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City of Hope scientists develop targeted chemotherapy able to kill all solid tumors in preclinical research

The City of Hope-developed investigational small molecule selectively disrupts DNA replication and repair in cancer cells, leaving healthy cells unaffected, a new study reports.

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LOS ANGELES /PRNewswire/ — Researchers at City of Hope, one of the largest cancer research and treatment organizations in the United States, today published a new study explaining how they took a protein once thought to be too challenging for targeted therapy, proliferating cell nuclear antigen (PCNA), and developed a targeted chemotherapy that appears to annihilate all solid tumors in preclinical research. As the scientists continue to investigate the foundational mechanisms that make this cancer-stopping pill work in animal models, they note that there is an ongoing Phase 1 clinical trial testing the City of Hope-developed therapeutic in humans.

City Of Hope
The City of Hope-developed small molecule AOH1996 targets a cancerous variant of the protein PCNA. In its mutated form, PCNA is critical in DNA replication and repair of all expanding tumors. Here we see untreated cancer cells (left) and cancer cells treated with AOH1996 (right) undergoing programmed cell death (violet). (Photo credit: City of Hope)

Most targeted therapies focus on a single pathway, which enables wily cancer to mutate and eventually become resistant, said Linda Malkas, Ph.D., professor in City of Hope’s Department of Molecular Diagnostics and Experimental Therapeutics and the M.T. & B.A. Ahmadinia Professor in Molecular Oncology. However, the cancer-killing pill Malkas has been developing over the past two decades, AOH1996, targets a cancerous variant of PCNA, a protein that in its mutated form is critical in DNA replication and repair of all expanding tumors.

“PCNA is like a major airline terminal hub containing multiple plane gates. Data suggests PCNA is uniquely altered in cancer cells, and this fact allowed us to design a drug that targeted only the form of PCNA in cancer cells. Our cancer-killing pill is like a snowstorm that closes a key airline hub, shutting down all flights in and out only in planes carrying cancer cells,” said Malkas, senior author of the new study published in Cell Chemical Biology today. “Results have been promising. AOH1996 can suppress tumor growth as a monotherapy or combination treatment in cell and animal models without resulting in toxicity. The investigational chemotherapeutic is currently in a Phase 1 clinical trial in humans at City of Hope.”

AOH1996 has been effective in preclinical research treating cells derived from breast, prostate, brain, ovarian, cervical, skin and lung cancers and is exclusively licensed by City of Hope to RLL, LLC, a biotechnology company that Malkas co-founded and holds financial interest in.

The researchers tested AOH1996, a small molecule PCNA inhibitor, in more than 70 cancer cell lines and several normal control cells. They found that AOH1996 selectively kills cancer cells by disrupting the normal cell reproductive cycle. It targets something called transcription replication conflicts, which occur when mechanisms responsible for gene expression and genome duplication collide. The investigational therapy prevented cells with damaged DNA from dividing in G2/M phase and from making a copy of faulty DNA in S phase. As a result, AOH1996 caused cancer cell death (apoptosis), but it did not interrupt the reproductive cycle of healthy stem cells.

“No one has ever targeted PCNA as a therapeutic because it was viewed as ‘undruggable,’ but clearly City of Hope was able to develop an investigational medicine for a challenging protein target,” said Long Gu, Ph.D., lead author of the study and an associate research professor in the Department of Molecular Diagnostics and Experimental Therapeutics at Beckman Research Institute of City of Hope. “We discovered that PCNA is one of the potential causes of increased nucleic acid replication errors in cancer cells. Now that we know the problem area and can inhibit it, we will dig deeper to understand the process to develop more personalized, targeted cancer medicines.”

Interestingly, experiments showed that the investigational pill made cancer cells more susceptible to chemical agents that cause DNA or chromosome damage, such as the chemotherapy drug cisplatin, hinting that AOH1996 could become a useful tool in combination therapies as well as for the development of new chemotherapeutics.

“City of Hope has world leaders in cancer research. They also have the infrastructure to drive translational drug discovery from the laboratory into the clinic for patients in need,” said Daniel Von Hoff, M.D., study co-author and a distinguished professor at Translational Genomics Research Institute, part of City of Hope.

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City of Hope’s groundbreaking translational research history includes developing the technology underlying synthetic human insulin, a breakthrough in diabetes management, and monoclonal antibodies, which are integral to widely used, lifesaving cancer drugs, such as trastuzumab, rituximab and cetuximab.

As a next step, the researchers will look to better understand the mechanism of action to further improve the ongoing clinical trial in humans. Individuals interested in the Phase 1 clinical trial should review the eligibility requirements at clinicaltrials.gov. If eligible, call 626-218-1133 or visit City of Hope’s clinical trials webpage.

The Cell Chemical Biology study entitled “Small Molecule Targeting of Transcription-Replication Conflict for Selective Chemotherapy” was supported by the Department of Defense (W81XWH-11-1-0786, W81XWH-19-1-0326 under BC181474 and BC181474P1), National Institutes of Health/National Cancer Institute (R01 CA121289, R01 CA225843), St Baldrick’s Foundation, the Alex Lemonade Stand Foundation, Tobacco-Related Disease Research Program (TRDRP-T31IP626), Melanoma Research Foundation (MRF-717178), the ANNA Fund, RDL Foundation, Analytical Pharmacology Core supported by the National Cancer Institute of the National Institutes of Health (P30CA033572).

About City of Hope
City of Hope’s mission is to deliver the cures of tomorrow to the people who need them today. Founded in 1913, City of Hope has grown into one of the largest cancer research and treatment organizations in the U.S. and one of the leading research centers for diabetes and other life-threatening illnesses. City of Hope research has been the basis for numerous breakthrough cancer medicines, as well as human synthetic insulin and monoclonal antibodies. With an independent, National Cancer Institute-designated comprehensive cancer center at its core, City of Hope brings a uniquely integrated model to patients spanning cancer care, research and development, academics and training, and innovation initiatives. City of Hope’s growing national system includes its Los Angeles campus, a network of clinical care locations across Southern California, a new cancer center in Orange County, California, and treatment facilities in Atlanta, Chicago and Phoenix. City of Hope’s affiliated group of organizations includes Translational Genomics Research Institute and AccessHopeTM. For more information about City of Hope, follow us on FacebookTwitterYouTubeInstagram and LinkedIn.

SOURCE City Of Hope

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Lifestyle

Get chronic UTIs? Future treatments may add more bacteria to your bladder to beat back harmful microbes

Researchers developed a biomaterial releasing beneficial E. coli to combat urinary tract infections by outcompeting harmful bacteria, aiming to reduce antibiotic resistance and manage chronic UTIs effectively.

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bacteria
Certain strains of E. coli can outcompete disease-causing microbes for resources. NIAID/Flickr, CC BY-SA

Sarguru Subash, Texas A&M University

Millions of people in the U.S. and around the world suffer from urinary tract infections every year. Some groups are especially prone to chronic UTIs, including women, older adults and some veterans.

These infections are typically treated with antibiotics, but overusing these drugs can make the microbes they target become resistant and reduce the medicines’ effectiveness.

To solve this problem of chronic UTIs and antibiotic resistance, we combined our expertise in microbiology and engineering to create a living material that houses a specific strain of beneficial E. coli. Our research shows that the “good” bacteria released from this biomaterial can compete with “bad” bacteria for nutrients and win, dramatically reducing the number of disease-causing microbes.

With further development, we believe this technique could help manage recurring UTIs that do not respond to antibiotics.

Bringing bacteria to the bladder

For the microbes living in people, nutrients are limited their presence varies between different parts of the body. Bacteria have to compete with other microbes and the host to acquire essential nutrients. By taking up available nutrients, beneficial bacteria can stop or slow the growth of harmful bacteria. When harmful bacteria are starved of important nutrients, they aren’t able to reach high enough numbers to cause disease.

Delivering beneficial bacteria to the bladder to prevent UTIs in challenging, though. For one, these helpful bacteria can naturally colonize only in people who are unable to fully empty their bladder, a condition called urinary retention. Even among these patients, how long these bacteria can colonize their bladders varies widely.

Current methods to deliver bacteria to the bladder are invasive and require repeated catheter insertion. Even when bacteria are successfully released into the bladder, urine will flush out these microbes because they cannot stick to the bladder wall.

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Micrograph of clusters of pink rods scattered across a blue textured wall, while yellow blobs extend thin tendrils across the clumps
This microscopy image shows the bladder of a mouse (blue) covered with E. coli (pink) and the white blood cells (yellow) attacking them. Valerie O’Brien, Matthew Joens, Scott J. Hultgren, James A.J. Fitzpatrick, Washington University, St. Louis/NIH via Flickr, CC BY-NC

Biomaterials to treat UTIs

Since beneficial bacteria cannot attach to and survive in the bladder for long, we developed a biomaterial that could slowly release bacteria in the bladder over time.

Our biomaterial is composed of living E. coli embedded in a matrix structure made of gel. It resembles a piece of jelly about 500 times smaller than a drop of water and can release bacteria for up to two weeks in the bladder. By delivering the bacteria via biomaterial, we overcome the need for the bacteria to attach to the bladder to persist in the organ.

We tested our biomaterial by placing it in human urine in petri dishes and exposing it to bacterial pathogens that cause UTIs. Our results showed that when mixed in a 50:50 ratio, the E. coli outcompeted the UTI-causing bacteria by increasing to around 85% of the total population. When we added more E. coli than UTI-causing bacteria, which is what we envision for future development and testing, the proportion of E. coli increased to over 99% of the population, essentially wiping out the UTI-causing bacteria. Moreoever, the biomaterial continued releasing E. coli for up to two weeks in human urine.

Our findings suggest that E.coli could stick around and survive in the bladder for extended periods of time and successfully decrease the growth of many types of bacteria that cause UTIs.

Person pressing hands against stomach. bacteria
UTIs can be painful. Images we create and what actually happens are always beautiful when we have imagination/iStock via Getty Images Plus

Improving biomaterials

Our findings show that E. coli can not only control harmful bacteria it’s closely related to but also a broad range of disease-causing bacteria in humans and animals. This means scientists might not need to identify different types of beneficial bacteria to control each pathogen – and there are many – that can cause a UTI.

Our team is currently evaluating how effectively our biomaterial can cure UTIs in mice. We are also working to identify the specific nutrients that beneficial and harmful bacteria compete over and what factors may help beneficial bacteria win. We could add these nutrients to our biomaterial to be released or withheld.

This research is still at an early stage, and clinical uses are not in development yet, so if it does reach patients it will be well in the future. We hope that our technology could be refined and applied to control other bacterial infections and some cancers caused by bacteria.

Sarguru Subash, Assistant Professor of Veterinary Pathobiology, Texas A&M University

This article is republished from The Conversation under a Creative Commons license. Read the original article.

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Our Lifestyle section on STM Daily News is a hub of inspiration and practical information, offering a range of articles that touch on various aspects of daily life. From tips on family finances to guides for maintaining health and wellness, we strive to empower our readers with knowledge and resources to enhance their lifestyles. Whether you’re seeking outdoor activity ideas, fashion trends, or travel recommendations, our lifestyle section has got you covered. Visit us today at https://stmdailynews.com/category/lifestyle/ and embark on a journey of discovery and self-improvement.


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Lifestyle

Does Your Favorite Brand of Dark Chocolate Contain Dangerous Metals?

According to a recent article from Consumer Reports, there are some brands of Dark Chocolate that contain dangerous levels of lead, and cadmium. 

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Consumer Reports found dangerous heavy metals in dark chocolate from popular brands.

Dark Chocolate

According to a recent article from Consumer Reports, there are some brands of Dark Chocolate that contain dangerous levels of lead, and cadmium. 

Dark Chocolate has become popular due to studies suggesting that they are rich in antioxidants,  which is beneficial to the heart, and it having low sugar properties that positively impact health. 

grey metal on soil. dark chocolate
Photo by Pixabay on Pexels.com

The article, which was posted in mid December, states that 28 popular brands were tested, and that 23 of them contained high levels of the dangerous metals. 

For more details, check out the article from Consumer Reports: https://www.consumerreports.org/health/food-safety/lead-and-cadmium-in-dark-chocolate-a8480295550/

STM Daily News is a vibrant news blog dedicated to sharing the brighter side of human experiences. Emphasizing positive, uplifting stories, the site focuses on delivering inspiring, informative, and well-researched content. With a commitment to accurate, fair, and responsible journalism, STM Daily News aims to foster a community of readers passionate about positive change and engaged in meaningful conversations. Join the movement and explore stories that celebrate the positive impacts shaping our world.

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    Rod: A creative force, blending words, images, and flavors. Blogger, writer, filmmaker, and photographer. Cooking enthusiast with a sci-fi vision. Passionate about his upcoming series and dedicated to TNC Network. Partnered with Rebecca Washington for a shared journey of love and art. View all posts

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Healthy Habits for Your Home

If you’re like most Americans, health is an important aspect of your resolutions when each new year rolls around. While factors like diet and exercise are keys to healthy living, so are the ways you care for your home and belongings.

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(Family Features) If you’re like most Americans, health is an important aspect of your resolutions when each new year rolls around. While factors like diet and exercise are keys to healthy living, so are the ways you care for your home and belongings.

Good Habits start at Home

Your home living environment plays a major role in your health and comfort, so incorporating some new habits like these from the cleaning experts at Swash Laundry Detergent can help you establish a healthier lifestyle.

Control Air Quality
Especially during the winter months when your home tends to be closed tight, air can grow stale. Do your best to keep air quality strong by opening windows on mild days to circulate fresh air, using an air purifier to remove irritants and pollutants, frequently vacuuming and sweeping to keep floor dust and debris under control and regularly cleaning textiles that can trap allergens and other particles.

Scale Back Detergent Use
Using too much laundry detergent isn’t just risking buildup and unnecessary wear on your washer and dryer; it can also increase the residue and buildup in your clothes, which can lead to skin irritation and damage fabric faster. Using only what you need helps protect your belongings and your skin. An option like Swash Laundry Detergent, which features a Precision Pour Cap, dispenses the detergent for you, so you only pour what you need to effectively clean each load and fight stains. A single bottle of the ultra-concentrated formula – available in Simply Sunrise, Free & Clear and Pure Linen scents – washes up to 83 loads while taking up less space than traditional, bulky detergent bottles.

Make Use of Natural Light
When winter brings day after day of dark, dreary weather, it can take a toll on your mood. Brightening your living space with natural light can positively influence your emotional state while helping with your electric bill. If you’re concerned about privacy, utilize window treatments at night, but let the sunlight bring good cheer to your living spaces during the day.

Switch Bedding on Schedule
While you sleep, your body sheds oils, cells and elements you carry into your home like pollen. Sheets should be washed once a week on the hottest water setting your fabric will tolerate (check tags for laundering directions on your sheets before washing). If your schedule makes weekly washing, drying and remaking the bed unrealistic, consider having a couple sets you can rotate so you always have fresh, clean sheets waiting to remake your bed on laundry day.

Work Up (and Wash Out) a Sweat
The materials that keep you feeling cool and fresh by wicking away sweat can quickly get stinky, but over-washing can make them lose their shape and fade. Even so, washing after every use is a must. Washing workout clothes inside out exposes the surfaces that have absorbed sweat and body oil to detergent and agitation. Be sure to close zippers, buttons, clasps and other fasteners to prevent snags. Pre-soaking with equal parts vinegar and cold water can also help eliminate odors, and washing in a gentle, cold-water cycle and drying on low heat can help protect the fabric’s elasticity and wicking properties.

Start your year off right with more advice for healthy habits around the home at Swash.com.

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5 Ideas for an Organized, Intentional Laundry Space

Having an organized and decorated laundry room can ease the weight of your to-do list and the tension you feel from the day-to-day grind. It can also help keep your laundry routine simple, orderly and organized. Consider these tips from the laundry experts at Swash:

1. Think like a minimalist.
Empty your laundry space and sort through what you need and what you don’t. Eliminating the extras leaves room to evaluate your space. Consider whether you could organize differently to make frequently used items more accessible and make the most of your storage space. Cutting down on clutter may even make it possible to incorporate shelves or cabinets that add stylish functionality.

2. Update your space with open shelving.
Open laundry shelves offer a sense of more space, and the horizontal lines can lend a sense of calm. For an easy and attractive upgrade, try hanging 2-3 open shelves within easy reach. If you’re hesitant about the open feel, limit to just one shelf for the everyday necessities and keep the rest of your laundry supplies out of sight in a complementing cabinet. Baskets offer another option for concealing your belongings, whether you use them on the open shelves or inside cabinets to keep things tidy and clutter-free.

3. Create a practical workspace.
Mundane laundry chores like folding can be more enjoyable when you have a comfortable, dedicated space for the job. An open counter or table that folds down from the wall gives you the surface you need to fold clothing within your laundry space without disrupting the rest of the house. Other ways to add practical space include areas for sorting garments that need special attention and a place to hang items that shouldn’t be dried in the dryer.

4. Use colors and materials that evoke calm.
Natural materials and a neutral color palette can lend to a more peaceful space. Lighter neutral colors reduce stress and anxiety, promote relaxation and can even make a space feel more expansive. For a calm, refreshing area, start with a base of white then add natural textures like woven baskets, faux or real plants and marble stone accents in the tile flooring or backsplash. Add a calming color like blue to evoke the tranquility of the sky or ocean, or consider green to incorporate the soothing effects of nature.

5. Invest in products that bring you joy.
Choose quality pieces that aren’t overly trendy and will stand the test of time. Consider how your investment of laundry decor, including your washer and dryer, will serve you in the space in the coming years.

Photo courtesy of Getty Images (woman making bed)

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Swash

Our Lifestyle section on STM Daily News is a hub of inspiration and practical information, offering a range of articles that touch on various aspects of daily life. From tips on family finances to guides for maintaining health and wellness, we strive to empower our readers with knowledge and resources to enhance their lifestyles. Whether you’re seeking outdoor activity ideas, fashion trends, or travel recommendations, our lifestyle section has got you covered. Visit us today at https://stmdailynews.com/category/lifestyle/ and embark on a journey of discovery and self-improvement.

Author

  • Rod Washington

    Rod: A creative force, blending words, images, and flavors. Blogger, writer, filmmaker, and photographer. Cooking enthusiast with a sci-fi vision. Passionate about his upcoming series and dedicated to TNC Network. Partnered with Rebecca Washington for a shared journey of love and art. View all posts


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