Tagged: research paper

Immunotherapy Safety for Hepatocellular Carcinoma in Latin America: Insights from a Real-World Study

July 2, 2025

“Latin America has been underrepresented in trials evaluating immunotherapy for hepatocellular carcinoma (HCC).”

Liver cancer, especially hepatocellular carcinoma (HCC), remains a major health concern worldwide. In Latin America, the situation becomes more difficult due to limited access to advanced treatments and the high prevalence of underlying liver diseases. A recent research paper, published in Volume 16 of Oncotarget by researchers from Argentina, Brazil, Chile, and Colombia, offers valuable insights into how patients in the region respond to a widely used immunotherapy regimen. This real-world study explores both the effectiveness of treatment and the risks of immune-related side effects.

Understanding Hepatocellular Carcinoma: Why It is So Difficult to Treat

Hepatocellular carcinoma is often diagnosed at an advanced stage and frequently occurs in people with pre-existing liver conditions such as cirrhosis. Standard treatments like surgery or local therapies are not always possible in these cases. In recent years, the combination of two drugs—atezolizumab and bevacizumab—has shown promise in extending survival. However, most of the evidence comes from controlled clinical trials that may not represent the realities faced by healthcare providers and patients in Latin America.

The Study: Immunotherapy for Hepatocellular Carcinoma in Latin America

In a multicenter study titled “Immune-mediated adverse events following atezolizumab and bevacizumab in a multinational Latin American cohort of unresectable hepatocellular carcinoma,” led by Leonardo Gomes da Fonseca from Hospital das Clínicas, Universidade de São Paulo, Brazil, and Federico Piñero from Hospital Universitario Austral, Argentina, researchers aimed to fill that gap. The study included 99 patients with advanced HCC from Argentina, Brazil, Chile, and Colombia. All patients received the combination of atezolizumab and bevacizumab. The main objectives were to assess how frequently immune-related side effects, known as immune-related adverse events (irAEs), occurred and whether these events affected overall survival.

The Results: Immune-Related Adverse Events

Immunotherapy works by boosting the immune system to fight cancer. However, this can also lead to unintended effects where the immune system attacks healthy tissues. These irAEs can range from mild symptoms to serious conditions like liver inflammation, which can be particularly dangerous for patients whose liver function is already damaged.

In this study, the median overall survival was 17 months, a result consistent with international clinical trials. About 18% of patients developed irAEs, most commonly hepatitis, thyroiditis, and nephritis. Nearly half of these cases required medical treatment such as corticosteroids. Even so, only about half of the irAEs were completely resolved. Importantly, the occurrence of irAEs did not appear to reduce overall survival, suggesting that while these side effects require attention, they are manageable.

An additional finding was that patients with higher levels of alpha-fetoprotein (AFP), a marker often used to assess liver cancer severity, were more likely to develop irAEs. This could help clinicians identify which patients need closer monitoring during treatment.

Implications for Hepatocellular Carcinoma Care in Latin America

This is one of the few studies assessing how HCC patients in Latin America respond to immunotherapy in everyday clinical settings. The results support the use of atezolizumab and bevacizumab in the region but also point out the importance of being prepared to detect and manage side effects. Building medical capacity for early identification and treatment of irAEs is especially important for patients with weaker liver function.

Future Perspectives and Conclusion

Although immune-related side effects did not seem to affect survival in this study, they add another layer of complexity to HCC treatment. More research is needed to understand which patients are most at risk and how to prevent these side effects. For the moment, this study provides useful information for clinicians and healthcare systems aiming to safely expand access to immunotherapy in Latin America for HCC.

Click here to read the full research paper in Oncotarget.

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

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

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Oncotarget

Experimental Triple Therapy Improves Survival in Glioblastoma Mouse Model

June 4, 2025

“There are more than 13,000 new cases of malignant brain tumors diagnosed each year in the US alone.“

Researchers at Brown University have developed a combination treatment that significantly increases survival in mice with glioblastoma (GBM), a highly aggressive and treatment-resistant brain cancer. The approach uses a new class of drugs called imipridones along with radiation therapy and standard chemotherapy. This triple therapy, known as IRT, was recently detailed in a study published in Oncotarget.

Understanding Glioblastoma and the Need for Better Therapies

Glioblastoma is the most common and aggressive malignant brain tumor in adults. It grows quickly and is difficult to treat, often leading to poor outcomes. Most patients survive less than 15 months after diagnosis, even when treated with surgery, radiation, and the chemotherapy drug temozolomide (TMZ). This treatment may slow the disease, but it does not typically stop it.

Glioblastoma cells can spread into surrounding brain tissue, making them difficult to eliminate. In addition, the blood-brain barrier prevents many drugs from reaching the tumor. Even when treatment reaches the tumor, it may be less effective due to the presence of MGMT, a protein that repairs DNA damage caused by TMZ, limiting the drug’s effectiveness.

To address these challenges, researchers are studying new treatment strategies that can reach tumors more effectively, reduce drug resistance, and target cancer cells without affecting healthy tissue.

The Study: Combining ONC201 and ONC206 with Standard Therapies

The study, titled “Imipridones ONC201/ONC206 + RT/TMZ triple (IRT) therapy reduces intracranial tumor burden, prolongs survival in orthotopic IDH-WT GBM mouse model, and suppresses MGMT,” was led by first author Lanlan Zhou, and corresponding author and Oncotarget Editor-in-Chief Wafik S. El-Deiry. In this work, researchers examined the effects of ONC201 and its analog ONC206, both members of a drug class known as imipridones. These compounds were combined with standard treatments for glioblastoma, including radiation therapy and the chemotherapy TMZ. While ONC201 and ONC206 are currently under research as individual agents in clinical trials, this study was the first to explore their combined use with existing therapies. The IRT combination was tested on tumor cells grown in the lab and in mice implanted with human glioblastoma tumors.

The Results: Longer Survival, Lower Resistance

The IRT combination slowed tumor growth, reduced the number of cancer cells, and extended survival in mice. Those treated with the triple therapy survived a median of 123 days, with some living over 200 days. In comparison, mice that received only one or two treatments lived between 44 and 103 days. ONC201 and ONC206 also changed the tumor environment, decreasing molecules that support tumor growth and immune evasion, while increasing those involved in immune response. Additionally, the drugs reduced MGMT levels, which can make tumors more sensitive to TMZ.

The Breakthrough: A New Way to Target Brain Tumor

It was shown that ONC201 and ONC206 can cross the blood-brain barrier and activate a stress response inside cancer cells that can lead to cell death. They also interfere with mitochondrial function, which helps produce energy in cells. This disruption increases the tumor’s sensitivity to radiation and chemotherapy. Their combined effects on tumor cell death and immune response may provide advantages over existing treatments.

The Impact: New Therapeutic Options for Brain Cancers

This study introduces a therapy combination that targets GBM through multiple mechanisms. In addition to targeting the tumor directly, the approach may help reduce resistance to existing drugs such as TMZ. The findings may also be relevant for other brain tumors, including those with specific mutations like H3K27M.

Future Perspectives and Conclusion

Although the study was conducted in preclinical models, the results support further investigation through clinical trials. ONC201 and ONC206 are already being tested in humans, and this research adds to the evidence for evaluating them in combination with current therapies. These findings may contribute to developing additional treatment strategies for GBM and other difficult-to-treat brain cancers.

Click here to read the full research paper in Oncotarget.

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Oncotarget

Engineered Proteins Show Promise in Stopping Glioblastoma Invasion

May 21, 2025

“The results demonstrated that the minimal TIMP variants, mTC1, and mTC3, effectively inhibit MMP activity underscoring their potential to limit tumor invasion and progression.”

Scientists have engineered small, targeted proteins that can penetrate brain cancer cells and prevent them from invading healthy tissue, offering a promising new approach to treating glioblastoma multiforme (GBM), one of the deadliest forms of brain cancer. This strategy was developed by researchers at the University of Nevada, Reno, and published recently in Oncotarget.

The Challenge of Treating Glioblastoma Multiforme

Glioblastoma is an aggressive and fast-growing brain tumor that infiltrates healthy brain tissue, making complete surgical removal nearly impossible. Standard treatments like chemotherapy and radiation can slow its growth but rarely prevent it from returning. One major reason for this invasiveness is a group of enzymes known as matrix metalloproteinases (MMPs), which break down surrounding tissue to allow cancer cells to spread. Among these, MMP-9 plays a particularly important role in driving tumor progression and resisting existing therapies.

Attempts to block MMPs using small-molecule drugs have failed in clinical trials due to problems like poor selectivity and harmful side effects. Researchers have been searching for safer, more targeted methods to interfere with these enzymes and limit glioblastoma’s spread.

The Study: Engineered Proteins to Inhibit Tumor Invasion

In the study called “Effect of TIMPs and their minimally engineered variants in blocking invasion and migration of brain cancer cells,” researchers Elham Taheri and Maryam Raeeszadeh-Sarmazdeh investigated tissue inhibitors of metalloproteinases (TIMPs), which are natural blockers of MMPs, and their engineered modified versions made to work better. Specifically, the team studied TIMP-1, TIMP-3, along with two engineered molecules, mTC1 and mTC3, in laboratory cell models of GBM.

According to the researchers, the minimal TIMP variants were designed with smaller molecular sizes to enhance their ability to enter cells and deliver their cancer-blocking functions more effectively. One of the variants was also equipped with a cell-penetrating peptide to help it pass through the blood-brain barrier—a key obstacle in brain cancer treatment.

The Results: Reduced Invasion, Minimal Toxicity

The engineered TIMPs significantly reduced the ability of glioblastoma cells to move and invade surrounding tissue, performing as well as or better than the natural TIMPs in wound healing and invasion tests. At low doses, they showed minimal toxicity to healthy cells, suggesting a safer profile than previous MMP-inhibiting drugs.

When combined with the cell-penetrating peptide, the engineered protein demonstrated improved entry into cancer cells, successfully reaching its targets and carrying out its blocking effect. This is particularly significant because many cancer therapies fail to reach the brain due to the protective blood-brain barrier, which prevents drugs from reaching their destination.

The Breakthrough: A Smaller, Smarter Tool Against Glioblastoma

This study represents a major advancement in the fight against GBM. The minimal TIMP variants (mTC1 and mTC3) offer a focused and potentially safer alternative to conventional drugs. Their small size and engineered design allow them to block the cancer-promoting enzymes more precisely, increasing the probability of reaching their targets deep within brain tissue.

The Impact: Toward Targeted, Safer Brain Cancer Therapy

With few effective treatments currently available for GBM, these engineered TIMPs may offer a new, viable therapeutic option. Their ability to block MMP-9 specifically, without affecting healthy cells, positions them as promising candidates for future drug development. They may further enhance patient outcomes when combined with currently available treatments like immunotherapy or chemotherapy.

Future Perspectives and Conclusion

Although the study was performed in laboratory cell models, the findings are highly promising. The next phase of research will involve testing these engineered TIMPs in animal models to evaluate their safety and long-term effectiveness. Researchers also aim to explore how these engineered proteins might enhance current treatments or prevent cancer recurrence.

Given GBM’s aggressive nature and limited treatment options, this study represents a major step forward. If future research supports these findings, engineered TIMPs could become a critical tool in controlling tumor spread and improving survival and quality of life for patients facing this devastating disease.

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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Oncotarget

Panitumumab and Low-Dose Capecitabine: A Promising Maintenance Therapy for Metastatic Colorectal Cancer

May 7, 2025

“Considerations around maintenance therapy are of particular importance when drugs associated with cumulative neurotoxicity like Oxaliplatin form part of adopted regimens.”

A recent study from Assiut University Hospital in Egypt, published in Oncotarget, presents a promising strategy for patients with metastatic colorectal cancer (mCRC). The research introduces a gentler yet effective maintenance therapy that may extend survival, enhance quality of life, and offer a more accessible treatment option for mCRC patients worldwide.

The Challenge of Treating Metastatic Colorectal Cancer

Colorectal cancer is one of the most common causes of cancer-related deaths worldwide. When it spreads to other parts of the body—a stage known as mCRC—it becomes much more difficult to treat. At this stage, clinicians often use strong drug combinations like FOLFOX or CAPOX, which mix chemotherapy drugs to stop cancer growth. FOLFOX combines three drugs given intravenously, while CAPOX includes two of the same drugs, with one taken as a pill.

While effective, these treatments can cause serious side effects. For example, one of the main drugs, oxaliplatin, can lead to nerve damage, making it painful or difficult to use the hands and feet. Fatigue, diarrhea, and other issues are also common. Over time, these side effects may force clinicians to stop or adjust the treatment, even if it is working.

That is where maintenance therapy comes in. After the cancer is controlled, clinicians often switch to a gentler treatment plan to keep it from returning. The challenge is finding a therapy that continues to work without causing too many side effects, especially in places where access to expensive or intensive treatments is limited.

The Study: A Targeted, Low-Intensity Maintenance Option for Metastatic Colorectal Cancer

In the study titled “Could Panitumumab with very low dose Capecitabine be an option as a maintenance regimen,” recently published in Volume 16 of Oncotarget, researchers Doaa A. Gamal, Aiat Morsy, and Mervat Omar from Assiut University Hospital focused on a combination of two well-established drugs. Panitumumab is a targeted therapy that blocks a protein called EGFR, which helps cancer cells grow and divide. Capecitabine is a chemotherapy drug that turns into 5-fluorouracil inside the body to stop cancer cell growth.

Instead of delivering Capecitabine in high, occasional doses, the researchers used a low, continuous dose—a method known as metronomic dosing—designed to reduce side effects while maintaining anti-cancer effects.

The study involved 25 patients with mCRC who had a specific genetic profile: wild-type KRAS and BRAF, meaning they did not have mutations in those genes. All patients first received six rounds of standard chemotherapy plus Panitumumab. Those who responded well were then switched to the maintenance phase: Panitumumab every two weeks, along with daily low-dose Capecitabine.

The Results: Longer Survival and Better Tolerability

Patients in this study experienced an average of 18 months without their cancer getting worse—a period known as progression-free survival (PFS). By comparison, patients without maintenance therapy typically see a PFS of only 4–8 months. Their overall survival—the average time they lived after starting treatment—reached 45 months, far exceeding the 12 to 30 months reported in earlier studies with more intensive regimens.

Patients whose cancer had spread at the same time as their initial diagnosis (called synchronous metastasis) had even better outcomes, with PFS extending beyond 23 months.

The treatment was also well-tolerated. Only 8% of patients experienced severe side effects such as skin rash or diarrhea, and those symptoms were managed with standard care. No one had to stop or change their treatment due to side effects.

The Breakthrough: A Simpler Approach to Metastatic Colorectal Cancer Maintenance

This study is one of the first to explore Panitumumab in combination with metronomic Capecitabine as a maintenance strategy. The results suggest that using this combination in a low-intensity, long-term setting can keep the disease stable while minimizing the harsh effects of more aggressive therapies. Because both drugs are already approved and widely used, this regimen could be more easily implemented—especially for mCRC patients who have responded well to earlier treatments.

Importantly, this strategy may also help delay resistance to Panitumumab, which is a common issue when targeted therapies are used over time.

The Impact: Expanding Access to Safer Long-Term Colorectal Cancer Care

For many mCRC patients—particularly those in countries with limited healthcare—access to affordable and tolerable treatments is a major barrier. By using widely available medications in a simpler format, this regimen could help make effective maintenance therapy more accessible to a broader group of patients. Compared with other maintenance regimens studied in large trials, this approach showed similar or better results with fewer serious side effects.

Future Perspectives and Conclusion

Though this was a small study conducted at a single center, the findings are promising. Panitumumab combined with low-dose Capecitabine could be a safe and effective maintenance option for patients with wild-type KRAS and BRAF mCRC, especially those who start with strong responses and limited side effects.

Larger trials will be needed to confirm these results. However, if future research supports this strategy, it could transform the management of mCRC from high-intensity, short-term treatments to sustainable, patient-friendly care that supports long-term well-being.

Click here to read the full research paper in Oncotarget.

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Oncotarget

New Insights into p53: A Powerful Gene’s Role in Cancer Therapy

April 22, 2025

“[…] studies that employ TP53-wild type cancer cells and their isogenic derivatives may systematically fail to appreciate the full scope of p53 functionality.”

A new study from the Sidney Kimmel Comprehensive Cancer Center and Johns Hopkins University School of Medicine, published in Oncotarget, reveals that the gene p53, long known as the “guardian of the genome,” may be even more powerful than previously thought. By studying it in non-cancerous human cells, researchers discovered how p53 stops risky cell growth and uncovered two new potential targets for cancer therapy.

Understanding p53: The Genome’s Guardian Against Cancer

The p53 gene is one of the most important natural defenses our body has against cancer. When functioning properly, p53 detects damage in a cell’s DNA and either stops the cell from dividing or pushes it to self-destruct. This process helps prevent potentially dangerous mutations from spreading. However, many cancers find ways to silence or mutate p53, allowing uncontrolled growth and resistance to treatments.

Studying p53 in a clear and accurate way has long been a challenge. Most cancer cell models used in research already carry numerous genetic mutations, which can mask or alter how p53 truly functions. To fully understand this vital tumor-suppressing gene, scientists needed a model that closely resembled healthy, genetically stable human cells—yet could still be maintained and studied over time in the laboratory.

The Study: Exploring p53 in Normal and Cancer Cell Models

Researchers Jessica J. Miciak, Lucy Petrova, Rhythm Sajwan, Aditya Pandya, Mikayla Deckard, Andrew J. Munoz, and Fred Bunz explored p53 activity using a uniquely suitable cell line: hTERT-RPE1. These non-cancerous human cells are immortalized using telomerase, meaning they continue dividing like cancer cells, but without the chaotic mutations seen in tumors. This makes them an excellent model for studying how p53 operates in near-normal conditions.

To understand how p53 influences cancer, the team also worked with DLD-1, a colorectal cancer cell line that carries a defective version of the p53 gene. By restoring wild-type (normal) p53 in DLD-1, the researchers could observe how p53 reactivation impacts tumor-like behavior.

To strengthen their findings, the study also included three more colorectal cancer cell lines: HCT116, RKO, and SW48. These lines originally contained wild-type p53, and researchers created p53-deficient versions of each to compare how gene expression changes depending on p53 status. This combination of models—normal and cancerous, mutated and corrected—allowed a comprehensive, side-by-side comparison of p53’s behavior when functional versus when it is absent.

This study, titled “Robust p53 phenotypes and prospective downstream targets in telomerase-immortalized human cells, was recently published in Oncotarget, Volume 16.

Results: p53 Restoration Slows Cancer Growth and Boosts Radiation Sensitivity

In DLD-1 cancer cells, restoring p53 slowed cell growth, triggered signs of aging (senescence), and made cells more vulnerable to radiation. In contrast, deleting p53 in hTERT-RPE1 cells had the opposite effect: it made them grow faster and resist radiation, clear signs that p53 was keeping them in check.

Interestingly, one of the hTERT-RPE1 cells developed a rare cancer-associated mutation (A276P) in p53, previously observed in breast and ovarian cancers. This mutated version not only failed to protect the cells, but it also blocked the remaining healthy p53 from working, a phenomenon known as a dominant-negative effect, common in aggressive cancers.

The study also identified two new genes—ALDH3A1 and NECTIN4—as being directly regulated by p53. ALDH3A1 helps neutralize harmful chemicals and oxidative stress. NECTIN4 is a cell-surface protein present in many cancers, like bladder and breast cancer, and it is already the target of an FDA-approved drug, enfortumab vedotin.

Breakthrough: Rare p53 Mutation and Two New Drug Targets

The use of a “clean” cell system to observe p53 in action was novel, since most cancer models hide its full abilities, but in hTERT-RPE1, p53 was able to control cell growth, cause the cell cycle to arrest, and regulate key genes—just as it would in the body. The discovery of a real-life p53 mutation (A276P) further proves that this system can mimic the pressures cells face during early cancer development.

The identification of ALDH3A1 and NECTIN4 as p53 direct targets adds even more value. NECTIN4 is especially exciting because it is already drug-targetable, meaning this new insight could lead to better use of existing therapies or even new ones.

Impact: New Paths for Cancer Therapy Using p53

This research highlights the value of hTERT-RPE1 as a reliable model for understanding cancer biology and p53’s role in it. By using genetically stable cells, scientists were able to uncover both expected and entirely new behaviors of p53 that are hidden in traditional cancer models.

Furthermore, pinpointing ALDH3A1 and NECTIN4 as direct targets leads the way for new treatments and elucidates the aggressiveness in some cancers with intact p53. Therapies that enhance p53 function or block harmful p53 mutations could make traditional treatments like radiation and chemotherapy more effective and less toxic.

Future Perspectives and Conclusion

Although this study was performed using laboratory cell models, its findings have the potential to influence cancer research and treatment far beyond the lab bench. The next step will involve testing these discoveries in animal models and eventually in clinical settings to determine the most effective ways to take advantage of these newly uncovered p53 pathways.

In particular, the identification of ALDH3A1 and NECTIN4 as p53-regulated genes presents exciting opportunities. These genes could serve as biomarkers to guide treatment decisions or as targets for new drugs, especially in cancers where p53 is still functional. Exploring these possibilities could help refine precision medicine strategies and lead to more personalized, effective therapies for patients.

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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Mikhail Blagosklonny

Call for Papers: Special Collection Honoring Dr. Mikhail (Misha) Blagosklonny

April 3, 2025

“This special collection will explore key themes central to Dr. Blagosklonny’s scientific contributions, with a focus on mechanistic insights, translational approaches, and theoretical perspectives.”

BUFFALO, NY — April 3, 2025 — Aging (Aging-US) is pleased to announce a special Call for Papers for a commemorative collection honoring the legacy of Dr. Mikhail (Misha) Blagosklonny, the founding editor of the journal and a pioneer in aging biology. His groundbreaking work shaped fundamental concepts in the field, particularly regarding the role of mTOR in aging and cancer, the use of rapamycin, bypassing senescence during the process of transformation, personalized medicine, and theories on why we age.

This special collection will explore key themes central to Dr. Blagosklonny’s scientific contributions, with a focus on mechanistic insights, translational approaches, and theoretical perspectives. We invite original research, reviews, and perspective articles covering topics such as:

The role of mTOR in aging and age-related diseases
Rapamycin and other pharmacological strategies to extend lifespan
Senescence bypass and its implications for cancer and regenerative medicine
Personalized medicine approaches in aging and longevity research
Theoretical models and evolutionary perspectives on aging

The special issue will be guest-edited by leading scientist in the field, David Gems, who will oversee the selection of high-quality contributions that reflect the depth and impact of Dr. Blagosklonny’s work.

We encourage researchers working on these topics to submit their manuscripts and contribute to this tribute to one of the most influential figures in aging research.

SUBMISSION DETAILS:

Submission Deadline: December 1, 2025
Manuscript Format: Please follow the journal’s submission guidelines
Peer Review: All submissions will undergo a rigorous peer-review process
Submission Link: https://aging.msubmit.net/cgi-bin/main.plex

We look forward to your contributions to this special issue and to honoring Dr. Blagosklonny’s enduring impact on the field of aging research.sue.

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Oncotarget

How a Simple Blood Test Could Predict Colorectal Cancer Surgery Success

February 26, 2025

“The concentration of cell-free DNA (cfDNA) before and after surgery may be related to the prognosis of patients with CRC, but there is limited information regarding cfDNA levels at the time of surgery.”

Imagine if a single blood test could tell clinicians in real time how successful a cancer surgery has been. A recent study from the University of Brasília, published in Oncotarget, suggests that such an approach might soon be possible. By tracking changes in cell-free DNA (cfDNA) levels before, during, and after colorectal cancer (CRC) surgery, researchers have found a potential new way to monitor tumor removal and predict patient outcomes.

Cell-Free DNA and Colorectal Cancer Surgery

Cell-free DNA consists of tiny fragments of genetic material that are released into the bloodstream when cells break down. In healthy individuals, these fragments come from normal cell turnover, but in cancer patients, some of this DNA originates from tumor cells. cfDNA detection has been used to track cancer progression and treatment response in diseases like lung, breast, and CRC. What had not been investigated until now was how cfDNA levels fluctuate during cancer surgery itself.

Since surgery is the primary treatment for CRC, understanding how cfDNA levels change during surgical intervention could provide valuable insights into whether the tumor has been fully removed and how the patient’s body reacts to the procedure.

The Study: Measuring Cell-Free DNA in Real-Time

In the study, titled “Assessment of cfDNA release dynamics during colorectal cancer surgery,” led by first author Mailson Alves Lopes and corresponding author Fabio Pittella-Silva, scientists analyzed blood plasma samples from 30 CRC patients at three critical time points—before, during, and after surgery. Using highly sensitive genetic tests, they measured changes in cfDNA concentration to determine whether surgery had a direct impact on its release. The goal was to check whether cfDNA could serve as a biomarker for evaluating surgical effectiveness and predicting the probability of cancer recurrence.

The Challenge: Improving Colorectal Cancer Surgery Outcomes

Despite advances in CRC treatment, up to 50% of patients experience cancer recurrence after surgery. One of the greatest challenges in cancer care is determining whether surgery has successfully removed all cancer cells. Current methods rely on imaging scans and periodic biomarker testing, which can take months to detect any signs of recurrence.

A real-time way to assess surgical success, such as monitoring cfDNA levels, could transform how clinicians track cancer patients, allowing for more informed decisions about follow-up treatments and postoperative care.

The Results: A Significant Spike in Cell-Free DNA Levels

The researchers found that cfDNA levels increased nearly three times during surgery and remained elevated after the procedure. This increase was even more pronounced in specific groups of patients. People over 60, people who already had diabetes or heart disease, and people who had high levels of carcinoembryonic antigen (CEA), a known cancer marker, had the highest cfDNA spikes.

Patients with larger or more aggressive tumors showed even greater cfDNA release during surgery, likely due to increased tissue damage. Furthermore, surgeries that lasted longer were also linked to higher levels of cfDNA, suggesting that more cells are breaking down, leading to more genetic material entering the bloodstream.

The Breakthrough: A Potential Game-Changer in Colorectal Cancer Monitoring

This study is the first to show that cfDNA levels can reflect the extent of surgical intervention in real time. Monitoring cfDNA during surgery could help determine whether a tumor has been fully removed and whether additional treatment is needed. For instance, if cfDNA levels remain high after surgery, it could indicate the presence of cancer cells undetectable by regular imaging. Such findings could lead to earlier treatment and closer monitoring.

The Impact in Colorectal Cancer Treatment

If validated in further studies, cfDNA testing could become a standard tool in CRC surgery. Real-time tracking of cfDNA levels could help personalize postoperative care by identifying high-risk patients, guiding follow-up treatments, and detecting potential recurrence sooner. Additionally, cfDNA may serve as a quality marker for surgical procedures, ensuring better patient outcomes.

The Future Perspectives and Conclusion

While these findings are promising, further research is needed to standardize cfDNA testing for surgical monitoring. Larger clinical trials will be essential to confirm its ability to predict cancer recurrence and surgical success. With continued advancements, a simple blood test could soon help clinicians optimize cancer surgeries and improve patient outcomes, from the operating room to long-term recovery.

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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Oncotarget

A New Approach for Cancer Treatment: The Surprising Relationship Between KLRG1 and PD-1

January 28, 2025

“The anti-correlation of PD-1 and KLRG1 expression in human tumor infiltrating CD8 T cells suggests the potential for combination therapy supra-additive benefits of anti-PD-1 and anti-KLRG1 therapies.”

An unexpected link between KLRG1 and PD-1, two key immune system proteins, was revealed in a study recently published in Oncotarget. This discovery could help explain why some cancer immunotherapy treatments are less effective for certain patients and lead to new therapeutic strategies.

How the Immune System Fights Cancer

The immune system is a powerful defense mechanism against cancer, with CD8 T cells acting as the primary soldiers. These specialized immune cells identify and destroy tumor cells. However, cancer can cleverly evade this attack by manipulating immune checkpoints—natural “breaks” on the immune system that prevent it from overreacting and damaging healthy tissue.

One of the most studied checkpoints is PD-1 (Programmed Death-1), a receptor on T cells that acts as an “off switch” when activated by tumor cells. This mechanism suppresses the immune response, allowing cancer to grow without control. In response, researchers have developed treatments called PD-1 inhibitors, which block this “off switch” and keep T cells active.

The Study: Investigating KLRG1 and PD-1 in Tumor-Fighting T Cells

In the study titled “Anti-correlation of KLRG1 and PD-1 expression in human tumor CD8 T cells,” Dr. Steven A. Greenberg from Harvard Medical School analyzed publicly available gene expression data from various cancer types, including lung cancer, melanoma, and colorectal cancer. His goal was to identify immune-related proteins that could complement existing therapies, such as PD-1 inhibitors.

The Challenge: Overcoming Limitations of PD-1 Immunotherapy

PD-1 inhibitors have transformed cancer treatment by enabling the immune system to fight back. However, these therapies have notable limitations. Some patients do not respond to treatment, and many experience only moderate or short-term benefits. Even combining PD-1 inhibitors with other therapies often provides only additive effects rather than true synergy, where the combined treatment outperforms the sum of its parts. This has left researchers searching for combinations that could deliver “supra-additive” effects.

Results: The Surprising Anti-Correlation Between KLRG1 and PD-1

One protein, KLRG1, stood out. This checkpoint receptor has received little attention in cancer research. Historically, it was thought to merely mark aging, or “senescent,” T cells—cells that are no longer active. However, Dr. Greenberg’s research revealed that KLRG1 plays a more dynamic role in regulating immune responses, challenging its previously underestimated significance.

The study found that in tumor-infiltrating CD8 T cells, which are crucial in the immune system’s fight against cancer, the levels of PD-1 and KLRG1 move in opposite directions. As these T cells mature and become more effective at killing cancer cells, they show an increase in KLRG1 expression while PD-1 levels decrease. This pattern of anti-correlation was consistently observed across the different types of cancer.

The Breakthrough: A New Approach to Combination Therapy

Unlike conventional combination strategies, which often target multiple positively correlated exhaustion markers (such as PD-1, TIM-3, and LAG-3), targeting the negatively correlated KLRG1 introduces a fresh approach.

KLRG1-positive T cells are highly differentiated and effective at destroying cancer cells, while PD-1-positive cells are in a more ‘exhausted’ state. Combining treatments to target both populations could achieve true synergy, offering a promising solution to the limitations of current immunotherapy.

The Potential for Cancer Patients

If future research confirms the therapeutic potential of targeting KLRG1, this could revolutionize cancer immunotherapy. Patients who do not respond well to PD-1 inhibitors alone might benefit from adding KLRG1-targeting therapies, offering a lifeline for those with limited options.

This approach also holds promise for treating difficult cancers like lung cancer and melanoma. By tailoring treatments to individual immune profiles, clinicians could deliver personalized and precise immunotherapy, improving outcomes and reducing the risk of cancer recurrence.

Combining KLRG1 with PD-1 inhibitors could provide cancer patients with renewed hope, leading to improved health and extended survival.

Conclusion and Future Directions

The discovery of the relationship between KLRG1 and PD-1 provides an exciting new avenue for cancer treatment. By addressing the limitations of current immunotherapies, this approach has the potential to deliver more effective and longer-lasting treatments.

The next steps will include preclinical studies and clinical trials to evaluate the safety and effectiveness of combining KLRG1-targeting therapies with PD-1 inhibitors. If successful, this approach could transform cancer immunotherapy and offer hope to millions of patients worldwide.

Click here to read the full research paper in Oncotarget.

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Oncotarget

Mastocytosis: Key Insights into KIT M541L Gene Mutation

January 15, 2025

“To our knowledge, this is the first case/control study to show a significant genetic association with mastocytosis at the KIT M541L locus.“

Scientists have discovered that a genetic variant called KIT M541L may play an important role in a rare immune disorder known as mastocytosis. The findings may help explain why some patients develop more severe forms of the disease.

Understanding Mastocytosis

Mastocytosis is a condition where the body produces too many mast cells. These cells are part of the immune system and help the body fight infections, but in excess, they release chemicals that can cause itching, swelling, and even serious organ damage.

There are two main types of mastocytosis. The first is cutaneous mastocytosis, which mostly affects the skin. The second is systemic mastocytosis, a more serious form where mast cells build up in internal organs like the liver, spleen, and bone marrow.

The disease is linked to mutations in the KIT gene, which regulates mast cell growth. The most studied mutation is KIT D816V, but recent research has highlighted another variant, KIT M541L.

The Study: Impact of KIT M541L Variant

A team of researchers at the National Institutes of Health (NIH), led by first author Luisa N. Dominguez Aldama and corresponding author Melody C. Carter, aimed to better understand the prevalence and impact of the KIT M541L genetic variant in mastocytosis patients. The study published in Oncotarget on July 22, 2024, titled “Prevalence and impact of the KIT M541L variant in patients with mastocytosis,” examined the presence of the KIT M541L gene variant in 100 patients with mastocytosis, both adults and children, alongside 500 healthy individuals. By comparing these two groups, the researchers wanted to see if there was a relation between the KIT M541L variant and mastocytosis severity.

The Challenge: Limited Knowledge of Genetic Influences

Clinicians and researchers still do not fully understand why some people with mastocytosis experience only skin-related symptoms, while others develop the more dangerous systemic form. Learning more about genetic differences could help explain this and lead to improved treatments.

Results: KIT M541L Influences Mastocytosis Severity

The study found that 19% of mastocytosis patients carried the KIT M541L variant, most of whom had European ancestry. This variant was observed in both pediatric and adult patients but was particularly associated with adult systemic mastocytosis.

“Our patients with mastocytosis mapped to the European control population with a higher frequency compared to other ancestral data points. Indeed, our patient cohort at the NIH mirrors this distribution with 92% having European ancestry […]”

Interestingly, nearly all patients with the KIT M541L mutation also had the KIT D816V mutation, suggesting that M541L may intensify disease severity without being a direct cause.

The findings also showed that individuals with two copies of the KIT M541L variant—one from each parent—were nearly five times more likely to have systemic mastocytosis than those without the variant.

Some differences in symptoms were also noted. For example, patients with two copies of the M541L variant were less likely to have an enlarged spleen, a common problem in systemic mastocytosis. Despite these findings, researchers did not observe significant differences in standard lab results, such as blood mast cell levels, between patients with and without the M541L variant.

The Breakthrough: KIT M541L Variant’s Role

This study is the first to demonstrate a significant genetic association between KIT M541L and systemic mastocytosis. Unlike prior research that overlooked this variant, this study shows that KIT M541L, especially when inherited in a homozygous form, significantly increases the risk of systemic mastocytosis.

“This investigation is the largest study to date of KIT M541L variant in both adults and pediatric patients with cutaneous and systemic disease, and the first to document a homozygous mutation in a patient that met criteria for systemic disease without an additional KIT mutation.”

The Potential: Toward Personalized Treatments

These findings could lead to more personalized treatment approaches. For instance, patients with the KIT M541L mutation may respond differently to mast cell-targeting therapies, making genetic testing an important step in disease management.

“Therefore, screening for this mutation in patients with mastocytosis may have some value for targeted therapy, (symptomatic vs. cytoreductive), however, larger numbers are needed for proof of concept.”

Conclusion and Future Directions

Although this study is a significant step forward, more studies are needed to confirm the findings and understand how the KIT M541L variant interacts with other genetic mutations. Future research may also explore whether knowing a patient’s genetic profile can help guide treatment decisions and improve outcomes. The discovery of KIT M541L’s role in mastocytosis highlights the complexity of genetic factors in rare diseases and may contribute to earlier diagnoses, more effective treatments, and improved care for those living with this challenging condition.

Click here to read the full research paper in Oncotarget.

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Oncotarget

Cancer Dormancy and Tumor Recurrence: New Insights for Breast Cancer

November 13, 2024

“Cancer dormancy, followed by recurrence remains a poorly understood phenomenon in both cancer biology and oncology.”

Cancer dormancy is a phenomenon in which, after treatment, residual cancer cells remain inactive in the body for months or even years. During this time, patients often show no signs of the disease. These dormant cells can unpredictably reawaken, leading to tumor recurrence—a significant challenge in cancer treatment. Despite progress in cancer research, the factors that control dormancy and subsequent reactivation remain poorly understood. Identifying these factors and understanding how cancer cells dormancy and reactivation occur could be crucial to preventing cancer recurrence. This question was the focus of a recent study titled “Initiation of Tumor Dormancy by the Lymphovascular Embolus,” published in Oncotarget Volume 15, on October 11, 2024. In this blog, we will look at the key findings and implications of this important work.

The Study: Investigating Dormancy in Breast Cancer Tumors

This study, led by Yin Ye, Justin Wang, Michael G. Izban, Billy R. Ballard, and Sanford H. Barsky from Meharry Medical College and Scripps Mercy Hospital, aimed to investigate the origins of cancer dormancy, an often overlooked aspect of cancer progression, focusing specifically on breast cancer.

Using various breast cancer study models—such as patient-derived mice, spheroids, and cell lines—the researchers investigated how dormancy might start within small clusters of cells known as lymphovascular emboli, which detach from the primary tumor. These clusters can travel through the bloodstream or lymphatic system, settle in distant organs, and remain inactive until conditions change, triggering their reactivation and growth. To further validate their findings, the team analyzed tissue samples using tissue microarrays, allowing them to observe dormancy indicators directly in human breast cancer cases.

The Challenge: Elusive Dormant Cancer Cells

Dormant cancer cells pose a unique challenge because they grow slowly and often evade immune system detection, making them difficult to target with conventional treatments. These cancer cells typically exist as small, inactive clusters called micrometastases, which can later transition back into an active state and lead to tumor recurrence. Preventing this recurrence requires understanding how these cells “decide” to stay dormant or reawaken.

Dormancy periods vary depending on the type of cancer and the individual patient, making it even more important to pinpoint the factors that influence cancer cell dormancy and reactivation. Identifying these factors could transform our approach to cancer treatment.

The Results: A Breakthrough in Cancer Dormancy Mechanisms

The team found that cancer cells within lymphovascular emboli may enter dormancy through a reduction in key cellular activities. Two important players in this process are mTOR signaling and E-cadherin proteolysis. mTOR is a cellular pathway involved in regulating cell growth and metabolism, which, when reduced, slows the cell’s activity to a near standstill, facilitating dormancy. Meanwhile, E-cadherin, a protein that helps cells stick together, undergoes a process called proteolysis, or breakdown, through enzymes like calpain 2. This proteolysis further stabilizes the dormant state, keeping the cells inactive until reactivation signals arise. The researchers also discovered that the PI3K signaling pathway influences these dormancy-associated changes in mTOR and E-cadherin. Together, these signaling modifications within the three-dimensional structure of lymphovascular emboli reveal how dormant cancer cells persist in a state of low activity until conditions favor their reactivation.

The Potential: Toward New Treatments for Preventing Cancer Recurrence

This study demonstrates the potential for targeted interventions to prevent dormant cells from reawakening. Developing therapies that act on mTOR and E-cadherin pathways might provide cancer patients with a new line of defense against recurrence, especially in cancers prone to prolonged dormancy, such as breast cancer. Although further research is needed to determine the exact clinical applications, these findings provide a promising roadmap for future treatment innovations.

Conclusion

This work represents a significant step forward in our understanding of cancer dormancy and recurrence. By uncovering the mechanisms behind cancer cell dormancy, this research brings us closer to a future where cancer recurrence can be controlled—or even prevented entirely. While more studies are necessary to explore the broader implications for other types of cancer, this study highlights a critical aspect of cancer biology and offers hope for more effective and targeted treatments in the near future.

Click here to read the full research paper in Oncotarget.

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