Oncotarget

BUFFALO, NY – July 1, 2025 – A new #review was #published in Volume 16 of Oncotarget on June 17, 2025, titled “Optimizing enfortumab vedotin plus pembrolizumab therapy.”

First authors Elias Antoine Karam of the Gustave Roussy and Saint-Joseph University of Beirut and Yaghi César Céline from the Saint-Joseph University of Beirut, along with their colleagues, reviewed recent developments about treating advanced urothelial carcinoma (aUC), an aggressive form of bladder cancer. Their review highlights how combining enfortumab vedotin and pembrolizumab as a first-line treatment offers a major improvement for patients with limited options and poor prognoses.

Advanced urothelial cancer has traditionally been treated with platinum-based chemotherapy, which often causes serious side effects and offers limited long-term benefit. Many patients are even ineligible for it due to underlying health conditions. The new combination presents a more effective and better-tolerated alternative, as shown in recent clinical trials reviewed by the authors.

Enfortumab vedotin targets Nectin-4, a protein present in most urothelial cancer cells, delivering a cancer-killing agent directly into tumors. Pembrolizumab helps the immune system detect and destroy cancer cells. Together, they have shown strong results in extending survival with fewer serious side effects than chemotherapy. These findings led to FDA approval in 2023 for use in a broad range of patients, including those unable to tolerate traditional treatments.

“In the phase II KEYNOTE-052 study, pembrolizumab demonstrated significant efficacy as initial therapy in patients with aUC who were ineligible for a cisplatin-based regimen.”

The review also compares this new approach with other evolving strategies, such as therapies using nivolumab and chemotherapy combinations. Among current first-line options, enfortumab vedotin and pembrolizumab have produced the most promising outcomes. However, the best course of action following disease progression remains unclear.

Other important challenges raised in the review include the high cost of the new therapies, limited patient access to them, and the absence of reliable biomarkers to predict individual response. The authors call for further studies to refine treatment strategies and explore blood-based tools that could guide therapy decisions and minimize side effects.

This review offers a clear summary of how recent clinical advances are reshaping the treatment of aUC. It reflects a shift away from traditional chemotherapy toward immunotherapy and targeted, personalized treatments that aim to extend survival and improve quality of life.

DOI - https://doi.org/10.18632/oncotarget.28741

Correspondence to - Elias Antoine Karam - [email protected]

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Keywords - cancer, advanced urothelial carcinoma (aUC), enfortumab vedotin, pembrolizumab, treatment strategies, bladder cancer

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BUFFALO, NY – June 27, 2025 – A new #research paper was #published in Volume 16 of Oncotarget on June 17, 2025, titled “Molecular landscape of HER2-mutated non-small cell lung cancer in Northeastern Brazil: Clinical, histopathological, and genomic insights.”

In this study, researchers led by first authors Cleto Dantas Nogueira from the Federal University of Ceará and Argos Pathology Laboratory and Samuel Frota from Argos Pathology Laboratory, along with corresponding author Fabio Tavora from the previously mentioned institutions and Messejana Heart and Lung Hospital, investigated how HER2 gene mutations appear in cases of non-small cell lung cancer (NSCLC) in Northeastern Brazil. The team found that HER2 mutations showed significant genetic diversity and were often associated with other cancer-related genetic changes. These findings revealed diagnostic and treatment challenges in a population that is rarely studied, emphasizing the need for expanded access to molecular testing and targeted therapies.

HER2 mutations are a known factor in several cancers, including breast and gastric cancers. In lung cancer—particularly NSCLC—these mutations are less common but remain clinically significant. Most existing research on HER2-mutated lung cancer focuses on high-income countries, leaving important gaps in knowledge about underrepresented regions such as Latin America. This study helps fill that gap by analyzing 13 patients with HER2-mutated NSCLC using clinical, pathological, and genomic data.

The patients ranged in age from 34 to 82 years, and more than half were women. About half had never smoked. Their tumors often displayed complex genetic profiles, including additional mutations in genes such as TP53, KRAS, and STK11. The most common HER2 mutation identified was an insertion in exon 20, a known hotspot for activating mutations.

“Trastuzumab deruxtecan (T-DXd) is the first HER2-targeted agent to show clinical efficacy in HER2-mutant non-small cell lung cancer (HER2m NSCLC).”

Treatment strategies among the patients varied. Only one individual received HER2-targeted therapy. Most were treated with surgery, chemotherapy, immunotherapy, or a combination of these approaches. Outcomes also differed, with some patients surviving for years and others dying within months of diagnosis. These findings reinforce the need for early diagnosis and improved access to advanced treatments, particularly in low-resource settings.

The study emphasizes the value of comprehensive molecular profiling in NSCLC. Because HER2 mutations often occur alongside other genetic alterations, full genomic analysis is crucial for guiding treatment decisions. Yet, such testing is not always available. The researchers propose a tiered diagnostic approach, beginning with basic screening and expanding to more advanced tests when necessary, to enhance patient care.

This study provides valuable insights into the molecular characteristics of HER2-mutated NSCLC in a Brazilian population, highlighting the complexity and clinical relevance of these alterations. Larger studies are needed to clarify the prevalence and prognostic significance of HER2 mutations, as well as their impact on treatment response and survival. This knowledge is essential for advancing effective HER2-targeted therapies. The findings also support broader implementation of international clinical guidelines in Latin America and highlight the critical need to include underrepresented populations in cancer research.

DOI - https://doi.org/10.18632/oncotarget.28737

Correspondence to - Fabio Tavora - [email protected]

Video short - https://www.youtube.com/watch?v=hr5R9iDBFFI

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BUFFALO, NY – June 24, 2025 – A new precision #oncology paper was #published in Volume 16 of Oncotarget on June 17, 2025, titled “Case Report WIN-MTB-2023001 WIN International Molecular Tumor Board A 62-year-old male with metastatic colorectal cancer with 5 prior lines of treatment.”

In this report, led by Alberto Hernando-Calvo from Vall d’Hebron University Hospital and Vall d’Hebron Institute of Oncology; Razelle Kurzrock from WIN Consortium and Medical College of Wisconsin; Oncotarget Editor-in-Chief Wafik S. El-Deiry from WIN Consortium and Legorreta Cancer Center at Brown University; and corresponding author Shai Magidi, also from WIN Consortium, along with colleagues, describe the case of a 62-year-old man with metastatic colorectal cancer who underwent multiple lines of therapy. After analysis, the WIN International Molecular Tumor Board proposed different personalized treatment plans based on the tumor’s unique genetic mutations. This case highlights the growing role of precision oncology in guiding therapies for patients with treatment-resistant cancers.

Colorectal cancer is one of the deadliest cancers worldwide, and managing advanced cases remains a significant challenge. This patient had already received five prior treatment regimens, including chemotherapy and targeted therapies. Although some treatments were initially beneficial, the cancer eventually developed resistance. Molecular analysis revealed key mutations in genes such as BRAF, MET, APC, TP53, and NRAS, which are often linked to aggressive tumor behavior and reduced treatment effectiveness.

With limited standard options left, the patient’s case was presented and reviewed by the WIN International Molecular Tumor Board, a global panel of cancer experts. The team analyzed the clinical history and genetic profile to design new treatment approaches. These involved off-label drug combinations tailored to the specific mutations found in the tumor. For example, one approach combined trametinib, a drug that blocks cancer cell growth signals, with amivantamab, an antibody that attacks cancer-related proteins MET and EGFR, and regorafenib, which helps cut off blood supply to tumors and may counteract effects from APC and TP53 mutations.

“Another option was trametinib at 1 mg daily, cetuximab (EGFR antibody), 250 mg/m² IV every two-weeks, and cabozantinib (MET and VEGFR inhibitor), 40 mg po daily.”

This case reflects a shift in cancer care from standardized protocols to precision approaches, where therapy is selected based on a tumor’s molecular features. Such strategies aim to delay resistance and slow disease progression more effectively. The WIN International Molecular Tumor Board also discussed practical challenges, including access to medications, combining off-label drugs, and the difficulties of enrolling patients in clinical trials after multiple prior treatments.

Although the ultimate treatment decision remained with the patient’s physician, this report shows how international collaboration and precision oncology can expand options for patients facing limited alternatives. It also emphasizes the value of repeat genetic analysis during disease progression to monitor new mutations in the tumor that may impact treatment.

While the patient ultimately died from cancer progression, this case serves as a model for how molecular analysis and expert input can be used to guide treatment even in complex and metastatic colorectal cancer. As personalized cancer strategies continue to evolve, they may offer potential pathways for patients who have exhausted standard treatment options.

DOI - https://doi.org/10.18632/oncotarget.28744

Correspondence to - Shai Magidi - [email protected]

Video short - https://www.youtube.com/watch?v=uWDtWNgpK7A

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BUFFALO, NY – June 20, 2025 – A new #review was #published in Volume 16 of Oncotarget on June 10, 2025, titled “Beyond DNA damage response: Immunomodulatory attributes of CHEK2 in solid tumors.”

In this paper, led by first author Helen Qian and corresponding author Crismita Dmello from Northwestern University Feinberg School of Medicine, researchers compiled growing evidence that the CHEK2 gene, long known for its role in repairing DNA damage, may also influence how tumors respond to immunotherapy. Their analysis suggests that problems in CHEK2 function might make cancer cells more vulnerable to immune system attacks, highlighting a new opportunity to improve treatment outcomes in solid tumors.

Immune checkpoint inhibitors (ICIs) have transformed cancer treatment; however, they are effective in only a subset of patients. This review suggests that tumors with reduced CHEK2 activity may accumulate more mutations that produce signals the immune system can recognize. These signals, known as neoantigens, help immune cells identify and destroy cancer cells more effectively. The review connects this process not only to CHEK2’s established role in the DNA damage response but also to a newly proposed function in shaping the immune environment of tumors.

CHEK2 normally helps maintain genomic stability by enabling precise DNA repair. When this function is lost, cells rely on more error-prone repair methods, leading to additional mutations. These mutations can increase tumor mutational burden, which has been linked to better outcomes with immunotherapy. Beyond DNA repair, the review highlights a second mechanism: activation of the cGAS-STING pathway. This pathway detects fragments of damaged DNA and triggers inflammation that attracts immune cells to the tumor.

The authors highlight studies where CHEK2-deficient tumors responded better to PD-1 inhibitors, a common type of immune checkpoint inhibitor. In both lab models and early-stage clinical settings, CHEK2 loss was associated with increased infiltration of CD8+ T cells—immune cells essential for attacking cancer cells. In cancers such as glioblastoma and renal cell carcinoma, which are typically resistant to immunotherapy, reduced CHEK2 expression was linked with more favorable immune activity and higher expression of interferon-related genes.

The compiled evidence points to CHEK2 as a potential biomarker for identifying patients likely to respond to immunotherapy. In addition, combining CHEK2 inhibitors with existing immunotherapies may enhance anti-tumor effects, particularly in cancers with limited treatment options. The review notes that some clinical trials using the CHEK1/2 inhibitor prexasertib alongside immune checkpoint therapies have already shown promising early results.

“The initial results from this Phase I clinical trial support the immunomodulatory role of CHEK2 expression and even suggest CHEK2 potentiates immunosuppression.”

Although more research is needed to confirm these mechanisms and improve treatment approaches, this review underscores the expanding role of DNA repair genes like CHEK2—not only in maintaining genome integrity but also in helping the immune system fight cancer.

DOI - https://doi.org/10.18632/oncotarget.28740

Correspondence to - Crismita Dmello - [email protected]

Video short - https://www.youtube.com/watch?v=C26pEBc0itk

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BUFFALO, NY - June 17, 2025 – A new #research paper was #published in Volume 16 of Oncotarget on June 10, 2025, titled “Exceptional responders to immunotherapy in pancreatic cancer: A multi-institutional case series of a rare occurrence.”

The study, led by first author Kavin Sugumar and corresponding author Jordan M. Winter, from University Hospitals Seidman Cancer Center, reports on a rare group of pancreatic cancer (PC) patients who responded remarkably well to immunotherapy, a treatment typically considered ineffective for this cancer type. The analysis, which includes data from 14 patients across multiple U.S. institutions, identifies outcomes that could help refine treatment strategies for one of the most aggressive and deadly forms of cancer.

“Between 2020–21, 471 oncologists from 91 major cancer centers in the United States were contacted.”

Pancreatic cancer has among the lowest survival rates and few effective therapies. While immunotherapy has transformed the treatment landscape for several other cancers, it generally offers little benefit for pancreatic cancer. However, this study highlights a small but important group of patients who experienced significant and sustained responses to immune-based treatment without chemotherapy. Most had advanced or metastatic disease and had already progressed after standard treatments.

Among the 14 patients, 82% had partial tumor shrinkage, and nearly one-third had a notable decrease in tumor markers. The median progression-free survival was 12 months, and most patients were still alive at follow-up, with survival rates of 80% at one year and 70% at two years. These outcomes contrast sharply with standard therapies, which often provide only a few months of benefit for similar patients.

Interestingly, while some patients had high microsatellite instability (MSI-high)—a known marker for immunotherapy success—more than half did not, suggesting other biological mechanisms may be involved. This result highlights the need for new biomarkers to be discovered to predict treatment response in future studies.

This case series is the largest focused exclusively on exceptional immunotherapy responders in pancreatic cancer. By excluding patients who received chemotherapy, the study isolates the effects of immune-based drugs, including PD-1 inhibitors such as pembrolizumab and nivolumab, CTLA-4 inhibitors like ipilimumab, and agents targeting macrophages.

While the sample size is small, the findings challenge the assumption that immunotherapy is ineffective for nearly all pancreatic cancer patients. The study suggests that, under certain biological conditions, this treatment can be remarkably successful. Further research is needed to understand the underlying mechanisms.

This work supports the need to reconsider how clinical trials are designed for pancreatic cancer and who is eligible for immunotherapy. Broader criteria and more personalized molecular profiling could help uncover hidden opportunities for treatment in this highly lethal cancer.

DOI - https://doi.org/10.18632/oncotarget.28739

Correspondence to - Jordan M. Winter - [email protected]

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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.

Full blog - https://www.oncotarget.org/2025/06/16/exploring-a-combined-approach-radiation-and-immunotherapy-in-bladder-cancer/

Paper DOI - https://doi.org/10.18632/oncotarget.28723

Correspondence to - Nazmul Hasan - [email protected]

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BUFFALO, NY - June 13, 2025 – A new #review was #published in Volume 16 of Oncotarget on June 4, 2025, titled “Applying the unattainable triangle in cardio-oncology care: Balancing cost, quality, and time.”

In this review, first author John Hoverson, corresponding author Stella Pak, and colleagues from the University of Texas Health Science Center at San Antonio explore how the “unattainable triangle”—a business concept describing the trade-offs between cost, quality, and time—can help improve healthcare delivery in cardio-oncology. As cancer treatments become more complex and often affect the heart, this model highlights the challenge of providing care that is fast, effective, and affordable.

Cardio-oncology is an emerging field focused on preventing and managing heart problems caused by cancer therapies. The review explains that high-quality cancer care often requires advanced diagnostics and close collaboration between oncologists and cardiologists, which can drive up costs and time demands. Understanding how to balance these pressures is essential for delivering better outcomes for patients.

Many cancer survivors face long-term cardiovascular complications due to their treatment. Early monitoring and intervention can reduce these risks. However, these improvements often come with financial burdens, especially when key tests are not covered by insurance. Meanwhile, both patients and clinicians must manage the burden of tight appointment schedules, long clinic visits, and increasing demands on their time.

To improve care quality, the authors emphasize the need for interdisciplinary teamwork and ongoing education. Surveys show that many clinicians are still unfamiliar with cardio-oncology guidelines, which can compromise care. The review also highlights the potential for artificial intelligence and digital tools to streamline care delivery, reduce wait times, and support both patients and providers.

Importantly, the authors point out that improving one area—such as quality—can come at the expense of others, like cost or time. They encourage healthcare systems to take a balanced approach, setting clear goals and using integrated care models that consider all three elements of the triangle together.

“While a perfect model for managing the unattainable triangle may be simply that, ‘unattainable’, investments in research, patient-centered care, data-driven decision-making, and financial alignment with payers will be crucial to the long-term success of both patient outcomes and the organization’s profitability.”

While achieving perfect balance may be difficult, the review suggests that using the unattainable triangle as a guiding framework can help hospitals and clinicians make smarter, more sustainable decisions. As cardio-oncology continues to expand in response to the growing number of cancer survivors with cardiovascular needs, this approach could help improve patient outcomes and strengthen healthcare systems.

DOI - https://doi.org/10.18632/oncotarget.28738

Correspondence to - Stella Pak - [email protected]

Video short - https://www.youtube.com/watch?v=65-5eUuVyyk

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Keywords - cancer, cardio-oncology, quality improvement, cardiology, oncology

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BUFFALO, NY - June 11, 2025 – A new #research paper was #published in Volume 16 of Oncotarget on May 29, 2025, titled “Durable complete response in leptomeningeal disease of EGFR mutated non-small cell lung cancer to amivantamab, an EGFR-MET receptor bispecific antibody, after progressing on osimertinib.”

A team led by first author Jinah Kim, from the University of Vermont Medical Center, and corresponding author Young Kwang Chae, from the Feinberg School of Medicine, reports a clinical case in which a patient with advanced non-small cell lung cancer (NSCLC) carrying rare EGFR mutations responded remarkably to amivantamab after other treatments had failed. The patient experienced a complete resolution of brain and spinal fluid metastases, suggesting that amivantamab may be a viable option for patients with uncommon genetic profiles and limited therapy options.

Lung cancer remains one of the leading causes of cancer-related deaths worldwide. Patients with NSCLC who have rare mutations in the EGFR gene often face limited treatment options and poor outcomes, especially when the disease spreads to the brain or spinal fluid. This case involved a 67-year-old man diagnosed with NSCLC who had two rare EGFR mutations—G719A and A289V. After disease progression on osimertinib and other therapies, the patient began amivantamab monotherapy.

Within six weeks, his lung tumor shrank by over 30 percent. By six months, imaging confirmed the disappearance of brain metastases and leptomeningeal disease, a serious condition affecting the membranes of the brain and spinal cord. Blood tests showed no detectable cancer-related mutations, and the patient, previously wheelchair-bound, regained the ability to walk and perform daily activities. This response has been sustained for more than 19 months.

“Treatment produced a durable response over 19 months, including a 32.2% reduction in tumor size at six weeks, and complete resolution of brain metastases and LMD by six months.”

Amivantamab is a bispecific antibody that targets EGFR and MET, two key drivers of tumor growth. While it is approved in combination regimens for common EGFR mutations, its effectiveness as a single agent in rare mutations or in treating brain metastases remains largely unproven. This case challenges the assumption that large antibody drugs cannot cross the blood-brain barrier and suggests that amivantamab may have potential in managing central nervous system involvement. Further research is needed to clarify how the drug achieves these effects and to explore its broader use in patients with rare EGFR mutations and limited treatment options.

This case highlights three key findings: amivantamab may be effective against rare EGFR mutations, can be used as monotherapy, and may overcome the challenges of the blood-brain barrier. Although based on a single patient, the results provide encouraging evidence to support further investigation of amivantamab in treating difficult-to-manage forms of NSCLC.

DOI - https://doi.org/10.18632/oncotarget.28730

Correspondence to - Young Kwang Chae - [email protected]

Video short - https://www.youtube.com/watch?v=RJX3rmtH7h8

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Keywords - cancer, amivantamab, monotherapy, rare EGFR mutation, NSCLC, leptomeningeal disease

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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.

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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.

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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BUFFALO, NY – June 9, 2025 – A new #research paper was #published in Volume 16 of Oncotarget on May 20, 2025, titled “Cigarette smoke and decreased DNA repair by Xeroderma Pigmentosum Group C use a double hit mechanism for epithelial cell lung carcinogenesis.”

In this study, led by first author Nawar Al Nasralla and corresponding author Catherine R. Sears, from the Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Indianapolis and the Richard L. Roudebush Veterans Affairs Medical Center, researchers investigated how cigarette smoke and reduced DNA repair capacity contribute together to the development of lung cancer. They found that when a critical DNA repair protein called XPC is decreased and lung cells are exposed to cigarette smoke, the combination causes extensive damage and significantly increases cancer risk.

Non-small cell lung cancer (NSCLC) develops through both genetic and environmental factors. This study focused on how cigarette smoke affects the body’s natural ability to repair DNA. The researchers studied the role of XPC, a protein essential for recognizing and repairing harmful DNA changes caused by tobacco smoke. They found that low levels of XPC — commonly seen in lung cancer patients — made lung cells less capable of repairing DNA. This made the cells unstable and more likely to become cancerous. These changes were most pronounced in normal lung cells, suggesting that the earliest stages of disease occur before cancer is even detected.

The findings support a “double hit” model, where both cigarette smoke and reduced DNA repair work together to drive cancer development. In laboratory experiments, normal lung cells with low XPC levels showed more damage and cell death after cigarette smoke exposure. By contrast, lung cancer cells were more resistant to smoke damage, even when XPC was low, indicating that critical changes had likely occurred earlier in the disease process.

“Our study suggests that cigarette smoke exposure leads to decreased XPC mRNA expression, exacerbates total and oxidative DNA damage, hinders NER, and may contribute to lung cancer development.”

The study also showed that DNA repair ability declined significantly in healthy cells after smoke exposure, but this effect was not seen in cancer cells. In addition, the researchers confirmed that XPC gene activity was lower in actual lung tumor tissue compared to nearby healthy lung tissue. This pattern was consistent across both adenocarcinoma and squamous cell carcinoma, the two main types of NSCLC.

These results add to our understanding of how lung cancer begins at the molecular level. By showing how cigarette smoke and reduced DNA repair combine to create genetic instability, the research points toward new strategies for prevention. A better understanding of XPC’s role could help identify high-risk individuals and inform future efforts to stop lung cancer before it begins.

DOI - https://doi.org/10.18632/oncotarget.28724

Correspondence to - Catherine R. Sears - [email protected]

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Keywords - cancer, DNA repair, DNA damage, lung adenocarcinoma, squamous cell carcinoma, Xeroderma Pigmentosum Group C (XPC)

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