Is Cancer Contagious?
Why Many People With Lung Cancer Who Have Never Smoked Don't Respond Well To Treatments
Non-smokers who develop non-small cell lung cancer (NSCLC) can be unusually resistant to treatment for the disease.
Researchers say they think genetic mutations may be the cause.
Their findings were published today in the journal Nature Communications.
Smoking is the leading cause of lung cancer, but not all people who get lung cancer are smokers. In fact, 10% to 20% of people who get lung cancer have never smoked, according to the U.S. Centers for Disease Control and Prevention (CDC).
The causes of lung cancer among people who have never smoked remain unclear, but experts suspect a combination of environmental, genetic, and lifestyle-related factors play a role.
Lung cancer among non-smokers is the fifth leading cause of death in the world, according to Dr. Eric Singhi, an assistant professor of thoracic head and neck medical oncology at the University of Texas MD Anderson Cancer Center.
"All you need to be at risk for lung cancer is to have lungs," Singhi, who was not involved in the study, told Medical News Today.
Targeted treatment is available for non-small cell lung cancer.
However, researchers from University College London, the Francis Crick Institute, and drugmaker AstraZeneca found that the combination of two genetic mutations may explain why standard treatment is often ineffective among non-smokers.
Targeted treatment fails in 10% to 15% patients, depending upon what kind of NCSLC is being treated, Dr. Manmeet Singh Ahluwalia of the Baptist Health Miami Cancer Institute who was not involved in the study told Medical News Today
In their new study, researchers reported that a mutation in the epidermal growth factor receptor gene (EGFR) — present in up to half of non-smokers with NCSLC — combined with a mutation in the p53 gene resulted in the development of drug-resistant tumors.
Researchers said that the only about a third of people with stage IV NSCLC and an EGFR mutation survive for up to three years.
EGFR enables cancer cells to grow more quickly, whereas the p53 gene plays a role in tumor suppression.
Typically, NSCLC is treated with drugs called EGFR inhibitors, but the study found while tumors in people with just the EGFR mutations got smaller in response to treatment, some tumors actually grew after treatment among those with both the EGFR and p53 mutations.
Lab and animal studies found that these growing, drug-resistant tumors had more cancer cells that had doubled their genome, giving them extra copies of all their chromosomes. In addition, cells with both the double mutation and double genomes were more likely to multiply into new drug-resistant cells.
"We've shown why having a p53 mutation is associated with worse survival in patients with non-smoking related lung cancer, which is the combination of EGFR and p53 mutations enabling genome doubling," said Charles Swanton, PhD, a study co-author and a professor at the UCL Cancer Institute and deputy clinical director at the Francis Crick Institute, said in a statement. "This increases the risk of drug-resistant cells developing through chromosomal instability."
"While whole genome doubling itself may not always cause cancer, it can contribute to cancer growth and disease progression in various ways," added Singh.
Researchers noted that while non-small cell lung cancer patients are tested for EGFR and p53 mutations, there is no test currently available that can detect this dangerous genome doubling.
Work on such a test is under way, however.
"Once we can identify patients with both EGFR and p53 mutations whose tumors display whole genome doubling, we can then treat these patients in a more selective way," said Crispin Hiley, PhD, a study co-author and an associate professor at the UCL Cancer Institute. "This might mean more intensive follow-up, early radiotherapy or ablation to target resistant tumors, or early use of combinations of EGFR inhibitors, such as (AstraZeneca's) osimertinib, with other drugs including chemotherapy."
"Treatment strategies such as combination therapies (targeted therapy plus another treatment) have begun to emerge, aimed at preventing the emergence of resistance to a treatment," said Singhi.
He noted that these include using osimertinib in combination with conventional chemotherapy or amivantamab, an bispecific antibody targeting EGFR and MET, a gene that manufactures a protein involved in cellular signaling, growth, and survival.
"These trials are looking to prove whether two types of treatments together and upfront, offer better clinical outcomes for our patients than one targeted therapy alone," he said. "A very valid concern, however, is that combination therapies tend to be more toxic for our patients, and it can be difficult to discern which patient would benefit more one therapy versus another."
Dr. Shuresh Ramalingam, an executive director of the Winship Cancer Institute of Emory University in Georgia and a non-small cell lung cancer expert who was not involved in the study, told Medical News Today that new therapies can be tailored to address NSCLC cases where EGFR inhibitors are ineffective.
"When targeted treatments stop working, it is not uncommon for physicians to conduct molecular testing to determine if there are new mutations in the tumor," said Ramalingam, who is currently working on a new intervention for treating Stage III NSCLC tumors that cannot be removed surgically. "This knowledge informs appropriate interventions that could overcome the resistance mechanism. For example, for patients with EGFR mutation, a known resistance mechanism with targeted therapy is a new mutation known as the C797S mutation. There are new experimental drugs that are capable of overcoming this specific resistance mechanism in clinical trials."
The proportion of lung cancers occurring in individuals who have never smoked has increased in the past several decades, particularly among women and in younger age groups, said Ahluwalia.
"Approximately two-thirds of [these] cases occur in women, making women who have not smoked more than twice as likely to develop lung cancer than men who have not smoked," he said.
Nano-immunotherapy Developed To Improve Lung Cancer Treatment
Researchers at Brigham and Women's Hospital have developed a new nanomedicine therapy that delivers anticancer drugs to lung cancer cells and enhances the immune system's ability to fight cancer.
The team showed promising results for the new therapy in cancer cells in the lab and in mouse lung tumor models, with potential applications for improving care and outcomes for patients with tumors that have failed to respond to traditional immunotherapy. Their findings are published in Science Advances.
"Nanoparticles have been used for years to deliver targeted medication to tumor cells, while immunotherapy has also had a paradigm-shifting impact on how we treat cancer, by stopping cancer cells from evading our immune system," said lead author Tanmoy Saha, Ph.D., an instructor of medicine and researcher in the Division of Engineering in Medicine at the Brigham.
"Here, we've essentially connected these two approaches in one drug delivery system to treat non-small cell lung cancer."
Lung cancer is the leading cause of cancer death globally, accounting for over a quarter of all cancer-related deaths. Non-small cell lung cancer (NSCLC) is the most common form, making up roughly 85% of all lung cancer cases.
One of the popular treatment methods for NSCLC is to use immune checkpoint inhibitors, a class of drugs that block certain proteins that stop the immune system from killing cancer cells. However, most patients with NSCLC do not respond to these drugs, primarily because the treatment only targets one protein (most commonly PD-L1), and that is not abundantly expressed in most lung cancer tumors.
As a result, many patients must undergo a combination of chemo and immunotherapies, resulting in enduring side effects and toxicities.
This new therapy works by bringing a nanoparticle filled with a cancer-fighting drug straight to the tumor site, while antibodies attached to the nanoparticle bind to two different proteins (CD47 and PD-L1) on cancer cells. This dual approach allows both the innate and adaptive immune systems to locate and destroy cancer cells while minimizing the toxicities commonly associated with existing cancer treatments.
"This system operates with a kind of Velcro effect. Rather than just looking for one protein on a cancer cell that the antibody can grab onto, these nanoparticles have two," said senior author Shiladitya Sengupta, Ph.D., an associate professor of medicine and bioengineer in the Division of Engineering in Medicine at the Brigham.
"So, if a cancer cell does not express one of the proteins that our nanoparticle targets, it can still attach to the other one, and deliver the drug loaded into the nanoparticle straight to the cancerous tissue."
The researchers set out to find which proteins were expressed by lung tumors. They screened more than 80 human lung cancer patients' tissue. Once the proteins were identified, they selected antibodies to target them. Next, they functionalized the antibodies with a nanoparticle that was already loaded with an anticancer drug.
Saha and his colleagues then tested the nanoparticle's efficacy by first visualizing how well the antibodies bound to cancerous cells in the lab. They performed a series of experiments to assess and visualize the nanoparticle's binding and drug delivery capabilities. Subsequently, they tested the complex's efficacy in mouse models of two forms of lung cancer.
They found that the mice's cancer cells internalized the drug, leading to a decrease in tumor size without any major side effects or toxicities.
The study's limitations include that, so far, the therapy has only been tested on human tissue in the lab and in mouse models. It must undergo much more exhaustive toxicology studies before moving on to clinical testing.
Looking ahead, the researchers hope to adapt this technology to treat other types of cancer by exploring additional antibodies and treatments that could work with this nanomedicine approach.
"While we are seeing some success with this drug delivery platform in preclinical testing, it's important to remember that mouse and human physiology are quite different. We need more studies before we can bring this concept to clinical trials, but we're excited to see how this approach could transform cancer care," said Saha.
More information: Tanmoy Saha et al, Antibody nanoparticle conjugate-based targeted immunotherapy for non-small cell lung cancer, Science Advances (2024). DOI: 10.1126/sciadv.Adi2046. Www.Science.Org/doi/10.1126/sciadv.Adi2046
Citation: Nano-immunotherapy developed to improve lung cancer treatment (2024, June 14) retrieved 14 June 2024 from https://medicalxpress.Com/news/2024-06-nano-immunotherapy-lung-cancer-treatment.Html
This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no part may be reproduced without the written permission. The content is provided for information purposes only.
Why Many Lung Cancer Patients Who Have Never Smoked Have Worse Outcomes
The reason targeted treatment for non-small cell lung cancer fails to work for some patients, particularly those who have never smoked, has been discovered by researchers from UCL, the Francis Crick Institute and AstraZeneca.
The study, published in Nature Communications, shows that lung cancer cells with two particular genetic mutations are more likely to double their genome, which helps them to withstand treatment and develop resistance to it.
In the UK, lung cancer is the third most common type of cancer and the leading cause of cancer death. Around 85% of patients with lung cancer have non-small cell lung cancer (NSCLC), and this is the most common type found in patients who have never smoked. Considered separately, "never smoked" lung cancer is the fifth-most common cause of cancer death in the world.
The most common genetic mutation found in NSCLC is in the epidermal growth factor receptor gene (EGFR), which enables cancer cells to grow faster. It is found in about 10–15% of NSCLC cases in the UK, particularly in patients who have never smoked.
Survival rates vary depending on how advanced the cancer is, with only around a third of patients with Stage IV NSCLC and an EGFR mutation surviving for up to three years.
Lung cancer treatments that target this mutation, known as EGFR inhibitors, have been available for over 15 years. However, while some patients see their cancer tumors shrink with EGFR inhibitors, other patients, particularly those with an additional mutation in the p53 gene (which plays a role in tumor suppression), fail to respond and experience far worse survival rates. But scientists and clinicians have so far been unable to explain why this is the case.
To find the answer, the researchers re-analyzed data from trials of the newest EGFR inhibitor, osimertinib, developed by AstraZeneca. They looked at baseline scans and first follow-up scans taken a few months into treatment for patients with either EGFR-only or with EGFR and p53 mutations.
The team compared every tumor on the scans, far more than were measured in the original trial. They found that for patients with just the EGFR mutations, all tumors got smaller in response to treatment. But for patients with both mutations, while some tumors had shrunk, others had grown, providing evidence of rapid drug resistance. This pattern of response, when some but not all areas of a cancer are shrinking in response to a drug treatment within an individual patient, is known as a "mixed response" and is a challenge for oncologists caring for patients with cancer.
To investigate why some tumors in these patients might be more prone to drug resistance, the team then studied a mouse model with both the EGFR and p53 mutation. They found that within resistant tumors in these mice, far more cancer cells had doubled their genome, giving them extra copies of all their chromosomes.
The researchers then treated lung cancer cells in the lab, some with just the single EGFR mutation and some with both mutations, with an EGFR inhibitor. They found that within five weeks of exposure to the drug, a significantly higher percentage of cells with both the double mutation and double genomes had multiplied into new drug-resistant cells.
Professor Charles Swanton, from UCL Cancer Institute and the Francis Crick Institute, said, "We've shown why having a p53 mutation is associated with worse survival in patients with non-smoking related lung cancer, which is the combination of EGFR and p53 mutations enabling genome doubling. This increases the risk of drug-resistant cells developing through chromosomal instability."
Non-small cell lung cancer patients are already tested for EGFR and p53 mutations, but there is currently no standard test to detect the presence of whole genome doubling. The researchers are already looking to develop a diagnostic test for clinical use.
Dr. Crispin Hiley, from UCL Cancer Institute and a Consultant Clinical Oncologist at UCLH, said, "Once we can identify patients with both EGFR and p53 mutations whose tumors display whole genome doubling, we can then treat these patients in a more selective way. This might mean more intensive follow-up, early radiotherapy or ablation to target resistant tumors, or early use of combinations of EGFR inhibitors, such as osimertinib, with other drugs including chemotherapy."
More information: Sebastijan Hobor, Heterogeneous responses to EGFR tyrosine kinase inhibition in non-small cell lung cancer result from chromosomal instability facilitated by whole genome doubling and TP53 co-mutation, Nature Communications (2024). DOI: 10.1038/s41467-024-47606-9
Citation: Why many lung cancer patients who have never smoked have worse outcomes (2024, June 13) retrieved 14 June 2024 from https://medicalxpress.Com/news/2024-06-lung-cancer-patients-worse-outcomes.Html
This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no part may be reproduced without the written permission. The content is provided for information purposes only.
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