Anti-Tumor Activity

The findings reveal a clear hierarchy of therapeutic impact. While aramchol alone showed modest anti-tumor activity, its combination with regorafenib significantly increased tumor cell death. Notably, the addition of metformin further amplified this effect, producing the strongest response across multiple tumor models, including uveal melanoma (UM) and cholangiocarcinoma cells.

This enhanced killing effect was associated with coordinated signaling changes, including AMPK activation and suppression of mTOR-related pathways—key regulators of cellular energy balance and survival.

Autophagy: A Central Mechanism of Tumor Cell Death

A defining feature of the study is the identification of autophagic flux as a central mechanism underlying tumor cell killing.

Using LC3-based fluorescence assays, the authors demonstrated that the drug combination markedly increased the formation of autophagosomes and autolysosomes, indicating robust activation of macroautophagy. Importantly, silencing essential autophagy regulators such as Beclin1, ATG5, and LAMP2 significantly reduced both autophagic activity and tumor cell death.

These findings suggest that autophagy is an important functional component of therapeutic efficacy in this context.

Dual Mechanisms: Autophagy and Death Receptor Signaling

Beyond autophagy, the study also highlights a second critical pathway: death receptor signaling via BID.

The researchers showed that BID knockdown reduced tumor cell killing, supporting a role for BID-dependent death signaling alongside macroautophagy in the response to treatment. Together, these findings suggest that the drug combination engages multiple stress-response pathways that contribute to tumor cell death.

Re-Evaluating the Role of SCD1

Although aramchol targets SCD1, the study provides an important nuance: SCD1 inhibition alone does not fully explain the observed anti-cancer effects.

While SCD1 knockdown modestly increased baseline cell death, it did not replicate the full potency of the drug combination. This suggests that aramchol likely engages additional molecular targets or pathways, expanding its therapeutic relevance beyond lipid metabolism alone.

Implications for Uveal Melanoma and Liver Metastasis

Uveal melanoma is a rare but aggressive cancer with a strong tendency to metastasize to the liver—a site where treatment options remain limited. Because aramchol concentrates in the liver, the findings suggest that this combination may hold particular relevance for metastatic UM, which most often spreads to that organ.

Looking Ahead

This study provides preclinical evidence that combining aramchol, regorafenib, and metformin can significantly enhance tumor cell killing through coordinated metabolic and stress-response pathways.

Future work will be needed to validate these findings in vivo and determine their clinical applicability. However, the results already point toward a promising strategy: integrating metabolic targeting with established anti-cancer therapies to overcome resistance and improve efficacy.

Conclusion

By uncovering how SCD1 inhibition synergizes with kinase inhibition and metabolic modulation, this study advances a more integrated view of cancer therapy. Rather than relying on single-target approaches, the findings emphasize the power of multi-pathway disruption—combining autophagy, apoptosis, and metabolic stress—to drive tumor cell death.

Click here to read the full research paper published 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).

Click here to subscribe to Oncotarget publication updates.

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Oncotarget

CREB5: A Master Regulator of Stem Cell-Like Programs in Prostate Cancer Progression

April 7, 2026

“In this study, through both computational and molecular characterization of PC cell lines, we determined that CREB5 is associated with basal PC and drives SCL traits.”

Androgen receptor (AR) signaling has long been the central driver of prostate cancer progression and the primary target of therapies for advanced disease. Yet, a significant subset of tumors either fail to respond or develop resistance, often by switching to AR-independent programs that resemble basal or stem cell-like states. Understanding what drives these aggressive, therapy-resistant phenotypes is a critical challenge in oncology.

A research paper, titled “CREB5 regulates stem cell-like transcriptional programs to enhance tumor progression in prostate cancer” was published in Volume 17 of Oncotarget by a multi-institutional team of researchers, identifies a key molecular regulator of this process and reveals how it promotes tumor progression.

The work was led by first author Allison Makovec from the Department of Medicine and the Masonic Cancer Center at the University of Minnesota – Twin Cities, and University of Kansas Medical Center, along with corresponding authors Emmanuel S. Antonarakis and Justin Hwang (both from the Department of Medicine and the Masonic Cancer Center at the University of Minnesota – Twin Cities). The team’s investigation demonstrates that the transcription factor CREB5 drives basal and stem cell-like transcriptional programs, interacts with AP-1 proteins, and enhances tumor-forming capacity in prostate cancer cells.

The Discovery: CREB5 Links to Basal and Stem Cell-Like Programs

The researchers began by analyzing transcriptomic data from 493 primary prostate tumors (TCGA) and 208 castration-resistant prostate cancers (CRPC) from the SU2C dataset. They ranked approximately 20,000 genes based on their correlation with gene signatures defining luminal, basal, club, and hillock epithelial cell identities.

CREB5 ranked among the top genes associated with basal, club, and hillock identities but was among the lowest associated with luminal identity—the opposite pattern of AR itself. In both primary and CRPC samples, CREB5 expression was inversely correlated with AR activity and positively correlated with KLF5, a transcription factor previously linked to AR-independent resistance.

Further analysis revealed that CREB5-high tumors had significantly lower expression of AR, FOLH1 (PSMA), KLK2, and KLK3 (PSA) compared to CREB5-low tumors. Interestingly, AR-V7—a constitutively active AR splice variant that drives therapy resistance—was also decreased in CREB5-high tumors, suggesting that CREB5 operates through AR-independent pathways rather than AR splice variants.

Molecular Associations: CREB5 and the AP-1 Network

To understand how CREB5 drives these transcriptional programs, the team used the Algorithm for Linking Activity Networks (ALAN), which compares gene behavior across all potential interactions. CREB5 showed highly concordant behavior with the 25 transcription factors that define the stem cell-like (SCL) subtype of CRPC, as previously defined by Tang et al. Notably, CREB5 exhibited nearly identical behavior to FOSL1, a key AP-1 transcription factor implicated in stem cell features, therapy resistance, and metastasis in other cancers.

This relationship was remarkably strong. In CRPC samples, CREB5 and FOSL1 expression were significantly correlated (r = 0.47, p < 0.001), and ALAN analysis showed an R² of 0.980 between their gene behaviors across all genes in the dataset. Even in benign prostate tissue (GTEx), the alignment remained strong (R² = 0.707).

Functional validation confirmed the regulatory relationship. In LNCaP cells overexpressing CREB5, RNA-seq showed increased FOSL1 expression across multiple conditions—including androgen deprivation (CSS), enzalutamide treatment, and androgen stimulation (R1881). In CWR-R1 cells, CREB5 overexpression significantly increased FOSL1 expression by RT-qPCR (p = 0.014).

Mechanisms: CREB5 Interacts with AP-1 Proteins and Binds Their Regulatory Elements

To determine how CREB5 exerts its effects, the team examined protein-protein interactions using rapid immunoprecipitation and mass spectrometry of endogenous proteins (RIME) from prior work. Compared to controls, CREB5 interacted with several AP-1 factors, including JUN, JUNB, JUND, ATF2, and ATF7.

Motif enrichment analysis of CREB5 binding sites (from ChIP-sequencing) revealed significant enrichment of AP-1 binding motifs, including those for JUN, JUNB, and ATF2. In enzalutamide-treated cells, CREB5-bound sites remained enriched near ATF2 motifs, and CREB5 binding patterns were highly consistent at these sites.

ChIP-sequencing further showed that CREB5 bound to the transcriptional start sites of several AP-1 genes, including ATF3 and FOSL2, and to FOSL1 itself—particularly in enzalutamide-treated cells. Moreover, CREB5 bound to the transcriptional start and end sites of all 25 SCL genes defined by Tang et al., confirming its role as a broad regulator of stem cell-like transcriptional programs.

Phenotypic Consequences: CREB5 Drives Tumor-Forming Capacity

If CREB5 promotes stem cell-like traits, it should enhance the ability of cancer cells to form tumors. The team tested this using 3D tumorsphere assays in three cell lines: LNCaP (AR-positive, hormone-sensitive), CWR-R1 (CRPC-like), and CWR-R1 enzalutamide-resistant (enzR).

CREB5 overexpression significantly increased the number of tumorspheres in LNCaP cells compared to luciferase (LUC) controls (p < 0.01), indicating enhanced tumor-forming capacity from single cells. This effect was not observed in the more aggressive CWR-R1 or CWR-R1 enzR lines, suggesting that CREB5 has the greatest impact in hormone-sensitive cells, consistent with prior studies.

In vivo, LNCaP cells with CREB5 overexpression were implanted into castrated and non-castrated male mice. After 56 days, CREB5 overexpression significantly increased tumor volume in both castrated (p = 0.002) and non-castrated (p = 0.008) mice. Notably, there was no significant effect on tumor growth rate, supporting the hypothesis that CREB5 promotes tumor formation (stemness) rather than simply accelerating proliferation.

Clinical Implications and Future Directions

These findings have several important implications. First, they identify CREB5 as a central regulator of lineage plasticity in prostate cancer—the ability of tumor cells to switch from an AR-driven luminal identity to an AR-independent basal or stem cell-like state. This plasticity is a major mechanism of resistance to AR-targeted therapies.

Second, the inverse relationship between CREB5 and AR activity was detectable even in primary, treatment-naïve tumors. This suggests that high CREB5 expression may serve as a future biomarker for identifying patients at risk of developing resistance or progressing to metastatic disease, even before therapy begins.

Third, the interaction between CREB5 and AP-1 transcription factors—particularly FOSL1—points to potential therapeutic strategies. AP-1 factors are known regulators of cancer cell plasticity across multiple malignancies, and there are now anti-cancer therapies targeting AP-1 factors. Whether such agents can perturb CREB5’s tumor-promoting activity remains an open question.

The authors acknowledge that the mechanistic relationship between CREB5 and KLF5—another SCL-associated transcription factor—remains unclear, as no direct biochemical interaction was detected. Future studies will need to explore whether these factors operate in parallel pathways or through indirect mechanisms.

Future Perspectives and Conclusion

This study does not claim to have fully mapped the regulatory network of CREB5 in prostate cancer. Rather, it establishes CREB5 as a key driver of basal and stem cell-like transcriptional programs and provides a mechanistic link to AP-1 transcription factors.

The perspective that emerges is one where lineage plasticity in prostate cancer is not a random event but is driven by specific transcriptional regulators like CREB5. By integrating computational modeling, molecular biology, and functional studies, the team demonstrates that CREB5 enhances tumor-forming capacity through interactions with AP-1 factors and regulation of SCL genes.

Continued research will be needed to determine whether targeting CREB5 or its interaction with AP-1 complexes can mitigate deadly stem cell-like phenotypes in prostate cancer and potentially in other malignancies where CREB5 has been implicated—including breast, colorectal, ovarian, and brain cancers. As the authors note, “increased CREB5 may lead to specific mechanisms of therapy response, and future therapeutic strategies may consider antagonizing CREB5 interactions with AP-1 complexes.”

Click here to read the full research paper published 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).

Click here to subscribe to Oncotarget publication updates.

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

Oncotarget

Predicting Colorectal Cancer Survival: How Machine Learning Combines Clinical and Biological Clues

March 25, 2026

“Understanding both the biological and clinical aspects of the patient is essential to uncover the mechanism underlying the prognosis of the disease.”

Colorectal cancer (CRC) ranks among the most common and lethal cancers worldwide, accounting for approximately 10% of all cancer diagnoses. While advances in prevention and treatment have improved outcomes, predicting which patients will survive remains a complex challenge—one that depends on an intricate interplay between molecular biology and clinical factors.

A research paper, titled “Machine learning-based survival prediction in colorectal cancer combining clinical and biological features” was published in Volume 16 of Oncotarget by an international team of researchers, demonstrating how machine learning can integrate these two domains to achieve highly accurate survival predictions.

The team’s investigation demonstrates that combining clinical features—such as pathological stage, age, and lymph node status—with biological markers—including the E2F8 gene and hsa-miR-495-3p—can significantly improve the ability to predict patient survival.

The Method: Integrating Clinical and Biological Data

The researchers constructed a three-phase pipeline using data from 545 colorectal cancer patients from The Cancer Genome Atlas (TCGA) database. The data spanned colon, rectum, and rectosigmoid junction cancers, with patient ages ranging from 31 to 90 years.

In the first phase, data pre-processing, the team extracted and normalized both clinical and biological features. For biological features, they performed differential expression analysis, constructed competing endogenous RNA (ceRNA) networks, and conducted survival analysis to identify 19 candidate molecules—including mRNAs, lncRNAs, and miRNAs—with potential roles in CRC prognosis. For clinical features, they selected 13 characteristics, including age, pathological stage, lymph node counts, chemotherapy status, and new tumor events.

To handle missing data, they created three distinct cases: Case 1 filtered out missing biological or core clinical features; Case 2 also excluded patients with missing demographic features like race and weight; and Case 3 replaced missing values with the most frequent category.

In the second phase, feature selection, the team applied LASSO (Least Absolute Shrinkage and Selection Operator) to rank features by importance, followed by SHAP (Shapley Additive Explanations) to understand each feature’s impact on survival prediction.

In the third phase, model construction, they trained and compared six machine learning classifiers: Logistic Regression (LR), Support Vector Machine (SVM), Random Forest (RF), AdaBoost (AB), Stacking, and Voting.

Key Findings: Features That Matter Most

Across the three data cases, certain features consistently emerged as critical for predicting survival.

Among biological features, E2F8 stood out as the most significant, appearing in all three models. This gene, known to be associated with cell proliferation and CRC staging, has been identified by other studies as a potential CRC biomarker. WDR77 and hsa-miR-495-3p also proved important in most groups, consistent with previous research linking them to cancer development.

Among clinical features, pathological stage consistently ranked as the most influential predictor. Higher stage correlated strongly with lower survival probability. Age, new tumor event (likely representing recurrence), lymph node count, and chemotherapy status also emerged as critical factors.

Notably, the study identified that the combination of these features outperformed models relying on clinical or biological data alone.

Predictive Performance: Accuracy Reaches 89.58%

The machine learning models achieved impressive results. For Case 1 (filtered for core clinical features), an SVM model achieved 86.87% accuracy with an AUC of 83.49%. For Case 2 (more strictly filtered), an AdaBoost model achieved the best overall performance: 89.58% accuracy, though with a lower AUC of 76.50% due to dataset size limitations. For Case 3 (with imputed missing values), a Voting ensemble achieved 82.57% accuracy.

Bootstrap analysis confirmed that these advanced models provided meaningful improvements over baseline logistic regression, with accuracy increases ranging from 4.6% to 11.1%.

Biological Insights: The ceRNA Network Perspective

The 19 candidate molecules used as biological features were not chosen arbitrarily. They originated from a prior analysis by the same research group that constructed competing endogenous RNA (ceRNA) networks—complex regulatory systems where mRNAs, lncRNAs, and miRNAs cross-regulate each other through shared microRNA response elements.

This ceRNA framework is particularly relevant in cancer, where disruptions to these networks can drive tumor progression. By incorporating molecules from these networks, the study captured not just individual biomarkers but the broader regulatory context in which they operate.

Clinical Implications and Future Directions

The study’s findings carry several implications for clinical practice and future research.

First, they validate the prognostic value of well-established clinical factors—age, stage, lymph node status—while also highlighting novel molecular markers like E2F8 that warrant further investigation. Second, they demonstrate that machine learning can effectively integrate diverse data types to generate clinically useful predictions. Third, they underscore the importance of complete data collection; missing clinical information, such as race and weight, limited the analysis and may introduce bias.

The authors acknowledge limitations, including the relatively small dataset (545 patients), the exclusive use of US-based TCGA data, and the lack of experimental validation for the identified biomarkers. They call for future studies with larger, more diverse cohorts and for further investigation into the molecular mechanisms linking E2F8, miR-495-3p, and WDR77 to CRC prognosis.

Future Perspectives and Conclusion

This study does not claim to have developed a clinically deployable tool. Rather, it offers a proof-of-concept that machine learning can meaningfully integrate clinical and biological data to predict colorectal cancer survival. By combining LASSO feature selection with SHAP interpretability and ensemble modeling, the team demonstrates a pipeline that balances predictive power with biological insight.

The perspective that emerges is one where the future of cancer prognosis lies not in choosing between clinical or molecular data, but in systematically combining them. As the authors note, even basic patient information—age, weight, lymph node status—when accurately recorded and integrated with molecular profiles, can contribute powerfully to our understanding of disease trajectory.

Continued research will be needed to validate these findings in independent cohorts, to expand the set of biological features, and ultimately to translate these models into tools that can guide treatment decisions and improve outcomes for patients with colorectal cancer.

Click here to read the full research paper published 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).

Click here to subscribe to Oncotarget publication updates.

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

Oncotarget

CAR-T Cell Therapy: A Revolutionary Approach to Cancer Treatment

March 10, 2026

“Given the small percentage of patients cured from advanced-stage disease, there is still a considerable journey ahead. Nonetheless, novel therapeutic approaches have, in some cases, demonstrated remarkable success in improving patient survival and longevity.”

Cancer treatment has long been a battle of attrition—surgery, radiation, and chemotherapy have saved countless lives, but for patients with advanced or refractory malignancies, the options remain limited. In recent years, however, a new approach has emerged that harnesses the power of the patient’s own immune system to seek and destroy cancer cells with unprecedented precision.

An editorial perspective, titled “CAR-T therapy: Trailblazing CAR(ing) in cancer treatment” published in Volume 17 of Oncotarget by researchers Uzma Saqib, Monika Pandey, and Krishnan Hajela from the School of Life Sciences, Devi Ahilya Vishwavidyalaya, Indore, India, provides an overview of this revolutionary therapeutic strategy. The paper presents the current state of CAR-T therapy, its clinical successes, and the formidable challenges that remain before it can fulfill its transformative potential.

The CAR-T Model

The concept of CAR-T therapy can be understood through a simple yet powerful analogy. Imagine cancer cells as an invading enemy army at a country’s borders. The body’s natural T cells act as soldiers, but they may be ill-equipped to counter the enemy’s advanced weaponry—the antigens that shield cancer cells from immune detection.

To overcome this, oncologists “recall” these soldiers (T cells) from the battlefield and arm them with specialized weapons called chimeric antigen receptors (CARs), designed to target the enemy’s specific artillery. Once multiplied into a large, reinforced army, these enhanced soldiers are redeployed to the patient’s body, where they recognize and eliminate cancer cells with improved precision.

Clinically, this process unfolds in three main stages. First, during T cell collection, white blood cells are extracted from the patient through leukapheresis. Second, in the editing and expansion phase, the collected T cells are genetically engineered in the laboratory to express CAR genes and are then multiplied over several weeks. Finally, during infusion, the modified cells are reintroduced into the patient, typically following chemotherapy that reduces competing immune cells to give the CAR-T cells a competitive advantage. Once infused, these engineered cells bind to their target antigens and initiate targeted cancer cell destruction.

Evidence from Clinical Studies

CAR-T therapy has demonstrated remarkable success across a spectrum of hematologic malignancies. In leukemia, lymphoma, and multiple myeloma, the approach has produced responses in patients who had exhausted all other options. Recent clinical trials have even shown superior outcomes compared to standard treatment in patients with non-Hodgkin lymphoma, positioning CAR-T therapy as a potential replacement for chemotherapy as the second-line standard of care.

Beyond blood cancers, investigators are making inroads into solid tumors, where CAR-T therapy has historically faced greater obstacles. Recent phase I reports have documented measurable clinical responses in glioblastoma and breast cancers, with additional reviews supporting the growing feasibility of CAR-T strategies in solid tumors. In thoracic cancers, a clinical study demonstrated that mesothelin-targeted CAR-T cells can achieve promising safety and anti-tumor activity across multiple patient cohorts. Similarly, a pivotal phase 2 trial evaluating CT041-ST-01 in gastric and gastro-oesophageal junction cancers has shown encouraging signs of efficacy alongside an acceptable safety profile.

Challenges and Limitations

Despite its promise, CAR-T therapy faces several critical challenges that limit its widespread application. The most immediate clinical concerns include cytokine release syndrome (CRS) and neurotoxicity, both of which can be severe and even life-threatening. CRS occurs when activated CAR-T cells release massive amounts of inflammatory cytokines, triggering fever, hypotension, and in severe cases, multi-organ dysfunction.

Resistance to CAR-T therapy has also emerged as a significant obstacle. In B-cell malignancies and multiple myeloma, only a limited percentage of patients achieve long-term remission. These failures may arise from host factors, tumor-intrinsic properties, the surrounding immunosuppressive microenvironment, and intrinsic limitations of the CAR-T cells themselves.

In solid tumors, the challenges multiply. Precise tumor-specific antigens are scarce, raising the risk of on-target/off-tumor effects where CAR-T cells attack healthy tissues. The tumor microenvironment actively suppresses T-cell function, and restricted trafficking limits the number of CAR-T cells that reach the tumor site.

Perhaps the most formidable barrier is accessibility. Socioeconomic and racial disparities continue to limit the availability of CAR-T therapy, leaving only a small fraction of eligible patients able to receive it. The complex manufacturing process, which requires weeks of laboratory work and costs hundreds of thousands of dollars per patient, places this potentially life-saving treatment out of reach for many.

Future Directions

Ongoing research is actively working to overcome these obstacles through multiple parallel strategies. Next-generation CAR constructs are being designed with improved safety features, including “off switches” that allow clinicians to terminate the therapy if toxicities become severe. Optimized supportive care, including the use of tocilizumab and corticosteroids, has already reduced the mortality associated with CRS.

The development of allogeneic or “off-the-shelf” CAR-T platforms, derived from healthy donors rather than the patient themselves, promises to reduce both manufacturing time and cost. Enhanced clinical management strategies, including prophylactic measures and specialized treatment centers, could further improve safety and therapeutic outcomes.

Future Perspectives and Conclusion

CAR-T therapy does not claim to be a universal solution for all cancers. Rather, it represents a proof-of-concept for a powerful new paradigm: harnessing the adaptive immune system as a living, evolving therapy that can persist in the body and respond to cancer over time. By integrating genetic engineering, cell therapy, and immunology, this approach has already transformed outcomes for patients with previously incurable hematologic malignancies.

The editorial perspective by Saqib, Pandey, and Hajela reminds us that while the journey is far from complete, the direction is clear. Continued research will be needed to extend these successes to solid tumors, reduce toxicity, and ensure equitable access. As the authors note, the silver lining offered by CAR-T therapy is real, but realizing its full potential will require sustained effort across the scientific, clinical, and social dimensions of cancer care.

Click here to read the full Editorial Perspective published 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).

Click here to subscribe to Oncotarget publication updates.

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

Oncotarget

mRNA COVID-19 Vaccination and Cancer Risk: A Case-Based Review

February 27, 2026

“The carcinogenic risk associated with these technologies, which has long been known within the gene therapy field, represents an area of research that cannot be ignored, given the fundamental principle of medicine “primum non nocere” (first, do no harm).”

The rapid development and global deployment of mRNA vaccines for COVID-19 represented a landmark achievement in public health. However, the novel mechanism of these “genetic vaccines”—technically pro-drug gene therapies encased in lipid nanoparticles—has prompted ongoing scientific inquiry into their potential long-term effects. 

A comprehensive case report and review, titled “Exploring the potential link between mRNA COVID-19 vaccinations and cancer: A case report with a review of haematopoietic malignancies with insights into pathogenic mechanisms” published in Oncotarget by an international team of researchers investigates a consequential scientific question: whether there could be a link between mRNA COVID-19 vaccines and the development of haematopoietic cancers.

Led by first author Patrizia Gentilini, along with corresponding author Panagis Polykretis of the “Allineare Sanità e Salute” Foundation and Independent Medical Scientific Commission (CMSi), Milano, the paper presents a detailed case study alongside a systematic review of existing literature. It does not claim to have proven a causal link, but instead argues that the convergence of clinical observations and proposed biological mechanisms warrants deeper, more urgent investigation.

The Case Report

The report centers on a 38-year-old, healthy, athletic woman with no significant family or medical history. Routine blood work in April 2021 showed only mild leukopenia (white blood cells at 2,450/μL), which her physician did not prioritize.

She received her first dose of the Pfizer/BioNTech (Comirnaty®) vaccine on June 20, 2021, with no immediate issues. However, the morning after her second dose on July 19, 2021, she experienced severe symptoms: fever, locked neck and jaw, tinnitus, nausea, diffuse pain, headache, and sweating. These symptoms worsened over subsequent days, accompanied by insomnia and hypersensitivity to temperature changes and noise.

Over the following months, laboratory testing revealed a pattern of progressive deterioration: persistent neutropenia, rising lymphocytosis, and a steadily climbing erythrocyte sedimentation rate (ESR) from 59 mm/hour in August to 118 mm/hour by October. A rheumatologic examination in late October suggested post-vaccination polymyalgia rheumatica. A PET scan on November 15, 2021, revealed intense uptake in the bone marrow of the entire axial and appendicular skeleton, as well as the spleen. Bone marrow biopsy on December 1, 2021, delivered the diagnosis: B-lymphoblastic leukemia/lymphoma, with approximately 95% of nucleated cells replaced by blast-like elements. The patient underwent chemotherapy and achieved remission, though she later suffered a central nervous system relapse in early 2025.

Broader Patterns: A Review of the Literature

To contextualize this single case, the authors conducted a systematic review of the medical literature from December 2020 to October 2025. They identified 30 studies documenting new-onset or rapidly recurring malignancies shortly after mRNA COVID-19 vaccination. The overwhelming majority (28 of 30) were hematolymphoproliferative disorders—cancers of the blood and lymph system.

Among the case reports, they found 9 cases of B-cell lymphoproliferative disorders, 13 involving the T-cell lineage, 6 affecting the myeloid line, and 2 cases of solid tumors. The Pfizer/BioNTech vaccine appeared most frequently (16 cases). The onset of symptoms following vaccination was often remarkably brief, in some cases occurring within days. Several lymphomas arose at the injection site itself, while others manifested in vaccine-draining lymph nodes such as the axillary and cervical regions.

One particularly instructive case involved angioimmunoblastic T-cell lymphoma, where rapid progression was observed immediately after a booster dose. A PET scan just eight days after boosting showed a dramatic increase in hypermetabolic lesions, with notably asymmetrical progression on the side of the booster injection.

Proposed Pathogenic Mechanisms

The paper’s core contribution is its detailed exploration of potential biological mechanisms by which mRNA vaccines could theoretically promote oncogenesis. These mechanisms are drawn from in-vitro, pre-clinical, and related scientific literature, and the authors emphasize that specific studies in humans remain lacking.

The first proposed mechanism involves the alteration of the PD-1/PD-L1 immune checkpoint. Studies have shown increased expression of programmed death-ligand 1 (PD-L1) on peripheral blood granulocytes and monocytes in vaccinated individuals. PD-L1 acts as an “off switch” for T-cells, suppressing their activity and potentially impairing the immune system’s ability to surveil and eliminate emerging cancer cells. This immune checkpoint alteration could create a permissive environment for malignant transformation.

A second mechanism suggests an interaction between the spike protein and tumor suppressors. The S2 subunit of the spike protein has been shown in silico to interact with critical tumor suppressor proteins including p53, BRCA1, and BRCA2. These proteins normally regulate cellular responses to stress and prevent cancer development. Interference with their function, as demonstrated in cancer cell lines where spike protein expression suppressed p53 activation, could disable fundamental safeguards against uncontrolled cell proliferation.

A third concerns the impairment of Type I interferon signaling. Type I interferons play essential roles in inflammation, immunomodulation, and tumor cell recognition. Differential gene expression analysis has revealed that while COVID-19 patients show dramatic upregulation of type I and type II interferons, vaccinated individuals do not. This suggests that the genetic vaccines may actively suppress type I interferon production, potentially blunting a key anti-tumor immune defense. Interferons normally induce cell cycle arrest, promote apoptosis, and activate natural killer cells and CD8+ T-cells—all critical for cancer surveillance.

The authors also explore additional mechanisms, including increased transforming growth factor beta production promoting epithelial-mesenchymal transition, DNA contamination with SV40 promoter elements posing insertional mutagenesis risk, reverse transcription of vaccine mRNA via LINE-1 elements, IgG4 class switching leading to immune evasion, and ribosomal frameshifting producing off-target proteins with unknown effects.

Future Perspectives and Conclusion

The proposed link between mRNA COVID-19 vaccines and cancer does not claim to provide a complete explanation of post-vaccination malignancies. Rather, it offers a structured framework for understanding how multiple mechanisms may combine to produce oncogenic outcomes in susceptible individuals. By integrating clinical observations, laboratory findings, and mechanistic insights from molecular biology, the review clarifies how vaccine components and host factors may interact.

The authors emphasize that the carcinogenic risk associated with gene therapy technologies has long been recognized and cannot be ignored in the context of genetic vaccines administered to healthy populations. They call for extensive pharmacodynamic, pharmacokinetic, and genotoxicity evaluations, as well as population-based observational studies comparing cancer incidence in vaccinated versus unvaccinated populations. Such research, they argue, is essential to assess potential carcinogenic risk and understand pathogenic mechanisms, reminding readers of the fundamental principle of medicine: primum non nocere—first, do no harm.

Click here to read the full case report published 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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Oncotarget

How HPV and COVID-19 Spike Proteins May Interact to Impact Cancer Suppression

February 9, 2026

“Thus, the present hypothesis is that virally encoded proteins such as HPV-E6 or SARS-COV-2 Spike may cooperate in suppressing host defenses including tumor suppressor mechanisms involving p53.“

The p53 protein plays a central role in preventing cancer by responding to cellular stress and DNA damage. When activated, it can repair damaged DNA or trigger cell death, preventing the survival of potentially malignant cells. Loss of p53 function is a hallmark of many cancers.

HPV is well known to inactivate p53 through its E6 protein, which promotes p53 degradation. This mechanism contributes to HPV-associated cancers, including cervical, anal, and head and neck cancers. SARS-CoV-2, while not traditionally classified as an oncogenic virus, has been shown to interfere with immune function and, in some cases, with cellular pathways that involve p53.

A recent article by Dr. Wafik El-Deiry of The Warren Alpert Medical School of Brown University, published in Oncotarget, proposes a scientific hypothesis suggesting that proteins from HPV and SARS-CoV-2 may both interfere with the body’s tumor-suppressing mechanisms, potentially compounding their effects on cancer-related pathways.

The Hypothesis: HPV E6 and SARS-CoV-2 Spike Proteins May Cooperatively Suppress p53

In the paper, titled “Hypothesis: HPV E6 and COVID spike proteins cooperate in targeting tumor suppression by p53,” Dr. El-Deiry proposes that the SARS-CoV-2 spike protein, whether introduced via infection or mRNA vaccination, may suppress p53 activity in a manner that complements the effects of HPV E6. In individuals with persistent HPV infection, this combined interference could further reduce p53 function, weakening tumor suppression mechanisms.

The Mechanistic Rationale: Dual Viral Impact on p53 and Immune Regulation

The proposed mechanism involves two converging effects on p53. HPV E6 promotes the degradation of p53 protein, while the SARS-CoV-2 spike protein may suppress its transcriptional function. This dual action could further compromise the cellular ability to detect and respond to oncogenic stress.

The hypothesis also considers the broader immunological environment. SARS-CoV-2 infection has been shown to alter innate immune responses, which may indirectly accelerate progression of HPV-related neoplasia or other pre-cancerous states.

The Supporting Observations

Although the hypothesis remains untested, it is based on several converging observations. Laboratory research has shown that the SARS-CoV-2 spike protein can reduce p53-related gene activity, like p21, DR5, and MDM2, and weaken the response of cancer cells to therapy. In addition, a clinical case shared in a public interview by Dr. Patrick Soon-Shiong involved a patient with long-term remission from HPV-associated head and neck cancer who experienced recurrence and liver metastases after COVID-19 vaccination. While this does not establish causality, it illustrates the kind of clinical context in which the hypothesis could be further explored.

The Impact: Potential Implications for Cancer Risk in HPV- Positive Individuals

If validated, this hypothesis may have implications for cancer surveillance in HPV-positive individuals, particularly in the context of SARS-CoV-2 exposure or vaccination. However, as emphasized by the author, there is currently no clinical evidence linking COVID-19 vaccination to increased cancer risk.

This hypothesis is intended to encourage further epidemiological and mechanistic investigations, not to alter clinical recommendations. It proposes a framework for evaluating whether co-exposure to two common viruses may jointly impair p53-mediated tumor suppression in a subset of patients.

Future Perspectives and Conclusion

Dr. El-Deiry outlines two avenues for future research: population-based studies to assess cancer outcomes in HPV-positive individuals following SARS-CoV-2 infection or vaccination, and laboratory experiments to model the combined effects of HPV E6 and spike protein on p53 activity in human cells.

At present, the hypothesis remains speculative but biologically plausible. It highlights the importance of continued research at the intersection of oncology, virology, and immunology, particularly as we learn more about the long-term consequences of widespread viral exposure.

Click here to read the entire hypothesis published by 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).

Click here to subscribe to Oncotarget publication updates.

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Oncotarget

Exploring Possible Links Between COVID-19 Vaccination, Infection, and Cancer

January 26, 2026

“These findings underscore the need for rigorous epidemiologic, longitudinal, clinical, histopathological, forensic, and mechanistic studies to assess whether and under what conditions COVID-19 vaccination or infection may be linked with cancer.“

A growing number of post-pandemic reports have described cancer diagnoses, recurrence, or progression following COVID-19 vaccination or SARS-CoV-2 infection. While no causal relationship has been established, these observations raise important questions that warrant careful, hypothesis-driven investigation.

​​The rapid development and global distribution of mRNA and viral vector vaccines during the pandemic was a landmark achievement in public health, essential in reducing severe COVID-19 cases and mortality. However, the novelty of these vaccines and the absence of long-term carcinogenicity or genotoxicity testing have led some researchers to ask whether rare but biologically plausible interactions with cancer pathways might exist.

At the same time, pandemic-related disruptions in routine cancer screening and treatment were anticipated to influence diagnosis patterns. Yet, some reports have described unexpected phenomena, such as rapid disease progression in previously stable cancers or tumor appearance near injection sites, that are not easily explained by delayed care alone.

The Review: Examining 69 Studies on Cancer Diagnoses After COVID-19 Vaccination or Infection

In a review published in Volume 17 of Oncotarget, titled “COVID vaccination and post-infection cancer signals: Evaluating patterns and potential biological mechanisms,” Charlotte Kuperwasser (Tufts University) and Oncotarget Editor-in-Chief Wafik S. El-Deiry (The Warren Alpert Medical School of Brown University) examined 69 peer-reviewed publications spanning January 2020 to October 2025. 

The review included 66 article reports representing more than 300 individual patients from 27 countries, as well as two retrospective population-level studies (from Italy and South Korea) and one longitudinal analysis of 1.3 million U.S. military personnel. These studies collectively examined cancer diagnoses, recurrences, or unusually rapid disease progression following COVID-19 vaccination or SARS-CoV-2 infection.

Rather than stating causation or quantifying risk, the review aimed to identify recurring clinical patterns and explore plausible biological mechanisms. The authors emphasize that their findings should be viewed as hypothesis-generating, reflecting an early phase of signal detection.

The Findings: Key Clinical Patterns Observed Across Cancer Case Reports and Population Studies

Most reports reviewed (81%) were single-patient case studies or small series. Hematologic malignancies, including non-Hodgkin lymphoma, cutaneous T-cell lymphoma, and leukemia, were most frequently described. Reports also included solid tumors such as breast cancer, glioblastoma, pancreatic cancer, melanoma, and sarcoma.

In several cases, patients experienced tumor recurrence or rapid disease progression shortly after vaccination, including individuals previously in remission. A subset of cases described tumor development at or near the injection site or in regional lymph nodes.

The two population-based studies found modest associations between vaccination and increased incidence of certain cancers, including thyroid, breast, lung, and colorectal cancer. However, both studies acknowledged limitations such as short follow-up periods, potential detection bias, and confounding factors related to healthcare access.

The Hypotheses: Exploring Biological Mechanisms Linking COVID-19 Vaccination or Infection to Cancer Activation

The core insight of the review was not a determination of causality, but the recognition of rare, temporally associated patterns that deserve further investigation. One proposed mechanism involves temporary immune dysregulation following vaccination or infection. Elevated levels of cytokines such as IL-6, TNF-α, and IL-1β, well-documented after mRNA vaccination, may impair immune surveillance, allowing latent tumors to emerge or existing disease to accelerate.

Another hypothesis focuses on the SARS-CoV-2 spike protein, which may persist in certain tissues longer than initially expected. In some studies, spike protein expression was identified in tumor samples, prompting questions about its potential effects on tumor behavior or microenvironmental signaling.

The review also discusses residual plasmid DNA fragments that may be present from the mRNA vaccine manufacturing process. While no evidence currently supports genomic integration in humans, the potential for host cell uptake and biological impact remains a theoretical concern.

These mechanisms are contextualized within broader literature on how viral infections and inflammation can affect cancer initiation and progression. As the authors note, “Establishing causality between SARS-CoV-2 infection, COVID-19 vaccination, and cancer requires a level of evidence far beyond temporal association.”

The Impact: Implications for Cancer Surveillance and Vaccine Safety Research

If any association between COVID-19 vaccination or infection and cancer exists, it is likely rare and limited to specific contexts such as individuals with immune dysregulation, latent oncogenic viral infections, or undiagnosed malignancies. Nonetheless, identifying and understanding these interactions is essential for refining vaccine safety profiles and informing long-term public health strategies.

Importantly, the review does not challenge the value of COVID-19 vaccination. Rather, it calls for deeper investigation of how immune stimulation, especially when repeated over time, may intersect with cancer biology in certain individuals.

Future Perspectives and Conclusion

The authors conclude with a call for more rigorous, multidisciplinary research. Future studies should include prospective epidemiological monitoring, histopathologic tissue analysis, immune profiling, and molecular tracking of spike protein or vaccine-derived elements.

Crucially, these questions can only be answered through well-designed, transparent investigations, not assumptions. While the evidence today does not justify changing clinical practice, it does suggest that the interface between immune stimulation and tumor biology is more complex than previously understood.

As the pandemic passes, there is an opportunity to conduct systematic research into these observations using established scientific methods and long-term surveillance frameworks.

Click here to read the entire review published by 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).

Click here to subscribe to Oncotarget publication updates.

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Oncotarget

Overcoming Aromatase Inhibitor Resistance in Breast Cancer: A New Therapeutic Strategy

January 13, 2026

“The estrogen receptor is overexpressed in and promotes 67-80% and 90% of female and male breast cancer cases, respectively.“

Most breast cancers depend on estrogen to grow. This dependence explains why hormone-based treatments, such as aromatase inhibitors, are among the most effective therapies for estrogen receptor–positive breast cancer. Despite their success, these treatments do not work indefinitely for all patients. 

Over time, many tumors adapt to estrogen deprivation and continue to survive, grow, and spread. This process, known as aromatase inhibitor resistance, represents a major clinical challenge and is often associated with more aggressive disease and poorer outcomes. 

One reason resistant breast tumors are difficult to treat is that cancer cells adapt their internal signaling systems. Instead of relying on estrogen, they activate alternative growth pathways, including the MAPK and PI3K/AKT pathways. These pathways promote cell survival, movement, and resistance to therapy and are frequently driven by proteins such as KRAS and related G-proteins, which have historically been difficult to target. A recent study published in Oncotarget suggests now that a new class of compounds may offer a way to overcome this resistance.

The Study: Targeting Aromatase Inhibitor–Resistant Breast Cancer with Novel PCAI Compounds

Researchers from the Florida A&M University College of Pharmacy and Pharmaceutical Sciences, Institute of Public Health, investigated a group of experimental compounds called polyisoprenylated cysteinyl amide inhibitors, or PCAIs. Their study, titled “PCAIs stimulate MAPK, PI3K/AKT pathways and ROS-mediated apoptosis in aromatase inhibitor-resistant breast cancer cells while disrupting actin filaments and focal adhesion,” focused on breast cancer cells that had developed resistance after long-term treatment with letrozole (LTLT-Ca cells), a commonly prescribed aromatase inhibitor.

The goal was to determine whether PCAIs could disrupt key survival mechanisms in these resistant cancer cells and ultimately trigger cell death.

The Results: NSL-YHJ-2-27 Activates MAPK and PI3K/AKT Pathways to Induce Apoptosis in Resistant Breast Cancer Cells

Among the tested compounds, one PCAI, NSL-YHJ-2-27, showed strong effects. Treatment with this compound significantly reduced the survival of aromatase inhibitor-resistant breast cancer cells and caused changes in cell shape. Many cells shrank, rounded up, and detached from their growth surface. Even after the compound was removed, treated cells showed a markedly reduced ability to proliferate and form colonies, indicating long-lasting effects.

At the molecular level, NSL-YHJ-2-27 increased activation of MAPK and PI3K/AKT signaling pathways. While these pathways are often associated with cancer cell survival, their excessive activation in this context led to cellular stress rather than protection. The treatment also caused a rise in reactive oxygen species, highly reactive molecules that damage DNA, proteins, and lipids inside the cell.

In addition, NSL-YHJ-2-27 reduced the levels of key proteins involved in cell movement and structure, including RAC1 and CDC42. The compound disrupted actin filaments and decreased levels of focal adhesion proteins such as vinculin and fascin, weakening the cells’ internal framework. As a result, cancer cell migration and invasion were significantly reduced in both standard cell cultures and three-dimensional tumor-like spheroids. The treated cells also showed clear signs of apoptosis, confirming that the compound effectively triggered programmed cell death.

The Breakthrough: Targeting Cancer Cells from Within to Trigger Stress-Induced Cell Death

Rather than blocking signals at the cell surface, PCAIs act inside cancer cells by interfering with proteins that control growth, movement, and survival. By disrupting these internal systems, PCAIs place cancer cells under intense stress. This stress leads to the buildup of reactive oxygen species and ultimately leads the cells toward self-destruction.

The Impact: A  Potential New Therapeutic Strategy for Hormone-Resistant Breast Cancer

These results suggest that PCAIs could represent a potential new strategy for treating breast cancers that no longer respond to hormone therapy. Because this approach does not rely on estrogen receptors or specific surface markers, it may be effective across a broader range of resistant tumors. Importantly, by weakening the structural and migratory machinery of cancer cells, PCAIs may also reduce the ability of tumors to spread to other organs.

Future Perspectives and Conclusion

Although this research was conducted using laboratory models, it provides a solid foundation for further investigation. Additional studies will be required to evaluate safety, determine appropriate dosing, and assess the effects of PCAIs in animal models and, ultimately, in clinical settings. While still at an early stage, these findings suggest a possible new approach for addressing hormone therapy resistance in breast cancer. With continued research, PCAIs may contribute to the development of additional therapeutic options for patients with treatment-resistant disease.

Click here to read the entire research paper published by 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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Oncotarget

Comprehensive Genomic Profiling in Cancer: Insights from Over 10,000 Tumors

December 15, 2025

“The OncoExTra® assay (formerly GEM ExTra) is a whole exome, whole transcriptome, tumor-normal genomic profiling assay that is designed to identify somatic (tumor-specific) SNVs, CNAs, indels, gene fusions, and alternative transcripts.“

Cancer treatment is moving toward a more precision-based approach, where therapies are guided not just by the tumor’s location but also by its genetic features. Mutations in cancer cells can point to specific drugs that may be more effective for certain patients. However, detecting these mutations often requires broad and detailed analysis. This is where comprehensive genomic profiling becomes especially important.

One of the main challenges in cancer care is that many existing genetic tools focus on only a limited number of mutations. As a result, some treatment opportunities may be missed. Certain mutations are also difficult to detect because they occur at low levels or exist in complex forms, such as gene fusions. Without advanced screening methods, these changes may go unnoticed.

To address these challenges, researchers from Exact Sciences Corporation conducted a large-scale study using a broad genomic screening approach. The findings were recently published in the journal Oncotarget.

The Study: Using OncoExTra to Analyze Genetic Alterations in Advanced Solid Tumors

In this study, titled “Comprehensive genomic profiling of over 10,000 advanced solid tumors” and led by Jean-Paul De La from Exact Sciences Corporation, researchers used a method called OncoExTra to analyze over 11,000 tumor samples from more than 10,000 patients with advanced solid tumors. The goal was to understand how often genetic alterations that could guide treatment were found using this type of broad assay. 

The Results: Actionable Mutations Found in Over 90% of Tumors

The study found that nearly 92 percent of the tumor samples contained at least one genetic alteration that could potentially guide treatment. About half of the samples had mutations that were linked to therapies already approved by the U.S. Food and Drug Administration, either for the cancer type being studied or for other types.

Some of these mutations were found at very low levels, which highlights the need for sensitive screening techniques. Gene fusions, alterations that can be difficult to detect with standard methods, were identified in 7.5 percent of the cases. These fusions are especially relevant in certain cancers like prostate cancer and sarcoma, where they can influence treatment and, in some cases, help clarify the diagnosis.

Mutations were also found in several key biological pathways that are involved in how cancer cells grow, divide, and repair themselves. These included the PI3K/AKT, MAPK, and DNA repair pathways. Changes in these pathways can affect how the cancer behaves and responds to treatment.

In addition, the study reported that about 8 percent of the samples had mutations in the promoter region of the TERT gene. These changes have been associated with increased tumor growth and worse patient outcomes in several cancers. Although there are no approved therapies that directly target these mutations yet, their detection may become more relevant as new treatments are developed.

The Breakthrough: A Genomic Method That Analyzes Both DNA and RNA

The OncoExTra assay stands out for its ability to analyze both DNA and RNA across all known genes. It also compares tumor tissue to the patient’s normal tissue, which helps reduce the risk of false-positive results. This broad and in-depth approach enables the detection of rare, low-level, and complex mutations that smaller screening panels might miss. The method also identifies biomarkers such as tumor mutational burden and microsatellite instability, which can help determine whether a patient is likely to benefit from certain types of immunotherapy.

The Impact: Improving Precision Oncology Through Genetic Insights

These findings suggest that comprehensive genomic profiling can provide valuable information to help guide treatment for patients with advanced cancer. By identifying relevant mutations, clinicians can make more informed decisions, whether that involves prescribing targeted therapies, recommending clinical trials, or confirming a diagnosis. This supports a more individualized approach to cancer care, aiming to match each patient with the most appropriate treatment options based on the biology of their tumor.

Future Perspectives and Conclusion

While further studies are needed to better associate genomic findings with patient outcomes, this research demonstrates the clinical value of comprehensive genomic profiling. As screening methods continue to improve and become more widely available, they may enable more patients to receive treatments guided by the biological features of their tumors rather than tumor location alone.

Overall, the study shows that large-scale genomic screening is both feasible and useful in real-world oncology practice. It supports a more precise and informed approach to cancer care, while underscoring the importance of continued research and careful integration of genomic tools into clinical decision-making.

Click here to read the full research paper 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 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.