MD Anderson Research Highlights for July 28, 2021

Featuring discoveries in B cell survival, epigenetics, genomic stability, COVID-19 cell therapies, pain treatment, CRISPR, aneuploidy and Hodgkin lymphoma survivorship

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 a newly discovered protein that controls B cell survival, understanding epigenetic changes in malignant peripheral nerve sheath tumors (MPNSTs) and melanoma, identifying a protein that protect genome stability, developing novel cell therapies for COVID-19, a new option for treating neuropathic pain, exosome delivery of CRISPR/Cas9 to pancreatic cancer, discovering how cancer cells tolerate aneuploidy and the role of health disparities in long-term survival of adolescent and young adult patients with Hodgkin lymphoma.

Discovery of a novel protein regulating B cell survival and malignancy

Normal signaling from the B cell-activating factor receptor (BAFFR) is critical for development and survival of B cells, but dysregulated signaling promotes autoimmune disease and certain cancers. However, it’s not clear how BAFFR works to regulate these important processes. Researchers led by Yanchuan Li, Ph.D., and Shao-Cong Sun, Ph.D., discovered a new protein, DYRK1a, and its precise role in connecting BAFFR to the downstream noncanonical NF-kB pathway to promote B cell survival. DYRK1a loss resulted in fewer mature B cells, whereas DYRK1a overexpression is found in some cases of B-cell acute lymphoblastic leukemia (B-ALL). The researchers showed that DYRK1a was important for the survival of B-ALL cells, suggesting a possible new therapeutic target. Learn more in Blood.

Epigenetic reprogramming points to therapeutic approach for MPNSTs

Malignant peripheral nerve sheath tumors (MPNSTs) are a rare and aggressive form of soft-tissue sarcoma. These tumors frequently have mutations in SUZ12 and EED, both of which are components of a protein complex called PRC2 that makes epigenetic modifications to regulate chromosome structures. Researchers led by Veena Kochat, Ph.D., Ayush Raman, Ph.D., Kunal Rai, Ph.D., and Keila Torres, M.D., Ph.D., discovered that MPNSTs with PRC2 defects have extensive epigenetic changes, resulting in alterations to chromosome structure and unique molecular traits. As a result, enhancer regions of the genome were activated, driving increased expression of genes that contribute to MPNST survival. Drugs that blocked the enhancer activity were effective against PRC2-mutant MPNSTs in laboratory models, pointing to a possible treatment approach for patients with these tumors. Learn more in Acta Neuropathologica.

Study finds novel role for protein in safeguarding genome stability

DNA breaks can occur as a normal part of replication and transcription, and they typically are fixed by DNA repair processes such as homologous recombination. In certain cases, a form of homologous recombination called break-induced replication (BIR) is used, although this process is less accurate and results in mutations and chromosome rearrangements. Xiao Wu, Ph.D., and Bin Wang, Ph.D. discovered that a BRCA1-interacting protein called Abraxas plays an important role in limiting the use of BIR repair and in protecting genome integrity. The researchers uncovered a complex mechanism by which Abraxas minimizes the specific types of DNA breaks that are fixed by BIR. When Abraxas is missing, the downstream molecular cascade results in excessive DNA end resection, BIR-mediated repair and chromosomal alterations. Learn more in Nature Communications.

Developing adoptive cell therapies for treating COVID-19

MD Anderson researchers are working to develop an adoptive cell therapy using viral-specific, steroid-resistant T cells that recognize SARS-CoV-2. Adapting previously developed techniques for creating antiviral T cell therapies, a team led by Rafet Basar, Ph.D., E.J. Shpall, M.D., and Katy Rezvani, M.D., Ph.D., described the successful isolation and expansion of SAR-CoV-2-specific T cells from the blood of donors who previously recovered from COVID-19. Further, the team utilized CRISPR/Cas9 gene editing to render these cells resistant to corticosteroids, which may allow the treatment to be used alongside routinely administered steroids. A clinical trial to evaluate the safety and efficacy of off-the-shelf SARS-CoV-2 T-cells in treating COVID-19 is now open at MD Anderson. Learn more in Cell Reports.

New understanding of mechanism behind gabapentinoids shows promise for treating neuropathic pain

Gabapentinoids, a first-line drug treatment used to reduce neuropathic pain and epilepsy for more than three decades, work by targeting α2δ‐1, previously considered a Ca2+ channel subunit. However, the underlying molecular mechanism behind α2δ-1’s role in neuropathic pain and gabapentinoids’ actions has not been well understood. In a study led by Hui-Lin Pan, M.D., Ph.D., researchers focused on the switch from Ca 2+-impermeable to Ca2+-permeable AMPA receptors in the spinal cord, which have been shown to contribute to chronic neuropathic pain. They demonstrated that nerve injury promotes Ca 2+-permeable AMPA receptors through α2δ‐1 – altering synaptic function and amplifying pain signals as a result. α2δ‐1 directly interacts with AMPA receptor proteins and can control Ca 2+ permeability by disrupting its heteromeric subunit assembly. These findings could lead to further exploration of α2δ‐1–coupled AMPA receptors as a potential target for treating other neurological conditions, including Alzheimer’s disease, epilepsy, stroke and drug addiction. Learn more in Cell Reports.

Profiling chromatin states points to new treatment target in metastatic melanoma

Melanoma sequencing studies have identified frequent mutations in genes responsible for regulating the epigenome – reversible chemical modifications that change chromosome structures and fine-tune gene expression. To understand how epigenetic alternations contribute to melanoma progression, researchers led by Christopher Terranova, Ph.D., Ming Tang, Ph.D., Mayinuer Maitituoheti, M.D., Ph.D., and Kunal Rai, Ph.D., profiled 46 melanoma tumors and cell lines, looking specifically at chromatin – the DNA, RNA and proteins that make up chromosomes. The researchers discovered that melanomas with BRAF, NRAS or WT mutations have unique chromatin states. They demonstrated that the unique states, marked by the PRC2 protein complex, regulate expression of genes driving metastasis. Results suggest that therapeutically blocking PRC2 in combination with MEK inhibitors is a promising treatment strategy for NRAS-mutant melanomas. Learn more in Cell Reports

Exosomes can deliver targeted genome editing to suppress pancreatic cancer cells

The CRISPR/Cas9 system is a useful tool for a variety of genome-editing applications. However, reliably delivering CRISPR/Cas9 specifically to cells of interest remains a challenge for the field. Research led by Kathleen McAndrews, Ph.D., Fei Xiao, Ph.D., Antonios Chronopoulos, Ph.D., and Raghu Kalluri, M.D., Ph.D., demonstrated that exosomes – small membrane-bound vesicles that shuttle information between cells – can efficiently deliver the CRISPR/Cas9 machinery to pancreatic cancer cells via systemic delivery, achieving targeted disruption of mutant KRAS G12D, the most common gene mutation in pancreatic cancer. As proof-of-principle, the researchers demonstrated this technique could block tumor growth in pancreatic cancer models, suggesting the technique warrants further evaluation as a therapeutic tool. Learn more in Life Science Alliance.

Discovering a mechanism for cancer cells to tolerate extra chromosomes

Cancer cells often have extra chromosomes present – a condition known as aneuploidy. Having extra copies of pro-tumor genes could benefit cancer cells, but aneuploidy often affects hundreds or thousands of genes, which can overwhelm the cell. By analyzing data from more than 5,000 tumors, researchers led by Vakul Mohanty, Ph.D., and Ken Chen, Ph.D., discovered that cancer cells have a mechanism to overcome this issue. Through a complex set of regulatory changes, cancer cells can uncouple gene expression from copy number, meaning that extra gene copies do not result in increased gene expression. The team also identified proteins that could be targets to disrupt this uncoupling mechanism, suggesting possible therapeutic possibilities. Learn more in Cell Reports Medicine.

Disparities play key role in long-term survival of AYA Hodgkin lymphoma patients

Hodgkin lymphoma (HL) is one of the most common cancers among adolescent and young adults (AYA), and many factors can impact long-term survivorship among this group. A team led by Michael Roth, M.D., used the Surveillance, Epidemiology, and End Results (SEER) registry to identify more than 15,000 AYA HL survivors five years post-diagnosis to determine if socioeconomic status (SES), race/ethnicity, age of diagnosis, gender or living in rural areas impact long-term survivorship. Results demonstrated many disparities in survival persist years after initial diagnosis, and there was no evidence of disparities in long-term survival changing over time for AYA HL survivors. These findings build upon previous studies indicating race/ethnicity and SES factors impact short-term survival in AYA HL survivors, and more targeted studies are needed to identify opportunities for early and successful interventions. Learn more in Cancer Epidemiology, Biomarkers & Prevention.

In case you missed it

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

Image courtesy of Torres/Rai Laboratory.