Tagged: Cancer Research

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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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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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 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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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).

Click here to subscribe to Oncotarget publication updates.

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

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

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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 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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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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Oncotarget

Dr. Blagosklonny’s Strategy: From Osimertinib to Preemptive Combinations

June 6, 2024

This article dissects Dr. Mikhail V. Blagosklonny’s paradigm-shifting perspective on preemptive combinations for treating EGFR-mutant non-small cell lung cancer.

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In the relentless battle against non-small cell lung cancer (NSCLC) driven by epidermal growth factor receptor (EGFR) mutations, the development of resistance has long been a formidable obstacle. Historically, first- and second-generation EGFR tyrosine kinase inhibitors (TKIs) like gefitinib, erlotinib, afatinib, and dacomitinib have faced a significant hurdle: the emergence of the T790M point mutation in approximately 50% of patients, rendering the tumor resistant to these therapies.

This resistance stems from a sobering reality – before treatment, a small subset of cancer cells already harbor the T790M mutation, conferring no selective advantage initially. However, once treatment commences, these rare mutated cells proliferate selectively, eventually dominating the tumor population and diminishing the effectiveness of first- and second-generation TKIs.

The Rise of Osimertinib: A Beacon of Hope

In 2015, the FDA approved osimertinib, a third-generation EGFR TKI, as a second-line therapy for NSCLC patients with the T790M mutation. This approval recognized that untreated tumors are typically T790M-negative, with the mutation potentially present in only a single cell initially. Moreover, approximately 50% of patients do not harbor this mutation at all, underscoring the rationale for administering osimertinib after resistance to first- or second-generation TKIs emerges.

However, a paradigm shift was on the horizon. Osimertinib’s ability to target the T790M mutation, coupled with its potential to eliminate the rare resistant cells before they proliferate, paved the way for a groundbreaking approach: administering osimertinib as a first-line treatment, without waiting for resistance to develop.

Preemptive Combinations: A Multifaceted Strategy

In a seminal 2018 clinical trial, osimertinib demonstrated its prowess as a first-line treatment, significantly extending median progression-free survival (PFS) compared to first-generation EGFR inhibitors (18.9 months vs. 10.2 months). Remarkably, while the objective response rates were similar between the two groups, the duration of response was nearly doubled with osimertinib (17.2 months vs. 8.5 months).

Capitalizing on these findings, Dr. Mikhail V. Blagosklonny introduced the concept of “preemptive combinations” – a multi-pronged approach to not only induce a therapeutic response but also eliminate the few resistant cells harboring pre-existing mutations. By combining osimertinib with first- or second-generation EGFR inhibitors like gefitinib and afatinib, these preemptive combinations could potentially prevent on-target resistance mechanisms, thereby extending PFS and overall survival (OS) for a substantial proportion of patients. On March 15, 2024, Dr. Blagosklonny’s research perspective was published in Oncotarget’s Volume 15, entitled, “From osimertinib to preemptive combinations.”

Expanding the Armamentarium: Comprehensive Preemptive Combinations

While osimertinib addresses the T790M mutation, other resistance mechanisms remain a concern. Approximately 50% of resistance cases involve on-target secondary mutations within EGFR, such as L718, G724, L792, G796, and C797, which can be targeted by first- or second-generation EGFR inhibitors. Additionally, off-target mechanisms like MET and HER2 amplifications contribute to resistance.

To combat this multifaceted challenge, Dr. Blagosklonny proposed a comprehensive preemptive combination comprising osimertinib, afatinib (or a first-generation EGFR inhibitor), and capmatinib (a potent MET inhibitor). This triple-threat approach could potentially prevent up to 75% of resistance mechanisms, dramatically extending median PFS from 18 months with osimertinib alone to an estimated 40 months.

Addressing Heterogeneity: The Bittersweet Reality

While osimertinib undoubtedly improves median PFS and OS compared to first-generation TKIs, a sobering reality emerges: approximately 20% of patients may experience a shortened PFS due to pre-existing mutations like C797S, which render the tumor resistant to osimertinib but sensitive to first-generation TKIs. In these cases, osimertinib inadvertently selects for resistant clones, potentially harming a subset of patients.

The solution, as proposed by Dr. Blagosklonny, lies in the simplicity of preemptive combinations. By combining osimertinib with gefitinib, or even a triple combination with afatinib, the risk of selecting for resistant clones is mitigated, ensuring that no patient is inadvertently harmed by the superior TKI.

Transient Combinations: A Flexible Approach

For clinicians who may be hesitant about administering three- or four-drug combinations, Dr. Blagosklonny suggests a flexible approach: a sequence of transient two-drug combinations. This strategy involves alternating between different combinations, such as osimertinib and gefitinib, followed by osimertinib and afatinib, and so on, effectively covering all potential resistance mechanisms while maintaining a manageable treatment regimen.

Extending the Paradigm: MET-Driven NSCLC

The insights gleaned from EGFR-driven NSCLC can be applied to other molecular subtypes, such as MET exon 14 skipping mutation (METex14)-driven NSCLC. Dr. Blagosklonny’s personal experience with this condition underscores the importance of preemptive combinations in this setting as well.

While the selective MET inhibitor capmatinib demonstrated remarkable efficacy in treating Dr. Blagosklonny’s brain metastases, resistance tends to emerge within a year, often driven by secondary mutations like D1228 and Y1230. To combat this, a preemptive combination of capmatinib, afatinib (to target EGFR and HER2 alterations), and cabozantinib (a type II MET inhibitor effective against resistance mutations) could potentially prevent up to 50% of resistance mechanisms, prolonging progression-free survival for a significant proportion of METex14-driven NSCLC patients.

Overcoming Hurdles: The Path Forward

Despite the promise of preemptive combinations, challenges remain. The development of novel targeted therapies and the exploration of immune checkpoint inhibitors in combination with these regimens offer exciting avenues for future research. Additionally, refining clinical trial designs to incorporate precision medicine approaches and tailored combination strategies will be crucial in translating these concepts into tangible benefits for patients.

Conclusion: A Paradigm Shift in Cancer Care

Dr. Blagosklonny’s perspective on preemptive combinations represents a paradigm shift in the treatment of lung cancer and potentially other malignancies. By proactively targeting resistance mechanisms before they can take hold, this approach offers a glimmer of hope for prolonging progression-free survival and improving outcomes for patients grappling with this disease. As research continues to unravel the complexities of cancer resistance, preemptive combinations may pave the way for a future where we can stay one step ahead of cancer.

Click here to read the full research perspective 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

Combating Doxorubicin-Resistant Acute Myeloid Leukemia

May 23, 2024

In this new study, researchers examined the impact of MIA-602 as monotherapy and in combination with Doxorubicin on three Doxorubicin-resistant acute myeloid leukemia cell lines.

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Upon diagnosing acute myeloid leukemia (AML), the initial step involves assessing a patient’s eligibility for intensive chemotherapy. The standard treatment protocol for newly diagnosed AML encompasses intensive chemotherapy to achieve complete remission, followed by post-remission therapy, which may include additional chemotherapy and/or stem cell transplantation. Complete response rates to this approach range from 60% to 85% in adults aged 60 or younger.

While this approach has proven effective, the risk of relapse within three years of diagnosis remains a significant concern. Numerous factors contribute to the likelihood of relapse, including short duration of remission, genetic derangements, prior allogeneic transplantation, advanced age, and concomitant comorbidities. These negative prognostic factors underscore the need for continuous exploration of novel therapeutic agents, as relapse remains a formidable barrier to treatment success.

In a new study, researchers Simonetta I. Gaumond, Rama Abdin, Joel Costoya, Andrew V. Schally (awarded the Nobel Prize in Physiology or Medicine in 1977), and Joaquin J. Jimenez from the University of Miami, Florida Atlantic University and Veterans Affairs Medical Center, Miami, investigated newly emerging therapies targeting drug resistance in AML. On April 8, 2024, their new research paper was published in Oncotarget’s Volume 15, entitled, “Exploring the role of GHRH antagonist MIA-602 in overcoming Doxorubicin-resistance in acute myeloid leukemia.”

Drug Resistance: A Persistent Obstacle

Drug resistance poses a substantial challenge in the treatment of AML, often hindering successful outcomes. This resistance can manifest in two distinct forms:

Primary Drug Resistance: Inherent resistance to specific therapeutic agents, present from the outset of treatment.
Acquired Drug Resistance: Resistance developed over the course of treatment, potentially due to various underlying mechanisms.

These resistance pathways involve intricate interplay between drug resistance-related proteins, enzymes, genes, microRNAs, and aberrant signaling pathways, highlighting the complexity of this phenomenon.

Exploring the Potential of GHRH Antagonists in AML Treatment

Growth hormone-releasing hormone (GHRH) is a neuropeptide hormone primarily released by the hypothalamus, canonically known for its role in inducing the release of growth hormone from the pituitary gland. However, GHRH’s influence extends beyond this endocrine axis, acting as a growth factor in various cancer types and normal tissues through an autocrine/paracrine mechanism.

Previous studies have demonstrated the expression of GHRH receptors (GHRH-R) in human AML cell lines, including K-562, THP-1, and KG-1A. Notably, the GHRH antagonist MIA-602 has exhibited the ability to inhibit the proliferation of these leukemic cells both in vitro and in preclinical mouse models.

MIA-602, a synthetic GHRH antagonist, has garnered significant attention for its potential in circumventing drug resistance and mitigating the adverse effects associated with conventional chemotherapy. Numerous studies have documented the anti-oncogenic mechanisms of GHRH antagonists, which encompass:

-Downregulation of NF-κB and beta-catenin

-Upregulation of caveolin-1 and E-cadherin

-Activation of pro-apoptotic pathways

-Modulation of inflammatory cytokines

-Inhibition of the Akt signaling pathway

These diverse mechanisms underscore the multifaceted approach through which MIA-602 exerts its anti-cancer effects, targeting various aspects of oncogenesis, including cellular proliferation, survival, and motility. Importantly, GHRH antagonists have been implicated in the in vitro inhibition of a wide range of cancer cell lines, spanning from acute promyelocytic leukemia (APL) and AML to estrogen-independent breast cancer, clear cell ovarian cancer, glioblastoma, gastric cancer, prostate cancer, and endometrial adenocarcinoma.

Investigating the Impact of MIA-602 on Doxorubicin-Resistant AML Cell Lines

In Vitro Evaluation: Unveiling Promising Results

In the current study, Gaumond et al. evaluated the impact of MIA-602 as a monotherapy and in combination with the chemotherapeutic agent Doxorubicin on three Doxorubicin-resistant AML cell lines: KG-1A, U-937, and K-562. The in vitro results revealed a remarkable reduction in cell viability across all treated wild-type cells, underscoring the efficacy of MIA-602.

Notably, the Doxorubicin-resistant clones exhibited a comparable susceptibility to MIA-602 as their wild-type counterparts. This finding suggests that MIA-602’s mechanism of action is distinct from that of Doxorubicin, enabling it to circumvent the resistance pathways that render Doxorubicin ineffective.

When treated with MIA-602 alone, the following decreases in cell viability were observed:

-KG-1A: 53.5% (wild-type) and 54.5% (Doxorubicin-resistant)

-U-937: 49% (wild-type) and 51.25% (Doxorubicin-resistant)

-K-562: 79.25% (both wild-type and Doxorubicin-resistant)

These results highlight the potent anti-proliferative effects of MIA-602 on AML cell lines, irrespective of their Doxorubicin resistance status. Furthermore, the combination treatment of Doxorubicin and MIA-602 yielded even more remarkable outcomes:

-KG-1A: 80.25% decrease in wild-type cell viability and 57.5% reduction in Doxorubicin-resistant cells

-U-937: 92.5% decrease in wild-type cells and 52.75% reduction in Doxorubicin-resistant cells

-K-562: 88.75% reduction in wild-type cell viability and 78.25% decrease in Doxorubicin-resistant cells

These findings suggest a potential synergistic effect between MIA-602 and Doxorubicin, highlighting the therapeutic potential of this combination approach in overcoming drug resistance.

In Vivo Validation: Corroborating the Therapeutic Efficacy

To further substantiate the in vitro observations, an in vivo experiment was conducted using nude mice xenografted with Doxorubicin-resistant K-562 cells. The mice were randomly divided into two groups: one receiving a control diluent and the other treated with MIA-602 at a dose of 10 μg twice daily for 28 days.

After the treatment period, the control group exhibited a tumor volume of 1114 mm³, while the MIA-602 monotherapy group demonstrated a significantly reduced tumor volume of 629 mm³ – a remarkable decrease of 485 mm³. This finding further reinforces the therapeutic potential of MIA-602 in combating Doxorubicin-resistant AML.

Exploring the Mechanisms of Action and Future Directions

While the anti-oncogenic mechanisms of GHRH antagonists have been extensively studied in various cancer types, further investigation is warranted to elucidate the specific transcriptional effects of GHRH antagonism in Doxorubicin-resistant AML cell lines. Understanding these molecular pathways could pave the way for more targeted and effective therapeutic strategies.

Another area of interest lies in exploring the potential influence of genetic AML subtypes on the response to GHRH antagonist therapy. By examining the expression levels of GHRH receptors across different AML subtypes, researchers can gain insights into the therapeutic potential of MIA-602 and its potential for personalized treatment approaches.

The observed synergistic effects of MIA-602 and Doxorubicin in combating Doxorubicin-resistant AML cell lines warrant further exploration of combination therapies. By strategically combining MIA-602 with other chemotherapeutic agents or targeted therapies, researchers may uncover novel treatment regimens with enhanced efficacy and reduced adverse effects.

Ultimately, the successful translation of these preclinical findings to clinical settings will be crucial in realizing the full potential of MIA-602 as a therapeutic option for Doxorubicin-resistant AML. Well-designed clinical trials will be essential to evaluate the safety, efficacy, and optimal dosing regimens of MIA-602, both as a monotherapy and in combination with other treatments.

Conclusion: Paving the Way for Improved Outcomes

The discovery of MIA-602’s ability to overcome Doxorubicin resistance in acute myeloid leukemia represents a significant step forward in the quest for more effective and targeted therapies. By leveraging the unique mechanisms of action of GHRH antagonists, researchers have unveiled a promising therapeutic approach that circumvents the limitations of conventional chemotherapy.

While further research is necessary to fully elucidate the underlying molecular pathways and optimize treatment strategies, the findings presented in this study offer hope for improved outcomes in patients with Doxorubicin-resistant AML. By continuing to explore the potential of novel agents like MIA-602, the scientific community moves closer to achieving the ultimate goal of personalized, effective, and well-tolerated treatments for this challenging malignancy.

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

SARS-CoV-2 Spike Protein Disrupts p53 Tumor Suppressor Pathway

May 9, 2024

In this new study, researchers investigated the interplay between the SARS-CoV-2 spike protein and tumor suppressor gene p53.

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The profound impact of the COVID-19 pandemic, caused by the SARS-CoV-2 virus, has been felt across various domains, including the realm of cancer research and treatment. As scientists delve deeper into the intricate mechanisms of this viral pathogen, intriguing revelations have emerged regarding its potential influence on cellular processes pivotal to cancer development and progression.

In a new study, researchers Wafik S. El-Deiry and Shengliang Zhang from Brown University and Lifespan Health System shed light on the intricate interplay between the SARS-CoV-2 spike protein and the tumor suppressor p53, a key guardian of genomic integrity. On May 3, 2024, they published their new research paper in Oncotarget’s Volume 15, entitled, “Transfected SARS-CoV-2 spike DNA for mammalian cell expression inhibits p53 activation of p21(WAF1), TRAIL Death Receptor DR5 and MDM2 proteins in cancer cells and increases cancer cell viability after chemotherapy exposure.”

The Study

In this study, researchers El-Deiry and Zhang uncovered a hitherto unknown facet of the SARS-CoV-2 spike protein’s impact on cancer cells. Their findings, meticulously detailed in their research paper, have ignited a newfound curiosity within the scientific community.

To appreciate the significance of this discovery, one must first comprehend the critical function of the p53 protein, often referred to as the “guardian of the genome.” This multifaceted tumor suppressor plays a pivotal role in safeguarding cellular integrity by regulating various processes, including cell cycle arrest, DNA repair, and apoptosis (programmed cell death). When cells encounter stress or DNA damage, p53 is activated, triggering a cascade of events aimed at preserving genomic stability or eliminating compromised cells.

The study has unveiled a remarkable phenomenon: the SARS-CoV-2 spike protein appears to disrupt the intricate balance of the p53 pathway, potentially compromising its tumor-suppressive capabilities. Through a series of meticulously designed experiments, the researchers demonstrated that the presence of the SARS-CoV-2 spike protein in cancer cells interferes with the binding of p53 to its negative regulator, MDM2.

This disruption, in turn, impedes the activation of key downstream targets of p53, including the cell cycle regulator p21(WAF1), the apoptosis-inducing TRAIL Death Receptor DR5, and even MDM2 itself. Consequently, cancer cells expressing the SARS-CoV-2 spike protein exhibited a diminished response to chemotherapeutic agents, manifested by a reduced induction of these critical p53 targets and an increased cell viability following treatment.

Implications for Cancer Therapy

The ramifications of this discovery are far-reaching, particularly in the context of cancer treatment. Chemotherapy remains a cornerstone of cancer management, and its efficacy is heavily reliant on the proper functioning of cellular mechanisms that detect and respond to DNA damage. The p53 pathway plays a pivotal role in this intricate process, acting as a sentinel that triggers cell cycle arrest or apoptosis in response to genotoxic insults.

However, the findings of this study suggest that the presence of the SARS-CoV-2 spike protein may compromise these critical defense mechanisms, potentially rendering cancer cells more resistant to chemotherapeutic agents. This revelation raises concerns about the potential impact of SARS-CoV-2 infection or the administration of spike protein-based vaccines on the efficacy of cancer treatments, particularly in individuals undergoing chemotherapy.

Mechanistic Underpinnings

While the study has shed light on the disruption of the p53 pathway by the SARS-CoV-2 spike protein, the precise mechanisms underlying this phenomenon remain to be fully elucidated. Several intriguing questions arise:

What are the structural determinants that govern the interaction between the SARS-CoV-2 spike protein and components of the p53 pathway?
Could post-translational modifications of the spike protein or p53 itself influence their functional interplay?
How do different cellular contexts, such as varying expression levels of p53 regulators or the presence of specific mutations, modulate the observed effects?
Can this newfound knowledge be leveraged to develop strategies that mitigate the potential impact of SARS-CoV-2 on cancer treatment outcomes?

Addressing these questions will require a concerted effort from the scientific community, involving multidisciplinary collaborations and a diverse array of experimental approaches.

Expanding the Scope of Investigation

While the current study focused on the interaction between the SARS-CoV-2 spike protein and the p53 pathway, it is essential to broaden the scope of investigation to encompass other viral proteins and their potential impact on cellular processes relevant to cancer development and progression. The SARS-CoV-2 genome encodes a multitude of proteins, each with the potential to interact with various host factors and signaling cascades.

Exploring these interactions may unveil additional mechanisms by which SARS-CoV-2 infection could influence tumorigenesis, metastasis, or therapeutic responses. Additionally, investigating the effects of viral proteins on DNA damage sensing, repair mechanisms, and other cellular stress response pathways could yield invaluable insights into the intricate interplay between viral infections and cancer biology.

Implications Beyond COVID-19

The findings of this study have implications that extend beyond the realm of SARS-CoV-2 and COVID-19. They underscore the importance of thoroughly evaluating the potential consequences of viral proteins or antigens employed in vaccine development on critical host pathways, such as those involved in tumor suppression and DNA damage response.

As the scientific community continues to develop novel vaccines and therapeutic interventions, it is imperative to consider the potential impact of these interventions on cellular processes essential for maintaining genomic integrity and preventing malignant transformation. Comprehensive preclinical studies and rigorous safety assessments should be undertaken to ensure that the benefits of these interventions outweigh any potential risks, particularly for individuals with pre-existing conditions or those undergoing cancer treatment.

Collaborative Efforts & Future Directions

Unraveling the complexities of the SARS-CoV-2 spike protein’s interactions with the p53 pathway and other cellular processes will require a concerted effort from researchers across various disciplines. Interdisciplinary collaborations between virologists, cancer biologists, structural biologists, and computational scientists will be crucial in elucidating the mechanistic underpinnings of these interactions and their potential implications for cancer development and treatment.

Furthermore, it is essential to conduct long-term studies to assess the potential long-term consequences of SARS-CoV-2 infection or spike protein exposure on cancer incidence and progression. Such investigations could shed light on the potential risks associated with repeated exposure to viral proteins or antigens, as in the case of booster vaccinations.

A Call for Vigilance & Proactive Measures

The findings of this groundbreaking study serve as a clarion call for increased vigilance and proactive measures within the scientific community. As we continue to navigate the complexities of viral pandemics and develop innovative therapeutic interventions, it is imperative to remain cognizant of the potential unintended consequences on critical cellular pathways, such as those involved in tumor suppression and DNA damage response.

By fostering interdisciplinary collaborations, embracing rigorous scientific inquiry, and maintaining a commitment to thorough preclinical evaluation, we can ensure that our efforts to combat viral threats do not inadvertently compromise our ability to combat cancer and other life-threatening diseases.

The path forward is one of cautious optimism, where scientific discoveries illuminate potential risks while simultaneously paving the way for novel strategies to mitigate these risks and safeguard human health. It is through this delicate balance of exploration and prudence that we can continue to make strides in our fight against both viral and malignant diseases, ensuring a brighter and healthier future for all.

Click here to read the full research paper in Oncotarget.

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