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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 an anti-CD19 chimeric antigen receptor (CAR) T cell therapy to treat follicular lymphoma, targeted therapies for urothelial cancers and advanced breast cancers, understanding the tumor microenvironment and immune landscape in pancreatic cancer, a link between depression risk and androgen deprivation for prostate cancer, and the discovery of new therapeutic targets for Alzheimer’s disease, liver cancer and aggressive breast cancer.
Tisagenlecleucel safe and effective against relapsed and refractory follicular lymphoma
While follicular lymphoma (FL), a type of non-Hodgkin lymphoma, is usually slow-growing, most patients relapse, and it is rarely curable. A research team led by Nathan Fowler, M.D., examined the use of tisagenlecleucel — an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy — to treat patients with relapsed or refractory FL who had already undergone two or more treatment lines or had an autologous stem cell transplant. In an interim analysis of 94 patients treated on the Phase II international ELARA trial, the complete response rate was 69% and the overall response rate was 86%. The therapy was well tolerated by the majority of patients, with mild to moderate cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome (ICANS) and neurological events, and no treatment-related deaths . These results suggest that tisagenlecleucel is a safe and effective option for treating patients with relapsed or refractory FL, including patients who have high-risk or advanced disease characteristics. Learn more in Nature Medicine.
Erdafitinib shows consistent results in follow-up of patients with urothelial cancer and FGFR mutations
Mutations in fibroblast growth factor receptor (FGFR) are present in approximately 15 to 20% of patients with metastatic bladder cancer and up to 35% of patients with other urothelial cancers of the renal pelvis or ureter. In the primary analysis, published in 2019, research led by Arlene Siefker-Radtke, M.D., showed that the FGFR inhibitor erdafitinib was effective after median 11 months follow-up. Those results led to approval of erdafitinib by the Food and Drug Administration, making it the first oral targeted therapy approved for advanced bladder cancer. In this final analysis, with a median follow-up of 24 months, the objective response rate was 40%. Responses lasted for a median of six months, while 31% of responses lasted for at least one year. Treatment benefit with erdafitinib was observed in patients regardless of previous chemotherapy or immunotherapy, and there were no new safety signals. Erdafitinib is currently being studied in other treatment settings. Learn more in Lancet Oncology.
RNF43 mutations accelerate KRAS-driven pancreatic cancer, stimulate immune microenvironment remodeling
Roughly 5-10% of all pancreatic cancers have loss-of-function mutations in the ring finger protein 43 (RNF43) gene, and this is one of the most commonly mutated genes in pancreatic pre-cancerous cysts. Unfortunately, no effective targeted therapies are available to treat patients with RNF43 mutations. Using a genetically engineered mouse model, researchers led by Abdel Nasser Hosein, M.D., Sonja Woermann, M.D., and Anirban Maitra, M.B.B.S., studied RNF43 in the context of mutant KRAS. They discovered that RNF43 acts as a tumor suppressor and its deletion cooperates with mutant KRAS to accelerate the development pre-cancerous lesions and pancreatic cancers. Additionally, RNF43 loss resulted in a distinct tumor immune microenvironment marked by increased numbers of anti-tumor lymphocytes and fewer suppressive myeloid cells, suggesting these tumors may be susceptible to immune checkpoint inhibitors. The immune signaling protein CXCL5 was decreased in RNF43-deficient tumors, pointing to a possible target to mediate the unique immune landscape in these cancers. Learn more in Gastroenterology.
Telomerase gene TERT identified as a novel therapeutic target for Alzheimer’s disease
Dysfunction in telomeres — the protective caps at the ends of chromosomes — can cause premature aging and neurodegeneration. The telomerase reverse transcriptase (TERT) gene is critical for maintaining telomeres. In a new study, researchers led by Hong Seok Shim, Ph.D., Y. Alan Wang, Ph.D., and Ronald A. DePinho, M.D., demonstrated that, independent of its role in telomere synthesis, TERT plays a key role in regulating gene networks central to the development of Alzheimer’s disease (AD). They discovered that epigenetic TERT repression is an early molecular event occurring before the development of AD. Experimental maintenance of physiological levels of TERT in mouse models and in neurons from AD patients alleviated toxic amyloid-β accumulation and blocked cognitive decline. Mechanistically, the researchers showed TERT interacts with β-catenin transcription complex to regulate genes governing neuron survival, amyloid clearance, learning and memory. The findings suggest that activating TERT therapeutically could be a novel strategy to slow or prevent AD progression. Learn more in Nature Aging.
Study identifies new therapeutic target to stimulate ferroptosis in liver cancer
Available systemic therapies for advanced hepatocellular carcinoma (HCC) provide only limited benefit, but evidence suggests that targeting ferroptosis — an iron-dependent form of controlled cell death — may have therapeutic potential. The liver cancer treatment sorafenib can stimulate ferroptosis, but many cancer cells are resistant. In a new study, researchers led by Fan Yao, Ph.D., Yalan Deng, Ph.D., and Li Ma, Ph.D., identified leukemia inhibitory factor receptor (LIFR) as a novel tumor suppressor and regulator of ferroptosis in HCC. Using genetically engineered mouse models and HCC patient-derived xenografts (PDXs), the researchers demonstrated that loss of LIFR activates the NF-kB signaling pathway to elevate levels of the iron-sequestering cytokine LCN2, leading to iron depletion and resistance to sorafenib-induced ferroptosis. In preclinical studies, an LCN2-neutralizing antibody enhanced sorafenib’s ability to induce ferroptosis and eliminate cancer cells in PDX tumors with low LIFR and high LCN2 levels. The findings suggest that anti-LCN2 therapy should be further explored to target ferroptosis and improve liver cancer treatment. Learn more in Nature Communications.
NDRG1 promotes brain metastasis in aggressive breast cancers
Up to 30% of patients with advanced breast cancer may develop brain metastases, which have limited treatment options and are associated with poorer outcomes. The stress response protein N-myc downstream regulated gene 1 (NDRG1) has a controversial role in metastasis, as it appears to block metastasis in certain cancer types while promoting it in others. Researchers led by Emilly Villodre, Ph.D., and Bisrat Debeb, D.V.M., Ph.D., discovered that NDRG1 drives tumor progression and brain metastasis in aggressive breast cancers. In laboratory models, cancer cells with high levels of NDRG1 were associated with a higher prevalence of brain metastases, greater tumor burden and reduced survival. In patient samples, high NDRG1 was associated with aggressiveness and served as an independent predictor of poor survival outcome. Blocking NDRG1 in preclinical studies slowed tumor growth and inhibited brain metastasis, suggesting this may be a novel therapeutic target for aggressive breast cancers. Learn more in the Journal of the National Cancer Institute.
Ribociclib and hormone therapy continue to demonstrate survival advantage in premenopausal advanced breast cancer patients
Breast cancers in younger women are known to be more aggressive and typically have a poorer prognosis. In the only trial of its kind dedicated to premenopausal women, the Phase III MONALEESA-7 trial led by Debu Tripathy, M.D., evaluated the CDK4/6 inhibitor, ribociclib, plus hormone therapy versus placebo plus hormone therapy for advanced hormone receptor-positive (HR+) breast cancer. Initial results published in 2019 were the first to show an overall survival benefit with a CDK inhibitor, which was reported at 42 months of follow-up. This analysis at a median follow-up of 53.5 months revealed a median overall survival of 58.7 months for patients receiving ribociclib compared to 48 months in patients receiving hormone therapy plus placebo. These results confirm the benefit of ribociclib and hormone therapy in the first-line setting and were consistent across multiple subsets in premenopausal HR+/human epithelial growth factor 2 negative (HER2-) advanced breast cancer. Learn more in Clinical Cancer Research.
Second-generation antiandrogens associated with depression risk in men with prostate cancer
Hormone therapy, including androgen deprivation therapy, is an established prostate cancer treatment. Most men advance to castration-resistant disease and are treated with second-generation anti-androgens, which work by blocking androgen production or the androgen receptor. Although prior studies showed an association between androgen deprivation therapy and depression, it is unknown if the increased potency of second-generation therapies would also increase the risk of depression. Kevin Nead, M.D., led a retrospective cohort study of 30,069 men and found a statistically significant twofold increase in depression among patients treated with second-generation antiandrogens compared with traditional forms of hormone therapy and no hormone therapy. These results suggest that additional research is needed to better understand the relationship between newer antiandrogens and the increased risk of depression. Learn more in JAMA Network Open.
In case you missed it
Read below to catch up on recent MD Anderson press releases across the spectrum of cancer research.
Li Ma, Ph.D., assistant professor in Experimental Radiation Oncology, reports in Nature Cell Biology that the protein ZEB1 may help breast cancer cells repair DNA damage caused by radiation treatment.
Ma’s team has demonstrated how ZEB1 helps the wily tumor cells push the panic button.
“The cancer stem cells have been shown to promote radioresistance through activation of the DNA damage response system,” says Ma. “Our studies have shown that ZEB1 can induce a process that allows certain tumors to acquire cancer stem cell properties, including radioresistance.”
The study was funded by the National Institutes of Health and a scholar award from the Cancer Prevention Research Institute of Texas.
Li Ma, Ph.D., assistant professor, Experimental Radiation Oncology, is co-winner of the American Association for the Advancement of Science (AAAS) Martin and Rose Watchel Cancer Research Award.
She shares the award with Jeffrey Tyner, Ph.D., an assistant professor at Oregon Health & Science University. Ma's laboratory investigates novel determinants of tumor invasion, metastasis and therapeutic targets in breast cancer. Ma's research focuses on understanding how to regulate breast cancer metastasis, breast tumor radioresistance, and key breast cancer proteins and pathways to develop treatments.
The annual Wachtel Award honors early career investigators. They each receive $25,000 and deliver a public lecture on their research. Their award entry essays are published in the journal Science Translational Medicine.
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. Clinical advances include positive data with targeted therapies for HER2 exon 20 mutant lung cancer, for older patients with mantle cell lymphoma and for BRAFV600E-mutant gliomas. Additional discoveries include insights into chromosomal instability and immunotherapy resistance in pancreatic cancer, the genomic landscape of small-cell lung cancer, hematopoietic stem cell decline with telomere shortening, identifying tumor suppressors in CRISPR screens, and physiological responses to fasting.
Multi-center study demonstrates clinical benefit for poziotinib in HER2 exon 20 mutant lung cancer
There is currently an unmet need for targeted therapies to treat the 2% to 5% of non-small cell lung cancers (NSCLC) with HER2 exon 20 oncogenic driver mutations. Cohort 2 of the Phase II ZENITH20 clinical trial assessed the small molecule inhibitor poziotinib in 90 patients with previously treated HER2 exon 20 mutant NSCLC. Xiuning Le, M.D., Ph.D., John Heymach, M.D., Ph.D., and colleagues reported an objective response rate of 27.8% after a median follow-up of nine months. Most patients (74%) saw their tumors shrink. The disease control rate was 70%, median progression-free survival was 5.5 months and median duration of response was 5.1 months. Thirteen percent of patients permanently discontinued treatment due to adverse events. The results echo the findings from a smaller, single-institution study previously published by MD Anderson researchers. Based on the results of this smaller study, the FDA granted fast-track designation to poziotinib in March 2021. Learn more in the Journal of Clinical Oncology.
Utilizing ibrutinib and rituximab combination as first-line “chemotherapy-free” treatment of older patients with mantle cell lymphoma
Patients with mantle cell lymphoma (MCL) are generally treated with systemic chemotherapy, although older patients tend to have poorer tolerance, quality of life and outcomes with chemotherapy. Since most MCL patients are older, alternative treatments are needed. A research study led by Preetesh Jain, M.D. Ph.D., and Michael Wang, M.D., investigated the safety and efficacy of a chemotherapy-free combination of ibrutinib and rituximab administered to 50 previously untreated older (≥ 65 years) patients with MCL. This single-institution single-arm Phase II trial treated patients with the combination for two years, then continued ibrutinib therapy alone. The overall response rate was 96%, and 71% of trial enrollees experienced a complete response. While 22% of patients experienced atrial fibrillation, the combination was found to be safe and no on-study deaths were noted. The combination of ibrutinib and rituximab is promising for MCL treatment, and the researchers suggest conducting a randomized trial to definitively prove its effectiveness. Learn more in the Journal of Clinical Oncology.
New combination therapy offers promising treatment for BRAFV600E-mutant gliomas
Standard treatments for gliomas — the most common primary brain tumors — consist of a combination of surgery, radiation and temozolomide-based or lomustine-based chemotherapy. However, because current options have been associated with poor response rates and prognoses, especially for patients with the BRAFV600E mutations, finding an effective treatment to improve outcomes remains an unmet clinical need. A team of researchers led by Vivek Subbiah, M.D., conducted the Phase II Rare Oncology Agnostic Research (ROAR) basket trial to assess the activity and safety of dabrafenib plus trametinib combination treatment in patients with BRAFV600E-mutated high-grade glioma (HGG) and low-grade glioma (LGG), as well as other rare cancers. In the glioma cohorts, the combination therapy demonstrated clinically meaningful activity — a 33% and 69% objective response rate in HGG and LGG, respectively — and was well tolerated, with a safety profile consistent with that in other indications. These findings suggest that BRAFV600E testing could potentially be adopted in clinical practice for patients with glioma. Learn more in The Lancet Oncology.
Glucocorticoid receptor in pancreatic cancer cells promotes immunotherapy resistance
Immune checkpoint inhibitors have not been effective in treating patients with pancreatic cancer, in part due to an immune-suppressive tumor microenvironment. Glucocorticoid signaling is thought to suppress immune cell activity, but new research led by Yalan Deng, Ph.D., and Li Ma, Ph.D., discovered an important role for the glucocorticoid receptor (GR) within pancreatic cancer cells. They demonstrated GR signaling in pancreatic cancer cell lines regulates expression of the immune checkpoint protein PD-L1 and the antigen presentation protein MHC-I. In preclinical models, either genetic depletion or therapeutic inhibition of GR lowered PD-L1 and elevated MHC-I levels, sensitizing otherwise immunotherapy-resistant pancreatic tumors to checkpoint inhibitors. High GR expression in pancreatic cancer patient samples correlated with high PD-L1 expression, low MHC-I expression and poorer clinical outcomes. The findings suggest that GR signaling plays an important role in cancer cells to suppress the anti-tumor immune response, pointing to a potential new therapeutic target. Learn more in Nature Communications.
Study provides new insights on genomic landscape of small-cell lung cancer
Small-cell lung cancer (SCLC) is an aggressive form of lung cancer with high rates of recurrence and early metastasis. Research has suggested that complex genomic intratumor heterogeneity contributes to treatment resistance. In this study, researchers applied whole-exome sequencing and T cell receptor sequencing to 50 samples from 19 limited-stage SCLC tumors to investigate the immunogenomic landscape and assess impact on patient survival. Jianjun Zhang, M.D., Ph.D., Lauren Averett Byers, M.D., and Alexandre Reuben, Ph.D., reported finding a homogeneous mutational landscape overall, but an extremely cold and heterogeneous T cell receptor repertoire, which was associated with higher chromosomal copy number aberration burden and lower overall survival. Learn more in Nature Communications.
Understanding hematopoietic stem cell decline in response to telomere shortening
DNA damage is a major cause of stem cell decline, and one precursor to persistent DNA damage is telomere erosion. Telomeres naturally shorten over time, but erosion can be accelerated by mutations in telomere maintenance genes. It is unclear how shortened telomeres lead to stem cell deg.traver_hartcline, but hematopoietic stem cells (HSCs) are particularly vulnerable to telomere-maintenance defects. Researchers led by Natthakan Thongon, Ph.D., and Simona Colla, Ph.D., sought to understand how shortened telomeres affect HSCs and lead to bone marrow failure syndromes. Using single-cell analysis, they discovered that shortened telomeres activate the innate immune response in HSCs, driving persistent metabolic activation and differentiation processes that limit their self-renewal capacity and lead to cell exhaustion. These processes were overcome by targeting the Ifi20x/IFI16 family of DNA sensors with an oligodeoxynucleotide comprised of telomeric repeats, suggesting that targeting the IFI16 signaling axis may prevent HSCs’ functional decline in the face of telomere shortening. Learn more in Nature Communications.
Harnessing CRISPR genetic screens to identify new tumor suppressors
Genetic screens using CRISPR gene editing allow researchers to efficiently inactivate individual genes to determine effects on cancer cell survival. Most screens look for cell death to identify genes essential for growth, but screens also can point to tumor suppressor genes when knockouts cause increased proliferation. Using more than 1,000 published screens, researchers led by W. Frank Lenoir, Ph.D., and Traver Hart, Ph.D., demonstrated a novel approach to identify potential tumor suppressors. Through this technique, they identified a network of 145 suppressor genes across 22 functional groups. The researchers discovered and validated that components of the fatty acid metabolism act as tumor suppressors in a subset of acute myeloid leukemia (AML) cells, and expression of those genes was correlated with patient survival outcomes. The study provides not only a new technique for identifying tumor suppressors, but also points to a potential prognostic marker and therapeutic target for AML. Learn more in Nature Communications.
A new understanding of how fasting protects against therapy toxicity
Normal tissue toxicity is a major limitation in delivering effective doses of chemotherapy and radiation. Preclinical studies from the laboratory of Helen Piwnica-Worms, Ph.D., showed fasting can blunt the effects of high-dose chemotherapy and — in collaboration with the laboratory of Cullen Taniguchi, M.D., Ph.D. — radiation in part by protecting intestinal stem cells, but the mechanism remains unclear. A new study led by Christopher Terranova, Ph.D., Kristina Stemler, Ph.D., Kunal Rai, Ph.D., and Piwnica-Worms discovered that fasting leads to epigenetic modifications in small intestinal crypt cells that activate specific metabolic pathways. During fasting, the major metabolite produced by the body is β-hydroxybutyrate (β-OHB), which the researchers demonstrated can directly modify histone proteins to trigger the expression of metabolic genes in the small intestine. This mechanistic understanding may help researchers develop approaches to protect against side effects without needing to fast, possibly expanding the therapeutic window of chemotherapy and radiation. Learn more in Cell Reports.
In case you missed it
Read below to catch up on recent MD Anderson press releases across the spectrum of cancer research.
While many times, the achievements of senior faculty members receive the greatest attention, MD Anderson is also taking steps to highlight the important work of junior faculty. Earlier this month, MD Anderson honored 16 promising young scientists and physicians with the first R. Lee Clark Fellow award. The award was established to recognize outstanding work by junior faculty members and to help support their future efforts.
The program is named in honor of MD Anderson’s first full-time director and president, Dr. R. Lee Clark, who served from 1946 to 1978.
The awards are being given to three groups of MD Anderson faculty members: those with a clinical (health care focus), those with a clinical and research focus (physician-scientists), and those with a scientific focus (scientists).
A distinguished panel of experts selected the winners based on their early career accomplishments and their innovative cancer research plans. In addition to the honor, each recipient receives $100,000 to fund their research over the next one to two years. The following is a list of all of the 2014 R. Lee Clark Fellows: Clinical Innovator Winners
- Courtney DiNardo, M.D., assistant professor, Leukemia
- Steven Lin, M.D., Ph.D., assistant professor, Radiation Oncology
- Simrit Parmar, M.D., assistant professor, Stem Cell Transplant and Cellular Therapy
- Kathleen Schmeler, M.D., associate professor, Gynecologic Oncology and Reproductive Medicine
- Jason Westin, M.D., assistant professor, Lymphoma and Myeloma
- Lauren Byers, M.D., assistant professor, Thoracic/Head and Neck Medical Oncology
- Don Gibbons, M.D., Ph.D., assistant professor, Thoracic/Head and Neck Medical Oncology
- Elizabeth Mittendorf, M.D., Ph.D., associate professor, Surgical Oncology
- Samuel Shelburne, M.D., Ph.D., associate professor, Infectious Diseases
- Jichao Chen, Ph.D., assistant professor, Pulmonary Medicine
- Francesca Cole, Ph.D., assistant professor, Molecular Carcinogenesis
- Michael Galko, Ph.D., associate professor, Biochemistry and Molecular Biology
- Han Liang, Ph.D., assistant professor, Bioinformatics and Computational Biology
- Hui-Kuan Lin, Ph.D., associate professor, Molecular and Cellular Oncology
- Li Ma, Ph.D., assistant professor, Experimental Radiation Oncology
- Xiaobing Shi, Ph.D., assistant professor, Biochemistry and Molecular Biology
MD Anderson-led team's preclinical study identifies new prognostic marker for survival
MD Anderson News Release 09/24/12
A receptor protein suppresses local invasion and metastasis of breast cancer cells, the most lethal aspect of the disease, according to a research team headed by scientists from The University of Texas MD Anderson Cancer Center.
Reporting in Nature Medicine, the team described using high-throughput RNA sequencing to identify the leukemia inhibitory factor receptor (LIFR) as a novel suppressor of breast cancer metastasis, the spread of the disease to other organs.
"Based on our findings, we propose that restoring the expression or the function of key metastasis suppressors like LIFR could be used to block breast cancer metastasis," said lead investigator Li Ma, Ph.D., assistant professor in MD Anderson's Department of Experimental Radiation Oncology.
"Lack of clinically proven prognostic markers and therapeutic agents for metastasis are major barriers for eradicating breast cancer deaths," Ma said. "Although many metastasis-promoting genes have been identified, they have not been translated into clinical practice. The exceptions are the HER2- and VEGF-targeting agents, which have shown measurable but moderate benefit in the clinic."
Only a few genes have been established as metastasis suppressors, Ma said, and many researchers believe that such genes play only a minor role in metastasis.
The investigators in this study, however, found that LIFR is "highly relevant in human tumors." While 94 percent of normal human breast tissues show high LIFR expression, LIFR is downregulated or lost in a significant fraction of patients with ductal carcinoma in situ (DCIS) or invasive breast cancer, and loss of LIFR closely correlates with poor clinical outcomes.
Protein works by activating Hippo cascade to throttle YAP
Ma said one of the major findings of the study is that LIFR suppresses both the invasion and colonization steps of metastasis by activating the Hippo kinase cascade that leads to functional inactivation of the transcriptional co-activator YAP.
"The LIFR protein is highly relevant in human cancer because it is down-regulated in about 40 percent of human breast cancers and completely lost in nearly 10 percent," Ma said. "Remarkably, in our study of approximately 1,000 patients, we found that loss of the LIFR protein in non-metastatic stages I to III breast tumors is highly associated with poor metastasis-free, recurrence-free and overall survival outcomes."
Ma noted that this work was regarded by peer reviewers as "a ground-breaking contribution" because it:
- Challenges the dogma that metastasis-suppressor genes are only a small component of metastasis compared with metastasis-promoting genes;
- Is the first report of a cell membrane receptor that activates Hippo signaling and has a critical function in cancer; and
- Might have a significant impact on clinical practice.
Ma said information about LIFR in cancer in the literature is very scarce. But some small studies have reported that LIFR is also lost in colon cancer and liver cancer through a gene-silencing mechanism called hypermethylation.
"There are many directions of research that should be pursued," Ma said. "For example, in order to develop LIFR-based methods of treatment, we must further understand the mechanism of its function and regulation of its expression."
Ma added that her group is generating LIFR conditional knockout mice to determine whether genetic deletion of LIFR in the breast will lead to tumorigenesis and metastasis.
Co-authors with Ma are Dahu Chen and Peijing Zhang, P h.D., of MD Anderson's Department of Experimental Radiation Oncology; Yutong Sun, Ph.D., Yongkun Wei, Ph.D., Abdol Hossein Rezaeian, Hui-Kuan Lin, Ph.D., and Mien-Chie Hung, Ph.D., all of MD Anderson's Department of Molecular and Cellular Oncology; Julie Teruya-Feldstein, M.D., of Memorial Sloan-Kettering's Department of Pathology; Sumeet Gupta of the Whitehead Institute for Biomedical Research; and Han Liang, Ph.D., of MD Anderson's Department of Bioinformatics and Computational Biology.
Lin, Hung and Ma are also affiliated with the Cancer Biology Program, Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston. Mien-Chie Hung is additionally affiliated with the Center for Molecular Medicine and the Graduate Institute of Cancer Biology at China Medical University.
This research was supported by the U.S. National Institutes of Health National Cancer Institute grants R00CA138572, R01CA166051, and P01CA099031; a Cancer Prevention and Research Institute of Texas Scholar Award and a University of Texas STARS Award to Ma; a Faculty Development Award from the MD Anderson Cancer Center Support Grant CA016672 from the U.S. National Institutes of Health; Center for Biological Pathways; a Susan G. Komen for the Cure grant; and the National Breast Cancer Foundation, Inc.
Researchers at The University of Texas MD Anderson Cancer Center have discovered that a form of RNA called metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) appears to suppress breast cancer metastasis in mice, suggesting a potential new area of therapeutic investigation. The findings, published in the Oct. 22 online issue of Nature Genetics, were surprising given that MALAT1, a long non-coding RNA (lncRNA), previously was described as a metastasis promoter.
“Our six-year study unearthed the unexpected metastasis-suppressing function of MALAT1 through highly rigorous genetics approaches,” said Li Ma, Ph.D., associate professor of Experimental Radiation Oncology and principal investigator for the study. “Our findings defy the conclusions drawn from previous MALAT1 studies and suggest the potential value of therapeutic agents targeting a cellular pathway linked to MALAT1. However, this will require further clinical investigation.”
Halting a key protein behind metastasis
Ma’s team observed that MALAT1 sequestered and inactivated a protein known as TEAD, a transcription factor, which when combined with a “co-activator” called YAP, causes cancer proliferation and metastatic progression. The researchers discovered that MALAT1 binds and inactivates TEAD, preventing it from partnering with YAP and targeting genes in promoting metastasis.
Although MALAT1 had been associated with metastasis, the team, using a breast cancer transgenic mouse model, inactivated the MALAT1 gene without altering expression of its adjacent genes and observed that MALAT1 inactivation promoted lung metastasis, which was reversed when MALAT1 was re-introduced.
Similarly, knockout of MALAT1 in human breast cancer cells induced their metastatic ability, which was reversed by the re-introduction of MALAT1. Additionally, overexpression of MALAT1 suppressed breast cancer metastasis in several mouse models.
“Taken together, our study reveals the unexpected function of MALAT1 through comprehensive gene targeting and genetic rescue approaches in multiple in vivo models,” said Ma. “These findings call for a reassessment of ongoing efforts to target MALAT1 as an anti-metastatic therapeutic strategy, and provide a general framework for pursuing a better understanding of lncRNAs.”
MD Anderson study team members included: Jongchan Kim, Ph.D., Hai-Long Piao, Ph.D., Fan Yao, Ph.D., Zhenna Xiao, Ashley Siverly, Sarah Lawhon, Baochau Ton, Hyemin Lee, Ph.D., Zhicheng Zhou, Ph.D., and Boyi Gan, Ph.D., all of the Department of Experimental Radiation Oncology; Mien-Chie Hung, Ph.D., Zhenbo Han, M.D., Ph.D., and Yutong Sun, Ph.D., of the Department of Molecular and Cellular Oncology; Yumeng Wang, Ph.D., and Han Liang, Ph.D., of the Department of Bioinformatics and Computational Biology; and M. James You, M.D., Ph.D., of the Department of Hematopathology.
Other participating institutions included: Dalian Institute of Chemical Physics, Dalian, China; Baylor College of Medicine, Houston; Hokkaido University, Sapporo, Japan; and China Medical University, Taichung, Taiwan.
MD Anderson News Release 08/04/14
Twist, Snail, Slug. They may sound like words in a children’s nursery rhyme, but they are actually the exotic names given to proteins that can generate cells with stem cell-like properties that have the ability to form diverse types of tissue.
One protein with the even more out-there name of ZEB1 (zinc finger E-box binding homeobox 1), is now thought to keep breast cancer cells from being successfully treated with radiation therapy, according to a study at The University of Texas MD Anderson Cancer Center in Houston.
Li Ma, Ph.D., an assistant professor of experimental radiation oncology at MD Anderson, reported in this month’s issue of Nature Cell Biology that ZEB1 may actually be helping breast tumor cells repair DNA damage caused by radiation treatment by ramping up a first-line of defense known as DNA damage response pathway.
“Radiation therapy causes cell death by inducing DNA ‘ breaks’,” said Ma. “The rationale for treating tumors with radiation without damaging normal tissues is that, compared with normal cells, tumor cells are actively dividing and often have defects in DNA damage repair machinery.”
Tumor cells are thus less able to repair DNA damage. But not always. Sometimes the body produces tumor cells resistant to radiation. They are somehow able to “turn on” the DNA damage response apparatus. Until now, the question has always been how?
Ma’s team has demonstrated that the wily tumor cell’s ability to push the panic button at the last second can be triggered by ZEB1’s penchant for launching an operation that generates cancer stem cells.
“The cancer stem cells have been shown to promote radioresistance through activation of the DNA damage response system,” said Ma. “Our studies have shown that ZEB1 can induce a process known as epithelial-mesenchymal transition (EMT) which allows certain tumor to acquire cancer stem cell properties including radioresistance.”
EMT is one way the body responds to wound healing and it is believed that cancer has found a method for using EMT to promote tumor progression.
ZEB1 achieves this unfortunate result through a complex chain of events that permit a gene known as ATM to stabilize the protein Chk1 that plays an important role in DNA damage response. ZEB1 promotes Chk1’s ability to allow tumor radioresistance through deployment of an enzyme called USP7.
The hope is that new approaches to addressing radiation resistance may be developed through gaining better insight into how this signaling pathway keeps tumor cells growing despite being bombarded with toxic radiation treatments.
“Radiation therapy plays a key role in breast cancer management,” said Ma. “To overcome the obstacle of radioresistant tumor cells, it is important to identify the critical causes and to develop safe and effective new methods for treatment including the possible use of agents that target ZEB1 and which inhibit CHK1.”
Ma’s study included collaborators in MD Anderson’s Departments of Molecular and Cellular Oncology, Radiation Oncology, and Bioinformatics and Computational Biology. Other participating institutions included the University of Louisville Health Sciences Center in Louisville, Ky., the Houston Methodist Research Institute, China Medical University, Taiwan, and The University of Texas Health Science Center Graduate School of Biomedical Sciences in Houston.
The study was funded by the National Institutes of Health (R00CA138572, R01CA166051, R01CA181029 and U54CA151668) and a Cancer Prevention Research Institute of Texas scholar award (R1004).