Category: Oncotarget

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 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.

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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

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

Exploring a Combined Approach: Radiation and Immunotherapy in Bladder Cancer

June 16, 2025

“Different treatment strategies are required for the non-muscle-invasive, muscle-invasive, and metastatic stages of bladder cancer.”

Bladder cancer remains a significant clinical concern, with more than 85,000 new diagnoses and nearly 19,000 deaths reported annually in the United States. While current treatments like surgery, chemotherapy, and radiation can be effective for early-stage disease, many patients with advanced or recurrent cancer face limited options.

A recent review, published in Oncotarget by researchers from the University of California, Irvine, analyzes the growing body of evidence supporting the combination of radiation therapy and immunotherapy for bladder cancer. Led by Nazmul Hasan, the work synthesizes clinical data and biological mechanisms that suggest this strategy could enhance anti-tumor responses in specific patient groups.

Understanding Bladder Cancer and Treatment Limitations

The type of treatment for bladder cancer depends on how far the disease has progressed. For early-stage cases, tumors are typically managed with transurethral resection followed by local therapies such as BCG (Bacillus Calmette-Guérin) to reduce the risk of recurrence.

If the tumor has grown deeper into the bladder wall (known as muscle-invasive bladder cancer), more aggressive treatment is needed. This often involves complete bladder removal (cystectomy) or using a combination of radiation, chemotherapy, and surgery to attempt bladder preservation.

Despite these interventions, recurrence remains common, particularly in more advanced stages. Immunotherapy, which helps the immune system recognize and attack cancer cells, has led to improved outcomes in some bladder cancer patients, yet overall response rates are limited. Radiation, while effective for localized tumors, generally does not achieve long-lasting results when used alone. Because of these limitations, researchers are now studying ways to combine treatments, like radiation and immunotherapy, to improve therapeutic outcomes.

Synthesizing Clinical Data

The review, titled “Advancements in bladder cancer treatment: The synergy of radiation and immunotherapy,” focuses on how these two modalities may interact to enhance anti-tumor activity. Radiation is known to induce immunogenic cell death, releasing tumor-associated antigens that stimulate an immune response. Immunotherapy enhances this immune activation by blocking checkpoint pathways—such as PD-1 or CTLA-4—that tumors use to evade immune detection.

The authors highlight several studies and clinical trials that have explored this combination in clinical practice, including BTCRC-GU15-023, ANZUP, and INTACT trials. These trials vary in design but all examine ways to integrate immunotherapy with radiation, either at the same time or sequentially, to evaluate safety and therapeutic potential.

Evidence from Clinical Trials: Potential Benefits and Known Risks

In the phase II BTCRC-GU15-023 trial, patients who were not eligible for surgery or cisplatin-based chemotherapy received radiation in combination with the PD-L1 inhibitor durvalumab. The majority experienced disease control, with over half achieving a complete response. Progression-free survival extended beyond 21 months, and the treatment was generally well-tolerated.

The ANZUP trial, conducted in Australia, tested a combination of pembrolizumab with chemoradiation in patients who opted for bladder preservation or were medically ineligible for surgery. The results showed an 88% complete response rate at 24 weeks. However, serious adverse events occurred in approximately one-third of patients, including a treatment-related death.

INTACT, an ongoing trial, is also investigating whether adding immunotherapy to standard bladder-preserving treatment—combining surgery, chemotherapy, and radiation—can improve outcomes for patients with advanced bladder cancer.

The review also highlights other studies where treatment combinations led to unacceptable toxicity, especially when high-dose radiation was paired with multiple immune-modulating drugs. These findings emphasize the importance of careful dosing and patient monitoring.

Mechanistic Insights: How the Combination Works

Radiation alters the tumor microenvironment by releasing tumor proteins and pro-inflammatory signals. This can increase the inflammation, infiltration and activity of immune cells. Immunotherapy boosts this process by reactivating suppressed T-cells, potentially leading to systemic responses beyond the targeted tumor site—a phenomenon known as the abscopal effect. The review also notes preclinical data suggesting that radiation may enhance tumor visibility and reverse immune evasion.

Implications for Treatment Planning

The review suggests that this combination strategy, radiation and immunotherapy, may be particularly relevant for patients who are not candidates for surgery or traditional chemotherapy. It may also expand the role of bladder-preserving approaches for advanced bladder cancer. However, variability in patient response and the risk of compounded toxicities remain barriers to broader clinical application.

Future Perspectives and Conclusion

While current findings point to potential benefits, the review emphasizes that additional studies are needed before this combined treatment can become standard clinical practice. A major focus moving forward will be identifying which patients are most likely to benefit—possibly through biomarkers such as tumor mutation burden or immune infiltration levels—and refining treatment combinations to reduce toxicity.

By examining the interaction between radiation and immunotherapy, this review contributes meaningfully to ongoing efforts aimed at developing more personalized and effective therapeutic strategies in bladder cancer.

Click here to read the full review in Oncotarget.

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Oncotarget

Oncotarget Sponsors Open Access Team in 2025 Ride for Roswell

June 10, 2025

Impact Journals, the publisher of Oncotarget, is once again proudly sponsoring the Open Access Team in the annual Ride for Roswell.

BUFFALO, NY — June 10, 2025 — The Ride for Roswell, one of the USA’s largest cycling events supporting cancer research, returns to Buffalo on Saturday, June 28, 2025. Hosted annually by Roswell Park Comprehensive Cancer Center, this community-wide event brings together riders, volunteers, and supporters to raise funds for cancer research, celebrate survivors, and honor those lost to the disease.

Among the returning participants is the Open Access Team, led by team captain Sergei Kurenov. This year, the team is once again proudly sponsored by Impact Journals, the publisher of open access journals Oncotarget, Aging, Genes & Cancer, and Oncoscience.

“For the last 10 years, I have continuously participated in the Ride for Roswell in honor of those who have bravely fought cancer,” said Kurenov. “This journey is deeply personal for me. My father battled cancer, and some of my closest friends have fought through prostate and lung cancer with incredible strength.”

This year, the Open Access Team rides in honor of Dr. Mikhail (Misha) Blagosklonny, a visionary scientist who dedicated his career to advancing cancer and aging research. As the founding Editor-in-Chief of Oncotarget, Aging, and Oncoscience, Dr. Blagosklonny was a pioneer of open-access publishing. His groundbreaking work on mTOR signaling and rapamycin transformed our understanding of cancer biology and healthy lifespan extension.

The 2025 Ride for Roswell features nine route options, ranging from 4 to 100 miles, all beginning at the University at Buffalo North Campus. Riders from across the USA and beyond are invited to participate and make a meaningful impact in the fight against cancer.

This ride is more than just a journey on two wheels—it’s a commitment to building a future where no one has to fear a cancer diagnosis. There is still time to support the Open Open Access Team in the 2025 Ride for Roswell. Whether by donating, joining the team, or sharing their story, every action brings us closer to better treatments, deeper understanding, and, ultimately, a cure.

Visit the Open Access Team page to join or donate today.

Click here to learn more about the 2025 Ride for Roswell.

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About Oncotarget:

Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science.

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

Click here to subscribe to Oncotarget publication updates.

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

Oncotarget

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).

Click here to subscribe to Oncotarget publication updates.

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