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.
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.
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 Facebook, Twitter, YouTube, Instagram and LinkedIn.
Workers who are in frequent contact with potentially sick animals are at high risk of bird flu infection.
Costfoto/NurPhoto via Getty ImagesRon Barrett, Macalester College
Disease forecasts are like weather forecasts: We cannot predict the finer details of a particular outbreak or a particular storm, but we can often identify when these threats are emerging and prepare accordingly.
The viruses that cause avian influenza are potential threats to global health. Recent animal outbreaks from a subtype called H5N1 have been especially troubling to scientists. Although human infections from H5N1 have been relatively rare, there have been a little more than 900 known cases globally since 2003 – nearly 50% of these cases have been fatal – a mortality rate about 20 times higher than that of the 1918 flu pandemic. If the worst of these rare infections ever became common among people, the results could be devastating.
Approaching potential disease threats from an anthropological perspective, my colleagues and I recently published a book called “Emerging Infections: Three Epidemiological Transitions from Prehistory to the Present” to examine the ways human behaviors have shaped the evolution of infectious diseases, beginning with their first major emergence in the Neolithic period and continuing for 10,000 years to the present day.
Viewed from this deep time perspective, it becomes evident that H5N1 is displaying a common pattern of stepwise invasion from animal to human populations. Like many emerging viruses, H5N1 is making incremental evolutionary changes that could allow it to transmit between people. The periods between these evolutionary steps present opportunities to slow this process and possibly avert a global disaster.
Spillover and viral chatter
When a disease-causing pathogen such as a flu virus is already adapted to infect a particular animal species, it may eventually evolve the ability to infect a new species, such as humans, through a process called spillover.
Spillover is a tricky enterprise. To be successful, the pathogen must have the right set of molecular “keys” compatible with the host’s molecular “locks” so it can break in and out of host cells and hijack their replication machinery. Because these locks often vary between species, the pathogen may have to try many different keys before it can infect an entirely new host species. For instance, the keys a virus successfully uses to infect chickens and ducks may not work on cattle and humans. And because new keys can be made only through random mutation, the odds of obtaining all the right ones are very slim.
Given these evolutionary challenges, it is not surprising that pathogens often get stuck partway into the spillover process. A new variant of the pathogen might be transmissible from an animal only to a person who is either more susceptible due to preexisting illness or more likely to be infected because of extended exposure to the pathogen.
Even then, the pathogen might not be able to break out of its human host and transmit to another person. This is the current situation with H5N1. For the past year, there have been many animal outbreaks in a variety of wild and domestic animals, especially among birds and cattle. But there have also been a small number of human cases, most of which have occurred among poultry and dairy workers who worked closely with large numbers of infected animals.
Pathogen transmission can be modeled in three stages. In Stage 1, the pathogen can be transmitted only between nonhuman animals. In stage 2, the pathogen can also be transmitted to humans, but it is not yet adapted for human-to-human transmission. In Stage 3, the pathogen is fully capable of human-to-human transmission.Ron Barrett, CC BY-SA
Epidemiologists call this situation viral chatter: when human infections occur only in small, sporadic outbreaks that appear like the chattering signals of coded radio communications – tiny bursts of unclear information that may add up to a very ominous message. In the case of viral chatter, the message would be a human pandemic.
Sporadic, individual cases of H5N1 among people suggest that human-to-human transmission may likely occur at some point. But even so, no one knows how long or how many steps it would take for this to happen.
Influenza viruses evolve rapidly. This is partly because two or more flu varieties can infect the same host simultaneously, allowing them to reshuffle their genetic material with one another to produce entirely new varieties.
Genetic reshuffling – aka antigenic shift – between a highly pathogenic strain of avian influenza and a strain of human influenza could create a new strain that’s even more infectious among people.Eunsun Yoo/Biomolecules & Therapeutics, CC BY-NC
These reshuffling events are more likely to occur when there is a diverse range of host species. So it is particularly concerning that H5N1 is known to have infected at least 450 different animal species. It may not be long before the viral chatter gives way to larger human epidemics.
Reshaping the trajectory
The good news is that people can take basic measures to slow down the evolution of H5N1 and potentially reduce the lethality of avian influenza should it ever become a common human infection. But governments and businesses will need to act.
People can start by taking better care of food animals. The total weight of the world’s poultry is greater than all wild bird species combined. So it is not surprising that the geography of most H5N1 outbreaks track more closely with large-scale housing and international transfers of live poultry than with the nesting and migration patterns of wild aquatic birds. Reducing these agricultural practices could help curb the evolution and spread of H5N1.
Large-scale commercial transport of domesticated animals is associated with the evolution and spread of new influenza varieties.ben/Flickr, CC BY-SA
People can also take better care of themselves. At the individual level, most people can vaccinate against the common, seasonal influenza viruses that circulate every year. At first glance this practice may not seem connected to the emergence of avian influenza. But in addition to preventing seasonal illness, vaccination against common human varieties of the virus will reduce the odds of it mixing with avian varieties and giving them the traits they need for human-to-human transmission.
At the population level, societies can work together to improve nutrition and sanitation in the world’s poorest populations. History has shown that better nutrition increases overall resistance to new infections, and better sanitation reduces how much and how often people are exposed to new pathogens. And in today’s interconnected world, the disease problems of any society will eventually spread to every society.
For more than 10,000 years, human behaviors have shaped the evolutionary trajectories of infectious diseases. Knowing this, people can reshape these trajectories for the better.Ron Barrett, Professor of Anthropology, Macalester College
This article is republished from The Conversation under a Creative Commons license. Read the original article.
SAN DIEGO, CA, USA /EINPresswire.com/ — Missing teeth can have obvious consequences for your smile, but many people are not aware of how tooth loss affects their oral health, general well-being, and even their facial shape. Once a tooth is detached from the gums, there is no tooth root to stimulate the underlying jawbone; unfortunately, this often causes the bone structure to recede and lose volume. Bone loss can raise a number of aesthetic and functional concerns — particularly when a tooth has been without a replacement for a significant amount of time — including the shifting of surrounding teeth, an increased risk of gum disease, and changes in your jaw structure. In general, greater bone loss is experienced the longer an absent space remains unfilled. While jawbone recession can be debilitating, San Diego cosmetic dentist Landon Libby, DDS discusses potential solutions for bone loss to prevent further damage and regenerate additional bone density.
According to Dr. Libby, implant dentistry can offer a myriad of benefits for individuals with missing teeth, including the ability to maintain bone volume and preserve the full integrity of the jawbone after tooth loss. Using dental implants, implant dentistry aims to replace a missing tooth with an artificial tooth root and a custom-made restoration indistinguishable from a patient’s natural teeth. A titanium post is implanted into the jawbone during treatment, which serves as the “replacement” tooth root. Unlike other tooth replacement options that are not surgically affixed to the underlying bone, dental implants and implant-supported restorations promote new bone regeneration. Not only can this enhance a patient’s oral health and strengthen their jawbone, but implant restorations are also considered to look and feel the most similar to natural teeth. Best of all, implants can be used to replace a single tooth, multiple teeth in a row, or even a full dental arch.
It’s important to understand that every patient may not be a good candidate for dental implants, and bone grafting may be necessary prior to treatment to provide more support for implant placement. As a multi-stage process involving oral surgery, Dr. Libby stresses the importance of selecting an experienced, compassionate, and qualified dental team to place implants and provide a seamless patient experience.
About Landon Libby, DDS Dr. Landon Libby is a Mission Valley-based cosmetic dentist who provides cosmetic, restorative, and family dentistry treatments for patients in and around San Diego. As a DOCS-certified dentist with training in sedation dentistry, Dr. Libby strives to enhance patient comfort during every stage of treatment and redefine what it means to “go to the dentist.” After receiving his Doctor of Dental Surgery (DDS) from the Loma Linda University School of Dentistry, Dr. Libby went into private practice and has been serving the dental needs of the San Diego community for years. Dr. Landon Libby is available for interview upon request.
PUNE, MAHARASHTRA, INDIA /EINPresswire.com/ — Healthcare Education Market Perspective
The Global Healthcare Education Market size was worth USD 103.64 billion in 2022 and is estimated to grow to USD 202.75 billion by 2030, with a compound annual growth rate (CAGR) of approximately 8.75% over the forecast period. The report analyzes the healthcare education market’s drivers, restraints/challenges, and their effect on the demands during the projection period. In addition, the report explores emerging opportunities in the healthcare education market.
Medical professionals watching webinar on online platform. People having virtual class flat vector illustration. Online education, medicine concept for banner, website design or landing web page
Healthcare Education Market Developments
• In 2023, HealthStream (US) purchased Electronic Education Documentation System, LLC (US). This acquisition will broaden Healthstream’s ecosystem by bringing a cutting-edge, cloud-based continuing education management system for healthcare organizations and delivering cutting-edge solutions in the form of Software-as-a-Service (SaaS).
• In 2022, To promote access for surgeons and benefit more patients across the US, GE Healthcare (US) and DePuy Synthes (US) worked together to make GE Healthcare’s OEC 3D Imaging System and DePuy Synthes’ extensive product line more widely available.
Increasing need for skilled healthcare workers to drive market growth
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The market for healthcare education is expanding significantly due to the increasing need for skilled healthcare workers. The market for healthcare education is being significantly shaped by the growing demand for qualified healthcare workers. The demand for skilled physicians, nurses, allied health workers, and administrators who can deliver high-quality healthcare services is rising as the world’s population continues to expand and get older. The rising incidence of chronic illnesses and complicated medical disorders that need specialized care has increased this demand. Additionally, the need for healthcare professionals is growing outside conventional clinical responsibilities. The demand for non-clinical positions such as healthcare administrators, informatics experts, and others is also growing. As a result, healthcare education incorporates a variety of academic fields to produce a workforce that is well-rounded and able to meet the many demands of the healthcare sector.
Healthcare Education Market: Regional Landscape
Asia Pacific dominated the Healthcare Education market in 2022
There is a sizable and constantly expanding population in the Asia Pacific region, which generates a sizable demand for healthcare services. The demand for qualified and trained healthcare personnel grows proportionally as healthcare systems enlarge to meet this demand. Additionally, greater investments in healthcare infrastructure, including educational institutions, have been made as a result of the Asia Pacific region’s economic expansion. Governments and commercial organizations are becoming more aware of how crucial a strong healthcare education system is to the development of healthcare services.
Healthcare Education Market Top Players: Stryker (US), SAP (Germany), Adobe (US), Infor (US), Oracle (US), HealthStream (US), Symplr (US), Elsevier (Netherlands), Articulate (US), PeopleFluent (US), Fujifilm Corporation (Japan), GE Healthcare (US), Trivantis Corporation (US), Koninklijke Phillips (Netherlands), Siemens Healthineers (Germany), Coursera (US), and IBM (US).
Healthcare Education Market: Segmentation
The global healthcare education market has been segmented into provider, delivery mode, application, and end-user.
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Based on universities, educational platforms, and medical simulation are segments of the global healthcare education market. The university segment to improve the business and department workers, the requirement for continuous learning in a field that is rapidly evolving, partnerships with healthcare organizations, and the emphasis on patient-centered care and interprofessional collaboration are all factors driving the growth of universities and academic institutions in the market for healthcare education solutions. The aforementioned elements help healthcare education programs grow and evolve to satisfy industry demands.
Based on delivery mode, the market is classified into classroom-based, and e-learning. In 2022, the e-learning processing category dominated the global market. Due to a variety of online learning platforms, students have access to educational resources like lectures, videos, quizzes, and other resources in a digital setting. Students can learn at their own pace and convenience in e-learning environments, which usually offer flexibility. Coursera, Blackboard, and Moodle are a few popular e-learning platforms. Because of the COVID-19 pandemic, e-learning platforms have proliferated as a medium of delivery, and this trend is anticipated to continue during the projected period. The overall revenue for Coursera in 2022 was US$523.8 million, a 26% increase over 2021, while the gross profit was US$249.5 million, a 33% increase over 2021.
Based on application, the market is classified into neurology, cardiology, and pediatrics. In 2022, the cardiology category dominated the global market. It is anticipated that factors including the increased prevalence of cardiovascular diseases (CVD), technological improvements, and online courses will raise demand for educational solutions. According to the WHO’s 2021 update, CVDs encompass illnesses like coronary heart disease, cerebrovascular disease, rheumatic heart disease, and others.
Based on end-users, the market is classified into students and physicians. In 2022, the student category dominated the global market. Student prospects have increased as a result of the growing accessibility and availability of healthcare education alternatives, notably online and remote learning options. Students can learn at their own pace, from any location, at any time, and with the help of digital tools and online platforms. This accessibility makes it easier for people from different backgrounds to enter the healthcare industry by allowing students to pursue healthcare education while juggling other responsibilities.
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Ron Barrett, Professor of Anthropology, Macalester College
This article is republished from The Conversation under a Creative Commons license. Read the original article.
