MD Anderson Research Highlights for November 3, 2021

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Newswise – HOUSTON – Research Highlights from the MD Anderson Cancer Center at the University of Texas provide an overview of recently published studies on basic, translational and clinical cancer research by experts at MD Anderson. Current advances include cost-effectiveness of expanded screening criteria for lung cancer, a new biomarker for predicting immunotherapy responses, development of a technique for multiplex single-cell chromatin profiling, combination immunotherapy for cancer of prostate bone metastasis, understanding the drivers of lung cancer metastasis, and enabling novel T cell therapies for the treatment of COVID-19.

Expanding lung cancer screening criteria has proven to be cost effective

In March 2021, the United States Task Force on Preventive Services (USPSTF) issued a new recommendation for lung cancer screening that nearly doubled the number of people eligible for screening by lowering the minimum age and the number of d ‘years of smoking history required. A study by Iakovos Toumazis, Ph.D., and the Lung Working Group of the Cancer Intervention and Surveillance Modeling Network (CISNET) found that the 2021 USPSTF recommendation was cost effective compared to the 2013 recommendation it replaced. . The team used a comparative modeling approach to determine whether the expected increased costs of screening justified the expected health gains. The 2021 recommendation was profitable at a threshold of $ 100,000 per quality-adjusted life year. Other strategies that further broaden the screening criteria to include people who have quit smoking for more than 15 years have proven to be even more cost-effective. Find out more in JAMA Oncology.

Gene signature predicts immunotherapy response in low-mutation cancers

Blocking immune checkpoints (ABIs) offers long-lasting responses for many cancer patients, but not all. A high tumor mutation burden (TMB) can predict responses in a subset of cancer types, but it is unreliable as a universal biomarker. A new study led by Daniel McGrail, Ph.D., and Shiaw-Yih Lin, Ph.D., discovered a new biomarker associated with the ICB response in cancers without high BMR. A gene expression signature indicating defects in the replication stress response (RSR), a type of DNA damage response pathway, accurately predicted responses in 12 independent patient cohorts across seven tumor types different. The researchers demonstrated that the regulation of RSR activity could alter ICB responses in preclinical models of breast and kidney cancer, and that RSR defects lead to accumulation of single-stranded DNA stimulating the immune system. In addition to identifying a new biomarker, these results suggest that induction of RSR defects may be useful in improving ICB responses in some patients. Find out more in Science Translational Medicine.

New technique enables single-cell chromatin profiling on multiple samples simultaneously

DNA is packaged with proteins in chromatin, a highly organized and condensed structure that makes up our chromosomes. The accessibility of DNA in chromatin has implications for gene expression, so researchers have developed unicellular approaches to study the accessibility of chromatin at high resolution. These techniques, called a single-cell assay for transposase-accessible chromatin with sequencing (scATAC-seq), allow the profiling of many single cells from a single sample, but technical hurdles have prevented researchers from easily combining multiple samples to speed up analysis and reduce costs. A research team led by Kaile Wang, Ph.D., Zhenna Xiao, Ph.D., Yun Yan, and Nicholas Navin, Ph.D., has developed a novel approach to single-core barcode (SNuBar) -ATAC to easily label and combine multiple samples together for parallel sequencing. The researchers validated the approach by multiplexing 28 lung tumor samples treated with different therapeutic combinations as well as by combining 32 different regions of a single human breast tumor. Their data suggests that the approach is very precise, easy to use and scalable. Find out more in Molecular cell.

Combined checkpoint blockade promotes suppressive immune microenvironment in bone metastatic prostate cancer

Prostate cancer has a “cold” immune microenvironment – with few infiltrating T cells and an increase in suppressor immune cells – and immune checkpoint therapies have generally provided limited benefits. Targeting the CTLA-4 immune checkpoint may increase T cells in prostate tumors, but it also leads to an increase in other inhibitory checkpoints, such as PD-1 / PD-L1, providing rationale for combined targeting of control points. Additionally, although bone is the most common site of metastasis in prostate cancer, patients with predominantly bone disease are often excluded from clinical trials. Therefore, in a Phase II pilot study led by Sumit Subudhi, MD, Ph.D., Bilal Siddiqui, MD, and Padmanee Sharma, MD, Ph.D., researchers investigated the combination of anti-CTLA- 4 and anti-PD. -1 therapies in 26 patients with castration-resistant prostate cancer with bone metastases. The combination therapy was safe and well tolerated, and it has shown activity in a subset of patients. Study of the bone microenvironment after treatment revealed an elevation of certain inhibitory immune signals, suggesting that it may be necessary to target additional pathways to overcome resistance to treatment in these patients. Find out more in the Journal for ImmunoTherapy of Cancer.

ZEB1 protein accelerates protein trafficking to promote lung cancer cell motility

Epithelial-to-mesenchymal transition (EMT) is a process by which cancer cells undergo changes in gene expression to establish polarity that facilitates invasion and metastasis. This process requires fine control of many cellular processes, including protein trafficking, although the details of this regulation are unclear. In a new study, a team of researchers led by Priyam Banerjee, Ph.D., Guan-Yu Xiao, Ph.D., and Jonathan Kurie, MD, demonstrated that the EMT-activating protein ZEB1 regulates transport dynamics proteins create a polarity axis in lung cancer cells. The increased levels of ZEB1 accelerated endocytosis, the process by which membrane-bound proteins are internalized, and the protein trafficking to lysosomes for degradation. The researchers found that ZEB1 accomplishes this by preventing microRNAs from silencing the KIF13A and AP1S2 proteins. These proteins, in turn, accelerate protein turnover and establish a benefit to the cell that facilitates motility and invasiveness. Find out more in Nature Communication.

Validation of SARS-CoV-2 immunogenic peptides for new therapeutic approaches in T cells

T cell responses to SARS-CoV-2 may provide long-lasting protection against infection, and virus-targeting T cells may be useful for COVID-19 treatments. To best use T cells for prevention and treatment, it is essential to understand the viral targets, or peptides, that T cells recognize. To date, researchers have relied on in silico methods to predict immunogenic viral peptides, but little has been done to experimentally validate the predicted targets. Researchers led by Ke Pan, Ph.D., Yulun Chiu, Ph.D., and Cassian Yee, MD, used mass spectrometry to sequence viral peptides on the surface of infected cells and verify which ones might trigger responses T lymphocytes. They have shown that many predicted peptides are not immunogenic and should not be investigated. The team also identified new immunogenic peptides from highly conserved viral proteins, which do not mutate frequently, offering ideal targets for therapeutic approaches. The researchers sequenced the T cell receptor (TCR) for one of these targets, allowing them to design the first reported TCR TCR cell capable of recognizing and targeting infected cells. Find out more in theProceedings of the National Academy of Sciences.

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About MD Anderson The MD Anderson Cancer Center at the University of Texas at Houston is one of the world’s most respected centers focused on cancer care, research, education and prevention. The institution’s sole mission is to end cancer for patients and their families around the world. MD Anderson is one of 51 comprehensive cancer centers designated by the National Cancer Institute (NCI). MD Anderson is No. 1 for cancer in the US News & World Report’s “Best Hospitals” ranking and has been named one of the nation’s top two hospitals for cancer since the rankings began in 1990. MD Anderson receives a cancer center support grant from NCI of the National Institutes of Health (P30 CA016672).

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