MD Anderson Research Highlights for June 15, 2022

Featuring preclinical therapeutic advances, a novel in vivo gene activation model, and a deeper understanding of factors regulating anti-tumor immune responses

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. Current advances include preclinical discoveries for combination therapies to treat breast, ovarian and colorectal cancers; a new treatment target for rare sarcomas; a novel CRISPR engineering approach to facilitate in vivo research; and multiple studies of signal pathways that enhance anti-tumor immune responses.

Immunotherapy plus radiation therapy enhances antitumor response in colorectal cancer

Radiation therapy is a well-established treatment used to prompt anti-tumor immune responses in colorectal cancer (CRC) cells, but irradiated tumors respond by upregulating the CD47 and PD-L1 immune checkpoints to protect themselves. In preclinical trials led by Rodney Cheng-En Hsieh, M.D., and Michael Curran, Ph.D., researchers found that irradiated CRC cells use ATR-mediated signaling to increase production of CD47 and PD-L1 and prevent activation of anti-tumor immunity. CD47 and PD-L1 interacted with their corresponding receptors, SIRPα and PD-1, on antigen-presenting cells to limit the anti-tumor immune priming. Combining radiation with SIRPα and PD-1 inhibitors significantly improved survival and complete remission rates in both irradiated and unirradiated tumors, and the treatment substantially enhanced anti-tumor T cell responses. This study shows the addition of SIRPα and PD-1 blockade is a promising therapeutic approach to amplify the effects of radiation therapy. Learn more in Science Immunology.

Study confirms androgen receptor is a therapeutic target in a sarcoma subtype that predominantly affects young males

Desmoplastic small round cell tumors (DSRCTs) are an aggressive soft-tissue sarcoma subtype with a poor prognosis that primarily occurs in young males. Previous studies have identified the androgen receptor (AR) as a driver of DSRCT growth, but the mechanism remained unclear. In the largest series of DSRCT protein and transcriptomic profiling to date, Joseph Ludwig, M.D., and colleagues analyzed tumor tissue from 60 DSRCT patients treated at MD Anderson to better understand the role of AR signaling. They confirmed the AR as an oncogenic driver and revealed that it acts to regulate epigenetic programs in a manner unique to DSRCT. The AR bound directly to DNA near other key cancer-promoting genes, including WT1 and FOXA1, and to DNA regions that regulate additional important signaling pathways. Given the availability of several FDA-approved AR-targeted agents, this study suggests that future clinical studies should evaluate these options as treatments for DSRCT. Learn more in Nature Communications.

Combination therapy enhances PARP inhibitor sensitivity in breast and ovarian cancer

Because they block important DNA repair pathways, PARP inhibitors can selectively kill cancer cells with DNA repair defects caused by mutations in BRCA1/2 and other related genes. However, many cancers will eventually develop PARP inhibitor resistance. In a study led by Zhen Lu, M.D., and Robert Bast, M.D., researchers discovered that targeting the SIK2 protein kinase sensitized ovarian cancer and triple-negative breast cancer cells to PARP inhibitors. The SIK2 inhibitors ARN3236 and ARN3261 blocked PARP enzyme activity and repressed DNA repair. Combining PARP and SIK2 inhibitors led to greater inhibition of tumor growth and prolonged survival in ovarian and breast cancer models compared to either inhibitor alone, and the effects were seen in cancers both with and without BRCA mutations. The study suggests the combination therapy potentially could enhance the benefits of PARP inhibitors in breast and ovarian cancers. Learn more in The Journal of Clinical Investigation.

CRISPR activation is a viable method to selectively activating oncogenes in lab models

Activating supposed oncogenes in mouse models provides valuable biological insights, but developing these models requires a lengthy, laborious process. A form of CRISPR gene editing known as CRISPR activation (CRISPRa) can be used to easily activate a particular gene, but it has been challenging to apply this technique in vivo. In a new proof-of-principle study, researchers led by Fredrik Thege, Ph.D., and Sonja M. Woermann, M.D., Ph.D., demonstrated a feasible approach to selectively activate presumed oncogenes in vivo. Using a new mouse model that incorporates a form of CRISPRa technology called Synergistic Activation Mediator (SAM), they overexpressed the Myc and Yap1 oncogenes in both pancreatic cancer cell cultures and directly in mice lungs through a viral delivery system, resulting in tumor formation. Analyzing MYC-driven lung tumors in this new model revealed similar tumor microenvironments to that of a known lung cancer subtype. Further exploration of that subtype also revealed elevated expression of MYC, suggesting that MYC-targeting therapies may improve responses to immunotherapy in those patients. The CRISPRa/SAM model serves as a viable platform to facilitate in vivo research and screening of cancer-related drivers in the future. Learn more in Cancer Research

Immune gene programs in lung cancer clarify differences in immunotherapy responses

Many patients with resectable non-small cell lung cancer (NSCLC) benefit from immunotherapy that inhibits the PD-1/PD-L1 checkpoint pathway, but the components driving different responses among patients are poorly understood. To better understand these mechanisms, researchers led by Pedro Rocha, Ph.D., Jiexin Zhang, Ignacio I. Wistuba, M.D., and Humam Kadara, Ph.D., performed targeted sequencing on tumor samples from NSCLC patients treated with either upfront surgery, neoadjuvant chemotherapy or neoadjuvant chemoimmunotherapy. They explored immune gene programs unique to PD-L1-positive and -negative cancers and categorized tumors from each treatment cohort into three distinctive immune microenvironment phenotypes (inflamed, cold, excluded) using spatial distribution of T cells. Comparative analyses highlighted correlations between immune cell scores and treatment response. Treatment-naïve NSCLCs had the lowest expression of genes involved in immune activation, whereas those treated with neoadjuvant chemoimmunotherapy had the highest expression and highest scores on various immune cell subsets associated with favorable survival. Learn more in Clinical Cancer Research.

Regulatory microRNAs stimulate anti-tumor immune response in lung cancer

Epithelial-to-mesenchymal transition (EMT) is an important part of normal development but can also enable cancer cells to become invasive and to metastasize. Previous studies demonstrated that a group of regulatory RNA molecules, the microRNA-183/96/182 cluster (m96cl), is highly repressed in cancer cells that have undergone EMT. In a new study led by Samrat Kundu, Ph.D., B. Leticia Rodriguez, Ph.D., and Don Gibbons, M.D., Ph.D., researchers discovered that the m96cl can block lung cancer progression and metastasis by activating an anti-tumor T-cell response. Loss of m96cl expression in mouse models accelerated KRAS-mutant lung cancer progression, whereas elevating m96cl expression suppressed tumor growth, migration and invasion. Elevated m96cl led to activation of the interleukin-2 signaling pathway, causing enrichment of CD8+ cytotoxic T cells that blocked tumor growth and metastasis. These findings provide a new understanding of the role of the m96cl in stimulating the anti-tumor immune response, perhaps suggesting new therapeutic approaches for lung cancer. Learn more in Genes & Development.

Follicular lymphoma has dynamic immune microenvironment that can influence treatment outcomes

Follicular lymphoma (FL) is a slow-growing type of non-Hodgkin lymphoma, but it can undergo aggressive transformation. The disease has a complex tumor microenvironment (TME), with normal immune cells that can influence the disease course. Researchers led by Guangchun Han, Ph.D., Qing Deng, Ph.D.Linghua Wang, M.D., Ph.D., and Michael Green, Ph.D., performed single-cell RNA sequencing on 20 FL lymph node biopsies, plus three reactive lymph node controls, to characterize immune cells in the FL TME. They identified major subsets of infiltrating T cells, including cytotoxic CD4+ T cells not previously thought to be part of the TME. The relative proportions of different T cells defined four subtypes of FL, and those marked by T cell depletion had poor clinical outcomes. Certain FL mutations were associated with lower expression of major histocompatibility (MHC) proteins — critical for immune recognition of abnormal cells — and corresponding changes in the types of immune cells in the TME. Further, expression of MHCII was associated with the expression of immune checkpoint proteins, such as LAG3 and CTLA-4, suggesting that FL subsets are likely to respond differently to immune checkpoint inhibitors. The findings provide a new understanding of the dynamic FL microenvironment and how it may influence treatment responses. Learn more in Blood Cancer Discovery.

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Immunofluorescent image of a CRISPRa MYC-activated lung tumor, showing MYC (red) inside of targeted cancer cells (green). Cell nuclei are shown in blue. Image courtesy of Fredrik Thege.