Category: 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.

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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.

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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Oncotarget

Next-Generation Antibodies for Cancer Therapy

October 24, 2024

“This study focuses on developing a new generation of antibodies that can get inside cancer cells and disrupt their DNA repair processes, offering a hopeful new way to treat cancer with more precision.”

Cancer research has made remarkable progress in recent years, with monoclonal antibody (mAb) therapy emerging as one of the most promising advancements. These treatments are designed to precisely target cancer cells, offering a more focused approach that helps patients fight different malignancies with fewer side effects compared to traditional chemotherapy.

Despite this progress, a major challenge remains: targeting cancer-related molecules inside cells rather than on the surface, which has been the main focus of available mAb therapies until now. This is where the groundbreaking research in the paper “Next-generation cell-penetrating antibodies for tumor targeting and RAD51 inhibition,” published in Volume 15 of Oncotarget on October 1, 2024, comes into play.

The Study

This study, led by researchers Madison Rackear, Elias Quijano, Zaira Ianniello, Daniel A. Colón-Ríos, Adam Krysztofiak, Rashed Abdullah, Yanfeng Liu, Faye A. Rogers, Dale L. Ludwig, Rohini Dwivedi, Franziska Bleichert, and Peter M. Glazer from Yale University School of Medicine, Yale University, and Gennao Bio, explores the potential of an innovative mAb called 3E10. This antibody offers a new way to target cancer cells. The researchers focused on creating humanized versions of 3E10 that can enter malignant cells and disrupt their DNA repair system, presenting a promising new approach to cancer treatment. In this blog, we will look at the key findings and implications of this important work.

The Challenge: Targeting Intracellular Molecules

To understand the importance of this research, let’s first look closer at the limitations of conventional monoclonal antibodies. mAbs are proteins designed to bind to specific targets, like a key fitting into a lock. Many of the current mAb therapies work by targeting proteins (antigens) found on the surface of cancer cells. The issue is that not all cancer-related targets are located on the cell surface. In fact, many important proteins that drive malignant tumor growth and therapy resistance are found inside the cells. Until now, it has been difficult to develop therapies that can penetrate the cell membrane and reach these intracellular targets. The few antibodies that can do this usually face degradation inside the cell, meaning they lose their power before they reach their intended target.

3E10: A Unique Antibody with Cell-Penetrating Abilities

The researchers in this study focused on 3E10, a monoclonal antibody (mAb) originally discovered in a mouse model used to study systemic lupus erythematosus, an autoimmune disease. Unlike most antibodies, 3E10 can enter cells and even reach the cell’s nucleus. What makes it unique is that it does not rely on the usual pathway most antibodies use to enter cells, which usually leads to them being inactivated in cellular compartments called lysosomes. Instead, 3E10 enters cells through a nucleoside transporter called ENT2, which is highly active in many cancers. This overactivity happens because cancer cells grow and multiply quickly, requiring extra nucleosides, the building blocks of DNA and RNA.

The way 3E10 enters cells makes it an exciting candidate for cancer therapy because it can reach targets inside cancer cells that are typically hard to access. One key target is a protein called RAD51, which is crucial for repairing damaged DNA. By binding to and blocking RAD51, 3E10 prevents cancer cells from repairing their DNA, making them more vulnerable.

Humanizing 3E10: Creating Antibodies Suitable for Human Use

While 3E10 holds great potential, the original version of the antibody was derived from mice, which is a problem for human therapy. Antibodies from other species can activate an immune response in humans, leading to reduced efficacy and side effects. To overcome this, the researchers aimed to “humanize” the antibody. This process involved modifying the 3E10 so that it closely resembles a human antibody, minimizing the risk of immune rejection.

In this study, researchers developed 22 different humanized versions of 3E10, each with modifications designed to increase its ability to enter cells and bind to nucleic acids (such as DNA and RNA). These variants were then tested to evaluate how effectively they could do so.

The Results

Tuning Antibody Properties for Optimal Cancer Targeting

The researchers discovered that different humanized versions of 3E10 showed different abilities to bind nucleic acids and penetrate cells. One variant, called V66, stood out for its high affinity for nucleic acids and strong ability to enter cells. In contrast, another variant, V31, had lower affinity for nucleic acids but showed higher binding to RAD51 (a DNA repair protein) and was also more effective at inhibiting DNA repair mechanisms in cancer cells that already had DNA repair problems.

These findings suggest that by adjusting the characteristics of 3E10, it is possible to create different versions of the antibody for different treatments. For instance, the V66 variant may be more suitable for delivering therapeutic molecules into cells because it enters them more efficiently, while lower-affinity variants like V31 might be better at directly blocking the DNA repair mechanisms in cancer cells.

Tumor Targeting Without Antigen Dependence

One of the most promising aspects of this research is that the 3E10 antibody can target malignant tumors without needing a specific protein on the surface of cancer cells. Instead, 3E10 detects tumors because of the high levels of certain molecules, like nucleosides and DNA, commonly found in cancer tissues. This gives a big advantage over many current treatments, which focus on specific proteins found on cancer cells. These proteins can vary in how much they are present between patients or even between different parts of the same tumor, making those treatments less reliable.

Therapeutic Potential

The ability of 3E10 to enter cells and block a crucial DNA repair protein like RAD51 makes it a strong candidate for treating different cancers, including breast, ovarian, and prostate cancers. Additionally, 3E10 can be modified for other purposes, opening up many possibilities for future cancer treatments. For instance, the study’s authors suggest that humanized 3E10 could also be used as a tool for delivering genetic material into cells for gene therapies. This could help create more personalized and effective cancer treatments in the future.

Conclusion

This study represents an important step in developing a new generation of mAb for cancer treatment. By humanizing and optimizing the 3E10 antibody, researchers have shown its potential to target cancer cells in new ways from the previously used. Whether it is used to prevent cancer cells from repairing their DNA or to deliver drugs directly into tumors, 3E10 is a promising new tool in the fight against cancer.

As cancer therapies continue to improve, innovations like 3E10 offer hope for more precise and effective ways to target even the toughest cancers. However, further testing will be needed to make sure these new-generation antibodies are safe and effective in humans.

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).

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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.”

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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.

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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).

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Oncotarget

CDR3s and Renalase-1 Correlate with Increased Melanoma Survival

September 26, 2024

“Our group has demonstrated that chemical complementarity between tumor resident, T-cell receptor, complementarity-determining region 3 (CDR3s), and MAGEA3/6 correlates with increased survival in patients with melanoma.”

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In this study, Saif Zaman, Fred S. Gorelick, Andrea Chrobrutskiy, Boris I. Chobrutskiy, Gary V. Desir, and George Blanck from Yale School of Medicine, Veteran’s Administration Healthcare System, Oregon Health and Science University Hospital, Morsani College of Medicine, and the H. Lee Moffitt Cancer Center and Research Institute, investigated the chemical complementarity between melanoma-resident T-cell receptor (TCR) complementarity-determining region 3 (CDR3) amino acid sequences (AAs) and the renalase-1 protein. On August 5, 2024, their research paper was published in Oncotarget ‘s Volume 15, entitled, “Chemical complementarity of tumor resident, T-cell receptor CDR3s and renalase-1 correlates with increased melanoma survival.”

The Study

The researchers investigated the potential of the RP220 peptide as an antigenic target for T cells by assessing the electrostatic and hydrophobic complementarity between T-cell receptor (TCR) CDR3s and the RP220 peptide of the renalase (RNLS) protein. They found that higher complementarity scores were linked to significantly improved survival probabilities, with hydrophobic forces further refining these distinctions. The associations varied depending on the dataset and method used.

The study also explored correlations between TCR CDR3-RNLS amino acid alignments and immune gene expression. Several immune signature genes, such as CD86, TIGIT, CIITA, and CD4, were significantly associated with better overall survival when showing higher complementarity scores.

Researchers also examined how RNLS expression levels affected these correlations. They found that higher RNLS mRNA expression was associated with worse survival, while lower RNLS expression combined with high complementarity scores predicted better outcomes. This trend held for both the full-length RNLS protein and the RP220 peptide.

The study revealed that specific regions of the RNLS protein, including the RP220 peptide, had higher complementarity with TCR CDR3s, suggesting they may serve as potential antigenic targets.

Discussion

The researchers explored the potential of the RNLS protein as a tumor antigen by examining the chemical complementarity between melanoma tumor-resident T-cell receptor (TCR) CDR3s and the amino acid (AA) sequence of RNLS. They found that increasing complementarity correlated with improved overall survival (OS) outcomes, supporting previous in vitro and in vivo data. This suggests that RNLS could be recognized by TCRs, triggering immune responses against melanoma.

Gene expression analyses revealed that as complementarity scores between TCRs and RNLS AAs increased, so did the expression of T-cell activation-associated genes, indicating enhanced T-cell activity and anti-tumor immune responses. The association between TCR complementarity and OS probabilities was more pronounced in cases with low RNLS expression levels, suggesting that high complementarity may be particularly beneficial in tumors with reduced RNLS-mediated immune inhibition.

These findings suggest that RNLS could serve as an antigen for TCRs in melanoma, supporting further exploration of its potential as a target for immunotherapy and vaccine design.

In conclusion, this research suggests that RNLS could potentially serve as an antigen for T-cell receptors (TCRs) in melanoma. The correlation between TCR complementarity to RNLS and improved overall survival supports the idea that T-cell responses targeting RNLS may play a role in antitumor immunity. These findings highlight the potential of RNLS as a valuable target for immunotherapy and vaccine development for melanoma treatment.

Further research in this area is warranted.

Click here to read the full research paper in Oncotarget.

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Oncotarget

Harnessing the Power of Nanobodies: Inhibiting Metastasis of 4T1-12B Breast Tumor Cells

September 12, 2024

In this study, researchers show that treatment of 4T1-12B mouse breast cancer cells with this nanobody inhibits V-ATPase-dependent acidification of the media and invasion of these cells in vitro.

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Researchers recently developed a nanobody directed against an extracellular epitope of the mouse V-ATPase c subunit. Zhen Li, Mohammed A. Alshagawi, Rebecca A. Oot, Mariam K. Alamoudi, Kevin Su, Wenhui Li, Michael P. Collins, Stephan Wilkens, and Michael Forgac from Tufts University School of Medicine; Tufts University; Dana Farber Cancer Institute, Harvard Medical School; University of Minnesota School of Medicine; Prince Sattam Bin Abdulaziz University; Korro Bio; SUNY Upstate Medical University; and Foghorn Therapeutics, suggest that plasma membrane V-ATPases represent a novel therapeutic target to limit breast cancer metastasis. The vacuolar H+-ATPase (V-ATPase) is an ATP-dependent proton pump that functions to control the pH of intracellular compartments as well as to transport protons across the plasma membrane of various cell types, including cancer cells.

On August 14, 2024, their research paper was published in Oncotarget’s Volume 15, entitled, “A nanobody against the V-ATPase c subunit inhibits metastasis of 4T1-12B breast tumor cells to lung in mice.”

The Research

Breast cancer is one of the most diagnosed cancers, accounting for almost one-third (30%) of all new diagnoses in women in 2022. At the time of diagnosis, 20–30% of patients with early-stage breast cancer will go on to develop metastatic breast cancer. 6–10% of all patients with breast cancer have stage IV disease at time of diagnosis. It has been shown that V-ATPase plays an important role in promoting the invasiveness of many cancer cell types, including breast cancer cells.

This study demonstrated that inhibiting cell surface V-ATPases can effectively block tumor cell invasion. The findings indicate that anti-V-ATPase antibodies targeting an extracellular region of the V-ATPase can suppress activity on the surface of cancer cells, as well as inhibit both in vitro invasion and in vivo metastasis in a mouse model. This represents a promising advancement toward developing a new therapy to limit breast cancer metastasis.

Results

A camelid nanobody against the N-terminus of the mouse V-ATPase c subunit was prepared using phage display. The nanobody was dimerized through disulfide bonding to create a bivalent molecule. The purified nanobody was detected using Coomassie blue staining and Western blotting. The apparent molecular weight of the dimer on SDS-PAGE was around 45 kDa, slightly faster than the predicted weight of 56.8 kDa. The nanobody was tested for its ability to inhibit V-ATPase-dependent acidification in mouse 4T1-12B cells. The nanobody treatment resulted in a similar increase in extracellular pH as treatment with concanamycin, a known V-ATPase inhibitor.

Combining both the nanobody and concanamycin did not significantly enhance the effect. The nanobody effectively inhibited V-ATPase-dependent extracellular acidification without affecting cell viability. The anti-V-ATPase nanobody was tested for its ability to inhibit in vitro invasion of 4T1-12B cells. Treatment with the nanobody significantly inhibited invasion, like its inhibition of extracellular acidification. The nanobody effectively inhibits both extracellular acidification and in vitro invasion of 4T1-12B cells with similar affinity.

The administration of the anti-V-ATPase nanobody was tested to determine its effect on tumor growth and metastasis in mice. Different amounts of the nanobody were administered to mice without any adverse effects. The effect of nanobody administration on in vivo metastasis was then tested using 4T1-12B cells implanted in the mammary fat pad. However, no significant difference in tumor volumes was observed between the control and nanobody-treated groups at the end of the study. Treatment with the anti-V-ATPase nanobody resulted in a significant reduction in lung metastasis but had no effect on tumor growth or leg metastases. No significant metastasis was observed in other organs. In contrast, treatment with the anti-GFP nanobody did not reduce lung metastases.

Discussion

The researchers’ previous results demonstrated that selective inhibition of cell surface V-ATPases using an antibody or bafilomycin showed potential in inhibiting invasion of breast cancer cells. However, the use of antibodies against the native c subunit proved challenging due to its conservation and limited exposure. To overcome this, a nanobody against a native epitope of the c subunit was developed through in vitro screening. This nanobody successfully inhibited cell surface V-ATPase activity in mouse 4T1-12B breast cancer cells and showed a correlation between inhibition of invasion and extracellular acidification. In mice, the nanobody treatment significantly reduced lung metastases, but had no effect on tumor growth or leg metastasis.

The study suggests that different mechanisms may be involved in tumor cell invasion in different tissues. The potential side effects of inhibiting cell surface V-ATPases were also discussed, highlighting the limited presence of these pumps in certain cells and the potential benefits of inhibiting osteoclast function for breast cancer metastasis to bone.

Overall, the findings support the use of inhibitory nanobodies against cell surface V-ATPases as a potential therapeutic approach to inhibit breast cancer metastasis.

“These results provide support for the use of an inhibitory antibody directed against an extracellular epitope of the V-ATPase as a potential anti-metastatic therapeutic to inhibit breast cancer metastasis.”

Click here to read the full research paper in Oncotarget.

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Oncotarget

Key Roles of MIF, DDT, and CD74 in Melanoma Prognosis and Therapy

August 28, 2024

In this new study, researchers present the first retrospective study evaluating differential gene expression of MIF, DDT, and relevant pathway markers in relation to clinical outcomes in melanoma patients.

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Macrophage Migration Inhibitory Factor (MIF) and its homolog D-dopachrome Tautomerase (DDT) have been implicated as drivers of tumor progression in various cancers. Recent evidence suggests that MIF could be a therapeutic target in immune checkpoint inhibition (ICI) resistant melanomas; however, clinical evidence for MIF, and particularly for DDT, remains limited.

Researchers Caroline Naomi Valdez, Gabriela Athziri Sánchez-Zuno, Lais Osmani, Wael Ibrahim, Anjela Galan, Antonietta Bacchiocchi, Ruth Halaban, Rajan P. Kulkarni, Insoo Kang, Richard Bucala, and Thuy Tran from Yale University; Oregon Health and Science University; Cancer Early Detection Advanced Research Center (CEDAR); and the Department of Veterans Affairs Portland Health Care System analyzed 97 patients treated at Yale for melanoma between 2002–2020. Their research paper was published in Oncotarget’s Volume 15 on July 19, 2024, entitled, “Prognostic and therapeutic insights into MIF, DDT, and CD74 in melanoma.”

In their study, the researchers noted that melanoma is one of the most aggressive and lethal forms of cancer, with an estimated 99,700 new cases expected in 2024. The development of immune checkpoint inhibitors (ICIs) has significantly transformed cancer treatment and is now a cornerstone for managing several cancers, including advanced melanoma. Anti-CTLA-4 inhibitors, which target regulatory T cells, and anti-PD-1/L-1 inhibitors, which target activated T cells, dendritic cells, and tumor cells, have reshaped melanoma management, leading to improvements in progression-free and overall survival, with up to 22% of patients experiencing a complete response (CR). Data suggests that the ratio of CD74:MIF and CD74:DDT expression in melanoma may provide prognostic value and potentially serve as clinical biomarkers for patients with melanoma.

The study significantly expands on previous research by including a larger cohort of individuals and employing a comprehensive approach to defining high and low MIF and DDT expression. The survival analysis findings are consistent with existing literature, demonstrating that increased MIF levels are associated with worse prognosis in patients with melanoma, particularly in those with advanced disease or evidence of metastases.

The data presented in this research paper supports existing evidence on the intratumoral effects of MIF and DDT on tumor permissiveness, primarily through immune modulation, with implications for melanoma prognosis. The findings suggest that MIF and DDT may serve as therapeutic targets and biomarkers for predicting treatment response and survival, with CD74:MIF and CD74:DDT showing promise as markers of ICI response in patients undergoing treatment. Further investigation is needed to fully understand the role and functions of DDT in the melanoma microenvironment, as well as its distinct, non-overlapping functions in tumorigenesis.

“Our study is the first to report survival findings in association with intratumor DDT expression and CD74:DDT expression level ratio.”

Click here to read the full research paper in Oncotarget.

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Oncotarget

Combining Regorafenib and TAS102 to Target Gastrointestinal Cancers and Overcome Cancer Stemness

August 9, 2024

In this research paper, researchers demonstrate a promising new treatment option for refractory metastatic gastrointestinal cancers using a combination of two FDA-approved drugs.

Researchers Jun Zhang, Lanlan Zhou, Shuai Zhao, and Wafik S. El-Deiry from Fox Chase Cancer Center and Brown University explore the potential of combining TAS102 (trifluridine/tipiracil) and regorafenib as a treatment option for gastrointestinal (GI) cancers. Their research paper, published in Oncotarget’s Volume 15 on July 2, 2024, is entitled, “Regorafenib synergizes with TAS102 against multiple gastrointestinal cancers and overcomes cancer stemness, trifluridine-induced angiogenesis, ERK1/2 and STAT3 signaling regardless of KRAS or BRAF mutational status.”

The Study

The combination of two FDA-approved drugs, TAS102 and regorafenib, has shown promising results in preclinical studies. TAS102 is an oral formulation consisting of trifluridine (FTD) and tipiracil hydrochloride (TPI). It has been approved by the US FDA for the treatment of refractory metastatic colorectal cancer and metastatic gastric cancer. Regorafenib is a multi-target tyrosine kinase inhibitor that inhibits tumor angiogenesis and cell proliferation and is approved for the treatment of gastrointestinal cancers.

Recent studies have shown that TAS102, in combination with regorafenib, can lead to improved survival and restrict tumor progression. The combination therapy has been found effective in multiple gastrointestinal cancer cell lines, including colorectal, gastric, and pancreatic cancers.

Cancer stem cells (CSCs) are a subpopulation of cancer cells that contribute to tumor growth, recurrence, and chemo-resistance. Targeting CSCs can be an effective approach to overcoming therapy resistance and preventing tumor progression. TAS102, in combination with regorafenib, has been shown to reduce the stemness of colorectal cancer cells, inhibiting the formation of colonospheres and reducing the CD133+ subpopulation.

Tumor angiogenesis, the formation of new blood vessels, is essential for tumor growth and metastasis. TAS102 monotherapy has been found to promote angiogenesis in tumors harboring a BRAF mutation. However, when combined with regorafenib, TAS102-induced angiogenesis is abrogated, as regorafenib inhibits the formation of microvessels in xenografted tumors.

The combination therapy of TAS102 and regorafenib regulates several signaling pathways, including ERK1/2 and STAT3, and modulates the expression of thymidylate synthase (TS), which is involved in drug resistance.

Conclusion

The combination of TAS102 and regorafenib shows synergistic effects in preclinical studies, inhibiting tumor growth, reducing the stemness of cancer cells, and inhibiting angiogenesis. Further research is needed to explore the efficacy of this combination therapy in clinical settings and to identify potential biomarkers of drug sensitivity. The TAS102 plus regorafenib drug combination may be further tested in gastric and other GI cancers.

“Recent studies have shown that TAS102 in combination with regorafenib can lead to improved survival and restrict tumor progression.”

Click here to read the full research paper in Oncotarget.

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Oncotarget is an open-access, peer-reviewed journal that publishes primarily oncology-focused research papers. 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), and Dimensions (Digital Science).

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Oncotarget

Novel Triple-Drug Combination to Fight Pancreatic Cancer

July 25, 2024

In this new study, researchers unveiled a promising synergistic strategy for combating pancreatic cancer.

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In the ever-evolving quest for effective cancer treatments, researchers are continuously exploring innovative combinatorial approaches that exploit the vulnerabilities of malignant cells. In a new study, researchers Benigno C. Valdez, Apostolia M. Tsimberidou, Bin Yuan, Yago Nieto, Mehmet A. Baysal, Abhijit Chakraborty, Clark R. Andersen, and Borje S. Andersson from The University of Texas MD Anderson Cancer Center unveiled a promising synergistic strategy for combating pancreatic cancer (a cancer known for its resistance to conventional therapies). On June 3, 2024, their research paper was published in Oncotarget’s Volume 15, entitled, “Synergistic cytotoxicity of histone deacetylase and poly-ADP ribose polymerase inhibitors and decitabine in pancreatic cancer cells: Implications for novel therapy.”

The Role of HDACs in Cancer

By harnessing the collective power of decitabine, histone deacetylase inhibitors (HDACis), and poly(ADP-ribose) polymerase inhibitors (PARPis), a multifaceted approach has demonstrated remarkable cytotoxic effects against pancreatic cancer cells, offering hope for improved treatment outcomes. Recognizing the pivotal role of HDACs in cancer pathogenesis, researchers have developed HDAC inhibitors, which induce gene expression, triggering cell differentiation, cell cycle arrest, and apoptosis in cancer cells. These inhibitors, including vorinostat, romidepsin, panobinostat, and belinostat, have received regulatory approval for treating hematologic malignancies. While HDACis have shown promise in preclinical studies, their clinical efficacy as monotherapy is limited. However, when combined with other anticancer drugs, enhanced anti-tumor activity has been observed, sparking interest in exploring synergistic combinations.

Histone acetylation, a critical epigenetic modification, governs gene expression and is catalyzed by histone acetyltransferases. This process involves the acetylation of positively charged lysine residues on the N-terminal tails of histones, reducing their interactions with negatively charged DNA and resulting in a relaxed chromatin structure that facilitates increased transcriptional activation and gene expression. Conversely, histone deacetylases (HDACs) remove acetyl groups, leading to a condensed, transcriptionally inactive chromatin state. Dysregulation of HDACs is implicated in the downregulation of tumor suppressor genes, contributing to the development and progression of various malignancies, including pancreatic cancer.

The DNA Repair Conundrum: Exploiting PARP Inhibitors

Another key player in the battle against pancreatic cancer is the poly(ADP-ribose) polymerase (PARP) enzyme family. These enzymes catalyze the process of poly(ADP-ribosyl)ation (PARylation), which is crucial for DNA repair mechanisms. By binding to DNA breaks, PARP enzymes self-ribosylate and recruit DNA repair proteins, facilitating the restoration of genomic integrity. Recognizing the pivotal role of PARP in DNA repair, researchers have developed potent PARP inhibitors (PARPis), such as olaparib and talazoparib. These agents have demonstrated remarkable efficacy in patients with metastatic pancreatic adenocarcinoma harboring BRCA1/2 germline mutations, which impair homologous recombination repair (HRR) pathways.

Decitabine, a nucleoside cytidine analogue, has emerged as a potent ally in the fight against pancreatic cancer. When phosphorylated, decitabine is incorporated into the growing DNA strand, inhibiting methylation and inducing DNA damage by inactivating and trapping DNA methyltransferase on the DNA. This process activates transcriptionally silenced DNA loci, potentially sensitizing cancer cells to other therapeutic interventions. Interestingly, decitabine has been associated with sensitivity in patients with KRAS-mutated pancreatic cancer, a prevalent genetic alteration in this malignancy.

The Synergistic Triad: Decitabine, HDACis, & PARPis Unite

In the current study, the researchers explored various combinations of HDACis (panobinostat and vorinostat), PARPis (talazoparib and olaparib), and decitabine in pancreatic cancer cell lines. The findings were nothing short of remarkable. The combination of HDACis and PARPis resulted in synergistic cytotoxicity across all tested cell lines, including those harboring wild-type BRCA1/2 (BxPC-3 and PL45) and a BRCA2 mutation (Capan-1).

The addition of decitabine further amplified the synergistic cytotoxicity observed with HDACis and PARPis, triggering increased apoptosis, as evidenced by elevated cleavage of caspase 3 and PARP1. Moreover, the triple-drug combinations induced heightened DNA damage, as demonstrated by increased phosphorylation of histone 2AX. The synergistic combinations disrupted various DNA repair pathways, as indicated by decreased levels of key proteins involved in the DNA damage response, such as ATM, BRCA1, and ATRX.

Remarkably, the triple-drug combinations altered the epigenetic regulation of gene expression by reducing the levels of subunits of the nucleosome remodeling and deacetylase (NuRD) complex, a crucial regulator of chromatin remodeling and deacetylation processes.

Mechanistic Insights & Clinical Implications

The synergistic cytotoxicity observed in this study can be attributed to the collective impact of HDACis, PARPis, and decitabine on various cellular processes. HDACis modulate the acetylation status of proteins, influencing genomic instability and potentially sensitizing cancer cells to DNA-damaging agents. Concurrently, PARPis inhibit protein PARylation, a critical process in DNA repair mechanisms. The addition of decitabine potentiates these effects by inducing DNA damage and activating transcriptionally silenced DNA loci. This multifaceted approach effectively disrupts DNA repair pathways, triggers apoptosis, and modulates epigenetic regulation, collectively amplifying cytotoxic effects against pancreatic cancer cells.

The findings of this study hold significant clinical implications for treating pancreatic cancer, a malignancy with a dismal prognosis and limited therapeutic options. By leveraging the synergistic interactions between HDACis, PARPis, and decitabine, this novel combinatorial approach has the potential to improve treatment outcomes and prolong survival for patients with this aggressive disease. The study provides a strong rationale for further exploration of these combinations in clinical trials, potentially leading to personalized therapeutic strategies tailored to individual patient profiles and tumor characteristics. However, additional preclinical investigations and rigorous clinical trials are necessary to validate these findings and address potential challenges, such as drug toxicities and pharmacodynamic interactions. By embracing a collaborative and multidisciplinary approach, the scientific community can transform these discoveries into tangible clinical benefits, advancing cancer care and offering hope to those battling this formidable disease.

Click here to read the full research paper in Oncotarget.

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Oncotarget

AI for Improved PET/CT Attenuation Correction in Prostate Cancer Imaging

July 11, 2024

In this new study, researchers investigated an artificial intelligence (AI) tool that produces attenuation-corrected PET images while reducing radiation exposure for patients.

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Positron Emission Tomography (PET) combined with Computed Tomography (CT) is a powerful imaging modality used in oncology for diagnosis, staging, and treatment monitoring. However, one limitation of PET/CT is the need for accurate attenuation correction (AC) to account for tissue density variations. Traditionally, low-dose CT scans are used for AC, but these contribute to patient radiation exposure.

In a new study, researchers Kevin C. Ma, Esther Mena, Liza Lindenberg, Nathan S. Lay, Phillip Eclarinal, Deborah E. Citrin, Peter A. Pinto, Bradford J. Wood, William L. Dahut, James L. Gulley, Ravi A. Madan, Peter L. Choyke, Ismail Baris Turkbey, and Stephanie A. Harmon from the National Cancer Institute proposed an artificial intelligence (AI) tool to generate attenuation-corrected PET (AC-PET) images directly from non-attenuation-corrected PET (NAC-PET) images, reducing the reliance on CT scans. Their research paper was published in Oncotarget’s Volume 15 on May 7, 2024, entitled, “Deep learning-based whole-body PSMA PET/CT attenuation correction utilizing Pix-2-Pix GAN.”

“Sequential PET/CT studies oncology patients can undergo during their treatment follow-up course is limited by radiation dosage. We propose an artificial intelligence (AI) tool to produce attenuation-corrected PET (AC-PET) images from non-attenuation-corrected PET (NAC-PET) images to reduce need for low-dose CT scans.”

The Study

The researchers developed a deep learning algorithm based on a 2D Pix-2-Pix generative adversarial network (GAN) architecture. They used paired AC-PET and NAC-PET images from 302 prostate cancer patients. The dataset was split into training, validation, and testing cohorts (183, 60, and 59 studies, respectively). Two normalization strategies were employed: Standard Uptake Value (SUV)-based and SUV-Nyul-based. The AI model learned to generate AC-PET images from NAC-PET images, effectively bypassing the need for CT scans during PET/CT studies. The performance of the AI model was evaluated at the scan level using several metrics:

Normalized Mean Square Error (NMSE): A measure of the difference between predicted and ground truth AC-PET images. Lower NMSE indicates better performance.
Mean Absolute Error (MAE): Similar to NMSE, lower MAE signifies improved accuracy.
Structural Similarity Index (SSIM): Measures image similarity. Higher SSIM values indicate better alignment between AC-PET and ground truth images.
Peak Signal-to-Noise Ratio (PSNR): Evaluates image quality. Higher PSNR values correspond to better image fidelity.

The AI model demonstrated promising results, achieving competitive performance across all metrics. The choice of normalization strategy (SUV-based or SUV-Nyul-based) did not significantly impact the model’s effectiveness.

The proposed AI tool has several clinical implications. By eliminating the need for low-dose CT scans, patients are exposed to less ionizing radiation during PET/CT studies. Additionally AC-PET images can be generated directly from NAC-PET data, simplifying the imaging process. The AI model also produces accurate AC-PET images, enhancing diagnostic confidence.

Conclusions

Deep learning-based AC-PET image generation using Pix-2-Pix GANs represents a promising approach to improve PET/CT imaging in prostate cancer patients. As AI continues to evolve, its integration into clinical practice may revolutionize how we acquire and interpret medical images, ultimately benefiting patient care. In summary, this research contributes to the ongoing efforts to enhance imaging techniques, reduce patient radiation exposure, and streamline clinical workflows.

“The Pix-2-Pix GAN model for generating AC-PET demonstrates SUV metrics that highly correlate with original images. AI-generated PET images show clinical potential for reducing the need for CT scans for attenuation correction while preserving quantitative markers and image quality.”

Click here to read the full research paper in Oncotarget.

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Oncotarget

Impact of Dual Immunotherapies Before Surgery in HR+/HER2-negative Breast Cancer

June 20, 2024

In this new study, researchers assessed the feasibility of treating HR+/HER2-negative breast cancer patients with the immunotherapies durvalumab and tremelimumab before standard neoadjuvant chemotherapy and surgery.

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Breast cancer immunotherapy has shown promise, but its clinical efficacy remains limited, especially for hormone receptor positive (HR+)/HER2-negative breast cancer. While immune checkpoint inhibitors combined with chemotherapy have benefitted some early-stage and metastatic triple-negative breast cancer patients, HR+/HER2-negative cases have seen fewer improvements.

Recent neoadjuvant trials indicate that early-stage HR+/HER2-negative breast cancers might respond better to immunotherapy strategies that amplify tumor-infiltrating lymphocytes (TILs) through dual PD-(L)1/CTLA-4 checkpoint inhibition before surgery and chemotherapy. This approach could enhance the immune response in the tumor microenvironment and improve outcomes for this challenging breast cancer subtype.

The Study

Increased TILs are associated with improved neoadjuvant chemotherapy (NACT) responses across breast cancer subtypes. Recently, researchers Haven R. Garber, Sreyashi Basu, Sonali Jindal, Zhong He, Khoi Chu, Akshara Singareeka Raghavendra, Clinton Yam, Lumarie Santiago, Beatriz E. Adrada, Padmanee Sharma, Elizabeth A. Mittendorf, and Jennifer K. Litton from the University of Texas MD Anderson Cancer Center, Brigham and Women’s Hospital, Dana-Farber Brigham Cancer Center, and Harvard Medical School hypothesized that amplifying TILs via dual checkpoint blockade would enhance the response to subsequent NACT in breast tumors.

Their new study aimed to assess the feasibility of enrolling untreated patients with stage II or III HR+/HER2-negative breast cancer for upfront treatment with combined PD-L1/CTLA-4 checkpoint inhibition before standard NACT and surgery. The research paper, published in Oncotarget’s Volume 15 on March 19, 2024, was entitled, “Durvalumab and tremelimumab before surgery in patients with hormone receptor positive, HER2-negative stage II–III breast cancer.”

“This feasibility study was conducted to begin testing the hypothesis that dual checkpoint blockade would increase TIL and enhance the response to subsequent NACT in patients with stage II or III HR+/HER2-negative breast cancer.”

Patient Screening, Recruitment, & Assessment

The study aimed to accrue 16 patients to evaluate the feasibility of enrolling patients with clinical stage II or III HR+/HER2-negative breast cancer onto a trial evaluating investigational immunotherapy agents before standard NACT. Patient tumor samples were collected to assess immunologic and molecular responses to combination checkpoint blockade.

Eligible patients had to have HR+/HER2-negative breast cancer, defined as estrogen receptor (ER) and/or progesterone receptor (PR) expression >10% by immunohistochemistry (IHC), and HER2-negative defined as 0/1+ by IHC or if 2+, negative by fluorescence in situ hybridization. Other inclusion criteria included an ECOG performance status of 0 or 1, planned NACT, and adequate blood counts and organ function.

Patients were excluded if they had received prior PD-1, PD-L1, or CTLA-4 inhibitors or any prior treatment for the primary breast cancer. Other exclusions included current or prior use of immunosuppressive medications within 28 days, active or previous autoimmune disease within 2 years, inflammatory bowel disease, or receipt of a live attenuated vaccination within 30 days before study entry or treatment.

Durvalumab was administered at 1500 mg IV, and tremelimumab at 75 mg IV for 2 cycles on days 1 and 28. Patients then proceeded to standard NACT followed by breast surgery. Baseline breast ultrasounds were performed within 21 days before the first immunotherapy cycle and again between 1 and 7 days after the second cycle. Research biopsies were collected at baseline and after 2 cycles of immunotherapy.

Results & Discussion

The trial’s target accrual of 16 patients was not met, as it was stopped early after three of the first eight enrolled patients experienced immunotherapy-related toxicity or suspected disease progression, indicating that this strategy is not clinically feasible.

Among the eight patients who did receive the study-specified combination immunotherapy, seven had pre- and post-immunotherapy ultrasounds performed, showing mixed responses. Three experienced an increase in tumor volume, three a decrease, and one showed stable disease. The impact of combination immunotherapy on TILs was also mixed. Though limited by the number of patients with available serial biopsies, there did not appear to be a significant increase in the immune response within the tumor microenvironment (TME).

The Phase II NIMBUS trial also assessed dual checkpoint blockade in breast cancer, though in a population of metastatic breast cancer patients with tumors harboring a high tumor mutation burden (TMB ≥9 mutations per megabase). Of the 30 patients enrolled, 20 had ER+/HER2-negative breast cancer. The overall response rate (ORR) was 16.7%, with four durable responses lasting at least 15 months. Three of the five responders had a TMB ≥14 mutations per megabase. The ORR among patients with TMB <14 mutations per megabase was 6.7%. Three patients (10%) experienced grade 3 immune toxicity.

The TAPUR basket trial similarly included patients with TMB-high metastatic breast cancer but utilized single-agent anti-PD-1 checkpoint blockade (pembrolizumab) rather than combination immunotherapy. Half of the 28 enrolled patients had ER+ breast cancer, and the majority had received multiple prior lines of systemic therapy. The ORR was 21% with a median progression-free survival (PFS) of 10.6 weeks. Five patients (17.9%) experienced one or more grade 3 adverse events possibly attributed to pembrolizumab, and six patients discontinued treatment due to side effects.

In summary, while a minority of patients with ER+ metastatic breast cancer may benefit from anti-PD-(L)1/anti-CTLA-4 checkpoint blockade, the majority risk exposure to immune-related adverse events without additional benefit.

Conclusion & Future Directions

The present study did not demonstrate a clear benefit for dual checkpoint blockade administered prior to NACT in patients with stage II or III HR+/HER2-negative breast cancer. Only one out of eight patients (12.5%) achieved a pathologic complete response (pCR) at the time of breast surgery after immune therapy and NACT. Two patients experienced grade 3 immunotherapy-related toxicity.

While the KEYNOTE-756 and CheckMate 7FL trials have demonstrated improved pCR rates with the addition of single-agent anti-PD-1 checkpoint blockade to NACT for patients with high-risk HR+/HER2-negative, stage II/III breast cancer, the risk/benefit calculus of adding immunotherapy for this subtype is different from metastatic triple-negative breast cancer (TNBC) or even stage II/III TNBC, where the risks of morbidity and mortality from disease are higher.

Hopefully, biomarkers such as PD-L1 expression and tumor mutation burden (TMB) will guide the use of single or dual-agent immunotherapy towards those patients most likely to benefit, sparing others from significant toxicity. Notably, immune-mediated adverse events of grade 3 or higher were reported in 12.9% of breast cancer patients receiving pembrolizumab in the KEYNOTE-522 trial and in 38% of patients receiving dual ipilimumab/nivolumab in a trial of patients with metastatic melanoma.

For immunotherapy to play a meaningful role in HR+/HER2-negative early breast cancer, a breast cancer subtype where most patients are cured with standard therapy, it will need to significantly increase the fraction of cured patients without disproportionately causing serious and/or long-term immune toxicity. Future research should focus on identifying predictive biomarkers and optimizing combination strategies to enhance the efficacy of immunotherapy in this challenging breast cancer subtype.

Click here to read the full research paper in Oncotarget.

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