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Biology

Study adds new sea cucumber species to the research toolbox – EurekAlert

image:

Larva of the sea cucumber, Holothuria tubulosa, showing nuclei (cyan) and actin (magenta).

Credit: Perillo et al, Front. Ecol. Evol. 2024

By Devon McPhee

WOODS HOLE, Mass. -- Scientists have a handful of standard research organisms, including fruit flies and mice, that they use to study the evolutionary development (evo-devo) of animal lineages over time. Yet the more research organisms they can study, the deeper our understanding of life and the more knowledge we have to advance biomedicine and ecological conservation.

Researchers at the Marine Biological Laboratory (MBL), Woods Hole, and the Stazione Zoologica Anton Dohrn (SZS) in Naples, Italy, have added to the evo-devo toolbox by establishing Holothuria tubulosa, a species of sea cucumber, as an experimental research organism. They published their protocols recently in Frontiers in Evolutionary Developmental Biology.

The sea cucumber, found abundantly in the Mediterranean Sea and the eastern Atlantic Ocean, is an echinoderm, a group of marine invertebrates that includes sea urchins, sea stars and sand dollars. Some species of echinoderms have been used as developmental models for over a century thanks to their low costs, high fecundity, optically clear larvae and, more recently, amenability to genetic studies.

Echinoderms are the closest invertebrates to humans genetically, which means we have most of our genes in common. If we understand how those genes function in an echinoderm, than we also know how they function in humans, said Margherita Perillo, a research scientist at MBL who led the study.

Sea cucumbers also have attributes and special skills such as being deposit feeders, which cleans the ocean floor, and the ability to completely regenerate their whole body that could be useful in conservation and biomedicine, she said.

The first step in establishing H. tubulosa as a research organism was to develop a protocol to efficiently produce embryonic cultures in a lab setting. Existing methods, including mimicking the animals natural breeding cycle and inducing the release of all the animals organs by evisceration (a behavior that sea cucumbers normally exhibit when threatened) were complicated, inefficient or both.

To overcome this, the team led by Rossella Annunziata (SZS) and Perillo pioneered a noninvasive technique to repeatedly harvest a small number of gametes (sperm and eggs) over a long period of time. The microsurgery involves a small incision near a sea cucumbers reproductive organs, allowing for the retrieval of testes or ovaries. The incision heals quickly and gives researchers the ability to harvest every few days from the same animal.

Since eggs retrieved using this technique have not reached maturation and cannot be fertilized, the researchers next expose the harvested ovaries to a synthetic peptide Thioredoxin-2 peptide, known to work in another species to make them receptive to sperm. They then grow the fertilized egg in a culture, where it reaches the metamorphosis stage in about eight weeks.

Our protocol removes a major bottleneck that has kept H. tubulosa from being used as a research organism and opens the door for more scientists to use it, Perillo said.

The team next used high-resolution microscopy coupled with immunohistochemistry to document the development of the larvae, with a focus on its unique structures. Their detailed description will serve as a foundation for future studies that aim to use genetic manipulations to functionally dissect development in H. tubulosa.

Additionally, they provided an example of how scientists can use echinoderm larvae to study the diversification of anatomical structures in closely related organisms. In this case, they used serotonin immunostaining to show how the location of serotonin neurons differed between types of echinoderms. Why and how this diversification occurs is an open question in evolutionary development biology.

Perillo received an Emerging Research Organisms grants from the Society of Developmental Biology to support her work and to continue her study of H. tubulosa.

The sea cucumber is a fascinating animal and the better we understand it, the more value it has as a research organism, said Perillo. My plan now is to develop genetic tools to help further characterize it as an emerging comparison model in evo-devo. At the same time, this collaborative work laid the foundation to establish a new sea cucumber species here at the MBL

Frontiers in Ecology and Evolution

Experimental study

Animals

Larval development of Holothuria tubulosa, a new tractable system for evo-devo

24-May-2024

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Study adds new sea cucumber species to the research toolbox - EurekAlert

Biology

Bruker Launches Transformative neofleX MALDI-TOF System for Spatial Biology Mass Spec Imaging (MSI … – BioSpace

ANAHEIM, Calif.--(BUSINESS WIRE)-- At the 72nd ASMS meeting, Bruker Corporation (Nasdaq: BRKR) announced the launch of a novel, high-performance MALDI-TOF/TOF system, the neofleX Imaging Profiler for mass spectrometry-based tissue imaging. It enables facile OME-TIFF file output via the new SCiLS Scope software. The transformative neofleX MALDI-TOF/TOF MSI system now conveniently fits on a bench-top.

This press release features multimedia. View the full release here: https://www.businesswire.com/news/home/20240603327426/en/

neofleX MALDI-TOF System for Spatial Biology Mass Spec Imaging (MSI) Applications (Photo: Business Wire)

The neofleX Imaging Profiler MALDI-TOF/TOF mass spectrometer comes standard with Brukers proprietary 10 kHz smartbeam 3D laser for true pixel fidelity and with enhanced imaging detectors designed for longitudinal robustness, stability, and reproducibility in linear and reflector modes. neofleX is also available as a TOF/TOF configuration that features a reimagined fragmentation module for significantly improved TOF/TOF sensitivity, speed and sequence coverage.

Created for the unmet needs of moving from discovery imaging to translational and clinical tissue research, neofleX was used by the group of Prof. Bernd Bodenmiller at ETH and University of Zuerich to simultaneously map 116 proteins across a lung FFPE tissue section in 7 hours, using the MALDI HiPLEX-IHC workflow. Multiplexed detection with neofleX and MALDI HiPLEX-IHC technology allows increasing the number of proteins to map cellular processes without increasing MSI measurement time for a given region of interest.

In addition to MALDI HiPLEX-IHC MSI immunohistochemistry, neofleX is also compatible with the MALDI-ISH (in situ hybridization) method announced at ASMS 2024 by AmberGen, Inc. MALDI-ISH multiplexes imaging of up to 12 oligomers of interest (RNA/DNA) for multiomic spatial tissue research in neuroscience, infectious disease, and oncology.

The novel neofleX excels at providing more insight per pixel through multiomic spatial biology data from tissue sections that can positively correlate targeted proteins with glycans, metabolites, lipids, endogenous peptides, xenobiotics, and now RNA/DNA. This additional multiomics context provides important adjacency information about cellular states, function, structure, and protein activity for a range of research areas, such as oncology and neurology.

Professor Carsten Hopf of the University of Mannheim, Germany, Center for Mass Spectrometry and Optical Spectroscopy (CeMOS) commented: The innovative neofleX presents an incredibly powerful, versatile and easy-to-use mass-spec imaging system for tissue spatial biology researchers for targeted proteomics. We appreciate the value of this instrument for performance and versatility, and our clinical research collaborators welcome the translational research capabilities.

Multiomic co-localization of lipids and glycans on a tissue section allows to not only localize protein targets using MALDI HiPLEX-IHC, but also assess protein activity and function. A study performed at CeMOS on brain tissues from a transgenic mouse model demonstrated co-localization of amyloid -42 (A42) protein with a targeted membrane-bound glycosphingolipid (GM3 d36:1), yielding important structural information.

Dr. Michael L. Easterling, Vice President MSI for Brukers Life Sciences Mass Spectrometry division, commented: The neofleX offers unique combination of outstanding performance, multimodal software and workflows on the benchtop for a wide range of biopharma and clinical researchers. Additionally, neofleX brings novel capabilities to spatial biology, including spatial proteomics combined with unique multiomics correlations for developing actionable biological insights.

The neofleX is compatible with Brukers MALDI Imaging software and consumables ecosystems, such as IntelliSlides and SCiLS autopilot that simplify sample tracking, preparation, and analysis and require minimal input from users to initiate and process automated mass-spec imaging runs. For ease of collaborations, the neofleX now delivers targeted imaging data via automatically generated OME-TIFF images that can be viewed within the SCiLS environment, or easily exported into custom pipelines or digital pathology systems.

Bruker also announced extension of the SCiLS portfolio with SCiLS Scope 1.0 for collaboration around targeted, multiomic translational workflows developed for neofleX. SCiLS Scope software supports OME-TIFF datasets from targeted imaging workflows such as MALDI HiPLEX-IHC. Ion images are visualized by false-color coding of selected channels, and image processing and distance measurements can be accomplished with simple tools.

Blaine R. Roberts, Ph.D., Associate Professor in the Department of Biochemistry and Department of Neurology at Emory University in Atlanta, GA, summarized: Fast and user-friendly visualization of targets is made easy by the addition of SCiLS Scope to the MSI software lineup.

About Bruker Corporation the Emerging Leader of the Post-Genomic Era (Nasdaq: BRKR)

Bruker is enabling scientists and engineers to make breakthrough post-genomic discoveries and develop new applications that improve the quality of human life. Brukers high-performance scientific instruments and high-value analytical and diagnostic solutions enable scientists to explore life and materials at molecular, cellular, and microscopic levels. In close cooperation with our customers, Bruker is enabling innovation, improved productivity, and customer success in post-genomic life science molecular and cell biology research, in applied and biopharma applications, in microscopy and nanoanalysis, as well as in industrial and cleantech research, and next-gen semiconductor metrology in support of AI. Bruker offers differentiated, high-value life science and diagnostics systems and solutions in preclinical imaging, clinical phenomics research, proteomics and multiomics, spatial and single-cell biology, functional structural and condensate biology, as well as in clinical microbiology and molecular diagnostics. For more information, please visit http://www.bruker.com.

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Bruker Launches Transformative neofleX MALDI-TOF System for Spatial Biology Mass Spec Imaging (MSI ... - BioSpace

Biology

Coral in New England? Yes, And It’s Rugged – College of the Holy Cross

In May, McAlister and Kelly Wolfe-Bellin, senior lecturer and director of biology laboratories, led a team of students from various academic disciplines to Bermuda to investigate and consider how societies and communities manage energy, water, food, waste management, nature, conservation, and environmental changes.

The students had to think about the decisions or tradeoffs that needed to be made about how resources would be generated and used. Those decisions might be different on a small island like Bermuda than what they would be coming from a big country like the U.S., he noted.

As a researcher, McAlister studies how natural and man-made environmental changes impact the biology and life history decisions made by organisms. Specifically, what these changes mean for marine invertebrates and their larvae, including classic sea creatures like cnidarians (corals, sea anemones and jellyfish) and echinoderms (sea urchins, sea stars and brittle stars).

When thinking about what is more important in controlling how an organism develops and grows, it used to be a battle between nature versus nurture, he said. Its actually both things together that lead to the development of the organism. That's true for humans just as much as it is true for every other organism.

An example of a brittle star.

While conducting doctoral research in Panama, he focused on species of echinoderms that lived in the Pacific Ocean and had cousins thriving in the Caribbean, separated only by about 50 miles of land and three million years of marine evolution. They experienced different food sources, water temperatures and predators, and had to make tradeoffs in order to survive: lay more and smaller eggs in the Pacific or fewer and larger more robust eggs in the Caribbean in order to thrive in their different marine environments. McAlister researched how the invisible-to-the-naked-eye larvae adapted to the changes.

When I talk to people about sea stars they have this mental image of an adult sea star. Thats not what the babies look like. They look like aliens, are microscopic and more sensitive [to environmental change] than the adults, and float around in the ocean water [instead of crawling along the seafloor]. Nobody's thinking about them, except for the few of us that do, McAlister said.

That is until there is a marine catastrophe, like warming oceans or a pollution event. Its the babies that are often killed off or most affected, McAlister said.

A jellyfish larvae moves through collected seawater.

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Coral in New England? Yes, And It's Rugged - College of the Holy Cross

Biology

Biden judicial nominee can’t say whether chromosomes determine sex: ‘I have never studied biology’ – Washington Times

One of President Bidens judicial nominees is under scrutiny for refusing to answer whether chromosomes determine ones biological sex, insisting that she never studied biology and is unqualified to answer.

Magistrate Judge Sarah Netburn pleaded innocence of the question when asked it in a written questionnaire by Sen. Lindsey Graham of South Carolina, the top Republican on the Senate Judiciary Committee.

Is it possible to determine a persons sex by only analyzing their chromosomes? the South Carolina Republican asked the nominee.

I have never studied biology and therefore I am unqualified to answer this question, Judge Netburn said.

The back-and-forth came in the form of written follow-up questions following the nominees confirmation hearing last month.

During the May 22 hearing, Republican senators quizzed Judge Netburn over her decision to transfer a biological male child sex abuser to a female prison after the inmate decided to identify as a woman.

Her decision to move the prisoner conflicted with the recommendation from the Bureau of Prisons.

The inmate had been convicted of raping two children: a 17-year-old girl and a nine-year-old boy. The inmate was also convicted of distributing child sex abuse material.

Judge Netburn has been a magistrate judge for more than a decade.

She was nominated by Mr. Biden to serve as a federal judge for the Southern District of New York.

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Biden judicial nominee can't say whether chromosomes determine sex: 'I have never studied biology' - Washington Times

Biology

Fish in schools have an easier time swimming in rough waters – EurekAlert

image:

A school of pink salmon (Oncorhynchus gorbuscha) in upper Nimpkish River, British Columbia, Canada.

Credit: Fernando Lessa (CC-BY 4.0, https://creativecommons.org/licenses/by/4.0/)

Swimming through turbulent water is easier for schooling fish compared to solitary swimmers, according to a study published June 6th in the open-access journal PLOS Biology by Yangfan Zhang of Harvard University, Massachusetts, US, and colleagues.

Locomotion is key to many aspects of animal behavior, from reproduction to feeding to migration, and so many species have developed adaptations to make moving around more efficient. In this study, Zhang and colleagues propose the turbulent sheltering hypothesis, which suggests that traveling in schools allows fish to shield each other from disruptive water currents, thus making it easier to swim through rough waters.

To test this hypothesis, the researchers ran trials with giant danios (Devario aeqipinnatus), observing these fish swimming alone or in groups of eight in both turbulent and steadily flowing water. High-speed cameras allowed researchers to observe the movements of the fish as they swam, and a respirometer allowed for measurements of fish respiration rates and energy expenditure.

These trials revealed that schooling fish expended up to 79% less energy while swimming in turbulent water compared to solitary fish. Schooling fish also clustered more closely together in turbulent water compared to steady water, while solitary fish had to beat their tails much more vigorously to maintain the same speed in more turbulent currents.

These results lend support to the turbulence sheltering hypothesis, indicating that locomotion efficiency might be a driving factor behind the evolution of schooling behavior. This information is valuable for understanding fish ecology, fundamentals of hydrodynamics and it might also be applied to the design and maintenance of habitats meant to harbor protected fish species or to hinder invasive ones. The authors note that future studies might build off of these findings to explore energy dynamics of group movements in further aquatic or aerial animals.

The authors add, What is the function of schooling behaviour in fishes? We show that being in a school substantially reduces the energetic cost for fish swimming in a turbulent environment, compared to swimming alone, providing support for the hypothesis that schooling behaviour protects individual fish from the increased energetic cost associated with swimming in turbulence.

#####

In your coverage, please use this URL to provide access to the freely available paper in PLOS Biology: http://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3002501

Citation: Zhang Y, Ko H, Calicchia MA, Ni R, Lauder GV (2024) Collective movement of schooling fish reduces the costs of locomotion in turbulent conditions. PLoS Biol 22(6): e3002501. https://doi.org/10.1371/journal.pbio.3002501

Author Countries: United States

Funding: Funding provided by the National Science Foundation grant 1830881 (GVL), the Office of Naval Research grants N00014-21-1-2661 (GVL), N00014-16-1-2515 (GVL), 00014-22-1-2616 (GVL), and a Postdoctoral Fellowship of the Natural Sciences and Engineering Research Council of Canada (NSERC PDF - 557785 2021) followed by a Banting Postdoctoral Fellowship (202309BPF-510048-BNE-295921) of NSERC & CIHR (Canadian Institutes of Health Research) (YZ). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Experimental study

Animals

Competing interests: The authors have declared that no competing interests exist.

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

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Fish in schools have an easier time swimming in rough waters - EurekAlert

Biology

WHS valedictorian to attend Hanover for biology | News | shelbynews.com – Shelbynews

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WHS valedictorian to attend Hanover for biology | News | shelbynews.com - Shelbynews

Biology

Shift the Focus: Is addiction biology or psychology? – Cecil Daily

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Shift the Focus: Is addiction biology or psychology? - Cecil Daily

Biology

Man’s remains identified after nearly 40 years | Biology | kvoa.com – KVOA Tucson News

TUCSON (KVOA) - For nearly 40 years an Idaho man and his mother had no idea if their loved one was dead or alive.

The man had a suspicion and a DNA test proved his worst fears.

A DNA test proved that the man's suspicions were correct.

But, it took four decades to learn the man's fate.

They didn't know for four decades.

The remains no longer belong to John Doe they belong to John Leigh III who died in a fiery plane crash in August of 1984.

The crash site was not found until 13 years later by hikers in the Rincon Mountains. They took a picture and asked to remain anonymous.

They told News 4 "The site was very steep, brushy and difficult. The shot obviously depicts some of the wreckage among the brush."

News 4 spoke to John IV "I really want to hike up to the crash site like I've said before that's the official burial site, and I want to pay my respects up there if I can get there."

He was just 4 years old when his dad disappeared.

"It really doesn't affect me like it affects my mom, because I never knew him, and to me, the biggest part is that I know now that he didn't skip out of town and it gives me peace."

Dr. Bruce Anderson works for the Office of the Medical Examiners. He said there were the remains of four adult men who were on the plane. He had to exhume the remains when Susan Leigh and her son John IV wanted to know if their loved one John III was on that ill-fated flight.

He sent DNA samples from the bones to three different labs, but it was the California Department of Justice Missing Persons DNA Program that not only identified Leigh's DNA but the three others as well.

Anderson said, "It took a while for DNA technology to improve to where they could get DNA profiles, good quality DNA profiles, out of degraded bone like this."

Also found in the wreckage besides remains, several personal effects. such as aviator glasses, a BIC lighter, a briefcase lock, and a pocket knife.

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Man's remains identified after nearly 40 years | Biology | kvoa.com - KVOA Tucson News

Biology

UK Researcher Named an Inspiring Woman in Plant Biology – Morning Ag Clips –

Aardra Kachroo, a professor in the Department of Plant Pathology in the Martin-Gatton College was nominated for her research on plant immunity and for selflessly serving to empower women in science and plant biology.

I am honored to be recognized amongst this incredible cohort of women in science and grateful for those who nominated me, said Kachroo. Our collective passion as well as that of the many plant science stalwarts not named here, offers a bright future of scientific discoveries that will improve our world and benefit all lives.

The ASPB Women in Plant Biology Committee called for nominations of remarkable women who shape the field to highlight career achievementsand celebrate their impact in plant biology.

Aardra Kachroos research at the University of Kentucky focuses on unraveling the molecular mechanisms of plant immunity, wrote one nominator. Using molecular biology and genomics, she explores how plants recognize and defend against pathogens, offering insights crucial for enhancing crop protection and global food security.

I am privileged to receive guidance from a remarkable woman who has truly been a beacon of inspiration on my journey, submitted another nominatokr.

Kachroo uses various plants and pathogens to research how primary metabolic and defense signaling pathways are connected to solve agricultural problems. Her lab focuses on systemic acquired resistance (SAR) a signaling mechanism that provides widespread plant immunity and can be passed on to other generations of plants and ones nearby.

Kachroos lab also explores SAR and the recently identified root-shoot-root signaling mechanism that regulates the associations between legumes and nitrogen-fixing bacteria on roots.

In addition to her research, Kachroo also serves on the board of the Kentucky Association of Professional African American Women while being an advocate and mentor. She also leads a biotech company that develops sustainable and environmentally friendly pest management products for plants.

Kachroo was recognized among other mid-career researchers. You can find ASPBsfull list here.

UK Martin-Gatton College of Agriculture, Food and Environment

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UK Researcher Named an Inspiring Woman in Plant Biology - Morning Ag Clips -

Biology

AACR 2024 Plenary: New Insights Into Early Cancer Biology – American Association for Cancer Research (AACR)

Seventy percent of cancer-related deaths are from cancer types with no available screening options, underscoring the importance of detecting cancer early when it is more easily treated. The American Association for Cancer Research (AACR) Annual Meeting 2024, held April 5-10, kicked off its plenary program with a session on Discovery Science in Early Cancer Biology and Interception, which was chaired by Daniel De Carvalho, PhD, a professor at University of Toronto and researcher at the Princess Margaret Research Centre.

[Early cancer detection] is where we can have the biggest impact from cancer research on clinical care, De Carvalho said. He noted that novel early detection approaches will depend on understanding the molecular changes that occur as cells evolve from normal to precancer to cancer.

We really need to understand early cancer biology and figure out ways to use this for cancer interception, he said.

Just in time for the newly declared National Cancer Prevention and Early Detection Month, the session featured four presentations that explored the early changes underpinning cancer development and efforts to target these for cancer treatment.

In the first presentation, Margaret Goodell, PhD, FAACR, a professor at Baylor College of Medicine, discussed mechanisms that may drive clonal hematopoiesis, a state characterized by the outgrowth of genetically distinct populations of hematopoietic stem cells. Clonal hematopoiesis commonly occurs with aging and increases an individuals risk for several blood cancers.

Understanding how clonal hematopoiesis develops is key to identifying novel approaches to prevent this premalignant condition from progressing to cancer, Goodell noted.

In three separate vignettes, she shared distinct mechanisms underlying clonal hematopoiesis, including commonly occurring mutations in PPM1D, the gene that encodes the p53 suppressor protein WIP1. Goodell showed that these mutations inactivated DNA repair and cell death mechanisms and made cells more likely to proliferate with unresolved DNA damage, particularly after exposure to chemotherapy drugs. Consistent with these preclinical findings, blood samples from patients who had received chemotherapy were enriched for PPM1D-mutated cells.

Chemotherapy exposure also increased the occurrence of mutations in the chromatin regulator SRCAP, the focus of Goodells second vignette. In contrast to PPM1D mutations, the commonly occurring SRCAP mutations increased DNA repair by upregulating the expression of DNA damage genes through histone alterations. Goodell noted that, although mutations in PPM1D and SRCAP had contrasting effects on DNA repair, they both provided survival advantages to hematopoietic stem cellsa phenomenon that might be explained by different environmental contexts.

Finally, Goodell discussed mutations in DNMT3A, which she described as the most important tumor suppressor in the hematopoietic system. She explained that hematopoietic stem cells with DNMT3A mutations exhibit enhanced self-renewal and suggested that this may be due to the mutants epigenetic impacts.

Goodell proposed that these mechanistic insights could lay the foundation for future cancer interception efforts. In the long term, she said, we think there will be great opportunities for interventions if we can understand which mutations are particularly bad, in which contexts they arise, and how we can interfere with their functions.

Most breast cancers are diagnosed in individuals 55 years of age or older, and research presented by Kornelia Polyak, MD, PhD, FAACR, a professor at Harvard Medical School and Dana-Farber Cancer Institute, shed light on the cancer-promoting changes that occur with aging.

Using rat models, Polyak and colleagues discovered that aging was associated with dysregulated proliferation of mammary epithelial cells (from which most breast cancers arise), altered gene expression, changes to the proportion of certain immune cells, modified tissue states, and the decline of various cellular functions.

Among the genes whose expression increased with aging was midkine (MDK), a growth factor that has been implicated in cancer and other diseases. Polyak shared data demonstrating that MDK was upregulated with aging in rat mammary tissue, as well as in plasma samples from older individuals and in human breast cancers. Additionally, individuals under the age of 55 whose normal breast tissue had higher levels of MDK were found to have a greater five-year risk of breast cancer, and young patients whose breast cancers had high levels of MDK had lower disease-free survival rates.

Further experimentation revealed that MDK may impact breast cancer development by activating the tumor-promoting PI3K signaling pathway, repressing tumor suppressive pathways, and enhancing metabolic activityconsequences mediated by SREBF1, a regulator of cell metabolism.

Don Cleveland, PhD, FAACR, a professor at the UC San Diego School of Medicine, shared mechanistic insights into chromothripsis (chromosome shattering) and its contributions to cancer development. He demonstrated that abnormal chromosomes accumulate in micronuclei, where they undergo chromothripsis through the action of the N4BP2 nuclease. Shattered chromosome fragments remain near one another due to tethering by the DNA repair protein TOPBP1, and this proximity facilitates aberrant ligation of the chromosome fragments into circular DNAs that amplify the expression of certain oncogenes and drive drug resistance.

Separately, he proposed that Epstein-Barr virus (EBV) may promote cancer through a similar tethering action as shattered chromosome fragments. He showed that the viral protein EBNA1 becomes tethered to an EBV-like DNA sequence in chromosome 11, which leads to chromosome breakage and the separation of the MLL gene from the rest of chromosome 11. The MLL-containing DNA fragment enters micronuclei and undergoes chromothripsis, re-ligation, and amplification of MLL. This, in turn, inactivates the DNA repair protein ATM and may promote the formation of cancer. (MLL is a negative regulator of ATM.)

The accumulation of DNA damage can lead to cancer and, if left unresolved, trigger cell death. For this reason, many researchers are exploring inhibiting DNA repair as a potential approach to treat cancer. Michael Kastan, MD, PhD, FAACR, a professor at Duke University and executive director of Duke Cancer Institute, demonstrated the potential of an investigational chemical inhibitor of the DNA repair proteins ATM and DNA-PK to sensitize cells to radiation.

ATM and DNA-PK are signal transducers activated early in the response to DNA damage and regulate a multitude of downstream effector proteins that ultimately repair the damage or trigger cell death.

Kastan explained that ATM and DNA-PK are logical targets because 1) they are important regulators of DNA repair, 2) their activity is not essential to the survival of cells, and 3) cells that lack either protein remain sensitive to radiation.

He and colleagues identified XRD-0394, a novel dual inhibitor of ATM and DNA-PK, that could be delivered systemically. In preclinical models, XRD-0394 inhibited both proteins in a dose-dependent manner. Importantly, it led to cell death only in the presence of radiation, which allowed the drug to be delivered systemically without widespread toxicities.

Based on these preclinical data, Kastan and colleagues initiated a phase I clinical trial to evaluate the safety and pharmacokinetics of the drug in patients. The drug has not led to any dose-limiting toxicities thus far, and patient tumor samples indicate that the drug successfully inhibits ATM in patients. Kastan plans to explore combining XRD-0394 with various other therapies, such as immune checkpoint inhibitors, PARP inhibitors, and cytotoxic drugs.

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AACR 2024 Plenary: New Insights Into Early Cancer Biology - American Association for Cancer Research (AACR)