MD Anderson Research Highlights for September 4, 2024

Featuring markers of immunotherapy response, spatial biology advances, new epigenetic targets and novel treatment approaches 

MD Anderson News Release September 04, 2024

The University of Texas MD Anderson Cancer Center’s Research Highlights showcases the latest breakthroughs in cancer care, research and prevention. These advances are made possible through seamless collaboration between MD Anderson’s world-leading clinicians and scientists, bringing discoveries from the lab to the clinic and back.

Protein expression atlas covers almost all cancer hallmarks
The Cancer Genome Atlas (TCGA) and Cancer Cell Line Encyclopedia (CCLE) provide DNA and RNA data from approximately 11,000 patient samples across 33 cancer types and 1,000 cancer cell lines, but limited protein information is available. Researchers led by Han Liang, Ph.D., Rehan Akbani, Ph.D., and Jun Li, Ph.D., previously generated protein expression data for approximately 200 proteins but did not include many cancer-related pathways. In a new study, the researchers characterized expression of nearly 500 proteins, using 8,000 TCGA samples and 900 CCLE samples. These results cover almost all known cancer hallmarks and targets, and the findings identified interactions and meaningful patterns among proteins with potential translational impact. This atlas highlights the value of considering protein expression as part of an integrated research approach to aid future diagnostic and treatment strategies for patients with cancer and other diseases. Learn more in Nature Cancer.

Immunological features predict treatment response for advanced solid tumors
Immune checkpoint therapy stimulates tumor infiltration by CD8 T cells to facilitate an antitumor response, but many advanced solid tumors do not respond to treatment. In the AMADEUS trial, researchers led by Padmanee Sharma, M.D., Ph.D., aimed to identify biomarkers that predict treatment response in patients with advanced solid tumors. The trial enrolled 39 patients who were divided into two groups based on pre-treatment levels of CD8 T cells. Those with low CD8 levels received a combination of nivolumab plus ipilimumab, while those with high CD8 levels received nivolumab alone. The disease control rate for low-CD8 and high-CD8 patients was 25% and 14.3%, respectively, and 39.5% of tumors that initially were low-CD8 had an influx of CD8 T cells after treatment. Treatment improved the inflammatory tumor microenvironment in low-CD8 responders, leading to better outcomes. These results provide insights into more efficient ways to stratify patients using immunological features to personalize treatment. Learn more in the Journal of Experimental Medicine.

Novel targets overcome treatment resistance in triple-negative breast cancer 
Patients with triple-negative breast cancer (TNBC), an aggressive subtype, currently have limited options and generally face a poor prognosis. Researchers led by Khandan Keyomarsi, Ph.D., Mi Li, Ph.D., and Amriti Lulla, Ph.D., discovered that increased levels of low molecular weight cyclin-E (LMW-E) and cyclin-dependent kinase (CDK1) phosphorylation are associated with poor outcomes following chemotherapy. High levels of LMW-E and CDK1 predicted the poorest treatment responses, suggesting they serve as potential biomarkers of chemotherapy resistance. The study showed that LMW-E upregulates and stabilizes PKMYT1, leading to enhanced CDK1 phosphorylation. TNBC cells with high LMW-E levels were more sensitive to the PKMYT1 inhibitor RP-6306, which induces DNA damage and mitotic arrest. Treatment with RP-6306 also led to tumor suppression, increased DNA damage and extended survival in vivo, using both patient derived xenograft and transgenic models. These findings highlight the therapeutic potential of PKMYT1 inhibitors for patients with TNBC. Learn more in Cancer Research.

New spatial profiling tool provides detailed molecular insights into cancer cells and the tumor microenvironment
Spatial transcriptomics techniques provide information on the location of gene expression patterns, uncovering cell organization and interactions within specific areas of the tumor microenvironment (TME). However, many analytical tools don’t take cell morphology or tissue histology into consideration. To improve these methods, researchers led by Linghua Wang, M.D., Ph.D., and Jiahui Jiang, Ph.D., developed the Morphology-Enhanced Spatial Transcriptome Analysis Integrator (METI). This tool integrates histology, spatial transcriptomics and domain knowledge of cancer genomics to map cancer cells and their microenvironment components, to stratify different cell types and states, and to analyze areas where cells interact within the TME. After testing METI on various tumor tissues from gastric, lung and bladder cancers, as well as premalignant tissues, the researchers found that this tool provides more accurate and detailed insights into the TME than existing methods. This highlights its potential to advance our understanding of tumor biology and to aid in the development of diagnostic and therapeutic strategies. Learn more in Nature Communications.

Epigenetic target drives multiple myeloma development
Multiple myeloma is a rare blood cancer that originates in bone marrow and has limited treatment options. Studies have shown that the SAGA complex – a histone acetyltransferase and transcriptional co-activator – is linked to disease progression, but how it contributes to cancer development is not well understood. To provide insights, researchers led by Ying-Jiun Chen, Ph.D., and Sharon Dent, Ph.D., examined the effects of losing ADA2B, a unique subunit of the SAGA complex, in multiple myeloma. They found ADA2B is essential for activating pathways and gene targets of the MAF and MYC transcription factors, which drive multiple myeloma survival and progression. The researchers also identified a specific domain of ADA2B that is necessary for its stability and interaction with SAGA, highlighting its potential as a therapeutic target for patients with multiple myeloma and other diseases. Learn more in Genes & Development.

Scientists identify new epigenetic target for chromosomal instability in ICF syndrome
Immunodeficiency, centromeric instability and facial anomalies (ICF) syndrome is a rare genetic disorder linked to the hypomethylation of certain chromosomal areas containing repetitive DNA sequences. These repetitive sequences are prone to forming DNA structures that are different from the predominant B-DNA configuration during replication, which can sometimes cause genomic instability. The CDCA7 protein is mutated in ICF syndrome, but its role in DNA methylation in these chromosomal regions is unknown. Researchers led by Taiping Chen, Ph.D., and Xiaodong Cheng, Ph.D., found that CDCA7 has a specific domain that normally binds non-B-DNA regions during cell replication, concentrating in these particular chromosomal areas and ensuring proper DNA methylation and stability. CDCA7 mutations in ICF syndrome disrupt that ability, which explains the loss of methylation in these regions. Understanding how CDCA7 and its mutants interact with DNA may help in developing therapeutic strategies for ICF syndrome and related disorders. Learn more in Science Advances.

New approach to treating lung fibrosis shows early promise in two preclinical models
Idiopathic pulmonary fibrosis (IPF), a disease that causes lung scarring, is associated with a low life expectancy and few treatment options. As such, it is a major cause of death. Currently, lung transplantation is the only effective treatment, but many patients are unable to receive an organ donation due to a shortage of suitable lungs and a high risk of mortality from the transplant procedure. To examine alternative options, researchers led by Yair Reisner, Ph.D., evaluated a lung stem cell transplant, using single-cell suspensions of an entire lung, in two distinct in vivo models of lung fibrosis. The transplant successfully attenuated disease progression, resulting in improved lung function and a reduction of fibrotic tissue compared to untreated controls. The study offers proof-of-concept for further investigation into the treatment of lung fibrosis using lung cell suspensions via intravenous infusions for patients with IPF and chemotherapy-induced lung injury. Learn more in Science Advances. 

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