Tagged: p53

A New Path to Tumor Suppression: The Promise of PG3

December 18, 2024

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

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

The Study: A New Approach to Tumor Suppression

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

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

The Challenge: The Limitations of Current Cancer Treatments

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

The Results: A Safer, More Effective Cancer Therapy

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

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

The Breakthrough: Unlocking a New Path to Treat Cancer

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

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

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

Therapeutic Potential: Advancing Toward Personalized Cancer Care

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

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

Next Steps: Bringing PG3 Closer to Patients

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

Conclusion

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

Click here to read the full research paper in Oncotarget.

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Oncotarget is 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

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

Click here to subscribe to Oncotarget publication updates.

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

Oncotarget

p53’s Protective Role in Extrahepatic Biliary Precancerous Lesions

November 2, 2023

In this editorial, researchers from Japan discuss their recent study investigating the role of p53 in preventing the development of extrahepatic biliary cancer.

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Extrahepatic biliary cancer is a specific type of biliary cancer that occurs outside the liver. It is considered rare, quite serious and often symptomless until later stages. The average age at diagnosis is 72. Extrahepatic biliary cancer typically involves the bile ducts, which carry bile from the liver and gallbladder to the small intestine. It can also involve the gallbladder, which plays a role in the digestion of fats by storing, concentrating and releasing bile as needed.

One of the main genetic factors that contribute to biliary cancer is the mutation of Kras, a gene that regulates cell growth and division. Mutated Kras can cause cells to grow uncontrollably and form tumors. Another important genetic factor is the mutation of p53, a gene that normally acts as a guardian of the genome and triggers cell death or repair when DNA damage occurs. Mutated p53 can impair this function and allow cells to survive and accumulate more mutations.

“[…] the exact role of p53 in the development of extrahepatic biliary cancer remains elusive.”

In a new editorial paper, researchers Munemasa Nagao, Kenta Mizukoshi, Shinnosuke Nakayama, Mio Namikawa, Yukiko Hiramatsu, Takahisa Maruno, Yuki Nakanishi, Tatsuaki Tsuruyama, Akihisa Fukuda, and Hiroshi Seno from Kyoto University Graduate School of Medicine discussed their recent study exploring the role of p53 in preventing the development of extrahepatic biliary cancer. On March 31, 2023, their editorial was published in Oncotarget, entitled, “p53 protects against formation of extrahepatic biliary precancerous lesions in the context of oncogenic Kras.”

The Editorial

The authors of the editorial discuss their 2022 study using a mouse model to investigate how Kras and p53 mutations interact in the development of extrahepatic biliary cancer. They found that mice with Kras activation and p53 inactivation developed lesions resembling human biliary neoplasms in the bile duct and gallbladder. These lesions are considered to be precursors of invasive biliary cancer.

“In this study, we found that simultaneous activation of Kras and inactivation of p53 induces biliary neoplasms that resemble human biliary intraepithelial neoplasia in the extrahepatic bile duct and intracholecystic papillary tubular neoplasm in the gall bladder in mice.”

However, they also found that p53 inactivation was not enough for the progression of these lesions into invasive cancer in the presence of oncogenic Kras within the observation period. This was also true when they added another genetic alteration, namely the activation of the Wnt signaling pathway, which is known to promote tumorigenesis in various cancers.

Therefore, they concluded that p53 has a protective role against the formation of extrahepatic biliary precancerous lesions in the context of oncogenic Kras. They suggested that additional genetic or environmental factors may be required for the malignant transformation of these lesions into invasive cancer.

Conclusions

The study the authors described in their recent editorial paper provides new insights into the molecular mechanisms underlying extrahepatic biliary cancer and highlights the importance of p53 as a barrier against tumorigenesis. It also raises questions about what other factors may contribute to biliary cancer progression and how they can be targeted for prevention or treatment. This work received support from a number of institutions, including Grants-in-Aid KAKENHI, the Japan Agency for Medical Research and Development, the Princess Takamatsu Cancer Research Fund, the Mochida Foundation, the Mitsubishi Foundation, the Uehara Foundation, the Naito Foundation, the Kobayashi Foundation, the Simizu Foundation, the Japan Foundation for Applied Enzymology, the SGH Foundation, the Kanae Foundation, Bristol Myers Squibb, the Ichiro Kanehara Foundation, the Takeda Science Foundation, and the Takeda Foundation.

“In conclusion, p53 protects against formation of extrahepatic biliary precancerous lesions in the context of oncogenic Kras in mice, however, inactivation of p53 is not sufficient for the progression into invasive cancer in the extrahepatic biliary system.”

Click here to read the full editorial paper in Oncotarget.

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