MD Anderson Research Highlights for June 19, 2024

Featuring a novel drug for glioblastoma, resources to understand tumor evolution, a lower-dose radiation approach, and a new target for ferroptosis sensitivity

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.

Recent developments at MD Anderson include resources to reconstruct tumor evolution using crowd-sourced algorithms, using lower doses of radiation to avoid toxicities in patients with a lymphoma subtype, a potential target for regulating cell sensitivity to ferroptosis, and a novel drug that reprograms the tumor microenvironment to target glioblastoma.

Crowd-based challenge benchmarks algorithms that reconstruct tumor evolution
Using a process called subclonal reconstruction, researchers can mathematically quantify individual tumor evolution from bulk DNA sequencing data. This helps them understand how cancers begin, progress and adapt to their environment in order to develop better treatment strategies. To assess the performance of various reconstruction techniques, researchers co-led by Peter Van Loo, Ph.D., launched a seven-year community-based challenge to benchmark 31 algorithms that analyzed data from 51 simulated tumors. The study tested each algorithm on seven tasks designed to evaluate different aspects of subclonal reconstruction, such as accuracy in estimating tumor purity, number of subclones and the prevalence of single-nucleotide variants. The researchers found that certain features of each algorithm, such as read depth and mappability, had a more significant impact on performance than tumor features. However, no single algorithm performed best at all tasks, highlighting a need for further research. All datasets and methods are publicly available to clinicians and researchers looking to develop improved methods for understanding tumor evolution. Learn more in Nature Biotechnology.

Lower-dose radiation is effective and reduces risk of side effects in lymphoma subtype
Patients with gastric mucosa-associated lymphoid tissue (MALT) lymphoma, a type of marginal zone lymphoma, receive moderate doses of radiation therapy but also experience side effects. To minimize toxicity, research led by Jillian Gunther, M.D., Ph.D., and Chelsea Pinnix, M.D., Ph.D., examined the use of a lower radiation dose using a response-adapted treatment approach. In this study, 24 patients with newly diagnosed or relapsed H. pylori-negative gastric MALT lymphoma were treated with a total dose of 4 Gy in two fractions, with the option of an additional 20 Gy dose after an incomplete response. Twenty patients (83%) had a complete response to the lower dose, while four patients received the additional higher dose. All patients experienced complete response, with a three-year local control rate of 96%. One relapse was successfully treated with an additional 20 Gy. The treatment was well tolerated with mostly mild side effects, such as nausea and abdominal pain. These results show that a lower dose is effective for most patients, sparing many from the side effects of a higher dose. Learn more in The Lancet Haematology.

Novel role for IRE1α suggests its therapeutic potential for regulating ferroptosis
Ferroptosis, a type of programmed cell death characterized by the accumulation of lipid peroxides, is a viable tumor-suppressing mechanism, but components of ferroptosis regulation and cell sensitivity remain unknown. Inositol-requiring enzyme 1 (IRE1α) is a key protein known to have a downstream role in regulating cellular sensitivity to various types of stress as part of the unfolded protein response. Researchers led by Dadi Jiang, Ph.D., and Albert Koong, M.D., Ph.D., discovered a novel role for IRE1α in regulating glutathione synthesis, which is crucial for protecting cells from oxidative damage and maintaining tissue health. By controlling the expression of key glutathione biosynthesis regulators, IRE1α can impact cell sensitivity to ferroptosis. These findings suggest that cell sensitivity to ferroptosis can be pharmacologically modulated by IRE1α inhibition, highlighting its therapeutic potential. Learn more in Nature Communications.

STING-targeting drug reprograms tumor microenvironment to eliminate glioblastoma
Patients with glioblastoma, the most common type of primary brain cancer, have a poor prognosis, with most deriving no benefit from existing immunotherapy. Previous studies demonstrated that targeting the STING pathway increases antitumor responses in other tumors and is well tolerated in preclinical glioblastoma models, suggesting it may be a promising strategy. Researchers led by Michael Curran, Ph.D., activated the STING pathway in glioblastoma tumors, which transformed immunosuppressive myeloid cells into antitumor inflammatory cells. These cells then recruited anti-glioblastoma T cells and supported them in eliminating brain tumors. Using a unique STING agonist in treatment-resistant preclinical glioblastoma models, the researchers showed that the agonist successfully reprogrammed the tumor microenvironment to induce a potent antitumor immune response. The results suggest the agonist has significant therapeutic potential, and the researchers currently are evaluating it in preclinical models following radiation therapy to prevent cancer recurrence. Based on these findings, they hope to launch a clinical trial in late 2025. Learn more in The Journal of Clinical Investigation.

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