Tag Archives: #lungcancer

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

Landmark Study Rings in the First Immune-based Therapy For Patients With Resected, High-risk Early-stage Non-small Cell Lung Cancer (Medicine)

  • Selected by the American Society of Clinical Oncology (ASCO) as an Oral Presentation during its 2021 Virtual Annual Meeting, 04 – 08 June, primary results from the phase III IMpower010 global trial show that treatment with an immune checkpoint inhibitor improves disease-free survival in patients with resected, stage II-III, non-small cell lung cancer (NSCLC).
  • Demonstrating improved disease-free survival compared to best supportive care, this pivotal trial is the very first phase III study to evidence the efficacy of immunotherapy atezolizumab in this patient population. 
  • Administered as adjuvant therapy following surgery and chemotherapy, atezolizumab showed improved disease-free survival in stage II-IIIA randomized patients, with greater benefit observed in the PD-L1-positive subgroup. 

With an estimated 2.2 million new cancer cases and 1.8 million deaths in 2020, lung cancer is the second most commonly diagnosed cancer and the leading cause of death from cancer, representing approximately one in 10 cancers diagnosed and one in 5 deaths (1). Non–small cell lung cancer (NSCLC) is the most prevalent type and accounts for approximately 84% of all lung cancers(2)

Considering these statistics, there is a critical need to seek out and develop more potent treatment opportunities aimed at treating lung cancer, especially in the early-stage setting. The phase III, global, open-label, randomized IMpower010 trial(3), enrolling 1280 participants across 231 sites, including the Vall d’Hebron Institute of Oncology (VHIO), was designed to assess the efficacy and safety profile of immune checkpoint inhibitor (ICI) atezolizumab as adjuvant therapy in patients with resected, high-risk early-stage NSCLC. 

Directed by Heather A. Wakelee, Stanford University Medical Center (CA, USA), and co-led by Enriqueta Felip, Principal Investigator of VHIO’s Thoracic Tumors Group, IMpower010 compared treatment with atezolizumab to best supportive care (BSC). Following surgical resection and adjuvant chemotherapy, a total of 1005 patients were randomized 1:1 to receive either 16 cycles of atezolizumab or BSC. 

Selected by the American Society of Clinical Oncology (ASCO) as an Oral Presentation(4), results showed that IMpower010 achieved its primary endpoint. Strikingly, treatment with atezolizumab showed a statistically significant DFS improvement in stage II-III NSCLC patients, with even greater benefit observed in the PD-L1-positive subgroup. 

In PD-L1 expressers, the two-year DFS rate was 74.6% for atezolizumab versus 61.0% for best supportive care. The overall risk of disease recurrence was reduced by 34% with atezolizumab, with a statistically significant p value of 0.004. Importantly, the safety profile was consistent with other previous studies of atezolizumab monotherapy across indications and lines of therapy. 

These positive findings show that atezolizumab after adjuvant chemotherapy may offer a promising treatment option that extends DFS in patients with resected Stage II-IIIA NSCLC, particularly in people whose tumors express PD-L1. 

 “These results open up a new therapeutic avenue for these patients. They also shine important light on more effectively treating high-risk cancer in the early-stage setting before it spreads, as well as potentially preventing the recurrence of disease,” concluded Enriqueta Felip, co-lead author of this present study, Head of the Thoracic Cancer Unit, Vall d’Hebron University Hospital (HUVH – Vall d’Hebron Barcelona Hospital Campus), and Vice President, Spanish Society of Medical Oncology (SEOM).

IMpower010 is supported by the pharmaceutical company F. Hoffmann-La Roche Ltd. 


References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018 Nov;68(6):394-424. https://acsjournals.onlinelibrary.wiley.com/doi/full/10.3322/caac.21492.
  2. Key Statistics for Lung Cancer. American Cancer Society. Last revised: January 12, 2021. https://www.cancer.org/cancer/lung-cancer/about/key-statistics.html.
  3. Study to Assess Safety and Efficacy of Atezolizumab (MPDL3280A) Compared to Best Supportive Care Following Chemotherapy in Patients With Lung Cancer (IMpower010). NCT02486718.
  4. American Society of Clinical Oncology’s (ASCO), 2021 Virtual Annual Meeting, 04 – 08 June.

Abstract 8500. IMpower010: Primary results of a phase III global study of atezolizumab versus best supportive care after adjuvant chemotherapy in resected stage IB-IIIA non-small cell lung cancer (NSCLC). https://meetinglibrary.asco.org/record/195950/abstract.

Featured image: Dr. Enriqueta Felip © VHIO


Provided by VHIO

Newly Approved Targeted Therapy Sotorasib Prolongs Survival in KRAS G12C-mutated Lung Cancer (Medicine)

Phase II study presented by MD Anderson at ASCO shows KRAS inhibitor is safe, offers durable clinical benefit

Results from the Phase II cohort of the CodeBreaK 100 study showed that treatment with the KRAS G12C inhibitor sotorasib achieved a 37.1% objective response rate and 12.5 months median overall survival in previously treated patients with KRAS G12C-mutated non-small cell lung cancer (NSCLC), according to researchers from The University of Texas MD Anderson Cancer Center. The findings were presented today at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting and published in the New England Journal of Medicine.

Trial results indicated the targeted therapy was safe and tolerable in a heavily pre-treated patient population. The reported findings make sotorasib the first KRAS G12C inhibitor to demonstrate overall survival benefit in a registrational Phase II clinical trial.

Sotorasib was approved by the Food and Drug Administration on May 28, 2021, based on previously reported results from the CodeBreaK 100 trial. It is the first ever direct KRAS inhibitor to earn regulatory approval.

“KRAS has been an elusive therapeutic target for more than 30 years and was deemed ‘undruggable.’ This trial provides convincing evidence that mutant KRAS can be successfully and selectively targeted, resulting in meaningful prolongation of survival without compromising quality of life,” said lead author Ferdinandos Skoulidis, M.D., Ph.D., assistant professor of Thoracic/Head & Neck Medical Oncology. “These results, along with the regulatory approval of sotorasib, represent a major landmark for patients with KRAS G12C-mutated lung cancer, who now have an approved targeted therapy option.”

KRASis the most common oncogenic driver in NSCLC, found to be mutated in 25-30% of patients. Sotorasib (AMG 510) is an irreversible and selective small-molecule inhibitor that targets a specific type of mutant KRAS protein called KRAS G12C, which is found in approximately 13% of all lung adenocarcinomas.

Study reveals rapid, durable clinical benefit with tolerable side effects

The single-arm, multi-center trial enrolled 126 patients with locally advanced or metastatic KRAS G12C-mutated NSCLC that had progressed after receiving immune checkpoint inhibitors and/or platinum-based chemotherapy. Sotorasib is a once-daily oral drug. The primary endpoint was objective response, assessed by independent central review.

The study found an objective response in 46 patients (37.1%), including four complete responses (3.2%) and 42 partial responses (33.9%). One hundred patients (80.6%) had disease control, with tumors shrinking or remaining stable. The median overall survival was 12.5 months, median duration of response was 11.1 months and median progression-free survival was 6.8 months.

Toxicities were manageable and primarily low grade, with only nine patients (7.1%) discontinuing therapy due to treatment-related adverse events. Of the 88 patients (69.8%) who had treatment-related adverse events, 25 (19.8%) were Grade 3 events and one (0.8%) was a Grade 4 event.

Study participants had a median age of 63.5 and were evenly split (50%) between men and women. The majority of patients (81.7%) were white, followed by Asian (15.1%), Black (1.6%) and other races (1.6%). Patients had received up to three previous lines of therapy and 96.8% had metastatic disease. A total of 81% of patients previously received both platinum-based chemotherapy and immune checkpoint inhibitors.

“In eight out of 10 patients, the tumor either shrank or remained stable, and these patients frequently saw improvement in their symptoms,” Skoulidis said. “They’re able to lead longer, active lives, because this targeted therapy is not associated with any major toxicities that would adversely affect the patient’s quality of life.”

Sotorasib effective in challenging subgroup and more research is underway

The study also analyzed responses among molecular subgroups and found particularly encouraging results among patients with STK11 co-mutations, without concurrent mutations in KEAP1. The 50% objective response rate and 11-month median progression-free survival in this group is notable because STK11-mutated tumors tend to respond poorly to standard of care therapies, including immunotherapy and chemotherapy.

Study investigators found response to sotorasib across other molecular subgroups, as well. The drug showed broad and consistent activity across patients with a wide range of baseline characteristics related to age, previous lines of therapy and other demographics.

“These study results are practice-changing, but our work isn’t done,” Skoulidis said. “Extensive efforts are underway to understand the determinants of response to sotorasib and to characterize the full spectrum of possible mechanisms of resistance. These results represent a foundational step in our progress against KRAS-mutant tumors and will likely be a stepping stone for even more effective combination regimens. The future looks promising.”

Skoulidis reports research support from Amgen Inc. A full list of co-authors and their disclosures can be found in the paper. The study was supported by Amgen Inc. and in part by the National Institutes of Health Cancer Center Support Grant (P30 CA008748) at Memorial Sloan Kettering Cancer Center.


Provided by MD Anderson Cancer Center

Oncotarget: Retaining Nanomolar Potency in Lung Cancer With Therapy-refractory Mutations (Medicine)

Oncotarget published “The acylfulvene alkylating agent, LP-184, retains nanomolar potency in non-small cell lung cancer carrying otherwise therapy-refractory mutations” which reported that KEAP1 mutant NSCLCs further activate NRF2 and upregulate its client PTGR1. LP-184, a novel alkylating agent belonging to the acylfulvene class is a prodrug dependent upon PTGR1.

The authors hypothesized that NSCLC with KEAP1 mutations would continue to remain sensitive to LP-184. LP-184 demonstrated highly potent anticancer activity both in primary NSCLC cell lines and in those originating from brain metastases of primary lung cancers.

LP-184 activity correlated with PTGR1 transcript levels but was independent of mutations in key oncogenes and tumor suppressors.

Correlative analyses of sensitivity with cell line gene expression patterns indicated that alterations in NRF2, MET, EGFR and BRAF consistently modulated LP-184 sensitivity.

These correlations were then extended to TCGA analysis of 517 lung adenocarcinoma patients, out of which 35% showed elevated PTGR1, and 40% of those further displayed statistically significant co-occurrence of KEAP1 mutations.

The gene correlates of LP-184 sensitivity allow additional personalization of therapeutic options for future treatment of NSCLC.

The gene correlates of LP-184 sensitivity allow additional personalization of therapeutic options for future treatment of NSCLC.

Dr. Aditya Kulkarni from The Lantern Pharma, Inc. said, “KEAP1, KRAS, TP53 and STK11/LKB1 are among the commonly altered genes with considerable clinical prevalence in non-small cell lung cancers (NSCLC).”

The authors profiled primary and metastatic in vitro models of NSCLC for their sensitivity to LP-184 as well as standard of care agents, evaluated gene correlates of LP-184 response, and obtained evidence on in vivo anti-tumor effect of LP-184.

Mutated KEAP1 and concomitant decreased KEAP1 activity in cancer cells induces greater nuclear accumulation of NRF2, causing enhanced transcriptional induction of antioxidants, xenobiotic metabolism enzymes, and drug efflux pumps, thereby rendering KEAP1 mutations predictive of chemotherapy resistance in NSCLC patients.

The identification of a trend toward detrimental overall survival among a subset of platinum-treated NSCLC patients harboring co-occurring KRAS and STK11 mutations could label a more aggressive molecular subtype of NSCLC.

They therefore investigated LP-184 sensitivity in NSCLC cell lines harboring individual or concomitant mutations in KEAP1, KRAS, TP53 and STK11.

They sought to assess LP-184 activity in a panel of selected NSCLC adenocarcinoma cell lines, determine associations between genomic and transcriptomic profiles and responses of cell lines tested, and compare in vitro potency of LP-184 with that of approved chemotherapy agents.

The Kulkarni Research Team concluded in their Oncotarget Research Output, “Our key findings demonstrate that the alkylating agent LP-184 has nanomolar potency in several NSCLC cell lines and is more potent than selected approved alkylating chemotherapeutics. Additionally, LP-184 has the potential to target tumors with elevated PTGR1 regardless of presence of other co-occurring mutations but is especially found to be effective in the background of clinically significant KEAP1 mutations. We propose further evaluation of LP-184 in multiple PTGR1 high NSCLC settings that may not necessarily be mutually exclusive, including in highly prevalent KEAP1 and KRAS mutant tumors (Figure above), and in patients with lack of actionable targets or resistance-related genes with no effective therapy options available.”

DOI – https://doi.org/10.18632/oncotarget.27943

Full text – https://www.oncotarget.com/article/27943/text/

Featured image: Clinical data analyses from TCGA reveal distinct patient subgroups with elevated PTGR1 that are likely to be predicted responders to LP-184. (A) Analysis of clinical data on 517 lung adenocarcinoma patients shows frequency of mutated genes across the observed PTGR1 relative gene expression range. The value adjacent to the highly mutated gene is a two-sided permutation test p-value of PTGR1 relative gene expression between driver mutated (red) and non-mutated (white) samples. (B) Analysis of clinical data on the same 517 lung adenocarcinoma patients as in (A) displays patient subsets by PTGR1 expression status, and mutational frequencies of selected driver genes within the PTGR1 elevated subset. © Correspondence to – Aditya Kulkarni – aditya@lanternpharma.com


Reference: Kulkarni A., McDermott J. Ryan, Kathad U., Modali R., Richard J., Sharma P., Bhatia K. The acylfulvene alkylating agent, LP-184, retains nanomolar potency in non-small cell lung cancer carrying otherwise therapy-refractory mutations. Oncotarget. 2021; 12: 791-806. Retrieved from https://www.oncotarget.com/article/27943/text/


Provided by Impact Journals LLC

Using Artificial Intelligence to Predict Which People with Lung Cancer Will Respond to Immunotherapy (Medicine)

NCI Awards $3 Million Grant to Perlmutter Cancer Center & Case Western Reserve University

Recent advances in immunotherapy have benefited people with locally advanced or metastatic non-small cell lung cancer, but unfortunately not all patients have a favorable response to these treatments. The complexity and dynamic nature of the tumor interactions with the immune system make it challenging to develop tests to develop predictive tests (biomarkers) for immunotherapy.

The National Cancer Institute (NCI) has awarded a 5-year, $3 million grant to researchers at NYU Langone Health’s Perlmutter Cancer Center and Case Western Reserve University in Cleveland to develop and apply artificial intelligence (AI) tools for predicting which people with lung cancer will respond to immunotherapy.

Vamsidhar Velcheti, MD, director of the Thoracic Medical Oncology Program at Perlmutter Cancer Center, in collaboration with Anant Madabhushi, PhD, director of Case Western Reserve’s Center for Computational Imaging and Personalized Medicine, developed new technologies to evaluate tumor response to immunotherapy. Using advanced computer image analysis tools and AI-based algorithms, they could identify signatures, or biomarkers, on CT scan images that could predict which patients would respond to immunotherapy. The NCI grant awarded to the team will allow further development of these tools and help with clinical translation of this research.

“One of the advantages of our approach and the tools that we have developed is that we can use routinely acquired contrast enhanced CT scans, which are used commonly in lung cancer,” says Dr. Velcheti, who is also a member of the Lung Cancer Center and an associate professor in the Department of Medicine at NYU Langone. “These tools can be used to predict response to treatment and longitudinally follow a patient’s progress on treatment.”

The signatures the researchers identified can quantitatively assess the tortuosity (twistedness) of blood vessels within and surrounding the tumors. Dr. Velcheti and his colleagues found that increased vessel tortuosity around a tumor is a strong predictor of response to immunotherapy. Patients who have tumors with increased vessel tortuosity tend to have poor response to immunotherapy possibly because of impaired immune cell trafficking into the tumor.

“Some lung tumors tend to have a lot of twists and turns in the blood vessels due to secretion of VEGF (vascular endothelial growth factor, a protein that causes an increase in the number of blood vessels, fueling tumor growth). These tumors do not respond well to treatment with immunotherapy,” Dr. Velcheti says. “Using the new radiomic biomarker that measures vessel tortuosity, we can identify patients who could potentially benefit from combining immunotherapy with drugs that inhibit VEGF.”

With the NCI grant, Dr. Velcheti and colleagues at Perlmutter Cancer Center plan to develop a clinical trial to test the effect of immunotherapy combined with drugs that inhibit the VEGF protein, which would enable immune cells to gain access to the tumor.

“The NCI funding is a critical step to help translate the exciting science from the lab to the clinic,” Dr. Velcheti says. “This grant will help us continue our multidisciplinary and multi-institutional collaborative research to bring novel and efficient diagnostic tools to help patients with lung cancer.”

Featured image credit: gettyimages


Provided by NYU Langone

CT Promising for Sublobar Resection in Early-Stage Non-Small Cell Lung Cancer (Medicine)

CT features help select patients with stage IA non-small cell lung cancer for sublobar resection, rather than more extensive surgery

According to an open-access Editor’s Choice article in ARRS’ American Journal of Roentgenology (AJR), CT features may help identify which patients with stage IA non-small cell lung cancer are optimal candidates for sublobar resection, rather than more extensive surgery.

This retrospective study included 904 patients (453 men, 451 women; mean age, 62 years) who underwent lobectomy (n=574) or sublobar resection (n=330) for stage IA non-small cell lung cancer. Two thoracic radiologists independently evaluated findings on preoperative chest CT, later resolving any discrepancies. Recurrences were identified via medical record review.

“In patients with stage IA non-small cell lung cancer, pathologic lymphovascular invasion was observed only in solid-dominant part solid nodules and solid nodules with solid portion diameter over 10 mm,” concluded corresponding author Mi Young Kim from the department of radiology at the University of Ulsan College of Medicine, Asan Medical Center. 

“Among such nodules,” the authors of this AJR article continued, “peritumoral interstitial thickening (odds ratio=13.22) and pleural contact (odds ratio=2.45) were independently associated with pathologic lymphovascular invasion.” Moreover, models incorporating these features independently predicted recurrence-free survival after sublobar resection (hazard ratio=5.37–6.05).

Featured image: (A) 70-year-old woman with pulmonary adenocarcinoma who underwent sublobar resection without evidence for pLVI. 15-mm solid nodule with irregular margins present in right lower lobe (arrow). No tumor recurrence on 37-month follow-up. (B) 75-year-old man with pulmonary adenocarcinoma who underwent wedge resection that exhibited pLVI. 19-mm solid nodule with irregular margins and peritumoral interstitial thickening (arrowheads) present in right upper lobe. Ipsilateral mediastinal and hilar lymph node metastasis occurred after 5-month follow-up (not shown). © American Roentgen Ray Society (ARRS), American Journal of Roentgenology (AJR)


Provided by ARRS

Single-cell Map Of Early Stage Lung Cancer & Normal Lung Sheds Light On Tumor Development, New Therapeutic Targets (Medicine)

Researchers at The University of Texas MD Anderson Cancer Center have developed a first-of-its-kind spatial atlas of early-stage lung cancer and surrounding normal lung tissue at single-cell resolution, providing a valuable resource for studying tumor development and identifying new therapeutic targets. The study was published today in Cancer Discoverya journal of the American Association for Cancer Research.

The findings reveal a heterogeneous lung cancer ecosystem, with extensive interactions between cancer cells and the surrounding microenvironment that regulate early cancer development. By studying the crosstalk between the tumor and surrounding immune cells, researchers identified and validated CD24, an immune checkpoint protein, as a new immunotherapy target for lung cancer treatment.

“Our study is the first to look at this through spatial mapping of multi-region normal tissues and the tumor itself at the single-cell level,” said co-senior author Humam Kadara, Ph.D., associate professor of Translational Molecular Pathology. “This work provides new insights into how lung adenocarcinomas evolve from a particular region in the lung and already has pointed us to a promising new therapeutic target in CD24.”

Through this work, the research team sought to gain a better understanding of how and why lung tumors develop in a particular region of the lung versus another. This understanding offers opportunities not only to better treat early-stage cancers, but also to improve screening and prevention strategies.

The research was led by Ansam Sinjab, Ph.D., postdoctoral fellow in Translational Molecular Pathology, and Guangchun Han, Ph.D., postdoctoral fellow in Genomic Medicine. To construct this single-cell map, the multidisciplinary team performed single-cell RNA sequencing of 186,916 cells from five early-stage lung cancers and 14 normal lung tissue samples.

“This high-resolution spatial mapping generated a much more complete picture of lung cancer than was previously available, and we believe this will be a valuable resource to the research community,” said co-senior author Linghua Wang, M.D., Ph.D., assistant professor of Genomic Medicine. “We now have a greater understanding of the tremendous heterogeneity of diverse cell populations within the tumor immune microenvironment and of the importance of tumor-microenvironment interactions in regulating cancer progression.”

The analysis revealed significant heterogeneity within a given tumor and across multiple tumors. Further, while normal lung epithelial cells were distinct from the tumor cells, those closer to the tumor shared more similarities with the tumor cells compared to distant normal tissue. These signatures also were evident in precancerous lesions compared to normal lung tissue, suggesting the data may be useful in identifying markers for early detection or prevention.

Similar trends were observed when looking at immune cells. With increasing proximity to the tumor, the researchers observed a shift in immune cell composition and signals toward a pro-tumor,  immunosuppressive environment. Interestingly, specific immune populations were present in samples from smokers that were absent in those from non-smokers.

By examining interactions between the tumor and immune microenvironment, the researchers discovered that CD24, highly expressed in lung cancer cells, is a pivotal point of interaction between cancer cells and immune cells. In independent cohorts of early-stage lung cancers, CD24 expression correlated with poor clinical outcomes and shortened survival. Further, blocking CD24 significantly reduced the growth of lung cancers in animal models.

Going forward, the researchers will continue experiments to identify the best strategy for targeting CD24 therapeutically, with the goal of performing future clinical studies to evaluate new treatment strategies for patients with early-stage lung cancer.

The research team continues to analyze additional patient samples to expand the data resource, taking a deeper dive to understand how immune cell populations change dynamically during early lung cancer development. The researchers also plan to look more closely at how different cancer drivers, such as smoking or genetic mutations, influence the tumor immune microenvironment and its role in the evolution of early-stage lung cancer.

The study was supported in part by research funding from Johnson & Johnson, the National Cancer Institute (R01CA205608, 1U2CCA233238, P50 CA016672), The University of Texas SPORE in Lung Cancer (P50CA070907), the National Institutes of Health (1S10OD024977), the Cancer Prevention and Research Institute of Texas (RP150079, RP160668) and MD Anderson. A full list of collaborating authors and their disclosures can be found here.

Featured image: CD24 (brown) shown on the surface of early stage lung cancer cells. Image courtesy Kadara laboratory.


Reference: Ansam Sinjab, Guangchun Han, Warapen Treekitkarnmongkol, Kieko Hara, Patrick M Brennan, Minghao Dang, Dapeng Hao, Ruiping Wang, Enyu Dai, Hitoshi Dejima, Jiexin Zhang, Elena Bogatenkova, Beatriz Sanchez-Espiridion, Kyle Chang, Danielle R. Little, Samer Bazzi, Linh M. Tran, Kostyantyn Krysan, Carmen Behrens, Dzifa Y. Duose, Edwin R. Parra, Maria Gabriela Raso, Luisa M Solis, Junya Fukuoka, Jianjun Zhang, Boris Sepesi, Tina Cascone, Lauren Averett Byers, Don L. Gibbons, Jichao Chen, Seyed Javad Moghaddam, Edwin J. Ostrin, Daniel Rosen, John V. Heymach, Paul Scheet, Steven M. Dubinett, Junya Fujimoto, Ignacio I. Wistuba, Christopher S. Stevenson, Avrum Spira, Linghua Wang and Humam Kadara, “Resolving the spatial and cellular architecture of lung adenocarcinoma by multiregion single-cell sequencing”, Cancer Discovery, 2021. DOI: 10.1158/2159-8290.CD-20-1285


Provided by MD Anderson Cancer Center