MD Anderson Research Highlights for June 7, 2023

Featuring positive ATR inhibitor results, AI predictions for immunotherapy responses, outcomes for prostate and appendix cancer treatments, and new miRNA discoveries

MD Anderson News Release June 07, 2023

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 include a molecularly driven Phase I trial of the ATR inhibitor camonsertib, an artificial intelligence model to predict immunotherapy responses in lung cancer, an analysis of cognitive and functional outcomes following treatment with second-generation antiandrogens, a novel miRNA-based target for sepsis, clinical evaluation of chemotherapy for a rare appendix cancer, and the role of estrogen on cell-to-cell communication in ER+ breast cancer.

Camonsertib demonstrates early antitumor activity in patients with selected DNA damage response-deficient advanced solid tumor
The DNA damage response (DDR) is important for cell survival, but mutations in DDR genes are frequently seen in cancer. ATR inhibitors, which target specific DDR defects in multiple tumors, are actively being evaluated in clinical trials. The TRESR trial, led by Timothy Yap, M.D., Ph.D., evaluated the ATR inhibitor camonsertib in 120 patients with advanced solid tumors harboring loss-of-function DDR mutations. This trial represents the most comprehensively analyzed and prospectively selected population of tumors treated with an ATR inhibitor. Patients were selected for specific tumor features, based on hypotheses derived from CRISPR/Cas9 screens, to identify those most likely to respond. The trial also included molecular evaluation of longitudinal tumor and circulating tumor DNA samples to study the drug’s activity in patients who responded. Patients with ovarian cancer had a 25% response rate and a median progression-free survival of 35 weeks, despite prior progression on multiple lines of therapy. Clinical benefit also was observed in patients with tumors with biallelic ATM loss. This study highlights the importance of enhanced precision medicine approaches for improving patient selection and optimizing treatment response, and it supports further clinical investigation of camonsertib. Learn more in Nature Medicine.

New AI model may better predict patient response to immune checkpoint therapy
Current tissue-based biomarkers cannot fully predict responses to immunotherapy for patients with non-small cell lung cancer (NSCLC). Therefore, a team led by Jia Wu, Ph.D., Jianjun Zhang, M.D., Ph.D., and John Heymach, M.D., Ph.D., developed an image-based deep-learning model for predicting benefit from immune checkpoint inhibitors in patients with EGFR/ALK wild-type NSCLC. The artificial intelligence (AI) model outperformed current methods, including radiomic features, indicating it identified imaging patterns that are not yet understood. The model was most successful when used in concert with current clinical and pathological biomarkers. Developed using a dataset from MD Anderson’s GEMINI database and validated with external datasets, the image-based model works by using routine radiologic images, overcoming some of the hurdles faced by tissue-based testing. The next step is to continue to validate the model with large prospective trials to further refine the findings. Learn more in The Lancet Digital Health.

Second-generation antiandrogens have an increased risk of adverse cognitive and functional outcomes
Hormone therapy, including androgen deprivation therapy, is an established prostate cancer treatment. However, most men advance to castration-resistant disease that no longer responds to hormone therapy, leading to increasing treatment with second-generation antiandrogens. Evidence suggests these more potent antiandrogens may be associated with declines in cognitive and functional abilities. In a meta-analysis led by Kevin Nead, M.D., researchers reviewed 12 randomized controlled trials comprising 13,524 participants. They found an increased risk of cognitive toxicity, fatigue and falls in prostate cancer patients treated with second-generation antiandrogens versus those in the control arm. The findings were consistent in studies that included traditional hormone therapy in both treatment arms. These findings highlight the need to prevent, identify and intervene on cognitive and functional declines in patients receiving second-generation antiandrogens for prostate cancer. Learn more in JAMA Oncology.

Study identifies potential miRNA-based therapeutic target for sepsis 
Sepsis — an extreme reaction to infection —  is a leading cause of death, yet its many different underlying triggers and mechanisms are poorly understood. However, recent studies have focused on how non-coding microRNAs (miRNAs), might serve as potential biomarkers and therapeutic targets. Researchers led by George Calin, M.D., Ph.D., and Sai-Ching Yeung, M.D., Ph.D., used samples from patients with sepsis as well as multiple animal models to screen for miRNA targets. They found that miR-93-5p was overexpressed across all models, was downregulated in human patients who survived sepsis, and was correlated with poor prognosis. Inhibiting miR-93-5p prolonged survival in preclinical models, especially in older organisms. Further, blocking miR-93-5p reduced inflammatory monocytes and increased circulating effector memory T cells, partially restoring the peripheral immune response. While further studies remain before starting clinical trials, this study uncovered miR-93-5p as a potential miRNA-based therapeutic target for sepsis. Read more in The Journal of Clinical Investigation. 

Fluoropyrimidine-based chemotherapy shows no benefit for patients with mucinous appendix cancer
Appendiceal adenocarcinoma is a rare cancer that originates in the lining of the appendix. With few clinical trials for this cancer, the currently standard treatment is the chemotherapy typically used for colorectal cancer, even though these tumors are very different. In a prospective trial led by Michael Overman, M.D., John Paul Shen, M.D., and Keith Fournier, M.D., researchers evaluated if fluoropyrimidine-based (5FU) chemotherapy was effective in patients with inoperable low-grade mucinous appendiceal adenocarcinoma. The study enrolled 24 patients, who were randomized to either six months observation followed by six months of chemotherapy, or initial chemotherapy followed by observation. Patients did not derive clinical benefit from 5FU-based chemotherapy, as there were no differences in tumor growth rates while receiving chemotherapy. These findings suggest that practice guidelines need to be changed to recommend against the use of 5FU-based chemotherapy for mucinous appendix cancer. Learn more in JAMA Network Open.

Estrogen promotes selective cell-to-cell communication in ER+ breast cancer
Extracellular vesicles (EVs) mediate cell-to-cell communication by transferring cargo, such as microRNAs (miRNAs) between cells, but little is known about the significance of EV production, especially in cancer. Researchers led by George Calin, M.D., Ph.D., hypothesized that estrogen could be involved in generating these EVs and in loading specific miRNAs by downregulating signal pathways in estrogen receptor-positive (ER+) breast cancer. They examined cell lines and uncovered a dose-dependent connection between estrogen levels and released EVs, as well as an enrichment of let-7 miRNAs in these EVs. In several patient cohorts, the researchers observed increased let-7 family miRNAs in EVs derived from the blood of premenopausal ER+ breast cancer patients. This study uncovers novel mechanisms of hormonal influence on cell communications, highlighting their therapeutic potential for ER+ breast cancer as well as other hormone-related cancers. Learn more in Proceedings of the National Academy of Sciences. 

MD Anderson at ASCO 2023
Read below for highlights from MD Anderson researchers at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting. More information can be found at MDAnderson.org/ASCO.

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