Category: Oncotarget

Targeting SETDB1: A New Strategy for Treating Osteosarcoma

April 9, 2025

“Osteosarcoma is characterized by a complex genetic profile that leads to significant genetic instability, which contributes to therapeutic resistance.”

Despite decades of research, treatment for osteosarcoma has remained largely unchanged, especially for patients whose cancer spreads or returns. However, a growing body of evidence, summarized in the review “SETDB1 amplification in osteosarcomas: Insights from its role in healthy tissues and other cancer types,” published in Oncotarget, highlights the gene regulator SETDB1 as a potential key player in cancer progression, immune system evasion, and resistance to therapy. Targeting this protein may offer a new direction for developing more effective treatments.

Understanding Osteosarcoma

Osteosarcoma is a rare but aggressive bone cancer that primarily affects teenagers and young adults. While current treatments like surgery and chemotherapy can help some patients, outcomes are much worse for those with relapsed or advanced disease.

One of the reasons osteosarcomas are so difficult to treat is their complex and unstable genetics. Unlike cancers with well-defined mutations, osteosarcomas involve chaotic DNA rearrangements, making it difficult to identify precise drug targets. Adding to the challenge, the immune system often fails to recognize these cancer cells, limiting the success of immunotherapy.

The Role of SETDB1 in Osteosarcoma

Researchers from the Gustave Roussy Cancer Campus in France recently published a review in Oncotarget examining the role of SETDB1, a protein that helps control which genes are turned on or off. SETDB1 does this by adding chemical tags called methyl groups to DNA-packaging proteins, effectively silencing certain genes.

In healthy tissue, SETDB1 helps stem cells develop into specific cell types like bone or fat. But in cancer, especially in aggressive osteosarcomas, SETDB1 often becomes overactive. Such activity can silence genes that would normally stop cancer from growing or help the immune system detect tumors. The review highlights how this overactivity is especially common in osteosarcoma tumors that come back after treatment.

Researchers also noted that SETDB1 is active in several other cancers, including melanoma, breast, and lung cancers. This data suggests that finding a way to inhibit SETDB1 could benefit not only osteosarcoma patients but also improve treatment options for various other cancers.

A New Strategy: Blocking SETDB1

Scientists are now exploring ways to block SETDB1 as a new approach to treating osteosarcoma. One experimental compound, SETDB1-TTD-IN-1, is the first to specifically target this protein. Although still in early research stages, it offers a valuable tool to better understand and possibly disrupt how SETDB1 supports cancer growth.

So far, efforts to inhibit SETDB1 have mostly relied on non-specific drugs like DZNep and paclitaxel, or experimental tools such as microRNAs and mithramycin A. While these agents show some ability to reduce SETDB1 activity, they also affect many other cellular processes, which limits their usefulness in treatment. New derivatives of mithramycin, called “Mithralogs,” may offer better results with fewer side effects, but they are still under investigation.

Another treatment strategy is targeting proteins that work together with SETDB1 to silence genes. For example, one molecule called T0070907 targets PPARγ, a factor regulated by SETDB1 that plays a role in bone cell development and osteosarcoma progression.

By turning off SETDB1, researchers hope to reactivate important protective genes and make tumors more visible to the immune system. This strategy could help make treatment-resistant cancers like osteosarcoma more responsive to radiation and immunotherapy.

Even more exciting, SETDB1 appears to play a similar role in other cancers, including melanoma, lung, and breast cancer. That means breakthroughs here could lead to wider, more targeted therapies, potentially offering treatments that are not only more effective but also cause fewer side effects than traditional chemotherapy.

Future Perspectives and Conclusion

Although SETDB1 research in osteosarcoma is still in its early stages, the evidence so far is compelling. This protein sits at a critical intersection of gene regulation, immune response, and cell development. Continued research is needed to develop safe and effective inhibitors, test them in laboratory models, and eventually evaluate them in human clinical trials.

If successful, therapies targeting SETDB1 could offer a long-awaited discovery for osteosarcoma patients, especially those who currently have few treatment options. It represents a promising direction in a field that has seen limited therapeutic advancements in recent decades.

Click here to read the full review 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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When the Cure Becomes the Cause: A Rare Case of Cancer from Donor Cells

March 26, 2025

“Donor cell-derived hematologic neoplasms are extremely rare complications that arise after hematopoietic stem cell transplantation.”

A young woman beat leukemia; however, nine years later, she faced a different blood cancer. This rare twist, reported recently in Oncotarget, reveals an unexpected risk of bone marrow transplants and opens new questions about long-term outcomes and donor screening.

Bone Marrow Transplant

Bone marrow transplants, also known as hematopoietic stem cell transplants, are often lifesaving for patients with blood cancers like leukemia. These transplants replace a patient’s damaged bone marrow with healthy cells from a donor, giving the body a fresh start. While this treatment can be remarkably effective, it comes with complex risks. Relapse of the original cancer is the most feared outcome. But in very rare cases, a different threat emerges; a cancer formed from the donor’s cells. This condition, called donor cell–derived hematologic neoplasm (DCHN), occurs in less than 1% of cases, and it can emerge years after a transplant.

The Case Report

Dr. Aleksandra Mroczkowska-Bękarciak and Dr. Tomasz Wróbel from Wroclaw Medical University in Poland recently published a new DCHN case report, titled “A case report of donor cell–derived hematologic neoplasms 9 years after allogeneic hematopoietic cell transplantation,” in Volume 16 of Oncotarget.

A female patient, diagnosed at age 12 with acute myeloid leukemia, received a bone marrow transplant from an unrelated donor. For nearly a decade, she lived cancer-free. But at age 23, an abnormal increase in platelet counts was noticed. Afterward, a series of extensive analyses, including advanced genetic sequencing, was performed to determine if the leukemia had returned. But it was not a cancer relapse. What was found was a new and distinct blood cancer: a triple-negative myeloproliferative neoplasm.

A New Cancer from Donor Cells

Genetic testing showed that the new cancer had developed from the donor’s cells, not from the patient’s own. These cells carried new mutations in three genes well-known in blood cancers: ASXL1, SETBP1, and EZH2. All three are associated with poor outcomes and aggressive disease progression.

Despite initial treatment, the patient’s condition deteriorated. Within two years, her illness had progressed to myelodysplastic syndrome and then to a new form of acute leukemia. Unfortunately, she died during therapy.

The Science Behind Donor Cell–Derived Hematologic Neoplasm

Researchers believe that a mix of factors can contribute to DCHN appearance: preexisting but undetected mutations in donor cells, damage to the patient’s bone marrow environment, stress on transplanted cells, and even the immunosuppressive therapies used to prevent transplant rejection.

What makes DCHN particularly difficult to detect is its delayed appearance. Years can pass before any symptoms appear.

The Importance of This Case

This case adds to a growing body of evidence that new cancers can originate from donor cells after a bone marrow transplant. It challenges the conventional understanding of relapse and highlights the need to reexamine how donor cells are screened and selected.

As stem cell transplants become more common, especially among younger patients, cases like this emphasize the need for better screening protocols and long-term monitoring. They also offer researchers valuable insights into how DCHN develops and how such complications might be prevented in the future, ultimately leading to more personalized and safer treatments.

Future Perspectives and Conclusion

This case illustrates that even the most advanced, life-saving treatments, like bone marrow transplants, can carry unexpected risks. It reinforces the need for continued vigilance, research, and innovation to make these therapies safer and more effective. Every patient’s story, especially the rare and complex cases like this one, adds to our understanding and brings us closer to more personalized, reliable treatments for all.

Click here to read the full case report in Oncotarget.
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A Rare Genetic Shift That Helped Lung Cancer Evade Treatment

March 12, 2025

“This case adds to the literature on bypass signaling as a mechanism of resistance to lorlatinib, providing evidence for RET activation as a novel escape mechanism […]”

What if a cancer treatment worked—until it suddenly didn’t? A new case report, “Acquired RUFY1-RET rearrangement as a mechanism of resistance to lorlatinib in a patient with CD74-ROS1 rearranged non-small cell lung cancer: A case report,” published in Oncotarget, reveals how a non-small cell lung cancer (NSCLC) patient developed drug resistance through a rare genetic alteration, allowing the cancer to evade therapy. This unexpected finding highlights the importance of advanced genetic testing and personalized cancer treatments.

Non-Small Cell Lung Cancer, Targeted Therapy and Drug Resistance

Non-Small Cell Lung Cancer is the most common type of lung cancer, accounting for nearly 85% of all cases. Some patients with NSCLC have genetic mutations, such as ROS1 gene fusions, that drive tumor growth. These patients often respond well to targeted therapies like lorlatinib, a ROS1 inhibitor that blocks cancer growth.

However, cancer is constantly evolving. Over time, it can develop resistance to targeted therapies, leading to treatment failure. Understanding these resistance mechanisms is crucial for precision oncology, the approach of tailoring cancer treatment based on a patient’s unique genetic profile.

The Case Report That Changed Our Understanding

Dr. Jenny L. Wu from Vanderbilt University School of Medicine and Dr. Wade T. Iams from Vanderbilt-Ingram Cancer Center describe a rare case of drug resistance in a 42-year-old man with advanced NSCLC (stage IV) carrying a ROS1 gene rearrangement. Initially, the patient responded to multiple treatments, including entrectinib and later lorlatinib, both FDA-approved ROS1 inhibitors.

After six months on lorlatinib, his cancer began progressing again. To determine why the treatment stopped working, clinicians performed RNA next-generation sequencing (NGS), a diagnostic tool used to detect genetic mutations in cancer cells.

A Hidden Genetic Mutation

The NGS revealed a previously unknown mutation: a RUFY1-RET gene fusion, which had never been linked to lorlatinib resistance before. RET fusions are commonly associated with thyroid cancer and lung adenocarcinoma, but this was the first documented case where a RET fusion emerged as a mechanism of resistance to ROS1 inhibitors.

This discovery suggests that NSCLC can activate alternative survival pathways when ROS1 inhibitors are used, making precision medicine strategies even more critical for advanced lung cancer patients.

A New Treatment Approach

After detecting the RET fusion, clinicians adjusted the patient’s treatment plan by introducing pralsetinib, a RET inhibitor, alongside lorlatinib to target both mutations.

Initially, the combination therapy showed promise. Scans revealed tumor shrinkage, and the patient responded positively. Unfortunately, the response lasted only four months before the cancer progressed again. The patient passed away shortly thereafter, highlighting the urgent need for more durable treatment options for drug-resistant lung cancer.

The Importance of This Case

This is the first documented case of a RET fusion emerging as a resistance mechanism to lorlatinib. It challenges previous assumptions about how NSCLC adapts to targeted therapies and emphasizes the importance of RNA sequencing in detecting hidden resistance mutations.

Standard DNA testing did not detect the RET fusion; only RNA sequencing revealed it. This finding suggests that more sensitive genetic testing should be used when patients develop treatment resistance.

This case also raises new questions about therapy combinations. While the mix of lorlatinib and pralsetinib provided temporary disease control, it was not enough for long-term remission. New strategies are needed to develop more long-lasting treatment combinations for patients who develop resistance.

Future Perspectives and Conclusion

Treatment resistance remains a major challenge in lung cancer care. While targeted therapies have revolutionized treatment, they must continuously adapt to stay ahead of the disease.

Although the combination of pralsetinib and lorlatinib initially showed some effectiveness, the response did not last. In the future, scientists must investigate why some RET fusions make drugs less effective and whether finding these genetic alterations earlier could help change treatment plans before resistance fully sets in.

By uncovering new resistance mechanisms, this case highlights the importance of advanced genetic testing and contributes to the growing field of precision oncology. The more we understand how cancer adapts, the better we can develop smarter, more effective treatments and improve survival rates for lung cancer patients.

Click here to read the full case report in Oncotarget.

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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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HER2-Low Breast Cancer: A New Understanding

February 12, 2025

“[…] HER2-low breast cancer is unlikely to represent a unique biologic or clinical subtype but rather a therapeutic target for a new class of HER2 targeted therapy: HER2-directed ADCs.”

For years, breast cancer has been classified as either HER2-positive or HER2-negative, determining whether a patient could receive HER2-targeted therapies like trastuzumab (Herceptin). However, a growing body of research suggests a middle category—HER2-low breast cancer—which has led to important changes in how clinicians approach treatment.

A recent review published in Oncotarget, titled “Evolving Concepts in HER2-Low Breast Cancer: Genomic Insights, Definitions, and Treatment Paradigms,” explores what this means for both patients and clinicians.

Understanding HER2-Low Breast Cancer

HER2-low breast cancer refers to tumors with some HER2 protein expression but not enough to be classified as HER2-positive. In medical terms this is defined by an immunohistochemistry (IHC) score of 1+ or 2+ without HER2 gene amplification. While this may seem like a minor distinction, it has major treatment implications.

Historically, HER2-negative and HER2-low cancers were treated the same way, primarily with hormone therapy (for hormone receptor-positive cases) or chemotherapy. However, the emergence of antibody-drug conjugates (ADCs), such as trastuzumab deruxtecan (T-DXd), has changed the treatment landscape. These drugs target HER2-positive cancers but have now been shown to work against HER2-low tumors as well, opening new options for patients who previously had few targeted therapies available.

The DESTINY-Breast04 trial was a breakthrough study proving that T-DXd significantly improves survival for patients with HER2-low metastatic breast cancer compared to standard chemotherapy.

Is HER2-Low Breast Cancer a Unique Breast Subtype?

One of the biggest questions in breast cancer research today is whether HER2-low breast cancer represents a distinct biological subtype or simply a new way of classifying tumors for treatment.

According to the Oncotarget review, led by first author Whitney L. Hensing from University of Missouri-KC School of Medicine, HER2-low breast cancer does not have a unique genetic profile that sets it apart from HER2-negative cancers. Instead, their characteristics seem to be primarily influenced by whether they are hormone receptor-positive (HR-positive) or triple-negative (TNBC).

Most HER2-low breast cancers fall into the HR-positive category, meaning they can also respond to hormone therapy. Additionally, the presence of low HER2 expression does not appear to significantly impact prognosis. This means that HER2-low breast cancer does not behave differently from HER2-negative breast cancer in terms of patient outcomes.

Rather than being a completely new biological subtype, HER2-low is better understood as a therapeutic category—a classification that helps identify patients who may benefit from newer HER2-directed treatments.

The Challenge of Defining HER2-Low Breast Tumors

Although the HER2-low classification is gaining importance, diagnosing and defining these tumors remains a challenge. One of the main issues is testing variability. Pathologists analyzing tumor samples often struggle to distinguish between HER2-low and HER2-negative cases. The difference between an IHC score of 0 and 1+ is very subtle, leading to inconsistencies in classification.

Adding to this complexity, HER2 expression can change over time. A tumor that was originally classified as HER2-low may later become HER2-negative, or vice versa, which raises important questions about how frequently HER2 status should be reassessed, especially in metastatic cases.

A newer concept, called HER2-ultralow, is also emerging. This term refers to tumors with barely detectable HER2 expression, which may still respond to drugs like T-DXd. Research into this category is ongoing, and future studies may further expand treatment possibilities for patients with ultralow HER2 expression.

New Treatment Options for HER2-Low Patients

The biggest impact of recognizing HER2-low breast cancer has been the availability of new treatment options.

Antibody-drug conjugates, such as T-DXd, are designed to attach chemotherapy directly to HER2-expressing cancer cells. Even with low levels of HER2, these tumors can still be targeted. The DESTINY-Breast04 trial confirmed that T-DXd offers significant survival benefits, making it the first HER2-targeted therapy for HER2-low patients.

Another promising drug is sacituzumab govitecan (SG), which has also shown effectiveness in HER2-low and triple-negative breast cancers. Unlike T-DXd, SG targets a different protein called TROP2 but has demonstrated significant benefits for patients with HER2-low tumors. The development of next-generation ADCs is already underway, with newer drugs being tested to improve efficacy and reduce side effects.

The Future of HER2-Low Breast Cancer Treatment

While recognizing HER2-low as a treatment category is a major step forward, several challenges remain. One key issue is standardizing HER2 testing to improve accuracy and reliability. Researchers are exploring digital pathology and AI-assisted imaging to reduce human variability and enhance precision in classification.

Another challenge is understanding how HER2 expression evolves over time, as tumors classified as HER2-low may later become HER2-negative, or vice versa. Ongoing research aims to determine the best strategies for retesting and adjusting treatments based on these changes, particularly in metastatic cases.

Researchers are also investigating whether combining ADCs with hormone therapy or immunotherapy could further improve outcomes. Clinical trials are already evaluating these approaches, offering hope for more tailored treatments.

Additionally, there is growing interest in HER2-ultralow tumors. The DESTINY-Breast06 trial is assessing whether these patients could also benefit from T-DXd. If successful, this could expand HER2-targeted therapy to an even larger group of patients.

Conclusion: A New Era in Breast Cancer Care

The recognition of HER2-low breast cancer is reshaping the way oncologists treat breast cancer. Although it is not a distinct biological subtype, identifying HER2-low tumors has expanded access to HER2-targeted therapies, significantly improving treatment options for thousands of patients.

With ongoing research and next-generation therapies on the horizon, the future holds promise for more personalized and effective breast cancer treatments. This shift is not just about changing classifications—it is about giving more patients access to life-saving treatments and improving survival rates.

Click here to read the full review in Oncotarget.

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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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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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The Hidden Risks of At-Home Genetic Cancer Tests

January 3, 2025

“While the test poses minimal physical risk, there is no assurance of “safety” from psychological distress.”

Would you take a test to find out your cancer risk? At-home genetic testing makes it easy, but experts warn that these tests may create more harm than good.

A New Approach to Genetic Testing

Genetic testing has traditionally been performed under the supervision of healthcare providers, with genetic counseling to help patients navigate their results. This approach ensures that individuals receive proper guidance, reducing the emotional and practical challenges of interpreting complex genetic information.

In September 2023, the United States Food and Drug Administration (FDA) approved a new test called the Invitae Common Hereditary Cancers Panel. This test checks for changes in 48 genes linked to hereditary cancers, including breast, ovarian, and Lynch syndrome-related cancers. What makes it different is that it can be ordered online and taken at home with no doctor required.

While the convenience of these tests is appealing, health experts have raised serious concerns. An editorial titled “Pitfalls and Perils from FDA-Approved Germ-line Cancer Predisposition Tests,” authored by Dr. Wafik S. El-Deiry, Editor-in-Chief of Oncotarget, and Dr. Eli Y. Adashi, both from Brown University, highlights the potential risks of using these tests without professional guidance.

Concerns Raised by Experts

Experts warn that while at-home genetic tests sound simple, they often leave users with more questions than answers. A common issue is the detection of Variants of Uncertain Significance, genetic changes that are not definitively linked to cancer risk. Without proper context, these ambiguous findings can lead to unnecessary anxiety or uninformed decisions.

Another concern is the potential impact on minors. Without medical oversight, children may take these tests without fully understanding their implications. If the findings are not shared with healthcare providers or added to medical records, critical follow-up care could be missed, leading to long-term health consequences. Additionally, these tests are rarely covered by health insurance, adding financial burden to individuals.

The Importance of Professional Guidance

Genetic counseling is essential to make sense of genetic test results. When testing is done under medical supervision, it can guide individuals toward proactive decisions, such as increased screenings or preventive treatments. Without this support, results may be misinterpreted, causing unnecessary worry or missed opportunities for intervention. Requiring access to genetic counseling ensures that all users fully understand their results and can take appropriate next steps.

What Needs to Change?

The editorial calls on the FDA to implement stricter regulations to ensure the safe and responsible use of at-home genetic tests. Ensuring that the test results are integrated into healthcare systems is another critical measure, particularly for minors who may need long-term follow-up.

Testing companies must also be transparent about the limitations of their products. For instance, not all detected genetic changes are linked to cancer risk, and this should be communicated clearly to set realistic expectations and avoid unnecessary alarm.

The Future of At-Home Genetic Testing

At-home genetic cancer tests mark a significant step forward in healthcare by providing easier access to information about hereditary cancer risks. However, to truly benefit individuals, these tests must include safeguards such as genetic counseling, integration with healthcare systems, and clear communication about their limitations.

With proper regulation and professional guidance, genetic testing has the potential to save lives by identifying risks early and enabling preventive care. Without these measures, however, the benefits of this innovation could be diminished by confusion and missed opportunities for effective healthcare.

Conclusion

At-home genetic cancer tests have great potential, but their convenience should not come at the cost of proper support. Without the right guidance, these tests can have negative consequences. Finding a balance between accessibility and healthcare support, such as genetic counseling, is crucial. This will help ensure they are safe and effective while empowering people to make informed decisions about their health.

Click here to read the full 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

A New Path to Tumor Suppression: The Promise of PG3

December 18, 2024

“Restoration of the p53 pathway has been a long-term goal in the field of cancer research to treat tumors with mutated p53 and aggressive clinical behavior.”

The p53 protein, often called the “guardian of the genome,” is crucial for preventing cancer by repairing damaged DNA or triggering cell death in cells that cannot be repaired. However, in about half of all cancers, the p53 gene is mutated, making the protein ineffective. A groundbreaking study has introduced PG3, a new compound that restores tumor suppression without relying on p53, offering a new option to treat resistant cancers.

The Study: A New Approach to Tumor Suppression

Published in Oncotarget on September 17, 2024, the study titled “Integrated stress response (ISR) activation and apoptosis through HRI kinase by PG3 and other p53 pathway-restoring cancer therapeutics,” introduces PG3, a small molecule with a completely new approach to treating cancer. This groundbreaking research was conducted by Dr. Xiaobing Tian and Oncotarget Editor-in-Chief Dr. Wafik S. El-Deiry from Brown University.

The researchers tested PG3 on cancer cell lines with various p53 mutations, as well as on cells that lacked p53 entirely.

The Challenge: The Limitations of Current Cancer Treatments

For years, scientists have focused on developing cancer treatments targeting p53, a protein that plays a central role in suppressing tumors. However, these treatments face significant challenges. With thousands of known p53 mutations, most therapies can only target specific mutations, limiting their effectiveness. Worse, these treatments fail entirely in cancers where the p53 protein is missing, which occurs in some of the most aggressive tumors. Additionally, many current drugs that target p53 are toxic for healthy cells, causing serious side effects. These limitations have driven researchers to find alternative approaches, like PG3, that do not rely on the presence of p53.

The Results: A Safer, More Effective Cancer Therapy

The study found that PG3 and its earlier version, PG3-Oc, were highly effective in killing cancer cells across five different types of cancer. Notably, PG3 worked regardless of whether the cancer cells had mutated, missing, or fully functional p53 proteins.

PG3 builds upon the earlier version PG3-Oc, retaining its potent anti-cancer effects while addressing key limitations. Unlike its predecessor, PG3 is more water-soluble and less toxic to normal cells. These improvements make PG3 a safer and more practical candidate for cancer therapy.

The Breakthrough: Unlocking a New Path to Treat Cancer

PG3 represents a groundbreaking advance in cancer therapy by employing a completely novel mechanism. Instead of trying to repair or reactivate the dysfunctional p53 protein, PG3 bypasses p53 altogether, taking an alternative and innovative route to kill cancer cells.

PG3 works by activating a protein called HRI kinase, which initiates the integrated stress response (ISR). The ISR is a natural mechanism that cells use to manage internal stress, such as damage caused by cancer. Through this pathway, PG3 activates ATF4, a transcription factor that switches on critical tumor-suppressing genes like PUMA and p21.

These genes are vital for inducing programmed cell death, or apoptosis, which eliminates damaged or cancerous cells. This novel mechanism enables PG3 to effectively destroy cancer cells, even in cases where conventional therapies fail, such as tumors that lack functional p53.

Therapeutic Potential: Advancing Toward Personalized Cancer Care

PG3 has the potential to revolutionize cancer treatment by overcoming the resistance of p53-deficient tumors to existing therapies. By restoring critical tumor-suppressing signals in cancer cells that are otherwise resistant, PG3 offers a new approach to treating some of the most aggressive and challenging cancers.

What makes PG3 especially promising is its combination of versatility and safety. It is effective across a wide range of cancer types, including colorectal, ovarian, and p53-null cancers, while being less toxic to healthy cells, significantly reducing the side effects commonly associated with cancer treatments. These qualities position PG3 as a great option in the future of personalized cancer therapy, offering new hope for patients with limited treatment options.

Next Steps: Bringing PG3 Closer to Patients

While these findings are promising, the study highlights areas for further research. Future work will focus on improving PG3’s delivery and stability in living organisms, ensuring it performs as effectively in clinical settings as it does in the lab. Clinical trials will be the next step to determine PG3’s real-world potential as a cancer therapeutic.

Conclusion

PG3 represents a potential paradigm shift in the treatment of p53-deficient tumors, addressing the limitations of therapies that target mutant p53. By activating an alternative pathway through the integrated stress response, PG3 offers a promising and innovative approach to combating some of the most aggressive cancers

Click here to read the full research paper in Oncotarget.

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

Click here to subscribe to Oncotarget publication updates.

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

Oncotarget

Small Cell Lung Cancer: Advancing Precision Medicine with Biomarker Research

December 4, 2024

“Precision medicine is an innovative approach to disease prevention and treatment that considers differences in people’s genes, injuries, environments, and lifestyles to target the right therapies to the right patients at the right time.”

Could a deeper understanding of one of the deadliest lung cancers lead to more effective treatments? Recent research offers a promising way forward, aiming to improve patient outcomes and provide clinicians with valuable insights.

Small Cell Lung Cancer (SCLC) is a particularly aggressive form of lung cancer. It spreads fast and does not always respond well to conventional therapies such as chemotherapy. Although SCLC accounts for around 15% of all lung cancer cases, survival rates are extremely low. Only less than 5% of patients live more than five years after diagnosis. These alarming statistics highlight the critical need for new treatments. A team of researchers from the Federal University of Ceará, working together with collaborators from Argentina and Spain, may have found part of the solution.

The Study: Finding Clues in Tumor Biomarkers

Published in Oncotarget Volume 15 on October 11, 2024, the study is titled “Relationship between the expressions of DLL3, ASC1, TTF-1 and Ki-67: First steps of precision medicine at SCLC.” Led by corresponding author, Dr. Fabio Tavora, the research team analyzed tumor samples from 64 adult patients diagnosed with SCLC between 2022 and 2024. Their focus was on specific biomarkers, molecules that reveal the unique biology of a tumor, and that could lead to better ways to improve diagnosis and treatment for SCLC.

The Challenge: Why Current Treatments Are Not Enough

Current treatments for SCLC, like chemotherapy, are based on a “one size fits all” approach. While chemotherapy can initially decrease tumor size, its effects are often temporary, in addition to the harsh side effects that the patients can experience. This type of universal treatment overlooks each tumor’s specific biological characteristics, which is one of the main reasons chemotherapy has such low long-term success rates for SCLC patients.

To address this problem, the researchers studied the presence of distinct biomarkers. Since these molecules usually differ from tumor to tumor, they can provide valuable insights into tumor behavior. The goal was to discover new ways to personalize treatments, making them more efficient.

Technology: Using Digital Tools for Precision

In addition to standard techniques like immunohistochemistry, the researchers used QuPath, a novel digital pathology tool. QuPath enabled the researchers to evaluate tumor samples with unprecedented precision and resolution, revealing differences in biomarker expression between patients and between tumors, thus demonstrating that no two tumors are identical. This highlighted the importance of tailored treatment options.

The Results: Two Important Biomarkers

The study revealed two key biomarkers with the potential to improve SCLC treatment: Delta-like ligand 3 (DLL3) and Thyroid Transcription Factor-1 (TTF-1).

The Breakthrough: DLL3 and TTF-1 as Game-Changing

DLL3, a protein identified almost exclusively on the surface of SCLC tumor cells, has emerged as a potential therapeutic target. In this study, DLL3 was found in more than 70% of the SCLC tumors and its expression was tumor-specific. This finding makes it a suitable target for precision medicine, as treatments can target DLL3-positive cells while avoiding healthy tissue.

TTF-1, traditionally used as a diagnostic marker for lung cancer, showed potential as a prognostic biomarker in this study. Patients with TTF-1-positive tumors demonstrated better survival rates. The study also discovered a link between the expressions of TTF-1 and DLL3, suggesting that these two biomarkers could be used together to help choose treatments.

Therapeutic Potential: Toward Personalized Treatments

Unlike traditional therapies, which take a generic approach, biomarker-based treatments are tailored to the unique characteristics of each tumor. This personalization could make treatments more effective while reducing the side effects that patients experience.

Samuel Silva, the study’s first author, during an interview, emphasized the importance of the relationship between TTF-1 and DLL3. TTF-1 serves as both diagnostic and survival prediction tool, while DLL3 creates new opportunities for targeted therapy. Together, these biomarkers offer hope for more effective and individualized treatments for SCLC.

One promising development is the recent FDA approval of Tarlatamab, a therapeutic compound that uses the body’s immune system to target and destroy DLL3-positive tumor cells. This is an example of how biomarkers like DLL3 can be successfully translated into clinical settings.

Looking Ahead: What’s Next for SCLC Research

While this study represents a significant step forward on SCLC treatment, there is still more work to be done. In his interview, Silva explained that his team plans “… to look into the genomics and transcriptomics landscapes and the interactions of all these molecules,” aiming to better understand the molecular mechanisms driving SCLC and to further refine the therapeutic strategies.

Future clinical trials will be necessary to validate these findings and assess how effective and reliable DLL3 and TTF-1 are in guiding treatment for SCLC patients. With continued research, the ultimate goal is to make precision medicine a standard option for all SCLC patients.

Conclusion

SCLC is one of the most challenging cancers to treat, but this study offers hope. QuPath played a key role in showing how biomarkers like DLL3 and TTF-1 can guide more personalized and effective treatments. By focusing on these biomarkers, researchers are leading the way for better ways to diagnose and treat this aggressive disease. Precision medicine, which tailors treatments to each patient’s unique needs, promises to improve survival rates and quality of life for those facing SCLC.

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.