Tagged: Cancer Research

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.

_______

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

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

Click here to subscribe to Oncotarget publication updates.

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

Oncotarget

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.
_______

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 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.

___

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

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.

___

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 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.

___

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

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.

—

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.

—

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.

—

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

Cancer Dormancy and Tumor Recurrence: New Insights for Breast Cancer

November 13, 2024

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

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

The Study: Investigating Dormancy in Breast Cancer Tumors

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

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

The Challenge: Elusive Dormant Cancer Cells

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

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

The Results: A Breakthrough in Cancer Dormancy Mechanisms

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

The Potential: Toward New Treatments for Preventing Cancer Recurrence

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

Conclusion

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

Click here to read the full research paper in Oncotarget.

—

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

Targeting Stem Cell-like Traits: How miR-10b Inhibition Treats Metastatic Breast Cancer

October 11, 2024

“Our results demonstrate that inhibition of miR-10b using MN-anti-miR10b decreases the stemness of breast cancer cells, supporting dedifferentiation as a mechanism through which the nanodrug may function as a therapy.”

—

While there have been significant improvements in breast cancer detection and treatment, the outlook for metastatic breast cancer remains bleak, with only a 30% five-year survival rate. This is largely due to existing therapies’ inability to effectively target the unique characteristics of metastatic cells. One key factor in metastasis is miR-10b, a small noncoding RNA known to influence cancer cell invasion, migration, viability, and proliferation.

In their paper, researchers Alan Halim, Nasreen Al-Qadi, Elizabeth Kenyon, Kayla N. Conner, Sujan Kumar Mondal, Zdravka Medarova, and Anna Moore from Michigan State University’s Precision Health Program, College of Human Medicine, and College of Veterinary Medicine, and Transcode Therapeutics Inc. in Newton, Massachusetts, shared findings showing that inhibiting miR-10b impairs breast cancer cell stemness. Their research paper, entitled, “Inhibition of miR-10b treats metastatic breast cancer by targeting stem cell-like properties” was published in Volume 15 of Oncotarget on August 26, 2024.

THE STUDY

In this study, researchers investigated the effects of repeated MN-anti-miR10b treatments on local and distant metastases. They observed over 93% inhibition of miR-10b in cryosectioned samples and noted reduced miR-10b expression in lymph node and lung metastases after weekly dosing. RNA sequencing revealed upregulation of genes, including ATP6V0D2, EPHB2, KLF4, KLF7, NCOR2, TMEM268, and VDR, associated with developmental processes. Functional enrichment analysis highlighted biological processes such as cell differentiation and tissue development in these upregulated genes.

The researchers also explored the link between miR-10b expression and stem-like properties in cancer cells. Elevated miR-10b levels were found in stem-like breast cancer cells. MN-anti-miR10b reduced stemness-related traits in MDA-MB-231 and MCF-7 cells, as shown by reduced aldehyde dehydrogenase activity and smaller spheroids in tumorsphere assays. These results suggest that inhibiting miR-10b effectively targets stem-like properties in metastatic breast cancer, offering potential therapeutic benefits.

DISCUSSION

Inhibition of miR-10b has been shown to be an effective treatment strategy for metastatic breast cancer. The nanodrug MN-anti-miR10b was found to significantly downregulate miR-10b expression in cancer cells, leading to decreased cell migration, invasion, proliferation, and viability. The researchers investigated the time course of miR-10b inhibition and confirmed that the nanodrug effectively reduced miR-10b expression in both regional and distant metastases. RNA sequencing analysis revealed that the inhibition of miR-10b by MN-anti-miR10b upregulated genes associated with developmental processes, indicating an effect on the stem cell-like properties of cancer cells.

The study also demonstrated a correlation between miR-10b expression and stemness in cancer cells. Cells with increased stemness, identified by the CD44+/CD24- surface marker phenotype, showed higher miR-10b expression. Treatment with MN-anti-miR10b resulted in decreased stemness-associated properties, as observed through the Aldefluor assay and tumorsphere formation assays. These findings suggest that MN-anti-miR10b has a differentiation effect on cancer cells and targets dedifferentiated, stem cell-like cancer cells. The upregulation of genes associated with developmental processes by MN-anti-miR10b further supports the notion that cancer cells overexpressing miR-10b are in a less-developed, more stem cell-like state.

Overall, the study provides valuable insights into the therapeutic effects of miR-10b inhibition using MN-anti-miR10b in metastatic breast cancer. The findings suggest that targeting miR-10b and stem cell-like properties in cancer cells could be a promising approach for the treatment of various types of metastatic carcinoma.

IN CONCLUSION

Despite the progress made in breast cancer detection and treatment, the prognosis for metastatic breast cancer remains poor. A significant factor contributing to metastasis is miR-10b, a small RNA molecule involved in cancer cell invasion and migration. The researchers have developed a nanodrug called MN-anti-miR10b that delivers antisense oligomers to inhibit miR-10b in cancer cells.

In mouse models of metastatic triple-negative breast cancer, MN-anti-miR10b has shown promising results. It prevents the development of metastases and can eliminate existing metastases when combined with chemotherapy, even after treatment cessation. Recent studies have also linked miR-10b to the acquisition of stem cell-like properties in cancer cells, including chemotherapy resistance.

In this study, the researchers provide transcriptional evidence that inhibiting miR-10b with MN-anti-miR10b activates developmental processes in cancer cells. They also demonstrate that stem-like cancer cells have higher expression of miR-10b. Importantly, treatment of breast cancer cells with MN-anti-miR10b reduces their stemness, indicating that the nanodrug can effectively target and impair the stem-like properties of breast cancer cells.

These findings highlight the potential of MN-anti-miR10b as a treatment option for breast cancer subtypes characterized by stem-like properties. By inhibiting miR-10b, the nanodrug could disrupt the stemness of cancer cells and may offer a new approach to improve the outcomes for metastatic breast cancer patients.

Click here to read the full research paper in Oncotarget.

—

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.