Tag Archives: #lungcancer

Combination of Experimental Drug Classes Shown to Extend Survival in Mice with Lung Cancer (Medicine)

combination of experimental drugs increased the attack of immune cells on non-small cell lung cancer (NSCLC) to extend survival in mice, a new study found.

Led by researchers at NYU Grossman School of Medicine and its Laura and Isaac Perlmutter Cancer Center, the study results revolve around the immune system, and specifically T cells, which can destroy cells infected with foreign organisms like viruses. The immune system also recognizes cancer cells as abnormal, but tumors produce proteins that turn down immune responses, while immunotherapies seek to counter immune suppression and enhance T cell assault.

Published online August 5 in Cancer Discovery, the new study focused on the effect of a compound called SHP099, which blocks the action of SHP2, an enzyme that plays a critical role in pathways abnormally activated in specific cancer types. Although SHP099 is a “tool compound” that itself cannot be used in patients, several SHP2 inhibitors are in clinical trials for a variety of cancers.

The action of SHP2 is required for efficient activation of KRAS—a molecular switch that becomes “stuck in growth mode” to cause cancerous growth. In the current study, SHP099 treatment of mouse lung tumors caused by a mutant KRAS prevented them from growing; during the same time period; untreated tumors increased in size by 150 percent. These findings showed that at least some T cells in these mice were capable of killing tumor cells. Their effects were limited, however, as the tumors ultimately regrew and killed the mice, which led the study authors to suspect that another cell population might be interfering with T cell action.

The researchers then found that, in addition to its beneficial effects, SHP2 inhibition also causes an influx of granulocytic myeloid-derived suppressor cells (gMDSCs) into tumors, which signal T cells to switch into a type that does not attack tumors well. Subsequent experiments showed that SHP2 inhibition with SHP099 caused cancer cells to produce specific “chemokines,” signaling molecules that attract cells to the source of production, in this case, tumor cells. The chemokine produced upon SHP099 treatment function by binding a surface protein (receptor) on gMDSCs called CXCR2. The infiltrating gMDSCs then impaired the anti-tumor actions of T cells.

To overcome this inhibition, the researchers then tried combining SHP099 with a CXCR2 inhibitor, SX682, designed by Syntrix Pharmaceuticals and currently in clinical trials. This combination significantly reduced gMDSC infiltration compared with SHP099 alone and completely suppressed tumor growth after two weeks of treatment, the time point at which tumor-bearing mice treated with an inert molecule (vehicle) for comparison started to die. The combination also prolonged the survival (median: 38 days) as compared to SHP099 alone (median: 27 days) or just SX682 (median: 21.5 days), and more than doubled overall survival compared with vehicle-treated (median: 18 days) mice. The team found no toxicity after five weeks of combination treatment.

“Our study results showed how one targeted drug could address a weakness in the other, creating a stronger anti-cancer immune environment around tumors,” says co-corresponding author Kwan Ho Tang, PhD, a research scientist in the laboratory of Benjamin G. Neel, MD, PhD, director of Perlmutter Cancer Center. “We would argue that this combination should be tried together in a clinical trial.”

Experiments by the team confirmed that SHP2 inhibition itself causes an influx into tumors of gMDSCs, which are part of normal immune defenses but are changed by signals given off by tumors. The abundance of the gMDSCs in patients with cancer have been linked by past studies to reduced overall survival in multiple solid tumor types.

“We also found in experiments in human NSCLC cells that the influx of gMDSCs brought about by SHP2 inhibitors through CXCR2 may be sabotaging the ability of other emerging drug classes to harness T cell attack as well,” says co-corresponding author Kwok-Kin Wong, MD, PhD, the Anne Murnick Cogan and David H. Cogan Professor of Oncology in the Department of Medicine at NYU Langone Health and director of the Division of Hematology and Medical Oncology. “These may include MEK inhibitors, a newly FDA-approved drug designed to interfere with a single cancer-causing mutant protein called G12C present in many lung cancers, as well as EGF receptor inhibitors, an important treatment for patients with lung tumors carrying mutations in the EGFR gene.”

Finally, say the authors, the study suggests that additional “immune checkpoint” inhibitors could be added to the study combination in future examinations. The immune system uses “checkpoints”—sensors on immune cells that turn them off when they receive the right signal—to spare normal cells from immune attack. Cancer cells hijack checkpoints to turn off immune responses.

Along with Dr. Tang and Dr. Wong, the study was led by co-corresponding author Dr. Neel, and by first author Shuai Li. Other NYU Langone study authors are Jayu Jen, Han, Kayla Guidry, and Ting Chen at Perlmutter Cancer Center; Cynthia Loomis in the Department of Pathology; and Aristotelis Tsirigos, Alireza Khodadadi-Jamayran, and Yuan Hao in the Applied Bioinformatics Laboratories. Other study co-investigators are John Zebala and Dean Maeda of Syntrix Pharmaceuticals; James Christensen and Peter Olson of Mirati Therapeutics; Argus Athanas of Monoceros Biosystems, Inc.; and Carmine Fedele of the Novartis Institutes for BioMedical Research. The study was funded by National Institutes of Health grants P01CA229086, R01CA252239, CA49152, CA248896, and P30 CA016087.

Dr. Wong holds equity in G1 Therapeutics and Recursion Pharmaceuticals; has sponsored research agreements with Mirati Therapeutics, Takeda, BMS, Merus, Alkermes, Ansun Biopharma, Tvardi Therapeutics, Delfi Diagnostics, and Dracen Pharmaceuticals; and has consulting agreements with Allorion, AstraZeneca, Genocea, Epiphanes, Hillstream, Novartis, Merck, Recursion, Navire, Mirati, Prelude, Ono, Janssen, Pfizer, and Zentalis. Dr. Neel holds equity in, and receives consulting fees from, Navire Pharma and Jengu Therapeutics, and holds equity in Northern Biologics, Arvinas, and Recursion. He also has a sponsored research agreement with Mirati and received consulting fees from MPM Capital and Gerson Lehrman Group. His spouse holds equity in Amgen and held equity in Moderna and Regeneron at times during the current study. These relationships are being managed in keeping with the policies of NYU Langone.

Featured image: Perlmutter Cancer Center researchers find a combination of experimental drugs increases the attack of immune cells on non-small cell lung cancer to help extend survival in mice. PHOTO: ROGER HARRIS/SCIENCE PHOTO LIBRARY/GETTY


Reference: Kwan Ho Tang, Shuai Li, Alireza Khodadadi-Jamayran, Jayu Jen, Han Han, Kayla Guidry, Ting Chen, Yuan Hao, Carmine Fedele, John A Zebala, Dean Y Maeda, James G Christensen, Peter Olson, Argus Athanas, Cynthia A Loomis, Aristotelis Tsirigos, Kwok-Kin Wong and Benjamin G Neel, “Combined Inhibition of SHP2 and CXCR1/2 Promotes Anti-Tumor T Cell Response in NSCLC”, Cancer Discovery, 2021. DOI: 10.1158/2159-8290.CD-21-0369


Provided by NYU Langone

Study Identifies MET Amplification as Driver for Some Non-Small Cell Lung Cancers (Medicine)

CU Cancer Center researchers get positive results treating patients with MET-inhibitor drug crizotinib.

A study led by D. Ross Camidge, MD, PhD, director of thoracic oncology at the University of Colorado School of Medicine and CU Cancer Center member, has helped to define MET amplification as a rare but potentially actionable driver for non-small cell lung cancer (NSCLC).

Camidge says many of the major developments in the treatment of non-small cell lung cancer have come from defining molecularly specific subsets of the disease for which researchers have been able to develop targeted treatments. Until now, all of these subsets have been based on either genetic mutations or gene rearrangements (where two separate genes fuse to create an oncogene).

“What we’ve started to realize is that non-small cell lung cancer isn’t just one disease,” Camidge says. “Over the last 15 or so years, we’ve started to pull apart separate diseases within that umbrella. Now, there are at least eight different molecularly specific subtypes with an FDA-approved therapy.”

Gene amplification as cancer driver

The new paper, titled “Crizotinib in Patients With MET-Amplified NSCLC,” and published in the June issue of the Journal of Thoracic Oncology, introduces a third means of defining NSCLC subsets that can be targeted with a specific drug. Rather than a mutation or a gene rearrangement, this third category represents oncogene activation through gene amplification. Gene amplification occurs when there is an increase in the usual number of copies of a particular gene, but the process can be difficult to identify.

“Unlike gene mutations or gene rearrangements — which are either there or not — gene amplification is a continuous variable,” Camidge says. “How many extra copies do you need for it to make a difference? Is it an increase in just that one gene because it’s so important to the cancer, or is it being dragged along for the ride by an increase in lots of other genes in the same part of the chromosome? Where do you put the cut point to say this level matters and this level does not? That’s why identifying gene amplification as a definable driver of NSCLC has been challenging.”

For this study, Camidge and the other investigators in the Pfizer-sponsored study focused specifically on MET amplification. MET is a gene that encodes a protein normally involved in cell growth. Although it is normally well-controlled, it can become dysregulated and drive some cancers’ behavior. This can sometimes occur as a result of genetic mutations or gene rearrangement, but it can also occur through gene amplification.

If MET amplification is a cancer driver in some patients, then it stood to reason that inhibiting MET could slow or stop the progression of NSCLC in those patients.

To test that theory, the study required hospitals and cancer centers to screen tumor samples from NSCLC patients for MET amplification using a genetic test called fluorescence in situ hybridization (FISH). At CU and for several other sites, the MET FISH testing was performed by Marileila Varella-Garcia, PhD, a former professor of medical oncology at the School of Medicine (now retired).

During the study, a total of 88 patients with varying levels of MET amplification received crizotinib. Although crizotinib is currently licensed as an ALK (anaplastic lymphoma kinase) and ROS1 (c-ros oncogene 1) inhibitor for treatment of some other subtypes of NSCLC., it is also a MET inhibitor.

The results showed that patients with the highest levels of MET amplification responded to therapy with crizotinib at the highest rates, experiencing longer periods of tumor-progression-free survival, while patients with lower levels of MET amplification responded less favorably to the treatment.

The study, which started in 2006, is one of the largest efforts to define the relevant diagnostic test for meaningful levels of MET gene amplification and prove that MET-inhibitor drugs are effective for treating patients with NSCLC driven by MET amplification.

“It has been a long and difficult course for this rare subtype of lung cancer, but I think this is fairly good proof that there are some patients where MET amplification alone is driving their cancer,” Camidge says.

Making the case for MET amplification testing and therapies

Camidge says that MET amplification-driven NSCLC is unique for a number of reasons. First, it’s extremely rare, accounting for less than 1% of all NSCLCs.

Second, it tends to occur in patients who are not normally identified as having lung cancers with oncogenic drivers, including smokers and the elderly.

“It’s not your classic driver oncogene subtype,” he says. “It tends to break most of the rules we normally associate with driver oncogenes, which is that they are normally found in younger people and people who have never smoked. So, even if you’re a smoker, even if you’re older, if your doctor hasn’t found a driver oncogene and they haven’t looked for MET amplification, they should think about it.”

“This is a truly actionable oncogene. It’s rare, but it’s real.” – D. Ross Camidge, MD, PhD


Because of this, Camidge says that NSCLC patients without an identified driver oncogene should consider getting tested for MET amplification. He specifically recommends using the FISH testing method utilized in the study rather than relying solely on next generation sequencing, a different type of genetic testing that can return false negatives when it comes to identifying MET amplification.

“While some sequencing tests can reliably pick up gene amplification in a comparable manner to the FISH testing, others cannot,” Camidge says. “It’s all buried in the software that each commercial company or academic lab uses to analyze their sequencing data. I think pulling that apart will come in the near future as we better define what exactly we are looking for to make MET copy number information clinically relevant.”

As for using MET inhibitors to treat patients with MET amplification-driven NSCLC, Camidge says drug companies are starting to explore MET amplification as an additional target for new and existing MET inhibitors, and that he hopes the team’s findings will help inform that research and development to eventually help patients.

“This is a truly actionable oncogene,” he says. “It’s rare, but it’s real.”

Featured image: D. Ross Camidge, MD, PhD © CU Cancer Center


Reference: D. Ross Camidge, Gregory A. Otterson, Jeffrey W. Clark, Sai-Hong Ignatius Ou, Jared Weiss, Steven Ades, Geoffrey I. Shapiro, Mark A. Socinski, Danielle A. Murphy, Umberto Conte, Yiyun Tang, Sherry C. Wang, Keith D. Wilner, Liza C. Villaruz, Crizotinib in Patients With MET-Amplified NSCLC, Journal of Thoracic Oncology, Volume 16, Issue 6, 2021, Pages 1017-1029, ISSN 1556-0864, https://doi.org/10.1016/j.jtho.2021.02.010. (https://www.sciencedirect.com/science/article/pii/S155608642101710X)


Provided by University of Colorado Cancer Center

A Brooklyn Breakthrough: Robotic Diagnosis & Surgery for Lung Cancer in a Single Day (Medicine)

At NYU Langone Hospital—Brooklyn, a Tag-Team Approach to Evaluating & Removing Nodules

Maria Rodriguez, 62, has been a pack-a-day smoker since she was a teenager, so her primary care physician orders an annual lung cancer screening. This year, the low-dose CT scan revealed a small nodule. Normally, the finding would lead to further imaging tests or a needle biopsy. Instead, Rodriguez, who lives in the Bensonhurst section of Brooklyn, skipped these steps thanks to a novel tag-team robotic approach being pioneered by NYU Langone Health’s Lung Cancer Center, part of Perlmutter Cancer Center.

In March, Rodriguez was wheeled into an operating room (OR) at NYU Langone Hospital—Brooklyn and sedated. There, Jorge M. Mercado, MD, associate section chief of pulmonary, critical care, and sleep medicine, inserted a first-of-its-kind robotic scope called the Monarch through her mouth and airways. Using a handheld controller, Dr. Mercado maneuvered the long, flexible camera deep into her lungs. The scope’s robotic features, which afford unprecedented control, allowed Dr. Mercado to safely travel further into the fragile airways, where he identified and biopsied the suspicious mass. Deepthi Hoskoppal, MD, clinical assistant professor of pathology, meanwhile, evaluated the sample in the OR rather than transporting it to the pathology lab. Within minutes, Dr. Hoskoppal identified the cancerous cells, and Dr. Mercado injected a contrast marker to aid in locating the cancer during surgery. The team then exchanged the robotic scope for a robotic surgical system. Thoracic surgeon Travis C. Geraci, MD, assistant professor of cardiothoracic surgery, identified the area with the cancer and removed a small segment of the lung. Rodriguez was discharged two days later, effectively cured of her stage I malignancy. “I was relieved they caught it and that I don’t require further treatment,” she says.

Diagnosing and treating early-stage lung cancer in one day is a first—for Brooklyn and for Perlmutter Cancer Center. The same-day approach spares patients weeks of worry between appointments. More important, it saves precious time. “Removing lung cancer as early as possible is critical to prevent it from spreading,” says Dr. Mercado.

Brooklyn patients like Rodriguez who require lung cancer surgery are in expert hands. Dr. Geraci was trained by two of the most accomplished robotic surgeons in the country, Robert J. Cerfolio, MD, MBA, director of clinical thoracic surgery and chief of hospital operations at NYU Langone, and Michael Zervos, MD, chief of thoracic surgery at NYU Langone’s Manhattan campus. Together, they have completed more than 3,500 robotic thoracic surgeries. “They’ve been at the forefront of robotic surgery for years and were a big reason why I came to NYU Langone,” says Dr. Geraci.

The robotic surgical system Dr. Geraci uses, like those at other NYU Langone locations, offers a minimally invasive approach for removing lung cancers. With a 3D camera providing visual guidance for the surgeon, who operates from a nearby console, tiny surgical instruments mounted on robotic arms permit precise movements. In addition to reduced scarring and a shorter recovery time compared with conventional surgery, “the robotic method has clear advantages for removing a small segment rather than an entire lobe,” says Dr. Geraci.

Robotic diagnostic and surgical procedures are only half the story of Perlmutter Cancer Center’s heightened emphasis on treating lung cancer in Brooklyn. “Our mission is to provide access to underserved, underrepresented communities,” says Abraham Chachoua, MD, the Jay and Isabel Fine Professor of Oncology and medical director of the Lung Cancer Center.

With that in mind, the Lung Cancer Center launched a screening initiative at the Sunset Park Family Health Center at NYU Langone—Second Avenue last August. The program leverages Epic, NYU Langone’s electronic health record system, to identify patients who should be scanned annually based on their smoking history and additional risk factors, including a family history of lung cancer and exposure to asbestos. The initiative has expanded to other Family Health Centers at NYU Langone in Brooklyn and NYU Langone Levit Medical in Midwood, with plans to add additional practices in Brooklyn, as well as in Queens, Manhattan, and Long Island.

Early detection is vital for robotic surgery, generally a viable option only for stage I and stage II tumors. It boosts the effectiveness of other lung cancer treatments as well. At Perlmutter Cancer Center, a National Cancer Institute–designated Comprehensive Cancer Center, these treatments include radiation therapy, chemotherapy, and clinical trials for patients whose mutations are likely to respond to investigational therapies. Brooklyn patients have access to all of these services through Perlmutter Cancer Center—Sunset Park, an airy, 25,000-square-foot facility that opened two blocks from NYU Langone Hospital—Brooklyn in 2019. “We are offering comprehensive lung cancer care and giving more patients access to it,” says Dr. Chachoua. “No other hospital in Brooklyn has a robust screening program like the one we’re building,” he notes.

Maria Rodriguez is a shining example of the difference stepped-up early detection and treatment can make. Two decades ago, she lost her older sister, also a smoker, at age 42 to lung cancer, just a month after diagnosis. “She didn’t get screenings, and by the time they found the cancer, she was at stage IV,” recalls Rodriguez. By contrast, Rodriguez’s scan revealed a suspicious lesion early on, and a team of doctors at NYU Langone was able to remove it quickly. “I’m grateful to Dr. Geraci and Dr. Mercado,” says Rodriguez. “This procedure saves patients time, and it will save lives.”

Featured image: Thoracic surgeon Dr. Travis Geraci and pulmonologist Dr. Jorge Mercado meet with their patient, Maria Rodriguez, after using a novel same-day robotic approach to diagnose and remove her early-stage lung cancer. PHOTO: NYU LANGONE STAFF


Provided by NYU Langone

Potential Marker For Success Of Immunotherapy in the Treatment of Lung Cancer (Medicine)

Lung cancer has the highest mortality rate of all cancers, and treatment options are extremely limited, especially for patients with oncogenic mutations in the KRAS gene. A great deal of hope was invested in the licensing of immune checkpoint inhibitors, but the reality is that some patients respond very well to this treatment while it is completely ineffective in others. In a paper just published in Science Translational Medicine, a MedUni Vienna research group led by Herwig Moll (Center for Physiology and Pharmacology) identified a potential marker for the success of immunotherapy in lung cancer patients and explained the underlying molecular processes.

K-Ras it is a monomeric G protein that plays a key role in the growth of malignant tumours. KRAS-mutated lung carcinomas frequently occur in chronically inflamed lungs, particularly in heavy smokers. The inflammatory processes promote the growth of cancer cells. The research group has now shown that the expression of the highly anti-inflammatory protein A20, formed in the body itself, is often very low in these malignant cells and that there is a direct correlation between a patient’s life expectancy and the expression of this protein. Moll explains: “Both in humans and in the animal model, the loss of A20 leads to downgraded immune surveillance of cancer cells. Cancer cells with low levels of A20 are able to escape detection by the immune system.” This results in significantly faster tumour growth.

During the course of this study, which was co-funded by MedUni Vienna’s Cancer Research Initiative and associated with the Comprehensive Cancer Center Vienna, the research team discovered that it is primarily an enhanced sensitivity of the cancer cells to the immunomodulatory cytokine interferon gamma that is responsible for this. Moreover, tumour cells with downregulated A20 responded particularly well to immune checkpoint inhibitors, in the same way as patients suffering from melanoma (skin cancer) with a similar gene expression structure.

“In A20 we have discovered a previously unknown tumour suppressor in lung cancer, the loss of which as an immune checkpoint contributes to the development of this malignant disease,” explains co-author Emilio Casanova from the Institute of Pharmacology. Since patients with low A20 expression have few tumour-fighting immune cells and so, in the advanced stage, express little of the important immune checkpoint molecule PD-L1, these patients could be excluded from immunotherapies directed against PD-L1. Indeed, the strength of expression of this molecule is currently regarded as an aid for deciding whether or not they should be treated with immune checkpoint inhibitors. “Based on our results and the data available from melanoma patients, we are convinced that we have identified a group of lung cancer patients who would really benefit from this immunotherapy. Exclusion from such treatment would significantly reduce the survival rate of such patients.”

In a further study, the researchers want to find out whether it is possible to manipulate the expression of A20 in the cancer cells, in order to intensify the effect of immunotherapies. “However, smoking is still the most easily avoided risk factor for lung cancer. We must therefore support laws to protect the general public from inhaling harmful smoke, while at the same time appealing to people’s personal responsibility to refrain from smoking altogether,” says Moll. According to the MedUni Vienna experts, it is nevertheless important to continue to investigate new therapeutic approaches to improve the quality-of-life and chances of survival of those affected.

Service: Science Translational Medicine
“Downregulation of A20 promotes immune escape of lung adenocarcinomas.” K. Breitenecker, M. Homolya, A. C. Luca, V. Lang, C. Trenk, G. Petroczi, J. Mohrherr, J. Horvath, S. Moritsch, L. Haas, M. Kurnaeva, R. Eferl, D. Stoiber, R. Moriggl, M. Bilban, A. C. Obenauf, C. Ferran, B. Dome, V. Laszlo, B. Győrffy, K. Dezso, J. Moldvay, E. Casanova, H. P. Moll.

DOI: stm.sciencemag.org/lookup/doi/10.1126/scitranslmed.abc3911


Provided by Medical University of Vienna

Scientists Discover Novel Oncogenic Driver Gene in Human Lung Cancer (Biology)

A research team led by Prof. WANG Yuexiang from the Shanghai Institute of Nutrition and Health (SINH) of the Chinese Academy of Sciences discovered a novel oncogenic driver gene in human lung cancer, the leading cause of cancer-related mortality worldwide.  

Their findings were published in Journal of Experimental Medicine on June 18.     

Approximately 85% of all lung cancer cases are non-small cell lung cancers (NSCLCs). Although tyrosine kinase inhibitors and immunotherapy have contributed to survival benefits in some patients, the overall survival rates for NSCLCs remain low.  

Patients with NSCLC that are driven by KRAS mutations are often unresponsive to tyrosine kinase inhibitors and have a poor prognosis. Although inhibitors for the KRASG12C mutant have been approved to treat NSCLC patients, a general strategy that targets all KRASmutants remains elusive. 

Central precocious puberty (CPP) is largely caused by germline mutations inthe MKRN3 gene. Interestingly, CPP has been epidemiologically linked to various diseases in adulthood, including cancers. Cohorts of individuals with CPP show an increased risk of malignancies such as lung cancers.  

To investigate whether central precocious puberty-associated MKRN3 gene is mutated in human cancers, the research team led by Prof. WANG Yuexiang queried The Cancer Genome Atlas (TCGA) Pan-Cancer genomic data sets. Strikingly, MKRN3 is frequently mutated in NSCLCs. MKRN3 aberrations are significantly enriched in human NSCLC samples harboring oncogenic KRAS mutations.   

The researchers further presented genetic, functional, mouse models and mechanistic data that identify the central precocious puberty-associated gene MKRN3 gene as a bona fide tumor suppressor in NSCLC. They uncovered its tumor suppressing mechanism and highlighted MKRN3-PABPC1 axis deregulation as a key pathway in lung cancer oncogenesis.  

MKRN3 inactivation led to lung cancer proliferation and progression through PABPC1 ubiquitination mediated global protein synthesis. MKRN3 restoration in MKRN3-inactivated NSCLC suppressed tumor growth in nude mice. Therefore, molecular interventions targeting MKRN3 deficiency may have therapeutic potential for KRAS-mutant NSCLC treatment.     

These findings showed that biological mechanisms of central precocious puberty are relevant in tumorigenesis, which may help in developing anticancer drugs.     

This project was supported by the National Natural Science Foundation of China, Ministry of Science and Technology of China, Science and Technology Commission of Shanghai Municipality, and Chinese Academy of Sciences.  

Featured image: A model depicting how the MKRN3-PABPC1 axis controls cell proliferation and progression in lung cancer. (Image by WANG Yuexiang’s group)  


Reference: Ke Li, Xufen Zheng, Hua Tang, Yuan-Sheng Zang, Chunling Zeng, Xiaoxiao Liu, Yanying Shen, Yuzhi Pang, Simin Wang, Feifei Xie, Xiaojing Lu, Yuxiang Luo, Zhang Li, Wenbo Bi, Xiaona Jia, Tao Huang, Rongqiang Wei, Kenan Huang, Zihao Chen, Qingchen Zhu, Yi He, Miaoying Zhang, Zhizhan Gu, Yichuan Xiao, Xiaoyang Zhang, Jonathan A. Fletcher, Yuexiang Wang; E3 ligase MKRN3 is a tumor suppressor regulating PABPC1 ubiquitination in non–small cell lung cancer. J Exp Med 2 August 2021; 218 (8): e20210151. doi: https://doi.org/10.1084/jem.20210151


Provided by Chinese Academy of Sciences

Loss Of Circadian Regulation Allows For Increase in Glucose Production During Lung Cancer Progression (Medicine)

New study identifies possible therapeutic target to suppress cancer cell growth

New research from the University of California, Irvine reveals how the circadian regulation of glucose production in the liver is lost during lung cancer progression, and how the resulting increase in glucose production may fuel cancer cell growth.

The new study titled, “Glucagon regulates the stability of REV-ERBα to modulate hepatic glucose production in a model of lung cancer-associated cachexia,” published today in Science Advancesillustrates how the circadian clock is regulated under conditions of stress such as during lung cancer progression and cancer-associated tissue wasting disease called cachexia.

“Our research shows that a critical circadian protein, REV-ERBa, controls glucose production in the liver. During lung cancer progression and specifically under conditions of cachexia, this circadian regulation is lost, resulting in increased glucose production from the liver,” said senior author Selma Masri, PhD, assistant professor in the Department of Biological Chemistry at UCI School of Medicine. “Based on our findings, we identified that lung tumors are able to provide instructive cues to the liver to increase glucose production, a major fuel source for cancer cells.”

This research places the circadian clock as a central regulator of glucose production during lung cancer progression and provides important insight toward the development of novel therapeutics to target REV-ERBa to suppress cancer cell growth.

“We are continuing to investigate the consequence of increased glucose production during lung cancer progression by tracing the metabolic fate of this newly generated glucose to determine if this fuel source can drive the heightened metabolic demand of lung cancer cells,” said Amandine Verlande, PhD, and Sung Kook Chun, PhD, postdoctoral scholars in the Masri Laboratory.

The circadian clock is our intrinsic biological pacemaker that maintains physiological homeostasis in all tissues of the body. Under conditions of stress, the biological clock is rewired as an adaptive mechanism to maintain synchrony and equilibrium throughout the body.

This research was supported in part by the National Institutes of Health, Concern Foundation, V Foundation for Cancer Research, Cancer Research Coordinating Committee, and shared resources supported through the UCI Chao Family Comprehensive Cancer Center.

Featured image: During lung cancer progression and the corresponding development of cachexia, circadian control of glucose production is disrupted, resulting in increased levels of glucose from the liver. These findings illustrate a tissue-tissue crosstalk whereby a lung tumor can disrupt the circadian metabolism of a distal tissue, potentially for its own growth advantage. © UCI School of Medicine


Provided by UCI School of Medicine

Early Lung Cancer Coopts Immune Cell Into Helping Tumors Invade the Lungs (Medicine)

Immune cells that normally repair tissues in the body can be fooled by tumors when cancer starts forming in the lungs and instead help the tumor become invasive, according to a surprising discovery reported by Mount Sinai scientists in Nature in June. 

The researchers found that early-stage lung cancer tumors coopt the immune cells, known as tissue-resident macrophages, to help invade lung tissue. They also mapped out the process, or program, of how the macrophages allow a tumor to hurt the tissues the macrophage normally repairs. This process allows the tumor to hide from the immune system and proliferate into later, deadly stages of cancer. 

Macrophages play a key role in shaping the tumor microenvironment, the ecosystem that surrounds tumors in the body. By investigating this microenvironment, researchers can find key players that drive tumor growth that can be tested as targets for immunotherapy. But modifying macrophages therapeutically has proven difficult. 

In this study, scientists studied tissue samples from lung cancer tumors and surrounding lung tissue in 35 patients to see the role of macrophages in the development of the tumors.  

The study’s lead author, Miriam Merad, MD, PhD, Director of the Precision Immunology Institute at the Icahn School of Medicine at Mount Sinai, and a multidisciplinary team of thoracic surgeons, pathologists, and medical oncologists within the Institute of Thoracic Oncology devised a comprehensive study that began when patients went into surgery to have cancerous lesions removed. The patients’ lung tumor samples, samples of surrounding healthy lung tissue, and blood samples were immediately analyzed on a cellular level at Mount Sinai’s Human Immune Monitoring Center to map out the immune system components they contained. 

Researchers identified the macrophages at play in the early development of lung cancer, identifying a potential target for future drug development. They also found that the process that allows the macrophages to help tumors invade lung tissues is present in mice as well, which will allow them to manipulate the macrophages in future mouse models knowing that the manipulation is relevant to humans.  

Half of all early-stage lung cancers relapse, and once they do and reach later stages, it is deadly and irreversible. Knowing how to attack the cancer at an early stage could have huge impacts on the number of patients relapsing and their overall survival. 

“These findings are very important for Mount Sinai in the future as we have a very strong lung cancer screening program that identifies patients with early lung cancer lesions before they become fully invasive,” said Dr. Merad, who is also the Director of the Human Immune Monitoring Center and a member of the Institute of Thoracic Oncology and The Tisch Cancer Institute at Mount Sinai. “These findings will help devise immunoprevention strategies to prevent tumor progression in patients at risk by reprogramming macrophages and killing the tumor without surgery.”


Reference: Casanova-Acebes, M., Dalla, E., Leader, A.M. et al. Tissue-resident macrophages provide a pro-tumorigenic niche to early NSCLC cells. Nature (2021). https://doi.org/10.1038/s41586-021-03651-8


Provided by Mount Sinai

Antibody Targets Mechanism That Enables Lung Cancer to Grow and Spread (Medicine)

An investigational antibody in clinical trials for lung cancer appears to disrupt a mechanism that tumor cells exploit to avoid being destroyed by the body’s innate immune system, researchers at Duke Health report.

In a study appearing online June 16 in the journal PLOS ONE, the researchers describe a mechanism by which the investigational antibody may potentially inhibit the growth and spread of cancer cells. The antibody, which was identified by Duke scientists, is currently being tested in a Phase 1 clinical trial among advanced non-small-cell lung cancer patients.

“These findings are an important insight to understand the mechanism of action for this antibody, which will help us select who are the most appropriate patients to receive it as a line of treatment,” said senior author Edward F. Patz, M.D., professor in the departments of Radiology and Pharmacology & Cancer Biology and member of the Duke Cancer Institute

Patz and his laboratory, in collaboration with investigators at the Duke Human Vaccine Institute, isolated the antibody. Patz has co-founded a spin-out company, Grid Therapeutics, to advance its development. 

He said the antibody works against a regulator called complement factor H (CFH), which protects host cells from attack and destruction by the body’s own immune system. Tumor cells use this same method to protect themselves from destruction by the immune system.

Notably, CFH also protects a type of tiny sac called an extra-cellular vesicle that is secreted by tumor cells. These bubble-like vesicles contain proteins and information-carrying molecules that they transport between cells. Lung cancer tumors have an abundance of CFH, which results in greater numbers of extracellular vesicles. Protected from immune attack, the vesicles transfer their cargo into other cells, enabling the cancer to grow and spread. 

“This is a way that tumors promote growth and metastasize,” Patz said. “Our antibody targets this by shutting down CFH, inhibiting the tumor growth. This was an unexpected but interesting finding, which helps us understand a complicated process. If we can better understand the mechanism of the antibody, we can use it more effectively.”

Patz said the antibody therapy will move to a Phase 2 clinical trial shortly, with patients enrolled at multiple sites. The study will combine the antibody with the current immunotherapy, pembrolizumab. 

In addition to Patz, study authors include Ryan T. Bushey, Elizabeth B. Gottlin and Michael J. Campa. In addition to Patz, Campa and Gottlin are also co-founders of Grid Therapeutics.

Featured image credit: gettyimages


Reference: Bushey RT, Gottlin EB, Campa MJ, Patz EF Jr (2021) Complement factor H protects tumor cell-derived exosomes from complement-dependent lysis and phagocytosis. PLoS ONE 16(6): e0252577. doi:10.1371/journal.pone.0252577


Provided by Duke Health

Lung Cancer’s Resistance to Chemotherapy Reveals New Treatment Approach (Medicine)

Garvan researchers uncover a mechanism behind lung cancer’s block to effective treatment.

New research at the Garvan Institute of Medical Research and ANZAC Research Institute has uncovered a mechanism that helps lung cancer cells resist standard chemotherapies.

A team led by Associate Professor David Croucher and Associate Professor Andrew Burgess found that individual lung adenocarcinoma cells, the most common form of lung cancer, were more likely to be resistant to platinum-based therapies when the treatment was administered during a certain stage of the cell life cycle.

The findings of the proof-of-principle study, recently published in the journal eLife, help explain why survival rates for lung cancer are so low and could prove to be an important piece in the puzzle of designing more effective treatments that improve patient outcomes, says co-senior author Associate Professor Croucher.

“Understanding the genetic factors that influence resistance to chemotherapy is hugely important to improving patient outcomes,” says Associate Professor Croucher, who heads the Network Biology Lab at the Garvan Institute.

“But this study has shown a non-genetic mechanism – essentially the replication of DNA which occurs as cancer cells rapidly grow and divide – that allows the cancer cells to be resistant to treatment. Having identified this mechanism, we now need to find ways to overcome it, because our standard approaches for targeted therapies do not take it into account,” says co-senior author Associate Professor Burgess, from the ANZAC Research Institute and the University of Sydney.

Current therapies fall short

Lung cancer is the leading cause of cancer-related deaths, claiming more than 1.5 million lives around the world each year. Better therapies for treating advanced stages of the disease are urgently needed as tumours are often diagnosed only once they have progressed to late stages of disease.

“Platinum-based chemotherapies, such as the drug cisplatin, have been used to treat lung cancer for more than 40 years despite only a small portion of patients responding positively to the treatment. The vast majority (70%) are resistant to these common therapies,” says Associate Professor Burgess.

To better understand what underpins adenocarcinoma drug resistance, the researchers investigated how adenocarcinoma cells responded to treatment during different stages of their life cycle, which all cells go through as they grow and divide to produce new cells.

Using RNA sequencing and fluorescent biosensors to track how the cells survived over time, the team administered cisplatin to the cancer cells in tissue culture using a method that closely simulates drug metabolism in patients.

“We identified that adenocarcinoma cells that were in the early S phase of their life cycle were better able to grow and divide after treatment than cells at other stages of growth,” says first author Dr Alvaro Gonzalez Rajal.

“These findings correlated with reduced DNA damage over multiple generations of these cells, where cells that had been in other stages of growth when cisplatin was administered maintained higher levels of DNA damage.”

Dr Alvaro Gonzalez Rajal
Dr Alvaro Gonzalez Rajal © Garvan

Path towards combination therapies

Associate Professor Croucher says that early S phase cancer cells are at the ideal stage of their life cycle to repair the damage caused by platinum-based chemotherapy because they are rapidly duplicating their DNA in preparation for cell division.

“We’ve shown that cells that are just starting to replicate their DNA are more resistant to this treatment, because the chemotherapy destroys the cancer cells by damaging the DNA. As the cells in early S phase are at a point where they’re actively replicating their DNA, they are primed to recognise and fix the damage and survive the treatment,” says Associate Professor Burgess.

“Encouragingly, further experiments have demonstrated that cells treated with PARP/RAD51 inhibitors, which prevent cancer cells from repairing themselves, also maintained damage similar to cells at other stages of the cell cycle.”

“This research demonstrates a path forward in developing treatments that improve on current standard therapies, by preventing resistance to treatment. If we can find a way to target this mechanism for resistance in patients, then we could hopefully increase the effectiveness of platinum-based therapies and drastically improve the outcomes for lung cancer patients,” says Associate Professor Croucher.

This research was supported by the Helen Guest Fellowship, the Cancer Institute NSW, National Breast Cancer Foundation, and Tour de Cure, with thanks to the ANZAC Microscopy and Flow Facility, the Sydney Informatics Hub, and the University of Sydney.

Featured image: Associate Professor David Croucher © Garvan Institute of Medical Research


Provided by Garvan