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Rethinking How Cancer Cells Evade Targeted Therapy

Glioblastomas (GBMs) are incurable brain tumors with a prognosis of about one-and-a half years on average. They are highly resistant to treatment and have defied all attempts at precision therapy.  

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UCSF Researchers Identify the Cellular Source of Recurrent Glioma

Newswise — Glioblastomas (GBMs) are incurable brain tumors with a prognosis of about one-and-a half years on average. They are highly resistant to treatment and have defied all attempts at precision therapy.  

In their study publishing December 20 in Nature Cancer, first author Lin Wang, PhD and senior author Aaron Diaz, PhD, found that phenotype switching, as opposed to genetic evolution, may be the escape mechanism that explains the failure of precision therapies to date. They found that some cells shift to a mesenchymal, radiation-resistant phenotype (state) as a stress response following standard therapy.  


Credit: UCSF
Aaron Diaz, PhD, Associate Professor, Neurological Surgery, UCSF Weill Institute for Neurosciences

“We asked if there is another mechanism that explains therapeutic resistance,” said Diaz, associate professor of neurological surgery at the UCSF Weill Institute for Neurosciences. “Our study concludes that, rather than a genetic evolution, there is a phenotypic plasticity or transition which allows these cells to evade therapy.”  

To identify what drives treatment resistance to standard therapy, as well as the cellular source of recurrent disease, UCSF researchers used single-nucleus RNA, open-chromatin, spatial profiling to analyze 86 primary-recurrent, patient-matched, paired GBM specimensThis unprecedented cohort represented decades of biobanking at UCSF. 

With access to thirty years’ worth of GBM’s, the scientists were able to present novel cell-intrinsic and cell-extrinsic targets as well as a single-cell multi-omics atlas of GBM under therapy. This was the first time that researchers were able to comprehensively map intra-cellular signaling in the tumor-anatomical niches of recurrent GBM and identify novel cell-extrinsic therapeutic targets.   

The 86 specimens contained the cellular tumor and adjacent non-malignant tissue from the surgical margin. This unique cohort enabled Diaz and his team to analyze communications between malignant and non-malignant glia. They found that cells in this surgical margin acted as niches of recurrence where non-malignant glia were broadcasting pro-growth signals that influenced the tumor cells to regrow. These paracrine (cell extrinsic) signals stimulated the activator protein (AP1) pathway, leading to mesenchymal transition, therapy resistance and tumor recurrence. 

These mesenchymal transitions were apparent in the tumor samples after therapy, along with increased numbers of cycling mesenchymal cells. Pro-growth signals from the tumor microenvironment, as well as the cell-intrinsic response to radiation therapy, drove the mesenchymal shift through a stress-response pathway mediated by AP1. 

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The researchers were able to combine two techniques to achieve a map of paracrine signals – single-nucleus RNA-sequencing of frozen tissue specimens and spatial transcriptomics profiling of formalin-fixed specimens. From each tumor biopsy, they performed single-nucleus RNA-seq which measures transcriptome-wide gene expression in individual cells, for thousands of cells at a time. They compared the expression of signal receptors to that of their known ligands, between the different cell populations sequenced. They then validated that cells from these populations physically interact and signal in situ, using spatial transcriptomics.

“This is the first single-cell longitudinal study of this scale in glioma,” said Diaz. “It’s also a study that could be done only at UCSF, because it represents decades of careful biobanking of surgical specimens. Since all the specimens came from UCSF, we know that the treatment histories are homogeneous, in that each patient received only standard-of-care therapy. It’s both this cohort’s scale and treatment uniformity that enable us to see past patient specific effects to the underlying biology of the disease.” 

The research was supported in part by the UCSF GBM Precision Medicine Program.

Authors: Other UCSF authors include: Jangham Jung, Husam Babikir, Karin Shamardani, Saket Jain, Xi Feng, Nalin Gupta, Susanna Rosi, Susan Chang, David Raleigh of the UCSF Department of Neurological Surgery; David Solomon of the UCSF Department of Pathology, and Joanna J. Phillips of the UCSF Departments of Neurological Surgery and Pathology.

Funding: This work has been supported by research awards from: NIH/NLM R01LM013897 and UC/CRCC CRN-19-586041 to A.D.; the UCSF Glioma Precision Medicine Program to A.D., S.C., J.J.P., D.S.; NIH/NINDS R01CA246722 to A.D, N.G., and S.R.; UCSF Brain Tumor SPORE Biorepository NIH/NCI 5P50CA097257 to J.J.P.; a gift from the Panattoni family to A.D. and J.J.P.

About UCSF Health: UCSF Health is recognized worldwide for its innovative patient care, reflecting the latest medical knowledge, advanced technologies and pioneering research. It includes the flagship UCSF Medical Center, which is ranked among the top 10 hospitals nationwide, as well as UCSF Benioff Children’s Hospitals, with campuses in San Francisco and Oakland, Langley Porter Psychiatric Hospital and Clinics, UCSF Benioff Children’s Physicians and the UCSF Faculty Practice. These hospitals serve as the academic medical center of the University of California, San Francisco, which is world-renowned for its graduate-level health sciences education and biomedical research. UCSF Health has affiliations with hospitals and health organizations throughout the Bay Area. Visit https://ucsfhealth.org. Follow UCSF Health on Facebook or on Twitter.

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Source: University of California, San Francisco (UCSF)

Health

Coordination of COVID-19 Vaccine Clinical Trials Produces a ‘Treasure Trove’ of Data and a Model for the Future

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Harmonized approach and vast database of trial participants could bolster future research well beyond SARS-CoV-2

Newswise — SEATTLE – The federally funded COVID-19 Prevention Network (CoVPN), headquartered at Fred Hutchinson Cancer Center in Seattle, was instrumental in the rapid development of safe, effective and lifesaving COVID-19 vaccines during earlier phases of the pandemic.

Its vital work to expedite Phase 3 COVID-19 vaccine clinical trials also resulted in a highly collaborative and harmonized approach that can serve as a national and even international model for major research initiatives while also guiding responses to future public health emergencies.

That’s the overarching theme from a new study published Monday, Jan. 23, in JAMA Network Open.

“Our success, which depended entirely on the investments into HIV vaccine research, can be replicated for other important research initiatives and highlights the importance of investments that boost pandemic preparedness for years to come,” explained James G. Kublin, MD, MPH, executive director of CoVPN and senior and corresponding author of the study.

Additionally, he and his colleagues, including  Alfredo Mena Lora, MD, assistant professor of medicine at the University of Illinois at Chicago, and co-first author Jessica Long, PhD, MPH, a postdoctoral fellow at the University of Washington Department of Medicine in Seattle, noted that the COVID-19 clinical trials produced a vast database of critical information that could help researchers answer pressing questions about this novel virus moving forward. 

“The harmonization of data across trials is a new strategy that will set the standard for collaboration in future clinical trials,” said Mena Lora. 

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The authors detail how CoVPN was able to help secure authorized vaccines in less than a year by the National Institute of Allergy and Infectious Diseases at the National Institutes of Health as part of Operation Warp Speed. Its mission was, and continues to be, to support the rapid development of vaccines for the U.S. and global populations by coordinating and implementing Phase 3 trials for COVID-19 vaccine candidates.

CoVPN officials were able to leverage existing resources, including clinical and laboratory infrastructure, community partnerships and research expertise, to get clinical sites to quickly pivot to conduct the vaccine trials as soon as investigational products were ready for Phase 3 testing.

“The CoVPN approach drew on years of experience and infrastructure from partnering networks and institutions, which not only allowed for rapid rollout of the trials, but also contributed to broader representation of trial participants,” said Long.

Overall, CoVPN deployed five Phase 3 clinical trials involving more than 136,000 participants to test the safety and effectiveness of COVID-19 vaccines. While doing so, it implemented several innovative procedures that were essential to its ultimate success. These included:

  • Harmonized study designs that were similar in relative size, number of endpoints and time to analysis.
  • A model that accelerated vaccine development by allowing phases to occur in parallel rather than sequentially. For example, vaccine manufacturing and scale-up were greenlighted while the trials were ongoing in anticipation of meeting efficacy targets.
  • Establishment of a single Data Safety Monitoring Board for review and oversight of all vaccine studies.
  • Targeted outreach and enrollment efforts supported by an online screening registry to ensure broad and diverse representation among study participants. Extensive engagement was conducted with communities and community leaders to build and enhance trust in the science to help enroll more Black, Indigenous and people of color (BIPOC) volunteers who are historically underrepresented in clinical trials.
  • A cross-platform approach that led to harmonization of data collection across trials and the ability to analyze data from all studies.

“This unique, cross-platform concept allowed for sharing of data from all of the studies and helped bridge gaps in understanding so we could better answer key research questions and guide policy decisions,” explained Kublin, who’s also a principal staff scientist at Fred Hutch. 

Larry Corey, MD, an internationally renowned expert in vaccine development, and principal co-investigator of CoVPN, believes the success of COVID-19 clinical trials should be thought of as an important model for developing vaccines for significant infectious diseases globally.

“Harmonizing study design, enrollment, clinical endpoints and methods for follow-up could very well become best practices that shape the future landscape of major research initiatives and pandemic responses,” he said. 

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Kublin and colleagues regard the vast database from more than 130,000 trial participants, including over 2,500 with documented COVID-19 cases, as a “treasure trove” of data that could help unlock mysteries about the virus. For example, they noted that the pooled data from five trials can help address specific questions such as:

  • How effective are vaccines for at-risk groups?
  • Can vaccines have an impact on long COVID?
  • Are safety, immunogenicity and vaccine efficacy different in special populations, such as people living with HIV?
  • What impact do chronic health conditions have on vaccine efficacy or protection duration?
  • What are the impacts of variants on both the population at large and within special communities?

Additional CoVPN publications planned for the months ahead will address many of these topics. Researchers who have ideas for further investigation and want to collaborate with CoVPN can find more information here.

Source: Covid-19 Prevention Network (CoVPN)

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Health

Observing World Cancer Day

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World Cancer Day is an international day marked on 4 February to raise awareness of cancer and to encourage its preventiondetection, and treatment. World Cancer Day is led by the Union for International Cancer Control (UICC) to support the goals of the World Cancer Declaration, written in 2008. The primary goal of World Cancer Day is to significantly reduce illness and death caused by cancer and is an opportunity to rally the international community to end the injustice of preventable suffering from cancer. The day is observed by the United Nations.

World Cancer Day targets misinformation, raises awareness, and reduces stigma. Multiple initiatives are run on World Cancer Day to show support for those affected by cancer. One of these movements are #NoHairSelfie, a global movement to have “hairticipants” shave their heads either physically or virtually to show a symbol of courage for those undergoing cancer treatment. Images of participants are then shared all over social media. Hundreds of events around the world also take place. (wikipedia)

https://stmdailynews.com/category/lifestyle/health-and-wellness/health/

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FDA CDC News

FDA Concludes that Existing Regulatory Frameworks for Foods and Supplements are Not Appropriate for Cannabidiol, Will Work with Congress on a New Way Forward

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Statement From:Janet Woodcock, M.D.
Principal Deputy Commissioner – Office of the Commissioner

January 26, 2023

Given the growing cannabidiol (CBD) products market, the U.S. Food and Drug Administration convened a high-level internal working group to explore potential regulatory pathways for CBD products. Today we are announcing that after careful review, the FDA has concluded that a new regulatory pathway for CBD is needed that balances individuals’ desire for access to CBD products with the regulatory oversight needed to manage risks. The agency is prepared to work with Congress on this matter. Today, we are also denying three citizen petitions that had asked the agency to conduct rulemaking to allow the marketing of CBD products as dietary supplements.  

The use of CBD raises various safety concerns, especially with long-term use. Studies have shown the potential for harm to the liver, interactions with certain medications and possible harm to the male reproductive system. CBD exposure is also concerning when it comes to certain vulnerable populations such as children and those who are pregnant. 

A new regulatory pathway would benefit consumers by providing safeguards and oversight to manage and minimize risks related to CBD products. Some risk management tools could include clear labels, prevention of contaminants, CBD content limits, and measures, such as minimum purchase age, to mitigate the risk of ingestion by children. In addition, a new pathway could provide access and oversight for certain CBD-containing products for animals.

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The FDA’s existing foods and dietary supplement authorities provide only limited tools for managing many of the risks associated with CBD products. Under the law, any substance, including CBD, must meet specific safety standards to be lawfully marketed as a dietary supplement or food additive. 

The working group, which I chair, has closely examined studies related to the CBD-based drug Epidiolex, published scientific literatureinformation submitted to a public docket, as well as studies both conducted and commissioned by the agency. Given the available evidence, it is not apparent how CBD products could meet safety standards for dietary supplements or food additives. For example, we have not found adequate evidence to determine how much CBD can be consumed, and for how long, before causing harm. Therefore, we do not intend to pursue rulemaking allowing the use of CBD in dietary supplements or conventional foods. 

CBD also poses risks to animals, and people could be unknowingly exposed to CBD through meat, milk and eggs from animals fed CBD. Because it is not apparent how CBD products could meet the safety standard for substances in animal food, we also do not intend to pursue rulemaking allowing the use of CBD in animal food. A new regulatory pathway could provide access and oversight for certain CBD-containing products for animals.

The FDA will continue to take action against CBD and other cannabis-derived products to protect the public, in coordination with state regulatory partners, when appropriate. We will remain diligent in monitoring the marketplace, identifying products that pose risks and acting within our authorities. The FDA looks forward to working with Congress to develop a cross-agency strategy for the regulation of these products to protect the public’s health and safety.

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