MD Anderson Research Highlights for September 8, 2021

Featuring discoveries in multiple sclerosis, pancreatic cancer profiling, pseudogenes, prostate cancer targets, RNA therapies, monitoring immunotherapy side effects and end-of-life care

The University of Texas MD Anderson Cancer Center’s Research Highlights provides a glimpse into recently published studies in basic, translational and clinical cancer research from MD Anderson experts. Current advances include understanding the role of microglia in multiple sclerosis, new methods for profiling pancreatic cancer, uncovering new functions for pseudogenes in breast cancer, a novel therapeutic target in prostate cancer, utilizing RNA therapies to improve muscle composition, monitoring side effects from immune checkpoint inhibitors and determining appropriate sedation goals for end-of-life care.

New discovery clarifies role of microglia in promoting multiple sclerosis

Microglial cells are specialized immune cells found specifically in the central nervous system (CNS) that are responsible for removing damaged neurons and infected cells. Microglia have been implicated in the development of multiple sclerosis (MS), a chronic inflammatory disease of the CNS, yet their role is not completely understood. Zuliang Jie, Ph.D., Chun-Jung Ko, Ph.D., and Shao-Cong Sun, Ph.D., led a team of researchers to clarify the role of microglia using an animal model of MS known as experimental autoimmune encephalomyelitis (EAE). They discovered that the noncanonical NF-kB signaling pathway is activated in microglia when EAE is induced, resulting in the production of chemokines and the recruitment of inflammatory T cells into the CNS, which leads to cascading effects that promote disease progression. The findings reveal an unknown mechanism for microglia in supporting EAE pathogenesis and may have therapeutic implications. Learn more in Science Advances.

Single-cell RNA sequencing of pancreatic cancer biopsies provides valuable insights

Precision medicine has the potential to improve outcomes for patients with advanced pancreatic cancer, but these targeted approaches require knowledge of mutations and molecular profiles that point to actionable vulnerabilities. Before the start of treatment, most patients have a tissue biopsy, which often provides only a limited number of cells for analysis. A research team led by Paola A. Guerrero, Ph.D., and Anirban Maitra, M.B.B.S., studied the feasibility of single-cell RNA sequencing on biopsy samples to recapitulate the complex population of cells seen within surgically resected tumors. Their results indicated an ability to accurately profile the tumor from a limited sample. They also were able to characterize molecular subtypes to guide treatment selection and identify potential mechanisms of immune suppression occurring in the tumor microenvironment. The study supports this approach as a useful tool in determining appropriate therapeutic strategies for patients. Learn more in Clinical Cancer Research.

Researchers discover pseudogenes play important roles in breast cancer

The human genome contains more than 14,000 pseudogenes, which are dysfunctional copies of protein-coding genes that have lost their coding potential during our evolutionary history. While these largely were thought to be nonfunctional, recent studies suggest that may not be the case. Researchers led by Han Xu, Ph.D., and Yiwen Chen, Ph.D., conducted the first large-scale study to characterize human pseudogene function. Using CRISPR interference, the researchers systematically inactivated 850 different pseudogenes in breast cancer cell lines. Approximately 70 pseudogenes affected fitness of the cancer cells. They discovered that a unitary pseudogene – a special class of pseudogene without a functional counterpart in the genome – called MGAT4EP interacts with the FOXA1 protein to regulate the expression of other cancer-causing genes. The researchers found that the expression of many unitary pseudogenes correlates with patient outcomes, suggesting an underappreciated functional role for these evolutionary relics. Learn more in Genome Biology

Scientists identify novel therapeutic target in treatment-resistant prostate cancer

Androgen receptor (AR) inhibitors are the standard therapeutic strategy to treat patients with prostate cancer, but many cancers develop resistance to these therapies by transitioning into an “AR-negative” state. To identify new vulnerabilities in these AR-negative prostate cancers, researchers led by Yohei Yoshihama, Ph.D., Traver Hart, Ph.D., and Ronald A. DePinho, M.D., analyzed publicly available data on CRISPR screens in cancer cell lines. They discovered that AR-negative prostate cancers rely on expression of the histone demethylase protein JMJD1C. The team demonstrated that loss of JMJD1C in an AR-negative setting stimulated TNFα signaling. AR-negative prostate cancer cells were sensitive to blocking TNFα, but past therapies targeting this pathway were associated with dramatic side effects. Therefore, JMJD1C represents an important new therapeutic target to explore for treating AR-negative prostate cancers. Learn more in the Proceedings of the National Academy of Sciences.

RNA may be useful as a therapy to enhance muscle performance, reduce obesity

Obesity remains a major health problem in the United States, contributing to the development of many diseases, including cancer. Obesity also can drive significant muscle loss, which limits an individual’s ability to exercise; medications to treat obesity do not restore muscle composition. A preclinical study led by Yajuan Li, Ph.D., Yaohua Zhang, Ph.D., Liuqing Yang, Ph.D., and Chunru Lin, M.D., Ph.D., discovered that modifying a specific RNA may be useful as a treatment to enhance muscle performance and reduce obesity. The RNA, called H19, is a long non-coding RNA, meaning that it does not code for a protein product. Instead, it interacts with dystrophin, an important structural protein in muscle cells. Modifying H19 to increase activity resulted in improved muscle performance and resistance to diet-induced obesity in a model system. Learn more in Genome Medicine.

Mobile device monitoring can alert care teams to toxic effects of immune checkpoint inhibitors 
Immune checkpoint inhibitors are known to produce immune-related toxic effects that may require medical intervention. Early identification and supervision of these effects are critical to decrease complications and interruption of treatment. Christopher Logothetis, M.D., and Pavlos Msaouel, M.D., Ph.D., led a team that developed an electronic application that could be downloaded to patients’ mobile devices. Patients could report their symptoms and the application would alert the care team to necessary clinical action. This analysis of the first 50 patients showed that electronic monitoring is feasible and effectively incorporates patient perspectives in clinical decision-making. Learn more in JAMA Network Open.

Study assesses personalized sedation goals for cancer patients with agitated delirium

A lack of evidence underpins the challenge of determining clinical guidelines for appropriate levels of sedation for cancer patients who develop delirium, restlessness and agitation during their last days of life. Too much sedation could cause the patient to be unable to communicate, while too little sedation could increase the chances of additional breakthrough restlessness. In an analysis of a randomized clinical trial on terminal agitated delirium in patients admitted to MD Anderson’s acute palliative care unit, Eduardo Bruera, M.D., and David Hui, M.D., conducted a first-of-its-kind study on personalized sedation goals (PSGs) as a novel treatment response criterion. The researchers discovered that caregivers preferred lighter sedation than nurses and that many patients were under-sedated in comparison with caregivers’ stated goals. Utilizing PSGs to establish sedation levels for patients with delirium could improve the assessment of treatment responses. Because PSGs balance agitation control, communication capacity and prognosis, and may vary significantly based on the individual, further research needs to be done to examine the use of PSGs in care management. Learn more in Cancer.

In case you missed it

Read below to catch up on recent MD Anderson press releases across the spectrum of cancer research.

Fluorescent image of pancreatic cancer shows epithelial cells (red) and proinflammatory cytokine MIF (green). Image courtesy of Paola Guerrero, Ph.D.