Health
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.
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.
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.
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Eye Health
(Family Features) Glaucoma, one of the leading causes of permanent blindness, often does its damage silently – with no noticeable symptoms – as vision is lost. Glaucoma affects an estimated 3 million Americans, but most people don’t know they have the condition until it’s revealed in an eye exam. Once vision is lost, it cannot be recovered. If left untreated, glaucoma can cause blindness. That’s why when it comes to detecting and treating glaucoma, the earlier, the better. What is Glaucoma? Glaucoma is an eye disease caused by increased pressure in the eye, which can damage the optic nerve and reduce vision, sometimes making objects look blurry or dark. Early on, most people don’t notice what’s happening, but as glaucoma progresses, you may notice some loss of peripheral vision. By this point, the disease has progressed significantly toward blindness, and treatment options may be limited. Diagnosing Glaucoma Regular eye exams, including specific glaucoma tests, are important for the early detection and diagnosis of glaucoma. If diagnosed early, an eye doctor can recommend treatment to manage glaucoma and help prevent vision loss. “Many patients are surprised to learn glaucoma often presents with no initial symptoms,” said Oluwatosin U. Smith, MD, glaucoma specialist and ophthalmologist at Glaucoma Associates of Texas. “That’s why routine, comprehensive eye exams are so vital. These screenings allow us to detect glaucoma in its earliest stages, often before any vision loss occurs. Early diagnosis and treatment are the cornerstone of effective glaucoma management and it empowers us to take proactive steps to protect your vision.” To check for glaucoma, your eye doctor tests your eye pressure, peripheral vision and overall eye health. The painless screening is the only way to accurately diagnose the condition and determine appropriate treatment. Traditional Glaucoma Treatment For decades, prescription eye drops have been the most common treatment to help lower eye pressure and slow the progression of the disease. Although prescription eye drops are commonly prescribed and generally effective at lowering eye pressure, they can cause challenges and unwanted side effects, including redness, irritation, burning, stinging or difficulty putting them in the eye. In addition, patients may find it difficult to remember to take their eye drops every day, and missing doses – even by accident – can put vision at risk by allowing eye pressure to rise unchecked. When prescription eye drops are unsuccessful at controlling eye pressure or managing glaucoma, an eye doctor may change treatment by prescribing additional prescription eye drops, which can make the challenges and inconveniences associated with prescription eye drops worse.
Modern Glaucoma Management Takes a Proactive Approach
Modern glaucoma management is evolving with a shift from reactive – that is, take prescription eye drops and “watch and wait” until glaucoma progresses before exploring alternative treatment – to proactive management.
Taking a proactive approach to glaucoma treatment means choosing a minimally invasive procedure earlier in the treatment journey to help slow the progression of glaucoma and minimize vision loss while reducing the challenges of daily prescription eye drops.
“The shift toward a more proactive approach represents a significant advancement in how we manage glaucoma,” Smith said. “Traditionally, we waited for vision loss before a procedural intervention. However, with modern minimally invasive procedures, we can now proactively lower eye pressure and protect the optic nerve much earlier. This approach helps us preserve our patients’ vision and quality of life for longer. I encourage anyone with a glaucoma diagnosis, or those with risk factors, to discuss proactive options with their ophthalmologist.”
- Procedural pharmaceuticals, or drug delivery systems, may include tiny, FDA-approved implants that deliver medication continuously to help lower eye pressure and protect vision.
- Micro-invasive, or minimally invasive, glaucoma surgery involves less-invasive procedures, devices (such as stents) and techniques with faster recovery times than traditional surgeries.
- Laser treatment commonly involves a laser being aimed through a special lens onto the drainage system of the eye, triggering a natural change that helps fluid drain from the eye to lower pressure.
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(Family Features) Hypertrophic cardiomyopathy, also called HCM, is the leading cause of sudden cardiac death in young athletes, sometimes with no warning signs. It is characterized by the thickening and stiffening of the heart walls, which can impede the heart’s ability to pump blood efficiently since the chambers cannot fill up.
In addition, HCM is the most common inherited heart disease, affecting 1 in 500 people in the U.S., according to the American Heart Association. Because HCM runs in families, first-degree relatives – including parents, siblings and children – should be screened if a family member has been diagnosed.
Consider this information to get a better understanding of this life-altering genetic condition’s symptoms and diagnosis, which can make a crucial difference in managing the disease effectively.
Recognizing the Signs and Symptoms
The symptoms and severity of HCM can vary widely among individuals. While some people may experience no symptoms at all, common symptoms include fatigue, fainting, shortness of breath, dizziness, chest pain and irregular heartbeats, especially during physical activity. Research shows Black male athletes in high-intensity sports like football and basketball may be at higher risk.
The Importance of Family History in Diagnosis
Because HCM is a genetic condition, family history is a critical component in its diagnosis. If someone in your family has been diagnosed with HCM, heart failure or cardiac arrest, children, siblings and parents should be screened for HCM. Genetic testing and echocardiograms are commonly used to catch HCM early. These tests assess the thickness of the heart muscle and observe blood flow, which can indicate the presence of the disease.
There are two main types of HCM – obstructive and nonobstructive – and treatment options vary depending on the type and severity of symptoms.
If HCM runs in your family, don’t wait. Talk to your doctor about screening options and encourage your loved ones to do the same. Early detection can be lifesaving. To learn more about HCM, visit heart.org/HCMStudentAthlete.
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(Family Features) Obesity is a lifelong health problem that affects more than 42% of American adults and impacts some ethnic and racial groups more than others. According to the U.S. Centers for Disease Control and Prevention, nearly half (47%) of Hispanic American adults live with obesity, making it one of the most serious health risks for Hispanics.
Obesity has been linked to serious conditions including diabetes, heart disease, cancer and digestive health issues, including gastroesophageal reflux disease and liver disease. Many patients do not make the connection between their weight and the impact on these other health conditions. They are unaware these conditions can be prevented and, in most cases, treated successfully by weight management.
“As a gastroenterologist, patients often come to my office for serious health issues such as liver disease, which they don’t realize is caused by obesity,” said Dr. Andres Acosta, an obesity doctor and gastroenterologist at the Mayo Clinic. “They often don’t know these issues can be prevented or reversed by staying at a healthy weight. This is very important for Hispanic American adults who have higher rates of obesity and liver disease than other ethnicities. Maintaining a healthy weight is an important way to prevent or reverse many conditions before they become severe.”
While some weight-loss programs, services and treatments are covered by insurance plans, many others are not, and without access to affordable, effective treatments, maintaining a healthy weight can be difficult.
There is an urgent need for expanded access to treatment and care, including screening and treatment of obesity from a diverse range of health care providers. This should include coverage of prescription drugs for long-term weight management, behavioral counseling and other prevention and treatment options.
People can act by advocating for changes in state-level policies to expand Medicaid coverage for obesity treatment and care by reaching out to their elected officials.
In addition to advocating for policy changes, consider these important obesity facts:
- Poor lifestyle choices alone do not lead to obesity.
- Certain health conditions caused by obesity can be reversed by losing weight.
- Obesity treatments are available from a variety of health care providers.
- You have the power to advocate for and impact the future of obesity treatment.
- There are many helpful ways patients can try to manage their weight.
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