Nano-based cancer therapies may be less effective in younger patients, finds study

Researchers at The University of Texas MD Anderson Cancer Center have discovered that certain nano-based cancer therapies may be less effective in younger patients, highlighting the need for further investigation into the impact of aging on the body's ability to respond to treatment.

The researchers found age-related differences are due to how effectively the liver filters the bloodstream. Younger livers are more efficient at this process, which helps limit toxins in the blood but also filters out beneficial treatments, potentially rendering them ineffective.

The study, published today in Nature Nanotechnology, was led by Wen Jiang, M.D., Ph.D., associate professor of Radiation Oncology, and Betty Kim, M.D., Ph.D., professor of Neurosurgery.

Put simply, our liver is designed to protect us, but for young people it might also be protecting them in a way that limits the effectiveness of nanotherapies. There's so much interest right now in nano-scale delivery systems and designs, but nobody has really considered how age plays a role in the effectiveness of these systems. In preclinical models, younger livers actually work so well that they filter out a significant amount of the nanomedicine. That means, in some cases, these drugs may be less effective in younger patients than in older ones."

Wen Jiang, M.D., Ph.D., Associate Professor of Radiation Oncology, Professor of Neurosurgery, University of Texas M. D. Anderson Cancer Center

Unlike traditional cancer therapies, in which medicine is directly introduced to the body, nanomedicines use nano-scale carriers to deliver treatments. Some of the advantages of nanomedicine formulations can include reduced toxicity, increased target specificity and increased dosage, depending on the goal of the treatment.

To date, more than 50 nano-based therapies have been approved by the Food and Drug Administration, including 19 currently listed by the National Cancer Institute for use in cancer. The study treatment was nanoparticle-albumin-bound paclitaxel, which has been used since 2005 for certain refractory or relapsed cancers.

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Scientists do not fully understand all the mechanisms for how, exactly, the liver filters the bloodstream, but previous studies have indicated a correlation between the rate of clearance and the expression of the scavenger receptor MARCO. This protein is expressed more in younger Kupfer cells, the immune cells that reside in the liver.

After confirming the disparity in results between young and old models, the team investigated therapeutic blockade of MARCO as a possible strategy to avoid drug clearance. Blocking MARCO reduced the uptake of the nanomedicine and improved the drug's antitumor effects from the cancer therapeutics, but only in the younger models.

"This is just one example, but these results show that there may not always be a one-size-fits-all drug delivery strategy that is effective across diverse patient populations, and that personalized design is warranted in future nanomedicines," Jiang said. "Hopefully, this study also opens the door for more thorough investigation of the clearance process and how to overcome it."

Jiang emphasized that while this study focuses on cancer, it examines a potential hurdle for any nanodrug delivery system. There are different proteins, antibodies and viruses with unique clearance mechanisms, but it all comes down to the liver, he explained.

Source:

University of Texas M. D. Anderson Cancer Center

Journal reference:

Wang, Y., et al. (2023) Age-associated disparity in phagocytic clearance affects the efficacy of cancer nanotherapeutics. Nature Nanotechnology. doi.org/10.1038/s41565-023-01502-3.

Study reveals cancer’s ‘infinite’ ability to evolve

By James Gallagher
Health and science correspondent


An unprecedented analysis of how cancers grow has revealed an "almost infinite" ability of tumours to evolve and survive, say scientists.


The results of tracking lung cancers for nine years left the research team "surprised" and "in awe" at the formidable force they were up against.


They have concluded we need more focus on prevention, with a "universal" cure unlikely any time soon.


Cancer Research UK said early detection of cancer was vitally important.


The study - entitled TracerX - provides the most in-depth analysis of how cancers evolve and what causes them to spread.


Cancers change and evolve over time - they are not fixed and immutable. They can become more aggressive: better at evading the immune system and able to spread around the body.


A tumour starts as a single, corrupted cell, but becomes a mixture of millions of cells that have all mutated in slightly different ways.


TracerX tracked that diversity and how it changes over time inside lung cancer patients and say the results would apply across different types of cancer.


"That has never been done before at this scale," said Prof Charles Swanton, from the Francis Crick Institute and University College London.


More than 400 people - treated at 13 hospitals in the UK - had biopsies taken from different parts of their lung cancer as the disease progressed.


"It has surprised me how adaptable tumours can be," Prof Swanton told me.


"I don't want to sound too depressing about this, but I think - given the almost infinite possibilities in which a tumour can evolve, and the very large number of cells in a late-stage tumour, which could be several hundred billion cells - then achieving cures in all patients with late-stage disease is a formidable task."

Prof Charles Swanton says challenge of tumours evolving inside our body means we need to focus on preventing cancer.


Prof Swanton said: "I don't think we're going to be able to come up with universal cures.


"If we want to make the biggest impact we need to focus on prevention, early detection and early detection of relapse."


Obesity, smoking, alcohol and poor diet all increase the risk of some cancers. Tackling inflammation in the body is also being seen as a way of preventing cancer. Inflammation is the likely explanation for air pollution causing lung cancers and inflammatory bowel disease increasing the risk of colon cancer.
Cancer rules rewritten by air-pollution discovery


The evolutionary analysis has been published across seven separate studies in the journals Nature and Nature Medicine.


The research showed:
Highly aggressive cells in the initial tumour are the ones that ultimately end up spreading around the body
Tumours showing higher levels of genetic "chaos" were more likely to relapse after surgery to other parts of the body
Analysing blood for fragments of tumour DNA meant signs of it returning could be spotted up to 200 days before appearing on a CT scan
The cellular machinery that reads the instructions in our DNA can become corrupted in cancerous cells making them more aggressive.


The researchers hope the findings could, in the future, help them predict how a patient's tumour will spread and to tailor treatment.


Dr David Crosby, the head of prevention and early detection at Cancer Research UK, said: "The exciting results emerging from TracerX improve our understanding that cancer is a disease which evolves as it progresses, meaning that late-stage cancers can become very hard to treat successfully.


"This underscores the crucial importance of further research to help us to detect cancers at the earliest stages of their development or even better, to prevent them from happening at all."


Follow James on Twitter.

Related Topics
Medical research
Cancer

An mRNA vaccine to treat pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, is one of the deadliest cancer types. Despite modern therapies, only about 12% of people diagnosed with this cancer will be alive five years after treatment.

Immunotherapies—drugs that help the body’s immune system attack tumors—have revolutionized the treatment of many tumor types. But to date, they have proven ineffective in PDAC. Whether pancreatic cancer cells produce neoantigens—proteins that can be effectively targeted by the immune system—hasn’t been clear.

An NIH-funded research team led by Dr. Vinod Balachandran from Memorial Sloan Kettering Cancer Center (MSKCC) have been developing a personalized mRNA cancer-treatment vaccine approach. It is designed to help immune cells recognize specific neoantigens on patients’ pancreatic cancer cells. Results from a small clinical trial of their experimental treatment were published on May 10, 2023, in Nature.

After surgery to remove PDAC, the team sent tumor samples from 19 people to partners at BioNTech, the company that produced one of the COVID-19 mRNA vaccines. BioNTech performed gene sequencing on the tumors to find proteins that might trigger an immune response. They then used that information to create a personalized mRNA vaccine for each patient. Each vaccine targeted up to 20 neoantigens.

Customized vaccines were successfully created for 18 of the 19 study participants. The process, from surgery to delivery of the first dose of the vaccine, took an average of about nine weeks.

All patients received a drug called atezolizumab before vaccination. This drug, called an immune checkpoint inhibitor, prevents cancer cells from suppressing the immune system. The vaccine was then given in nine doses over several months. After the first eight doses, study participants also started standard chemotherapy drugs for PDAC, followed by a ninth booster dose.

Sixteen volunteers stayed healthy enough to receive at least some of the vaccine doses. In half these patients, the vaccines activated powerful immune cells, called T cells, that could recognize the pancreatic cancer specific to the patient. To track the T cells made after vaccination, the research team developed a novel computational strategy with the lab of Dr. Benjamin Greenbaum at MSKCC. Their analysis showed that T cells that recognized the neoantigens were not found in the blood before vaccination. Among the eight patients with strong immune responses, half had T cells target more than one vaccine neoantigen.

By a year and a half after treatment, the cancer had not returned in any of the people who had a strong T cell response to the vaccine. In contrast, among those whose immune systems didn’t respond to the vaccine, the cancer recurred within an average of just over a year. In one patient with a strong response, T cells produced by the vaccine even appeared to eliminate a small tumor that had spread to the liver. These results suggest that the T cells activated by the vaccines kept the pancreatic cancers in check.

“It’s exciting to see that a personalized vaccine could enlist the immune system to fight pancreatic cancer—which urgently needs better treatments,” Balachandran says. “It’s also motivating as we may be able to use such personalized vaccines to treat other deadly cancers.”

More work is needed to understand why half the people did not have a strong immune response to their personalized vaccines. The researchers are currently planning to launch a larger clinical trial of the vaccine.

—by Sharon Reynolds

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, Aug. 1, 2023 /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.

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).

Cannabis Effective at Reducing Symptoms in Children With Cancer, but More Research Needed

Children with cancer who suffer from multiple symptoms related to the disease and its treatment can benefit from the use of cannabis, but more research needs to be done on correct dosing and safety, according to a recent study published in the journal Cancer.1

Survival rates in childhood cancer have significantly improved thanks to the development of advanced diagnostic, surgical, and radiation techniques. However, these new technologies have come with numerous treatment-related side effects, including nausea, vomiting, pain, and anorexia, which are often uncontrolled.

Cannabis products have gained popularity over the last decade to manage these symptoms in children with cancer, but little is currently known about its safety, efficacy, and dosing in this patient population.

“Pediatric oncologists are understandably reluctant to authorize cannabis because of a lack of evidence supporting the safety and efficacy of its use in children with cancer,” the authors of the study wrote.1 “There is a strong need to map the evidence on the current use of cannabinoids in children with cancer to inform the development of clinical trials evaluating the safety, dosing, and efficacy of various cannabis products in children with cancer.”

Investigators from the University of Manitoba conducted a systematic review and meta-analysis to assess the literature on the use of medical cannabis for symptom management in children with cancer. Data was gathered from 4 different databases: MEDLINE, Embase, PsycINFO, and the Cochrane Library.

A total of 34611 total citations were identified based on types of cannabis products, doses, formulations, frequencies, routes of administration, indications, clinical and demographic details, reported efficacy outcomes, and adverse events. Of those, 19 studies consisting of 1927 participants were included in the study.

Investigators found that the studies reported various cannabis products for the management of different symptoms, the most common of which was chemotherapy-induced nausea and vomiting. Adverse events associated with the use of cannabis products included somnolence, dizziness, and dry mouth.

Additionally, there were no serious adverse events related to the use of cannabis for the management of cancer-related symptoms in children across all of the studies that were included.

“It was difficult to measure benefit across studies, given a range of different outcomes and study designs; however, in interventional studies with active control groups, cannabinoids performed better in managing nausea and vomiting,” Lauren E. Kelly, PhD, lead author on the study, said in a release.2 “Data are lacking on cannabinoids’ effects on pain, mood, sleep, and health-related quality of life.”

Study limitations include number of studies included in the review, lack of uniformity in the outcomes of the included studies, inability to conduct quantitative synthesis of outcome data due to a high variability in reporting of data, and no included case-controlled or cohort studies in the review.

“Given that some children report benefits and some children experience adverse events, it is critical that more rigorous studies evaluating the effects of cannabinoids on children with cancer are conducted and shared with parents, patients, and the health care community,” Kelly said.

References

1. Chhabra, M, Ben-Eltriki, M, Paul, A, et al. Cannabinoids for symptom management in children with cancer: a systematic review and meta-analysis. Cancer. 2023; 1-15. doi:10.1002/cncr.34920

2. Are cannabis products safe and effective for reducing symptoms in children with cancer? News Release. University of Manitoba. August 28, 2023. Accessed August 28, 2023. https://news.umanitoba.ca/are-cannabis-products-safe-and-effective-for-reducing-symptoms-in-children-with-cancer/

How a simple blood test can help detect lung cancer earlier

• Lung cancer is the leading cause of cancer death worldwide.
• The overall lung cancer five-year survival rate is about 25%, which varies depending on the type of cancer and how early it was detected.
• Researchers from The University of Texas MD Anderson Cancer Center have developed a blood test that they say can help predict a person’s risk of dying from lung cancer when combined with a lung cancer risk model.

Lung cancer is considered the leading causeTrusted Source of cancer death worldwide.

Previous research shows lung cancer causes three times as many deaths in men as prostate cancer and three times as many deaths in women as breast cancer.

The survival rate for people with lung cancer depends on the type of cancer and how quickly it is diagnosed.

For example, the overall lung cancer five-year survival rateTrusted Source is about 25%. However, that increases to about 63% if the cancer is detected when only in the lungs. For lung cancer that spreads to other body organs, the five-year survival rate drops to about 8%.

Now, researchers from The University of Texas MD Anderson Cancer Center have developed a blood test they say can help predict a person’s risk of dying from lung cancer when combined with a lung cancer risk modelTrusted Source.

This study was recently published in the Journal of Clinical Oncology.

Why are lung cancer mortality risk tests needed? 

Because lung cancer symptoms may not develop until it is at a later stage, only about 16% of cases are diagnosed at an early stage.

This is important because the earlier lung cancer is detected, the better a person’s outlook will be.

“Lung cancer is the leading cause of cancer death worldwide,” said Dr. Edwin Ostrin, an assistant professor of general internal medicine at The University of Texas MD Anderson Cancer Center and co-corresponding author of this study.

“A major reason for this is that small lung cancers usually do not lead to symptoms and around two-thirds of lung cancers are thus diagnosed when they are large and have already started to spread,” Ostrin explained to Medical News Today.

“While we have made tremendous headway in treating both early and late-stage lung cancer, long-term survival is dramatically lower in more advanced lung cancer,” he added. “Any tools to provide early detection of lung cancer, and thus shift the stage at diagnosis to an earlier stage, would save lives.”

Why a blood test for lung cancer? 

According to Ostrin, doctors have known since 2011 that for those at the highest risk for lung cancer — those with a significant smoking history — screening using an annual low-dose computerized tomography (CT) scan can reduce death from lung cancer by 20%.

“However, only those with the heaviest smoking history are eligible for CT-based screening,” he said. “Additionally, screening finds lots of indeterminate pulmonary nodulesTrusted Source, the vast majority of which are not cancer but still require follow-up.”

For this reason, Ostrin and his colleagues have been working on a four-protein biomarker panel (4MP) for lung cancer early detection for most of the past decade.

“The blood test is a simple measurement of four proteins measured using immunoassayTrusted Source,” he explained. “Lab tests measuring blood proteins, including tests like prostate specific antigenTrusted Source or even pregnancy tests are almost universally measured in a similar fashion. Immunoassays are reliable, accurate, and inexpensive, and can be rapidly deployed into a variety of healthcare settings.”

The journey to a new lung cancer test 

Ostrin and his team first publishedTrusted Source their work in JAMA Oncology in 2018, where their findings showed the ability to identify those at risk for developing lung cancer when combined with smoking history.

“In 2021, we revealedTrusted Source that the same panel could help to identify which indeterminate findings found on chest CT could be cancers and which were more likely to be benign,” Ostrin noted.

Then in 2022, Ostrin and his team published a Journal of Clinical Oncology paperTrusted Source, where, using samples from the Prostate, Lung, Colorectal, and Ovarian (PLCO) studyTrusted Source, the 4MP improved upon a well-validated clinical lung cancer risk score (PLCOm2012) to identify those at highest risk for cancer.

“The combination of 4MP+PLCOm2012 performed better when it came to identifying those who may benefit from CT-based screening versus the current or previous criteria and thus could be a key tool to improving lung cancer screening, especially if combined with the ability of the 4MP to help sort out indeterminate findings after a CT,” Ostrin said.

Lung cancer blood test current research 

In this study, Ostrin said his team has now reanalyzed data from the PLCO trial, instead looking at lung cancer death.

“Individuals enrolled in PLCO were meticulously followed for as long as 20 years after enrollment,” he explained. “This allowed us to evaluate how the 4MP performed not only in predicting the development of lung cancer but in predicting those who may develop lethal lung cancer. This emphasizes the potential usefulness of the 4MP in CT-based screening because those at (the) highest risk (of) dying from lung cancer would presumably benefit the most from earlier detection of cancer at an earlier stage when it is more curable.”

For this study, researchers analyzed pre-diagnostic blood samples from more than 2,700 participants in the PLCO cancer screening trial. Of those analyzed, 552 participants later developed lung cancer and slightly more than 2,100 did not.

Of the 552 participants diagnosed with lung cancer during the six-year study period, 70% died from the disease.

Using hazard ratios, scientists evaluated the relationship between the combined risk scores generated by the use of the 4MP blood test and lung cancer risk model against lung cancer death incidence.

Researchers found the combination risk scores showed improved sensitivity, specificity, and positive predictive value when compared to the 2013 and 2021 U.S. Preventive Services Task Force (USPSTF) criteriaTrusted Source for predicting lung cancer-specific mortality among individuals who smoked at least 10 pack-years.

Research next steps

As for the next steps for the 4MP blood test, Ostrin said they are actively working to develop it into a clinical-grade test and hope to have it ready within the next few months.

Ostrin said they will also be looking to answer other questions, such as how the 4MP blood test could be used for early lung cancer detection in people with light or no tobacco use history.

Ostrin’s broader lab group is also taking parallel approaches they used for the 4MP and looking at other cancers, including pancreatic, breast, gastric, and colorectal cancer.

“In the end, we conceive of a situation where these tests could be combined into accurate and inexpensive blood tests to indicate cancer risk from a variety of cancers,” he said. “Such a test may become part of a yearly assessment of health risk, much the way cholesterol and blood pressure checks are used to assess risk from cardiovascular disease.”

Improving assessment of lung cancer

Medical News Today also spoke with Dr. Manmeet S. Ahluwalia, the deputy director, Fernandez Family Foundation Endowed Chair in Cancer Research, chief of medical oncology, and chief scientific officer of Miami Cancer Institute, part of Baptist Health, about this study.

Ahluwalia said it is important to be able to predict a person’s lung cancer early as it is often diagnosed at later stages and stage 4 lung cancerTrusted Source is incurable.

“Hence if using effective screening we can diagnose more people at early stages 1 and 2Trusted Source we can cure more people with lung cancer,” Ahluwalia said. “Estimating an individual’s risk of contracting lung cancer can effectively diagnose lung cancer at earlier stages with a screening low-dose CTTrusted Source (LDCT) where treatment modalities offer a more concrete solution.”

“The proposed model of incorporating biomarker and subject characteristics offers improved means for individualized risk assessment for lung cancer, compared to the current USPSTF criteria,” he added.

• Lung Cancer

Biomarker To Help Improve Lung Cancer Treatment Identified

 

Nonsmokers who develop lung cancer can be treated effectively with new drugs, but their tumors refuse to surrender without a fight. The drugs stop working in the long term because the tumors acquire secondary mutations that allow them to evade the medications’ therapeutic effect.

In research published today in the journal Cell Reports Medicine, investigators from the Weizmann Institute of Science report findings that may lead to relapse-free treatment for a sizeable subgroup of lung cancer patients. In a study in mice, the scientists have identified a biomarker that may help physicians select lung cancer patients who can be treated with a single antibody-based drug that is likely to bring about full remission, without cancer relapse.

“We have found a potential biomarker that may change the way patients with lung cancer are treated worldwide,” says Prof. Yosef Yarden of Weizmann’s Immunology and Regenerative Biology Department, who led the study. “Similar to how the presence of BRCA mutations predicts how breast and ovarian cancer patients will respond to drugs, the new biomarker might make it possible to match some lung cancer patients with the specific medication most likely to help them.”

Focusing on the mutations that matter

Most lung cancers are due to tobacco smoking, but the second-largest fraction of cases affects nonsmokers, and it’s characterized by mutations in a gene called EGFR. The current research began when Dr. Ilaria Marrocco, then a postdoctoral researcher in Yarden’s lab, reviewed the literature from clinical trials and realized that all patients with EGFR-positive lung cancer were being treated using the same multidrug protocol – regardless of which of the 30 known EGFR mutations were harbored in their individual tumors. These patients eventually developed drug resistance that led to cancer relapse. Marrocco wondered whether, by sorting lung tumors according to specific EGFR mutations, it might be possible to create a more personalized drug protocol and achieve better results.

"Similar to how the presence of BRCA mutations predicts how breast cancer patients will respond to drugs, the new biomarker might make it possible to match lung cancer patients with a specific medication"

“Dr. Marrocco’s observation inspired us to search for a biomarker that would predict which patients would respond well to therapy, according to the specific mutations they carry,” says Yarden. The scientists decided to focus on one of the two most common gene variants associated with EGFR in lung cancer: the L858R mutation, in which a single amino acid, out of several hundred, is replaced with another one, at point 858 in EGFR. This mutation occurs in about 40 percent of lung cancer patients whose tumors are characterized by EGFR mutations.

The scientists chose to study L858R because, unlike other mutations that affect EGFR, it has a unique impact on EGFR function. “Unlike all other mutations, this mutation requires that receptors pair up in the cancer cell membrane, after which, signals instructing the cell to start replicating are sent to the nucleus,” Yarden explains. “Using a mouse model of lung cancer with the L858R mutation, we discovered that, if this pairing does not occur, it’s like a short-circuit – the signal to initiate cellular replication cannot be sent to the nucleus, and the tumor does not grow.”

The researchers then blocked the pairing by treating the mice with an antibody drug called cetuximab, known by its trade name Erbitux, developed on the basis of research by Yarden and the late Prof. Michael Sela. Erbitux has been approved by the FDA for the treatment of colon and head and neck cancers.

“After the treatment with Erbitux, the lung tumors of mice shrank and did not reappear, not even after a long while,” Yarden says. “These results indicate that, for the large number of human lung cancer patients who have the L858R mutation, a single drug might offer a path toward full recovery, without the devastating phenomenon of cancer relapse.”

The new study also explains why previous attempts to treat EGFR-mutated lung cancer with Erbitux had failed or, at best, produced conflicting results. Explains Yarden: “Since new EGFR inhibitors were approved as lung cancer drugs nearly 10 years ago, all patients now receive these anti-EGFR medications, irrespective of the identity and number of their EGFR mutations. They are highly effective for a while, but they permit the emergence of secondary mutations that accelerate cancer relapse. By the time Erbitux is given, it is usually ineffective because it can work only against certain EGFR mutations. Our study demonstrates the importance of preselecting lung cancer patients who can be effectively treated with Erbitux from the start, based on their mutation profile.”

The scientists say that the next step would be to launch a clinical trial to establish the effectiveness of this treatment for human lung cancer patients, something that will be made easier by the fact that Erbitux has already been approved for treating other cancer types. In the meantime, Yarden and Marrocco are excited about the potential for their research to eventually have an impact on clinical practice. Marrocco: “The L858R biomarker could help save lives by offering physicians a way to provide personalized drug treatment for lung cancer patients who carry the relevant mutation.”

Reference: Marrocco I, Giri S, Simoni-Nieves A, et al. L858R emerges as a potential biomarker predicting response of lung cancer models to anti-EGFR antibodies: Comparison of osimertinib vs. cetuximab. CR Med. 2023;0(0). doi: 10.1016/j.xcrm.2023.101142