Tagged: summary

New Antibody Removes Tregs to Boost Immune Response Against Cancer

November 19, 2025

“Treg play a deleterious role in the tumor microenvironment by suppressing anti-tumor effector T cells.”

Cancer is a disease caused by the uncontrolled growth of cells that escape the body’s natural defenses. One way cancer protects itself is by taking advantage of certain immune cells called regulatory T cells, or Tregs. Normally, Tregs help prevent autoimmune diseases by controlling the immune system. But inside tumors, they behave differently. Instead of defending the body, they suppress the immune cells that could attack the cancer.

Many cancer treatments aim to activate the immune system to fight tumors more effectively. However, the presence of Tregs within the tumor makes this difficult. These cells act like bodyguards for the cancer, blocking the immune response that might otherwise slow or stop tumor growth.

Researchers have tried to eliminate Tregs by targeting a protein called CD25, found on their surface. However, earlier efforts often failed because these treatments also interfere with interleukin-2 (IL-2), a molecule that is essential for other immune cells to function. Blocking IL-2 weakens the entire immune response, limiting the treatment’s effectiveness.

To overcome this challenge, scientists recently developed a new antibody called 2B010. This study, titled “A novel anti-human CD25 mAb with preferential reactivity to activated T regulatory cells depletes them from the tumor microenvironment,” was published in Oncotarget (Volume 16)

The Study: Finding a New Antibody Against Tumor Tregs

To develop a more selective tool for targeting Tregs, researchers from the National Institute of Allergy and Infectious Diseases, in collaboration with Boehringer Ingelheim and led by Maja Buszko and Ethan M. Shevach, conducted an experiment using mice. The animals were exposed to human regulatory T cells that had been activated and expanded in the laboratory. This exposure triggered the mice’s immune systems to produce antibodies against the Tregs. Among the resulting hybridomas, one named 2B010 stood out for producing an antibody capable of binding to CD25, a protein commonly found on the surface of active Tregs.

The Results: 2B010 Shows Selective Treg Depletion and Immune Activation

The 2B010 antibody was effective in both cell-based and animal studies. It was able to detect and remove regulatory T cells that were actively protecting tumors, without disrupting IL-2 signaling. This allowed the rest of the immune system to stay functional.

In a mouse model of human breast cancer, treatment with 2B010 significantly reduced the number of Tregs inside the tumors. As a result, CD8+ T cells, which are responsible for killing cancer cells, became more active. While the tumors themselves did not shrink, the immune system clearly showed signs of stronger activity against the cancer.

What makes 2B010 different is its ability to distinguish between harmful and helpful immune cells. Although many immune cells express CD25 when activated, 2B010 preferentially binds to highly active Tregs within the tumor. This selectivity allows it to target only the cells that shield tumors, while sparing other important parts of the immune system.

The effect of 2B010 was not limited to the tumor site. Increased immune activity was also observed in the spleen, suggesting that this antibody may help support the body’s general immune response.

The Impact: Potential Role of 2B010 in Enhancing Cancer Immunotherapy

This discovery offers a potential direction for advancing cancer treatment. By removing the regulatory T cells that shield tumors from immune attack, the 2B010 antibody could improve the effectiveness of current immunotherapies. It may be particularly valuable when used alongside checkpoint inhibitors, drugs that help lift the immune system’s natural brakes. Together, these therapies could produce a stronger, more sustained anti-tumor response.

Since high levels of Tregs are linked to poor outcomes in many types of cancer, selectively eliminating these cells may help overcome a major obstacle in immunotherapy. In addition, because 2B010 does not interfere with IL-2 signaling, it may avoid the unintended side effects seen with earlier anti-CD25 antibodies. Together, these features make it a good candidate for more precise and better-tolerated cancer treatments.

Future Perspectives and Conclusion

While the 2B010 antibody shows strong potential in preclinical studies, its performance in human patients remains to be seen. Clinical trials will be essential to assess its safety, effectiveness, and compatibility with current cancer treatments. Researchers suggest that, with further development, 2B010 may become a valuable addition to combination immunotherapy strategies in the future.

Click here to read the full research paper published by Oncotarget.

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How Low Oxygen Shields Prostate Cancer from Ferroptosis Therapies

November 6, 2025

“Preclinical and clinical studies indicate that ferroptosis suppresses tumor growth, and dysregulation of ferroptosis promotes treatment resistance in cancer.”

Prostate cancer is one of the most common cancers in men. While treatment options have improved, advanced stages of the disease remain difficult to manage. One promising approach involves a process called ferroptosis. This is a type of programmed cell death that relies on iron and lipid oxidation to kill cancer cells by damaging specific fats in their outer membrane. These fats are especially vulnerable in environments with normal oxygen levels.

However, many prostate tumors grow in low-oxygen areas of the body, a condition known as hypoxia, where ferroptosis becomes less effective. A recent study, titled “Hypoxia induced lipid droplet accumulation promotes resistance to ferroptosis in prostate cancer,” and published on Oncotarget (Volume 16), explores how oxygen-poor environments help prostate cancer cells resist treatment and what strategies could help overcome this resistance.

The Study: How Low Oxygen Helps Prostate Cancer Resist Ferroptosis Treatments

A research team from the University of Arizona, led by Dr. Noel Warfel and Dr. Shailender Chauhan, studied how prostate cancer cells respond to ferroptosis-inducing drugs when oxygen levels are low. Their goal was to understand what changes happen inside cancer cells that help them survive under these conditions.

The Results: Prostate Cancer Cells Store Fats to Survive Ferroptosis in Low Oxygen Conditions

The researchers found that prostate cancer cells exposed to low-oxygen conditions were much less sensitive to ferroptosis-inducing drugs such as Erastin and RSL3. Even when the two drugs were combined to boost their effect, the cancer cells remained resistant.

Under hypoxia, the cancer cells changed how they processed fats. They produced fewer of the fragile fats that are typically targeted by ferroptosis and instead created more stable fats, which were stored in small compartments called lipid droplets. These droplets acted like protective storage units, shielding the vulnerable fats from oxidative damage.

The study also showed that hypoxia reduced the activity of genes like ACSL4 and LPCAT3, which help incorporate polyunsaturated fatty acids into cell membranes, fats that are crucial for making cells susceptible to ferroptosis. At the same time, the levels of oxidation-prone fats like phosphatidylethanolamines decreased, while more stable lipids such as cholesteryl esters and triglycerides increased.

The researchers attempted to block lipid droplet formation, but the results varied depending on the cell type, suggesting that other factors may also contribute to this resistance.

The Impact: Targeting Fat Storage May Improve Prostate Cancer Treatment

This study highlights the critical role of the tumor microenvironment, especially oxygen levels, in shaping how cancer cells respond to treatment. It suggests that ferroptosis-inducing drugs alone may not be effective against tumors growing in low-oxygen conditions.

To overcome this resistance, future therapies could include inhibitors that block the enzymes or pathways responsible for lipid droplet formation, making cancer cells more vulnerable to ferroptosis.

Future Perspectives and Conclusion

This study provides valuable insight into how prostate tumors resist ferroptosis-based therapies and points to new treatment strategies. Targeting how cancer cells manage and store fats, by preventing the buildup of lipid droplets or releasing stored fats, may help restore their sensitivity to ferroptosis. While more research is needed to fully understand this mechanism, the findings mark a step toward more effective cancer treatments. This approach could also be applied to other solid tumors that show similar resistance in low-oxygen environments.

Click here to read the full research paper published by Oncotarget.

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Genetic Study Identifies Potential Diagnostic Marker for Rare Blood Cancer BPDCN

October 22, 2025

“Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy with poorly characterized molecular features.”

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare blood cancer that primarily affects older adults. One of the key challenges in diagnosing and treating BPDCN is that it closely resembles other forms of leukemia in both appearance and behavior. This overlap often leads to delays or uncertainty in diagnosis, especially since currently there is no single, reliable marker that clearly distinguishes BPDCN from related diseases.

To address this issue, researchers from the City of Hope Comprehensive Cancer Center investigated the genetic profile of BPDCN. Their study, titled “Genetic characteristics of blastic plasmacytoid dendritic cell neoplasm: A single institution experience,” was published in Oncotarget (Volume 16).

Understanding BPDCN: A Rare and Aggressive Blood Cancer

BPDCN is an aggressive cancer that commonly affects the skin, bone marrow, and lymph nodes. Diagnosing it remains difficult due to its overlap with other blood cancers. Although targeted therapies and stem cell transplantation have led to some progress, overall outcomes remain poor. Most patients survive only one to two years after diagnosis, emphasizing the need for earlier detection and more effective treatment options.

The Study: Genetic Sequencing in BPDCN Patients

Led by first author Fei Fei and corresponding author Michelle Afkhami, from the City of Hope Comprehensive Cancer Center, researchers performed targeted DNA and RNA next-generation sequencing (NGS) on samples from 21 patients with BPDCN—nineteen male and two female.

Their goal was to better understand the genetic mutations associated with this disease and evaluate whether any of these changes could be used to improve diagnosis or predict disease progression.

The Results: Genetic Alterations in BPDCN

The study revealed frequent mutations in genes such as TET2 (57%) and ASXL1 (33%), both of which are involved in regulating DNA activity. These mutations were often associated with shorter survival, particularly when multiple mutations occurred in a single patient. Other mutated genes were NRAS (29%), SRSF2 (14%), ZRSR2 (14%), and KMT2D (14%).

Another important finding was the gene CCDC50, which showed significantly higher expression in BPDCN compared to related cancers like acute myeloid leukemia (AML) and chronic monomyelocytic leukemia (CMML). In patients who responded well to treatment, CCDC50 levels declined, suggesting its potential usefulness in monitoring treatment response.

The Impact: CCDC50 as a Diagnostic Marker

The study highlights CCDC50 as a potential marker for BPDCN. Its high expression in this cancer—and not in related blood malignancies—suggests it could support both diagnosis and monitoring of treatment response. If validated in larger studies, it could become a valuable tool for clinicians seeking earlier and more accurate diagnoses.

Additionally, the association between mutations in genes like TET2 and ASXL1 and patient outcomes may help guide risk assessment and inform more personalized treatment decisions.

Future Perspectives and Conclusion

While these findings offer important insights, the study was based on a relatively small patient group. Further research is needed to confirm the role of CCDC50 and increase the understanding of how genetic mutations affect BPDCN progression. Nonetheless, this study represents a step toward more precise diagnostic tools and tailored treatments for a disease that remains challenging to manage.

Click here to read the full research paper published by Oncotarget.

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New Insights into HER2-Mutated Non-Small Cell Lung Cancer in Brazil

October 8, 2025

“In non–small cell lung cancer (NSCLC), alterations in the HER2 (ERBB2) gene define a unique molecular subtype.”

Lung cancer remains one of the leading causes of cancer-related deaths worldwide. Although precision medicine has improved outcomes for many patients, certain rare genetic mutations are still poorly understood, particularly in regions with limited access to genomic testing. Such mutations involve the HER2 gene, better known for its role in breast cancer but also implicated in a small subset of lung cancers.

HER2 mutations are found in approximately 2–4% of non-small cell lung cancer (NSCLC) cases and create unique challenges. These tumors can vary significantly in how they appear under a microscope and in how they respond to treatment. Adding to the complexity, most diagnostic and treatment guidelines are based on research from high-income countries, which may not reflect the genetic diversity seen in other parts of the world.

To help close this knowledge gap, researchers in Northeastern Brazil conducted one of the first detailed investigations into HER2-mutated NSCLC in Latin America. Their study, recently published in Volume 16 of Oncotarget, reveals a complex and often overlooked form of the disease, highlighting the need for broader access to targeted therapies in underserved populations.

The Study: HER2-Mutated NSCLC in Northeastern Brazil

In the study titled “Molecular landscape of HER2-mutated non-small cell lung cancer in Northeastern Brazil: Clinical, histopathological, and genomic insights,” researchers led by first authors Cleto Dantas Nogueira from the Federal University of Ceará and Argos Pathology Laboratory and Samuel Frota from Argos Pathology Laboratory, along with corresponding author Fabio Tavora from the previously mentioned institutions and Messejana Heart and Lung Hospital, analyzed 13 cases of HER2-mutated NSCLC. They used clinical, pathological, and genomic data.

The Results: A Complex Clinical and Molecular Landscape

The analyzed patients ranged in age from 34 to 82 years. More than half were women. About half had never smoked.

The research team discovered different HER2-related mutations. Most tumors carried the well-known A775_G776insYVMA insertion in exon 20 of the HER2 gene. However, rarer mutations such as V842I and Q709L were also identified, indicating substantial genetic diversity. More than half of the patients had additional mutations in other key cancer-related genes, especially TP53, a gene associated with aggressive tumor behavior and resistance to treatment.

Interestingly, most tumors did not overexpress the HER2 protein, even though they carried HER2 mutations. Only one patient showed strong protein expression based on standard immunohistochemistry (IHC) testing. This finding suggests that relying only on protein-level tests may miss cases that could benefit from targeted treatment. Additionally, all tumors had a low tumor mutation burden (TMB), which has been linked to limited effectiveness of immunotherapies.

Treatment access emerged as a major concern. Only one patient received trastuzumab deruxtecan, a promising new drug specifically designed for HER2-mutated cancers. Most were treated with surgery, chemotherapy, immunotherapy, or a combination of these approaches. While a few patients lived for years after diagnosis, most experienced rapid disease progression, especially those diagnosed at more advanced stages.

The Breakthrough: Mutations in Underserved Populations

This study underscores the molecular diversity of HER2-mutated NSCLC and highlights the importance of using comprehensive genetic testing, not just protein-level tests, to detect targetable mutations. It also shows that patients in underserved regions can harbor complex cancers that need personalized treatment approaches.

The Impact: Making the Case for Genomic Equity in Lung Cancer

This research has the potential to reshape NSCLC diagnosis and treatment strategies in Brazil and other low- to middle-income countries. By confirming that HER2 mutations are present in regions where they are rarely investigated, it strengthens the case for expanding access to next-generation sequencing and innovative targeted therapies like trastuzumab deruxtecan.

Future Perspectives and Conclusion

Although the study’s sample size was small, its implications are important. HER2-mutated NSCLC is more genetically diverse than previously recognized, and this variability must be reflected in both diagnostic and treatment strategies. The authors advocate for the establishment of regional molecular tumor boards to guide personalized care and increase access to clinical trials.

As more data becomes available, the goal is to tailor therapies not just to specific mutations but also to the unique characteristics of local patient populations, marking a crucial step toward more equitable cancer care worldwide.

Click here to read the full research paper published by Oncotarget.

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Precision Oncology in Metastatic Colorectal Cancer: A Real-World Case Study

September 24, 2025

“Heavily pretreated metastatic colorectal cancer (mCRC) poses significant therapeutic challenges.”

Colorectal cancer is one of the most common—and deadliest—cancers worldwide. Once it spreads and reaches the metastatic stage, treatment becomes far more difficult. Tumors can also behave very differently from one patient to another, especially after multiple rounds of therapy. Precision oncology is helping to overcome these challenges by enabling clinicians to analyze each tumor’s unique genetic profile and tailor treatment accordingly.

This approach was recently highlighted in a case study published in Volume 16 of Oncotarget. The report detailed how a 62-year-old man with advanced colorectal cancer received a highly personalized treatment plan, developed by an international panel of experts, after completing all standard treatment options.

The Case: Personalized Cancer Care in Action

Titled “Case Report WIN-MTB-2023001: WIN International Molecular Tumor Board – A 62-year-old male with metastatic colorectal cancer with 5 prior lines of treatment,” the paper illustrates how precision medicine can be applied in real-world cancer care. The paper was led by Alberto Hernando-Calvo from Vall d’Hebron University Hospital and Vall d’Hebron Institute of Oncology; Razelle Kurzrock from WIN Consortium and Medical College of Wisconsin; Oncotarget Editor-in-Chief Wafik S. El-Deiry from WIN Consortium and Legorreta Cancer Center at Brown University; and corresponding author Shai Magidi, also from WIN Consortium.

The patient had already undergone five different treatment regimens, including chemotherapy and targeted therapies. While some approaches initially showed results, the cancer repeatedly returned. With standard options exhausted, his case was submitted to the WIN International Molecular Tumor Board (MTB)—a global network of cancer experts representing 13 countries.

Comprehensive tumor genetic profiling revealed mutations in key genes such as BRAF, MET, APC, TP53, and NRAS. These alterations are known to promote tumor growth, contribute to treatment resistance, and predict a poor prognosis. Based on these findings, the MTB proposed a series of personalized treatment strategies, using off-label drug combinations designed to target the tumor’s specific genetic vulnerabilities.

Results: A Multi-Drug Treatment Approach

The team proposed several personalized treatment options. One strategy combined amivantamab (a dual-action antibody against MET and EGFR), trametinib (a MEK inhibitor), and regorafenib (a multi-target drug with effects on VEGF and WNT pathways). These combinations were not standard but were based on previous responses and the patient’s mutational profile. The plan was to start with reduced doses to avoid side effects, a method supported by earlier studies. Though access to some drugs was uncertain outside the United States, the goal was to attack the tumor from multiple angles based on its unique weaknesses.

The Breakthrough: Rethinking Cancer Therapy with Precision Oncology

This case highlights a key innovation in cancer treatment—not a new drug, but a new way of thinking. Instead of relying on a one-size-fits-all approach, clinicians matched the therapy to the patient’s tumor genetic characteristics. Importantly, these decisions were developed collaboratively and in real time by an international panel of experts.

The Impact: Expanding Options for Patients with Advanced Tumors

If applied more broadly, this personalized strategy could improve outcomes for patients with hard-to-treat cancers. Especially for those who have failed standard treatments, precision oncology can offer a way forward when no other effective options remain. It is a shift from treating cancer generally to treating the individual behind the diagnosis.

Future Perspectives and Conclusion

Although the patient in this case ultimately passed away, his case shows how much progress has been made in precision medicine. With detailed genetic testing and input from experts around the world, it is now possible to create treatment plans that would have been unthinkable just a few years ago. This case highlights the urgent need for wider access to advanced testing and new treatments, especially in countries where some drugs may not be available. Precision medicine is no longer just an idea for the future; it has become a present-day necessity in complex cancer care.

Click here to read the full Precision Oncology in Oncotarget.

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Immunotherapy Response in Pancreatic Cancer: What a New Study Reveals

September 11, 2025

“Identification and analyses of exceptional responders could eventually offer hints as to why PC is resistant to immunotherapy.”

Immunotherapy is not usually effective against pancreatic cancer (PC), but a new study published in Oncotarget (Volume 16, 2025) highlights rare cases where it did help. These examples, though uncommon, may offer valuable insights for future treatment.

Pancreatic Cancer and Immunotherapy

Pancreatic cancer is often diagnosed at an advanced stage, which limits treatment options and contributes to its poor prognosis. While chemotherapy remains the standard treatment, it usually offers only modest benefits in terms of survival. Immunotherapy—an approach that activates the immune system to fight cancer—has been effective in other cancers but has shown limited success in PC.

This is largely due to the tumor’s ability to suppress immune responses and create an environment that protects it from attack. Currently, these drugs are only approved for a small subset of patients whose tumors have a specific genetic feature called high microsatellite instability (MSI-high), found in just 1 to 2 percent of cases.

The Study: Pancreatic Cancer Immunotherapy Responders

The study, titled “Exceptional responders to immunotherapy in pancreatic cancer: A multi-institutional case series of a rare occurrence,” was led by first author Kavin Sugumar and corresponding author Jordan M. Winter, from University Hospitals Seidman Cancer Center.

The researchers examined medical records from 14 patients with pancreatic ductal adenocarcinoma (PDAC) who had responded unexpectedly well to immune checkpoint inhibitors—drugs that help reactivate immune cells to attack cancer. The drugs included PD-1 inhibitors such as pembrolizumab and nivolumab, CTLA-4 inhibitors like ipilimumab, and agents targeting tumor-associated macrophages. To find these rare cases, the research team contacted 471 oncologists from 91 major U.S. cancer centers between 2020 and 2021.

Most of the patients in this study had already tried chemotherapy, without lasting success. These patients received immunotherapy alone. They were selected because they showed either a reduction in tumor size on imaging or a drop in CA 19-9, a blood marker used to monitor PC.

This case series is the largest to focus exclusively on PC patients who responded well to immunotherapy. By excluding those who received chemotherapy simultaneously, the study aimed to isolate the effects of immune-based treatments alone.

The Results: Immunotherapy Shows Effectiveness in Both MSI-High and MSI-Stable Pancreatic Cancer

After starting immunotherapy, 82% of the patients showed a partial response, meaning their tumors became smaller. Around one-third of the patients had a meaningful decrease in CA 19-9 levels. On average, their disease remained stable for about 12 months, which is longer than typically seen with other treatments at this stage. Some patients lived for more than two years after beginning immunotherapy.

What stood out most was that more than half of these patients did not have MSI-high tumors. This challenges the current understanding that only MSI-high patients are likely to benefit from immunotherapy and suggests that other, less well-understood factors may also play a role.

The Impact: Expanding the Role of Immunotherapy in Pancreatic Cancer

Although this study includes only a small number of patients, the results suggest that immunotherapy may benefit more individuals with PC than previously assumed. While the standard of care still centers on chemotherapy, this case series shows that a small but meaningful group of patients—some without the usual MSI-high genetic marker—can respond well to immune-based treatments. These observations support the idea that immunotherapy may have a broader role in PC care.

Future Perspectives and Conclusion

These findings highlight the need to understand why certain PC patients respond to immunotherapy despite lacking known predictive markers like MSI-high. Exploring tumor biology, immune interactions, and patient-specific characteristics may help identify new indicators of response.

Although immunotherapy remains ineffective for most PC cases, rare outcomes like those in this study offer valuable clues. Investigating these exceptions more closely could support the development of more personalized and effective treatment approaches.

Click here to read the full research paper in Oncotarget.

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Amivantamab Monotherapy in Rare EGFR-Mutated Advanced NSCLC

August 26, 2025

“Amivantamab, an anti-EGFR/MET bispecific antibody, shows efficacy in EGFR-mutated NSCLC, but its role in rare EGFR alterations and CNS involvement, including leptomeningeal disease (LMD), remains insufficiently characterized.“

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality. While the development of targeted therapies has improved outcomes for many patients with EGFR-mutated NSCLC, those with rare EGFR variants often face limited treatment options, especially when the disease involves the central nervous system (CNS).

A recent research paper, titled “Durable complete response in leptomeningeal disease of EGFR mutated non-small cell lung cancer to amivantamab, an EGFR-MET receptor bispecific antibody, after progressing on osimertinib” published in Volume 16 of Oncotarget, describes a patient with NSCLC harboring two uncommon EGFR mutations—G719A and A289V—who experienced a prolonged and clinically significant response to amivantamab monotherapy, after prior treatments had failed.

Rare EGFR Mutations and Leptomeningeal Spread

EGFR mutations are present in a subset of NSCLC cases, with most data and drug approvals focused on common variants such as exon 19 deletions and L858R. Mutations like G719A and A289V are far less common and have limited clinical evidence to guide treatment.

The presence of leptomeningeal disease (LMD)—a late-stage manifestation involving the membranes surrounding the brain and spinal cord—further complicates treatment, given the difficulty many therapies face in crossing the blood-brain barrier.

Case Overview: Advanced NSCLC with Leptomeningeal Disease

This case, reported by Jinah Kim from the University of Vermont Medical Center, Young Kwang Chae from Feinberg School of Medicine and colleagues, involved a 67-year-old man with stage IV NSCLC and no history of smoking. Genetic testing identified the presence of EGFR G719A and A289V mutations. Initial therapy with osimertinib, followed by chemotherapy and immunotherapy, failed to control disease progression, which eventually involved both the brain and spinal fluid.

Given his declining performance status, combination therapies were not feasible. As an alternative, clinicians initiated amivantamab monotherapy, a bispecific antibody targeting EGFR and MET receptors. While amivantamab is currently approved in combination regimens, its activity as a single agent in rare EGFR mutations and CNS disease is not well established.

The Results: Response to Amivantamab

Within six weeks of starting amivantamab treatment, imaging showed a 32% reduction in lung tumor size. By six months, Magnetic resonance imaging confirmed complete resolution of brain metastases and LMD. In parallel, blood tests showed a molecular response. Circulating tumor DNA carrying the EGFR mutations dropped from detectable levels to undetectable. The patient, previously wheelchair-bound, recovered the ability to walk and manage activities of daily living. As of the latest follow-up, 19 months into treatment, the disease remained stable, with no signs of recurrence in either the lungs or CNS.

The Breakthrough: Monotherapy in Rare EGFR-Mutated NSCLC

This case challenges several prevailing views in the treatment of EGFR-mutated NSCLC. Amivantamab demonstrated activity against two rare mutations—G719A and A289V—that are poorly characterized and lack established treatment protocols.

The drug was administered as monotherapy, which diverges from current standard use involving combination regimens. Most notably, the clinical response included resolution of CNS involvement, suggesting that amivantamab may possess a degree of blood-brain barrier penetration not typically expected of large antibody-based therapies.

The Impact: A Potential Strategy for Patients with Limited Options

This case shows that amivantamab might be effective in more patients than previously thought, including those with rare mutations and brain metastases. It also raises the possibility of using the drug alone in patients who cannot tolerate combination therapies. These findings are especially significant because current clinical trials often exclude patients with untreated brain metastases, leaving a gap in NSCLC care.

Future Perspectives and Conclusion

This case provides a detailed example of amivantamab monotherapy being associated with sustained disease control in a patient with advanced NSCLC, rare EGFR mutations, and leptomeningeal involvement. Although it reflects a single patient’s experience, the outcome raises important questions for further research.

Key areas for investigation include the mechanism by which amivantamab may cross the blood-brain barrier—a longstanding challenge in treating CNS metastases. Additional studies are also needed to evaluate its efficacy against other rare EGFR mutations and to determine whether monotherapy could be a feasible option for patients who are unable to tolerate standard combination regimens.

While limited in scope, this case underscores the need for broader clinical data and suggests that amivantamab may have a role in complex, treatment-resistant NSCLC presentations.

Click here to read the full research paper in Oncotarget.

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Cigarette Smoke and Weak DNA Repair: A Double Hit Behind Lung Cancer Risk

August 11, 2025

“Lung cancer remains the leading cause of cancer-related fatalities in the United States and worldwide, with cigarette smoking the most well-established risk factor for lung cancer.“

Lung cancer, particularly non-small cell lung cancer (NSCLC), is the deadliest cancer worldwide. Cigarette smoking is one of the main causes, but not every smoker develops the disease. This suggests that other biological factors help determine who develops cancer.

Researchers from the Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Indianapolis, and from the Richard L. Roudebush Veterans Affairs Medical Center have now found that cigarette smoke, combined with a weakened DNA repair system, can trigger the early stages of lung cancer, particularly NSCLC. This work, led by first author Nawar Al Nasralla and corresponding author Catherine R. Sears, was recently published in Volume 16 of Oncotarget.

Understanding the Link Between Cigarette Smoke and DNA Repair

NSCLC develops through a mix of genetic and environmental factors, with tobacco smoke as a major driver. Cigarette smoke contains thousands of harmful chemicals, many of which can damage DNA in the cells covering the airways. The body has natural systems to repair DNA damage and keep cells healthy. For example, one key protein, Xeroderma Pigmentosum Group C (XPC), detects specific types of DNA damage and starts the repair process, helping to maintain cellular genetic stability.

When DNA repair does not work properly, damaged DNA can remain in cells. Over time, these alterations may accumulate and lead to uncontrolled cell growth, raising the risk of NSCLC, and other lung diseases, such as chronic obstructive pulmonary disease (COPD).

The Study: Investigating the Relation Between DNA Repair and Lung Cancer Development

In the paper “Cigarette smoke and decreased DNA repair by Xeroderma Pigmentosum Group C use a double hit mechanism for epithelial cell lung carcinogenesis,” the research team investigated how cigarette smoke affects DNA repair when XPC function is reduced and whether this combination accelerates lung disease and cancer development.

They studied both healthy lung cells and lung cancer cells to compare how each type reacted to cigarette smoke exposure. By analyzing these differences, the team aimed to better understand how weakened DNA repair systems might set the stage for NSCLC and other lung diseases.

The Results: XPC Reduction is Part of NSCLC Development

The study found major differences between healthy lung cells and lung cancer cells when DNA repair was compromised. In healthy bronchial cells, cigarette smoke reduced DNA repair ability, increased DNA damage, and caused more cell death. These effects became stronger when XPC levels were lower.

Lung cancer cells responded differently, showing greater resistance to cigarette smoke. They required higher exposure to cause similar DNA damage, and lowering XPC had little effect on their survival, suggesting they rely on other mechanisms to manage the damage.

The researchers also examined genomic instability—signs that DNA is becoming dangerously unstable. In healthy cells, reduced XPC made cigarette smoke damage more likely to produce micronuclei, small DNA fragments that indicate higher cancer risk. In lung cancer cells, lowering XPC did not significantly change these markers.

Finally, in human NSCLC tumor samples, both lung adenocarcinomas and squamous cell carcinomas had much lower XPC levels than nearby healthy tissue. This was true regardless of smoking history, indicating that XPC loss is part of tumor biology rather than simply a result of cigarette smoke.

The Breakthrough: A Double Hit Driving Lung Disease Development

The findings point to a dangerous partnership between cigarette smoke and weakened DNA repair. Cigarette smoke delivers the first hit by directly damaging DNA. Reduced XPC delivers the second hit by limiting the cell’s ability to repair that damage. Together, these effects allow genetic errors to accumulate, increasing the probability that lung cells become cancerous. This “double hit” mechanism may help explain why some smokers develop lung diseases while others do not.

The Impact: Lung Cancer Prevention and Care

Testing for DNA repair capacity, especially XPC levels, could help identify people at higher risk for lung cancer, even before symptoms appear. Such screening could guide targeted prevention strategies for smokers and previous smokers.

Future Perspectives and Conclusion

This research highlights the importance of protecting cells’ DNA repair systems, particularly XPC, to reduce lung cancer risk. The next step will be to understand why XPC levels drop in lung cells. Identifying and addressing the causes could lead to prevention strategies for people exposed to cigarette smoke, including those who have already quit but remain at risk. Preserving or restoring XPC function could be a therapeutic strategy to slow or even prevent the earliest stages of NSCLC caused by cigarette smoke.

Overall, when cigarette smoke and reduced DNA repair act together, they can cause severe damage to lung cells, increase genetic instability, and raise the chances of developing NSCLC.

Click here to read the full research paper in Oncotarget.

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Oncotarget

A New Way to Target Resistant Prostate Cancer Cells

July 29, 2025

“Currently, there is no effective therapy for CRPC.“

Prostate cancer is the second most diagnosed cancer among men worldwide and remains a leading cause of cancer-related death. While early forms of the disease can usually be treated successfully, advanced cases remain a major challenge. Scientists have now discovered a new potential way to slow the growth of advanced, treatment-resistant prostate cancer. These results were recently published in Volume 16 of Oncotarget by researchers from the University of Cincinnati College of Medicine.

Understanding Advanced Prostate Cancer

Early-stage prostate cancer can often be treated successfully. Most treatments work by lowering testosterone levels or blocking the hormone from activating the androgen receptor (AR), which drives cancer growth.

In some patients, however, the disease progresses to castration-resistant prostate cancer (CRPC). Even with drastic reductions in testosterone levels, the tumors continue to grow at this stage. CRPC is much more difficult to treat, and current therapies such as hormone blockers or chemotherapy typically extend life by only a few months.

One reason for this resistance is that cancer cells often switch to a different form of the androgen receptor called AR-V7. This variant remains permanently active, even without testosterone, making hormone-based drugs less effective. Because of this, new treatment strategies that work independently of hormone levels are needed.

The Study: Targeting a New Weakness in Prostate Cancer Cells

In the study titled “Targeting PCNA/AR interaction inhibits AR-mediated signaling in castration resistant prostate cancer cells,” researchers Shan Lu and Zhongyun Dong from the University of Cincinnati College of Medicine investigated a new way to block CRPC growth.

They focused on an unexpected partnership between two proteins. One is the AR, the key driver of prostate cancer. The other is proliferating cell nuclear antigen (PCNA), a protein known for helping cells repair their DNA and grow.

The goal was to block the connection between AR and PCNA. To do so, researchers carried out experiments on several types of prostate cancer cell models: LNCaP cells (which express the full-length AR), 22Rv1 cells (which express both full-length AR and the resistant AR-V7 variant), R1-D567 cells (which express another AR variant), and PC-3 cells (which do not express AR and were used as a control).

The Results: Blocking PCNA Slows Prostate Cancer Cell Growth

The researchers discovered that PCNA binds to AR in two specific regions. In normal AR, testosterone strengthens this binding, but in the AR-V7 variant, the binding constantly happens, regardless of testosterone levels.

To break this link, the team designed a small peptide called R9-AR-PIP. This peptide places itself between AR and PCNA, preventing them from connecting. Once separated, AR could no longer attach to DNA or activate genes that promote prostate cancer growth, such as PSA and cyclin A2. As a result, cancer cell proliferation decreases, and cell death increases.

Researchers also tested another small molecule called PCNA-I1S, which blocks PCNA from entering the cell nucleus. This molecule produced similar effects as R9-AR-PIP, reducing AR activity, including the resistant AR-V7 form.

One key finding was that both small molecule treatments lowered the levels of cyclin A2, a protein often overproduced in CRPC and associated with poor outcomes.

Implications for Advanced Prostate Cancer Treatment

This study is the first to show that blocking the PCNA–AR partnership, either by blocking their direct interaction or by preventing PCNA from entering the nucleus, can slow the growth of prostate cancer cells, including those driven by AR-V7. Unlike current treatments, these approaches target the interaction itself rather than testosterone.

If developed into a clinical therapy, it could open a new path for treating late-stage prostate cancer, particularly for patients whose cancer no longer responds to hormone therapy. It also offers a way to slow cancer growth without the heavy side effects of chemotherapy.

Future Perspectives and Conclusion

These new findings are currently only available in preclinical studies. The next step will be to test these PCNA-targeting compounds in animal models and, eventually, in clinical trials. If successful, this strategy could lead to a new generation of treatments for advanced prostate cancer, even in cases that have become resistant to all current therapeutic options.

Click here to read the full research paper in Oncotarget.

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Oncotarget

PRDX1 Identified as Key to Chemotherapy Resistance in Cancer Cells

July 14, 2025

“[…] targeting PRDX1 should sensitize tumours to DNA-damaging agents.”

Scientists have uncovered a promising new strategy to weaken cancer cells’ natural defense mechanisms, potentially making chemotherapy more effective. In a study published in Volume 16 of Oncotarget, researchers identified the protein PRDX1 as a key player in helping tumors resist treatment. By targeting this protein, they propose a novel way to combat aggressive, treatment-resistant cancers.

Understanding Why Some Cancers Resist Treatment

Chemotherapy works by damaging the DNA of cancer cells, forcing them to self-destruct. However, many cancers develop robust repair systems that fix this damage, allowing the tumor to survive and grow. A central component of this repair machinery is a protein called ATM, which acts like a first responder in the cell, detecting DNA damage and coordinating its repair.

In ovarian cancer and other aggressive tumors, high levels of ATM have been associated with poor survival rates and resistance to chemotherapy.

The Study: How PRDX1 Protects Cancer Cells

The study, titled “PRDX1 protects ATM from arsenite-induced proteotoxicity and maintains its stability during DNA damage signaling,” was led by first author Reem Ali and corresponding author Dindial Ramotar from Hamad Bin Khalifa University in Qatar, in collaboration with researchers from the University of Nottingham in the UK.

To investigate PRDX1’s role, the team used human cell line models where they inactivated the PRDX1 gene to see how the cells would behave without it. Next, they exposed these cells to arsenite—a toxic substance that damages DNA—as well as to chemotherapy drugs and ATM inhibitors. This allowed them to observe how the absence of PRDX1 affected the cells’ ability to survive and repair damage.

They also analyzed 183 tumor samples from ovarian cancer patients, studying the levels of PRDX1, ATM, and another DNA repair protein called MRE11, and associating these findings with patient outcomes.

The Results: PRDX1 as a Key Protector

The researchers discovered that PRDX1 physically interacts with ATM, acting as a stabilizer and protector for this critical DNA repair protein. When PRDX1 was removed from cancer cells in laboratory experiments, ATM levels decreased dramatically. Without PRDX1, the cells lost their ability to repair DNA damage and became highly sensitive to DNA-damaging agents, such as arsenite, known to harm DNA and proteins. These compromised cells were even more vulnerable when exposed to a combination of arsenite and ATM inhibitors, resulting in rapid cell death.

In tissue samples from ovarian cancer patients, tumors that had high amounts of both PRDX1 and ATM were associated with worse patient’ survival rates and were less responsive to platinum-based chemotherapy, which is a standard treatment for ovarian cancer.

Implications: A New Strategy Against Chemotherapy Resistance

This research positions PRDX1 as both a protector of cancer cells and a potential weak point. By disrupting PRDX1’s protective role, scientists believe they can sensitize resistant tumors to platinum-based chemotherapy, which is widely used for ovarian and other cancers.

The findings also raise the possibility of using PRDX1 as a biomarker to predict which tumors are more likely to respond to DNA-damaging therapies. For patients whose cancers show high PRDX1 levels, combining existing drugs with PRDX1 inhibitors, or even small doses of arsenite, might enhance treatment outcomes.

Future Perspectives and Conclusion

While these study findings are still in the experimental stage, they offer a new approach to overcoming one of cancer treatment’s greatest challenges: resistance. The next steps involve developing safe ways to block PRDX1 in patients and testing this strategy in clinical trials.

If successful, targeting PRDX1 could open the door to combination therapies that make chemotherapy more effective, reduce toxic side effects, and improve treatment options for patients with some of the hardest-to-treat cancers.

Click here to read the full research paper in Oncotarget.

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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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