NEW ORLEANS ― The University of Texas MD Anderson Cancer Center's Research Highlights provides a glimpse into recent basic, translational and clinical cancer research from MD Anderson experts. This special edition features presentations by MD Anderson researchers at the American Association for Cancer Research (AACR) Annual Meeting 2022, including early-stage clinical trials on immunotherapy and targeted therapies plus laboratory studies to improve immunotherapy responses, to understand early lung cancer development, to clarify the role of ZEB1 in lung cancer metastasis and to develop new treatments for cancers with KRAS mutations.
In addition to these studies, forthcoming press releases will feature groundbreaking studies on natural killer (NK) cell therapies for patients with lymphoma (Abstract CT003), targeted therapies for cancers with DNA damage repair defects (Abstracts CT006, CT007), neoadjuvant combination therapies for lung cancer (Abstract CT011) and a bioinformatics platform to optimize treatment combinations based on co-occurring alterations (Abstract LB119). More information on AACR content from MD Anderson can be found at MDAnderson.org/AACR.
Giving abatacept after checkpoint inhibitors can improve immunotherapy responses (Abstract 662)
Combining immune checkpoint inhibitors, such as those targeting CTLA-4 and PD-1, can improve responses over single agents but also increases immune-related side effects. Abatacept (CTLA-4 Ig) — an inhibitor of T cell costimulation — can reverse those side effects but, because it works counter to immunotherapy, it is unclear if it will dampen anti-tumor responses. Therefore, Stephen Mok, Ph.D., and James Allison, Ph.D., investigated the effects of abatacept when combined with checkpoint inhibitors at different stages over the course of treatment. In laboratory melanoma models treated with either anti-CTLA-4, anti-PD-1 or combination therapy, adding abatacept early during treatment blunted the effects of the checkpoint inhibitors. Surprisingly, using abatacept after the completion of therapy improved anti-tumor responses; the effects were dependent on stimulation by CD80/86 and the activity of specific T cells called Tregs. The results suggest a potential combination strategy to improve immunotherapy responses and minimize toxicity. Mok will present the findings on April 10.
ZEB1's role in lung cancer progression and metastasis deciphered in new studies (Abstract 673, 676)
Epithelial-to-mesenchymal transition (EMT) is a process that can change polarized epithelial cells into motile mesenchymal cells. Important for normal development, EMT also enables cancer cells to become more invasive and to metastasize. The ZEB1 transcription factor is known to activate EMT in lung cancer, and two new studies shed light on its role in this process.
Previous studies have shown that ZEB1 silences specific RNA molecules, called miRNAs, that normally block the cell polarity shift occurring in EMT. These results suggest that ZEB1 affects the cancer cells specifically, but a new study led by Guan-Yu Xiao, Ph.D., and Jonathan Kurie, M.D., demonstrated that ZEB1 activity also affects the surrounding environment. ZEB1 miRNA silencing drove protein secretion at the cell's leading edge, ultimately triggering degradation of the extracellular matrix and enhancing cell migration. This ZEB1-driven secretion also increased certain immune signaling proteins to create a suppressive immune environment. The findings point to new opportunities for targeting secretory pathways to block lung cancer metastasis. Xiao will present the findings on April 10.
Post-translational modifications (PTMs) to the ZEB1 protein can affect its activity, but it is unclear how specific protein changes can regulate EMT. Researchers led by Mabel G. Perez-Oquendo and Don Gibbons, M.D., Ph.D., used mass spectrometry to identify a novel PTM that regulates the stability to ZEB1 and, in turn, its ability to promote lung cancer progression through EMT. Acetylation of lysine 811 (K811) on ZEB1 protected the protein from degradation and encouraged dimerization (the binding of two ZEB1 proteins). The increased stability of acetylated ZEB1 stimulated invasion and metastasis in laboratory models compared to mutant ZEB1 that cannot be acetylated at K811. This stability was essential for promoting mesenchymal features in lung cancer cells, suggesting potential therapeutic approaches. Perez-Oquendo will present the results on April 10.
Inhibiting MCT4 reduces immunotherapy resistance in LKB1-mutant lung cancer (Abstract 2160)
Mutations causing loss of function of the tumor suppressor STK11/LKB1 occur in approximately 30% of lung cancers, and these mutations have been identified as drivers of therapeutic resistance. LKB1-mutant non-small cell lung cancers (NSCLCs) have higher rates of hypoxia and glycolysis, which results in increased lactate production and secretion. To determine whether inhibiting the lactate pathway may improve responses with immune checkpoint inhibitors for LKB1-mutant tumors, researchers, led by Yu Qian, Ph.D., and John Heymach, M.D., Ph.D., characterized the immune landscape of LKB1-mutant clinical samples, including patients in MD Anderson's ICON and PROSPECT trial cohorts, and preclinical models. They found that LKB1-mutant tumors displayed enhanced upregulation of the lactate transporter MCT4, ultimately contributing to immunotherapy resistance. Based on the team's findings, inhibiting MCT4 may be a promising strategy for overcoming immunotherapy resistance in patients with LKBI-mutant NCSLC. Qian will present the findings on April 11.
Single-cell sequencing of early-stage lung cancers gives insight into tumor development (Abstract 2126)
Despite significant treatment advances in recent years, lung cancer remains the leading cause of cancer deaths in the U.S. Understanding the earliest stages of lung cancer development may pinpoint opportunities for early intervention, when treatments are more likely to be successful. Researchers led by Guangchun Han, Ph.D., Linghua Wang, M.D., Ph.D., and Humam Kadara, Ph.D., performed single-cell RNA sequencing on 257,481 epithelial cells from 16 early-stage lung tumors and 47 matched normal lung tissue samples. The findings revealed extensive heterogeneity both within and across tumors. Comparing tumor cells revealed distinct cell states and gene patterns that are driven by key oncogenic mutations, especially in KRAS. In addition, the group discovered novel cell states that are tightly associated with lung cancer evolution. The depth of these data provides new insights into early lung cancer development and points to potential therapeutic targets for future studies. Han will present the findings on April 11.
Stapled DIRAS3-derived peptides are potential targeted therapy option for KRAS-mutant pancreatic and ovarian cancers (Abstract 3599)
Pancreatic cancer has a high mortality rate and limited treatment options, while low-grade serous ovarian cancer grows slowly but is usually resistant to chemotherapy. Both cancer types commonly express mutationally activated KRAS, which blocks apoptosis and promotes cell migration and metastasis. Utilizing previous findings that novel endogenous physiological RAS inhibitor DIRAS3 blocks mutant KRAS activity, a research team led by Joshua Gray, Ph.D., and Robert C. Bast, Jr., M.D., developed drug-like, helical 10-mer stapled peptides derived from the DIRAS3 α5 domain. The peptides decreased cell viability and caused cell apoptosis in pancreatic and ovarian cancer cells with mutant KRAS, while daily treatment improved survival in xenograft models. The findings suggest that stapled DIRAS3-derived peptides may be a novel targeted therapy for mutant KRAS-driven cancers. Gray will present the findings on April 12.
Early-stage clinical results from novel immune and targeted therapy approaches to be presented
MD Anderson researchers will present promising results from a variety of early-stage clinical trials evaluating safety and clinical activity of immunotherapy combinations and molecularly targeted therapies. The minisymposium presentations include:
- Phase I trial of ZN-c3, an oral WEE1 inhibitor, in patients with advanced or recurrent uterine cancer, presented by Funda Meric-Bernstam, M.D. (Abstract CT029)
- Determining biomarkers of response to RP-3500, an ATR inhibitor, from the Phase I/II TRESR trial in cancers with DNA damage repair defects, presented by Timothy Yap, M.B.B.S., Ph.D. (Abstract CT030)
- Phase I/II trial of sotigalimab, a CD40-targeting antibody, with pembrolizumab in patients with metastatic melanoma, presented by Salah-Eddine Bentebibel, Ph.D. (Abstract CT039)
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