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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

Clinical Trials Expand Patients’ Treatment Options

Clinical trials play a crucial role in developing effective treatments for chronic health conditions. They evaluate safety and efficacy, but low enrollment delays drug approvals, limiting patient options.

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Clinical Trials

(Family Features) For health conditions with no cure, effective treatments are the next best option. However, in order to make medical interventions including new drugs, devices, vaccines and lifestyle modifications available, they must undergo a thorough evaluation process to demonstrate their benefits.

Clinical trials are an important part of this process because they provide data for researchers on the effectiveness of various treatments and interventions. However, many myths about clinical trials deter people from enrolling. In fact, more than 70% of clinical trials are delayed at least one month due to unfulfilled enrollment, according to the “Journal of Medical Internet Research.”

Delays create barriers to the drug approval process and result in fewer available treatments for chronic conditions like Crohn’s disease and ulcerative colitis. The experts at the Crohn’s & Colitis Foundation offer these facts about the importance of clinical trials:

  1. More patients can benefit from clinical trials While hundreds of participants may take part in a trial, the results can lead to new care and treatment options for an entire patient community.
     
  2. Clinical trials lead to better and improved medications. For a new treatment to be approved, it needs to demonstrate a meaningful benefit to patients, such as improved outcomes, treating a wider range of symptoms, fewer side effects or more convenience for patients.
     
  3. They provide information. Clinical trials provide evidence of a treatment’s effectiveness and safety that can be used to guide patient care.
     
  4. Trials test safety and efficacy. Clinical trials are conducted in four phases. During the first phase, the main objective is to assess the safety of a new treatment. Experimental treatments only advance to the next stages if they pass certain safety and efficacy standards
    .
  5. They help prevent bias. In a randomized controlled trial, the effects of treatment with a new drug are compared with that of a control group – either a placebo (a treatment that looks identical to the new drug but contains no active medicine) or the current standard of care. Treatment assignments are “randomized,” which means neither the trial doctors nor the participants choose which treatment each participant will receive.

How Clinical Trials Work
Before a clinical trial begins, a research team develops a clinical trial protocol. This is the research plan that describes who can join the trial, which treatments the participants will receive, what questions the researchers will try to answer, how long the trial will last and how participant privacy and safety will be protected.

Conducting clinical research relies on volunteer trial participants. Those interested in joining a clinical trial meet with clinical research professionals to discuss the trial, treatments, eligibility requirements and expectations.

Joining a Trial
If you are interested in participating in a clinical trial, do some research. Your doctor may not be aware of or proactively tell you about trials you may be eligible to join. If you find a clinical trial you may be interested in joining, discuss the trial with your doctor and other health care professionals on your research team.

Foundations supporting chronic conditions can be a good source of information. For example, you can learn more about trials affecting individuals with inflammatory bowel disease by exploring the Clinical Trials Community at crohnscolitisfoundation.org.

Photo courtesy of Shutterstock

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SOURCE:
Crohn’s & Colitis Foundation


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Why community pharmacies are closing – and what to do if your neighborhood location shutters

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Photo by Pixabay on Pexels.com

Lucas A. Berenbrok, University of Pittsburgh; Michael Murphy, The Ohio State University, and Sophia Herbert, University of Pittsburgh

Neighborhood pharmacies are rapidly shuttering.

Not long ago, Walgreens, one of the nation’s biggest pharmacy chains, announced plans to close 1,200 stores over the next three years. That’s part of a larger trend that has seen nearly 7,000 pharmacy locations close since 2019, with more expected in the coming years.

Many community pharmacies are struggling to stay open due to an overburdened workforce, shrinking reimbursement rates for prescription drugs and limited opportunities to bill insurers for services beyond dispensing medications.

As trained pharmacists who advocate for and take care of patients in community settings, we’ve witnessed this decline firsthand. The loss of local pharmacies threatens individual and community access to medications, pharmacist expertise and essential public health resources.

The changing role of pharmacies

Community pharmacies – which include independently owned, corporate-chain and other retail pharmacies in neighborhood settings – have changed a lot over the past decades. What once were simple medication pickup points have evolved into hubs for health and wellness. Beyond dispensing prescriptions, pharmacists today provide vaccinations, testing and treatment for infectious diseases, access to hormonal birth control and other clinical services they’re empowered to provide by federal and state laws.

Given their importance, then, why have so many community pharmacies been closing?

There are many reasons, but the most important is reduced reimbursement for prescription drugs. Most community pharmacies operate under a business model centered on dispensing medications that relies on insurer reimbursements and cash payments from patients. Minor revenue comes from front-end sales of over-the-counter products and other items.

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However, pharmacy benefit managers – companies that manage prescription drug benefits for insurers and employers – have aggressively cut reimbursement rates in an effort to lower drug costs in recent years. As a result, pharmacists often have to dispense prescription drugs at very low margins or even at a loss. In some cases, pharmacists are forced to transfer prescriptions to other pharmacies willing to absorb the financial hit. Other times, pharmacists choose not to stock these drugs at all.

And it’s not just mom-and-pop operations feeling the pinch. Over the past four years, the three largest pharmacy chains have announced plans to close hundreds of stores nationwide. CVS kicked off the trend in 2021 by announcing plans to close 900 pharmacy locations. In late 2023, Rite Aid said that thousands of its stores would be at risk for closure due to bankruptcy. And late in 2024, Walgreens announced its plans to close 1,200 stores over the next three years.

To make matters worse, pharmacists, like many other health care providers, have been facing burnout due to high stress and the lasting effects of the COVID-19 pandemic. At the same time, pharmacy school enrollment has declined, worsening the workforce shortage just as an impending shortfall of primary care physicians looms.

Why pharmacy accessibility matters

The increasing closure of community pharmacies has far-reaching consequences for millions of Americans. That’s because neighborhood pharmacies are one of the most accessible health care locations in the country, with an estimated 90% of Americans living within 5 miles of one.

However, research shows that “pharmacy deserts” are more common in marginalized communities, where people need accessible health care the most. For example, people who live in pharmacy deserts are also more likely to have a disability that makes it hard or impossible to walk. Many of these areas are also classified as medically underserved areas or health professional shortage areas. As pharmacy closures accelerate, America’s health disparities could get even worse.

So if your neighborhood pharmacy closes, what should you do?

While convenience and location matter, you might want to consider other factors that can help you meet your health care needs. For example, some pharmacies have staff who speak your native language, independent pharmacy business owners may be active in your community, and many locations offer over-the-counter products like hormonal contraception, the overdose-reversal drug naloxone and hearing aids.

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You may also consider locations – especially corporate-owned pharmacies – that also offer urgent care or primary care services. In addition, most pharmacies offer vaccinations, and some offer test-and-treat services for infectious diseases, diabetes education and help with quitting smoking.

What to ask if your pharmacy closes

If your preferred pharmacy closes and you need to find another one, keep the following questions in mind:

What will happen to your old prescriptions? When a pharmacy closes, another pharmacy may buy its prescriptions. Ask your pharmacist if your prescriptions will be automatically transferred to a nearby pharmacy, and when this will occur.

What’s the staffing situation like at other pharmacies? This is an important factor in choosing a new pharmacy. What are the wait times? Can the team accommodate special situations like emergency refills or early refills before vacations? Does the pharmacist have a relationship with your primary care physician and your other prescribers?

Which pharmacies accept your insurance? A simple call to your insurer can help you understand where your prescriptions are covered at the lowest cost. And if you take a medication that’s not covered by insurance, or if you’re uninsured, you should ask if the pharmacy can help you by offering member pricing or manufacturer coupons and discounts.

What are your accessibility needs? Pharmacies often offer services to make your care more accessible and convenient. These may include medication packaging services, drive-thru windows and home delivery. And if you’re considering switching to a mail-order pharmacy, you should ask if it has a pharmacist to answer questions by phone or during telehealth visits.

Remember that it’s best to have all your prescriptions filled at the same pharmacy chain or location so that your pharmacist can perform a safety check with your complete medication list. Drug interactions can be dangerous.

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Community pharmacies have been staples of neighborhoods for more than a century. Unfortunately, current trends in pharmacy closures pose real threats to public health. We hope lawmakers address the underlying systemic issues so more Americans don’t lose access to their medications, health services and pharmacists.

Lucas A. Berenbrok, Associate Professor of Pharmacy and Therapeutics, University of Pittsburgh; Michael Murphy, Assistant Professor of Pharmacy Practice and Science, The Ohio State University, and Sophia Herbert, Assistant Professor of Pharmacy, University of Pittsburgh

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

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A How-To Guide for Participating in Clinical Trials

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(Family Features) Clinical trials help researchers studying chronic conditions answer important questions about the diseases and their treatment options. However, uncertainty about what to expect and a lack of knowledge about how to get started can prevent patients from joining a clinical trial.

Choosing to take part in a clinical trial means helping a study team figure out if a new method of diagnosis, treatment or prevention is effective. If you live with a chronic condition, such as Crohn’s disease or ulcerative colitis, and want to help find answers for others who share your experience, a clinical trial is an option to consider.

Once you identify a study that interests you, you’ll want to talk with the professionals involved in your ongoing treatment, a clinical research coordinator and your family to gather information necessary to determine whether the clinical trial is a good fit.

To find additional information about clinical trials and begin exploring trials in your area, visit crohnscolitisfoundation.org, and consider these steps for participating in a trial.

Clinical Trials

1. Talking with Your Doctor
Your gastroenterologist and other care providers can help determine whether a clinical trial is right for you and may be able to help point you toward recommended trials. It’s important to ask if or how your doctor will continue to be involved in your care if you participate in a trial.

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2. Finding a Study
If you need help beyond your care team in identifying clinical trial opportunities in your area, organizations dedicated to your condition can be a good resource. For example, the Crohn’s & Colitis Foundation offers an online Clinical Trial Finder for individuals with inflammatory bowel disease.

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3. Talking with the Research Coordinator
A clinical trial research coordinator can provide details specific to your circumstances and needs. You can discuss potential benefits and risks, why the trial is being conducted and who is involved in the health care team. You can talk about past treatments and how this study may differ from your previous experiences. Other questions you might ask include what your options are if the trial doesn’t work, any costs you might expect and what your personal commitment will be.

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4. Evaluating the Fit for You
Once you have the necessary information, you’ll be able to consider whether you’re ready to move forward with registering for the trial. You’ll want to weigh factors like your time commitment, travel distance and whether the trial will affect your personal or professional obligations.

Photos courtesy of Shutterstock

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SOURCE:
Crohn’s & Colitis Foundation


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