Oncotarget

BUFFALO, NY - January 21, 2025 – A new #research paper was #published in Oncotarget's Volume 16 on January 20, 2025, titled “Anti-correlation of KLRG1 and PD-1 expression in human tumor CD8 T cells."

The study, authored by Dr. Steven A. Greenberg from Harvard Medical School, has discovered a potential new way to improve cancer treatment by studying two key molecules found in immune cells: KLRG1 and PD-1. Analysis of data from cancer patients and healthy individuals revealed that these molecules work in opposite ways in cancer-fighting cells, suggesting that targeting both at the same time could enhance the effectiveness of cancer immunotherapy.

“Much effort in the field of immuno-oncology has involved the study of combination therapies, including combinations involving blockade of more than one T cell inhibitory receptor.”

The immune system helps fight cancer through specialized cells called T cells. Treatments known as checkpoint inhibitors, which block proteins like PD-1, have been successful in helping these cells attack cancer. However, combining different checkpoint inhibitors has not always provided the expected improvements.

This new research focuses on KLRG1, a lesser-known protein, and its relationship with PD-1. The findings suggest that targeting both markers simultaneously could create a stronger and more effective immune response against cancer. Most existing immunotherapy treatments focus only on blocking PD-1, which is commonly found in “exhausted” T cells that struggle to fight cancer. In contrast, KLRG1 is linked to more active, mature T cells that are better at attacking tumors. By blocking both PD-1 and KLRG1, new treatment strategies could help patients with hard-to-treat cancers, such as lung cancer, melanoma, and colorectal cancer.

KLRG1 has not been widely studied in cancer immunotherapy, but this research highlights its potential to revolutionize treatment strategies. While current combinations of checkpoint inhibitors have shown only limited improvements, using therapies that target both PD-1 and KLRG1 could lead to more significant and long-lasting benefits.

“Whereas much of the T cell inhibitory drug development efforts over the last decade have been focused on combinations of expression-correlated inhibitory receptor targets, the targeting of anti-correlated inhibitory receptors has greater potential to produce supra-additive benefit, and KLRG1 has this distinct property.”

Further studies and clinical trials are needed to explore how combining PD-1 and KLRG1 treatments could benefit different types of cancer. If successful, this strategy could open the door for the creation of new combined immunotherapies.

DOI - https://doi.org/10.18632/oncotarget.28679

Correspondence to - Steven A. Greenberg - [email protected]

Video short - https://www.youtube.com/watch?v=PME2xfyYN18

About Oncotarget

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

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

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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.

Full blog - https://www.oncotarget.org/2025/01/15/mastocytosis-key-insights-into-kit-m541l-gene-mutation/

Paper DOI - https://doi.org/10.18632/oncotarget.28614

Correspondence to - Melody C. Carter - [email protected]

Video short - https://www.youtube.com/watch?v=zpiBbSfkTX4

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Keywords - cancer, mastocytosis, KIT M541L, KIT D816V, adults, pediatrics

About Oncotarget

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

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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.

Full blog - https://www.oncotarget.org/2025/01/03/the-hidden-risks-of-at-home-genetic-cancer-tests/

Paper DOI - https://doi.org/10.18632/oncotarget.28677

Correspondence to - Wafik S. El-Deiry - [email protected]

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

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Keywords - cancer, cancer predisposition, germline, marketing authorization, hereditary cancer, direct to consumer

About Oncotarget

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

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

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BUFFALO, NY - December 30, 2024 – A new #editorial was #published in Oncotarget's Volume 15 on December 24, 2024, 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 from Brown University, the article highlights concerns about the risks of a newly approved genetic test for cancer risk. This test, called the “Invitae Common Hereditary Cancers Panel," was approved in 2023 and examines 48 genes linked to inherited cancers, including breast, ovarian, and Lynch syndrome-related cancers. Although the test increases access to genetic information, the authors warn that using it without professional guidance may lead to confusion, stress, and potential harm.

One concern is that people can order this test online without consulting healthcare professionals or genetic counselors. Without expert help, users might struggle to understand their results especially if they indicate risks that are unclear or difficult to act on. This can cause unnecessary anxiety and confusion.

“The DTC option of germ-line testing for cancer susceptibility should be discouraged given the risks of anxiety, lack of adequate interpretation for variants not strongly associated with cancer, potential for minors to be tested outside the healthcare system and potential for loss of follow-up if test results are not shared with health care professionals or never make it into the medical record.”

The editorial also points out ethical and medical issues when minors use these tests. If a child’s test is done without medical oversight, results might not be added to their health records, making follow-up care harder to manage and potentially risking their long-term health.

Cost is another issue. These tests are often not covered by insurance, which can place a financial burden on families who might need additional testing or medical advice.

The researchers emphasize that genetic testing for cancer risk should always include healthcare providers and genetic counseling. This ensures users fully understand their results and receive proper guidance. The authors also call on the US Food and Drug Administration (FDA) to provide clear rules for using these tests, particularly for minors.

In conclusion, while genetic testing holds great potential for improving cancer prevention and care, its benefits must not come at the cost of safety and public health. Responsible use of these tests will require collaboration between regulators, healthcare professionals, and testing companies to address the risks and ensure these tools are used effectively.

DOI - https://doi.org/10.18632/oncotarget.28677

Correspondence to - Wafik S. El-Deiry - [email protected]

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

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

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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.

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.

Full blog - https://www.oncotarget.org/2024/12/18/a-new-path-to-tumor-suppression-the-promise-of-pg3/

Paper DOI - https://doi.org/10.18632/oncotarget.28637

Correspondence to - Wafik S. El-Deiry - [email protected]

Video short - https://www.youtube.com/watch?v=eBp_UGrkii8

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Keywords - cancer, mutant p53, integrated stress response (ISR), ATF4, HRI, ClpP

About Oncotarget

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

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

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BUFFALO, NY - December 11, 2024 – A #news feature on the #research paper “Next-generation cell-penetrating antibodies for tumor targeting and RAD51 inhibition” by Rackear et al. was #published in Oncotarget's Volume 15 on November 22, 2024, titled “Advancements in cell-penetrating monoclonal antibody treatment."

This new publication by Sai Pallavi Pradeep and Raman Bahal from the Department of Pharmaceutical Sciences at the University of Connecticut highlights significant advancements in monoclonal antibody (mAb) therapies. The focus is on the 3E10 antibody, originally derived from autoimmune mouse studies in systemic lupus erythematosus. Unlike traditional mAbs, which struggle to reach intracellular targets, this cell-penetrating antibody targets cancer cells by addressing a major limitation of current therapies. By targeting RAD51, a key intracellular protein involved in DNA repair, the 3E10 antibody shows great promise for cancer treatment, particularly in cancers with defective DNA repair pathways.

mAbs have already changed the landscape of cancer therapy, offering treatments that are more targeted and have fewer side effects compared to chemotherapy. However, current therapies are limited since mAbs only target proteins on the surface of cancer cells. This research pushes the boundaries by demonstrating how 3E10 antibodies can penetrate cells and access their internal molecules. This unique capability expands the potential of mAb therapies and targeted cancer treatments.

Different humanized versions of the 3E10 antibody were created and carefully tested. Some versions were particularly effective at blocking RAD51, while others showed promise for carrying other therapeutic molecules like genetic material into the cancer cells. This flexibility means that 3E10 could be used to treat different cancer types and deliver various therapeutic molecules directly into tumor cells. This progress offers exciting new possibilities for treating cancer tumors that are resistant to conventional therapies.

In conclusion, the 3E10 antibody’s dual function—targeting DNA repair pathways and delivering therapeutic molecules—positions it as a transformative tool in cancer research and targeted cancer treatments.

DOI - https://doi.org/10.18632/oncotarget.28674

Correspondence to - Raman Bahal - [email protected]

Video short - https://www.youtube.com/watch?v=3uMdPvThFHA

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Keywords - cancer, monoclonal anti-bodies, cell penetration, nucleic acid delivery, 3E10

About Oncotarget

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

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BUFFALO, NY - December 9, 2024 – A new #research paper was #published in Oncotarget's Volume 15 on November 22, 2024, entitled “Computed tomography-based radiomics and body composition model for predicting hepatic decompensation."

Mayo Clinic researchers Yashbir Singh, John E. Eaton, Sudhakar K. Venkatesh, and Bradley J. Erickson have developed an innovative AI tool to predict hepatic decompensation in individuals with primary sclerosing cholangitis (PSC). PSC is a chronic disease that damages the bile ducts and can lead to liver failure.

Hepatic decompensation marks a critical stage of advanced liver disease, and clinicians have long faced challenges in predicting who is at risk. The Mayo Clinic's new AI tool addresses this gap by combining body fat and muscle composition data with insights extracted from computed tomography (CT) scans using computational radiomics. By analyzing these tissues, the AI model identifies patterns linked to an increased risk of liver failure.

The study involved 80 PSC patients, including 30 with hepatic decompensation, 30 without, and 20 patients in an external validation set. The AI model achieved impressive results, correctly identifying at-risk patients with 97% accuracy. By recognizing these risks early, clinicians may be able to intervene sooner and improve patient outcomes.

While the study focused on PSC, the team emphasized the broader implications of their work.

“It may hold promise for the detection of other PSC-related complications, such as cholangiocarcinoma, as well as applications in more prevalent chronic liver diseases like non-alcoholic fatty liver disease (NAFLD).”

This non-invasive, data-driven approach offers a powerful way to assess health risks and provide more tailored treatments. Despite the promising findings, the researchers acknowledge the limitations of the study, which include a limited sample size and a single-center design.

“However, further research is necessary to validate our findings on a large-scale, independent dataset, ensuring the robustness and generalizability of the model.”

In conclusion, this study shows how detailed information from CT scans can help clinicians predict severe liver problems in patients with PSC. By identifying hidden patterns in the images, they can better understand risks and create personalized treatment plans. This approach could improve care for PSC and other long-term liver diseases.

DOI - https://doi.org/10.18632/oncotarget.28673

Correspondence to - Bradley J. Erickson - [email protected]

Video short - https://www.youtube.com/watch?v=QCekNtYni4w

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Keywords - cancer, radiomics, body composition, machine learning, primary sclerosing cholangitis, computer tomography

About Oncotarget

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

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

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“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.

Full blog - https://www.oncotarget.org/2024/12/04/small-cell-lung-cancer-advancing-precision-medicine-with-biomarker-research/

Paper DOI - https://doi.org/10.18632/oncotarget.28660

Correspondence to - Fabio Tavora - [email protected]

Author interview - https://www.youtube.com/watch?v=bJO2MD8AXkY

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Keywords - cancer, DLL3, pathology, biomarkers, qupath, small cell carcinoma

About Oncotarget

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

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BUFFALO, NY - December 4, 2024 – A new #editorial was #published in Oncotarget's Volume 15 on November 22, 2024, entitled “B7-H4: A potential therapeutic target in adenoid cystic carcinoma."

Researchers Luana Guimaraes de Sousa and Renata Ferrarotto from The University of Texas MD Anderson Cancer Center made an important discovery about adenoid cystic carcinoma (ACC), a rare and aggressive cancer of the secretory glands. The study found that B7-H4, an inhibitory immune checkpoint, helps ACC tumors avoid attacks from the immune system. This discovery could lead to new treatments for ACC, which currently has very limited options for patients, especially when the cancer spreads to other organs.

ACC is known for behaving in two distinct ways. The aggressive form, called ACC-I, spreads quickly to organs like the liver and lungs and leads to a short survival time of approximately three years. The less aggressive form, ACC-II, grows more slowly and often allows patients to live much longer, sometimes over 20 years. However, treatment options for both forms are limited, and once the cancer spreads, it becomes difficult to treat.

The study showed that the protein B7-H4 is found at high levels in the aggressive ACC-I tumors. This protein blocks immune cells from entering the tumor, allowing the cancer to grow without being attacked by the immune system. Patients with high levels of B7-H4 in their tumors were found to have worse survival outcomes.

To explore possible treatments, the researchers tested a new drug called AZD8205, designed to specifically target and block B7-H4. In preclinical tests on mice, the drug showed remarkable success. Tumors derived from patients shrank in every case, and in many cases of aggressive ACC, the tumors disappeared completely. Importantly, the drug had little effect on less aggressive ACC-II tumors, which have lower levels of B7-H4. This shows that the treatment is highly specific to tumors with high B7-H4 levels.

These results have already led to clinical trials that are testing similar drugs in patients with ACC.

“These trials represent attractive, rationale therapeutic opportunities for patients facing this rare, aggressive, and chemo-refractory disease, for which no systemic therapy is currently available.”

In conclusion, this discovery represents a significant breakthrough in ACC research, identifying B7-H4 as a crucial factor in cancer growth and immune evasion. By leading the way for personalized treatments, it offers promising new therapeutic options and the potential for improved outcomes for ACC patients.

DOI - https://doi.org/10.18632/oncotarget.28661

Correspondence to - Renata Ferrarotto - [email protected]

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

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

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BUFFALO, NY - December 3, 2024 – A new #review was #published in Oncotarget's Volume 15 on November 22, 2024, entitled “Mesenchymal stem cells - the secret agents of cancer immunotherapy: Promises, challenges, and surprising twists."

Authored by Theia Minev, Shani Balbuena, Jaya Mini Gill, Francesco M. Marincola, Santosh Kesari, and Feng Lin from CureScience Institute, Sonata Therapeutics, and Pacific Neuroscience Institute and Providence Saint John’s Health Center, this review explores the potential role of mesenchymal stem cells (MSCs) in cancer treatment. These stem cells can naturally target tumors and deliver therapeutic agents directly to cancer cells, potentially improving treatment outcomes while reducing side effects commonly associated with traditional therapies like chemotherapy. However, the authors also note significant challenges, pointing out that under certain conditions, MSCs may unintentionally promote tumor growth, highlighting the need for careful therapeutic design.

MSCs are cells that can develop in different types of tissues, such as bone, fat, or cartilage, and act as natural repair agents. What makes them particularly special is their ability to respond to biological signals, like inflammation, which is often present in cancer. This enables them to locate tumors, and once there, they can deliver cancer treatments directly to the affected area.

Clinical trials are already investigating MSC-based treatments for cancers such as brain tumors, melanoma, and ovarian cancer. Some results are promising, showing that MSCs can effectively deliver treatments and boost the immune system’s fight against cancer. However, other trials have also revealed the complexities of MSC behavior, including variability in their effects and the potential to create conditions that support tumor growth.

“This variability may be due to the tumor immune microenvironment’s effects, where immune cells are inhibited by various factors, creating a conducive environment for tumor growth.”

The authors also suggest that “Developing personalized MSC therapies tailored to the specific characteristics of a patient’s tumor and immune system could enhance the efficacy and safety of MSC-based treatments.” Achieving this requires a deeper understanding of how MSCs interact with cancer cells and their surrounding environment.

In conclusion, this review highlights both the potential and challenges of (MSCs in cancer therapy. With ongoing research and technological advancements, MSCs could become a key component of personalized cancer treatments, offering new hope for patients worldwide.

DOI - https://doi.org/10.18632/oncotarget.28672

Correspondence to - Feng Lin - [email protected]

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