ZEB1

Studying a deadly type of breast cancer called triple negative, scientists say they have identified key molecular differences between cancer cells that cling to an initial tumor and those that venture off to form distant tumors. Studying a deadly type of breast cancer called triple negative, Johns Hopkins Medicine scientists say they have identified key molecular differences between cancer cells that cling to an initial tumor and those that venture off to form distant tumors. The research, using mouse models and human tissues, could pave the way for developing new treatments that target such molecular variations. A report on the findings is published Aug. 3 in Science Translational Medicine. "We have long needed new treatment targets and options for triple negative breast cancers," says Andrew Ewald, Ph.D., the Virginia DeAcetis Professor in Basic Science Research and Director, Department of Cell Biology at the Johns Hopkins University School of Medicine and co-leader of the Cancer Invasion and Metastasis Program at the Johns Hopkins Kimmel Cancer Center. "These cancers often return within three years of diagnosis, and treatments used for other breast cancers don't typically work for triple negative." An estimated 10%-20% of the 280,000 breast cancers diagnosed in the U.S. each year are triple negative, and the rate is higher among African American women, who are twice as likely as others to experience this form of the disease. The lethal nature of this type of cancer is marked by the fact that its cells lack molecular flags on its surface that connect with the hormones estrogen and progesterone and a cancer growth-promoting protein called Her2-neu. Many current breast cancer therapies work by targeting those flags, rendering them of little use to those with triple negative tumors. For the current study, the research team looked at molecular differences between initial, or primary, triple-negative breast cancer sites and areas where it spread, or metastatic sites, among three different types of cells: mouse models, human cancers implanted into mice and samples of both primary and metastatic tissues taken from eight patients treated at The Johns Hopkins Hospital. The researchers used a combination of machine learning, cellular imaging, and biochemical analysis to identify differences in the genetic expression patters of initial and metastatic tumors. "The bad news from our study is that cells from metastatic sites are super optimized for migration and resisting treatment," says Ewald. "The good news is that we identified several proteins called transcription factors that these cells require to handle the challenges of migrating and thriving at metastatic sites, and we may be able to design new therapies that target these transcription factors." More specifically, Ewald and Johns Hopkins postdoctoral fellow Eloïse Grasset, Ph.D., and others on the research team found several unique properties in the cells of mice engineered to have the mouse-version of triple negative breast cancers, and mice implanted with tumors from people with triple negative breast cancer. The scientists found that when triple negative breast cancer cells invade other tissues on their way to another part of the body, they gain two cellular properties: better movement and survival. To do this, breast cancer cells gain a cellular skeleton protein dubbed vimentin, which enhances the migratory ability of so-called mesenchymal cells, a cell type typically found in bones and bone marrow that moves around and makes new cells. Triple negative breast cancer cells also gain survival advantages by producing a protein called E-cadherin, typically found in epithelial cells that line the ducts and coverings of organs and frequently renew themselves. When triple negative breast cancer cells gain such survival and migratory qualities, scientists classify their cellular state as so-called hybrid epithelial mesenchymal (EMT) cells. To look more closely at molecules involved in hybrid EMT states, the scientists sought the help of Elana Fertig, Ph.D., division director and associate director of quantitative sciences and co-director of the Convergence Institute at the Johns Hopkins Kimmel Cancer Center, to track the molecular patterns of individual cells in cell assays that model invasion out of the primary tumor and formation of a colony in a metastatic site. Fertig's computational team used machine learning techniques to find patterns among each cell's expression of RNA, a cousin of DNA involved in protein production. The scientists found that most of the metastatic cells morph into the more mobile, better surviving, hybrid EMT state. Ewald's team then validated these states in samples from eight patients with triple negative tumors, examining both primary tumors and tissues from metastatic sites of the same patients. At the molecular level, the most metastatic cells produced five proteins called transcription factors (Grhl2, Foxc2, Zeb1, Zeb2 and Ovol1) that foster the making of proteins involved in either cancer cell invasion or colony formation. "The molecular differences between metastatic and primary tumors are likely the reason why metastatic tumor cells are so resistant to current treatments," says Ewald. His team is studying ways to block the transcription factors' genes or their resulting proteins to halt metastatic cancer growth as well as whether the same molecular and cellular changes happen in other cancers, such as those in the colon, adrenal glands, stomach, and small intestine. Other Johns Hopkins researchers who contributed to the study include Matthew Dunworth,Gaurav Sharma, Melanie Loth, Joseph Tandurella, Ashley Cimino-Mathews, Melissa Gentz, Sydney Bracht and Meagan Haynes. The research was supported by the Breast Cancer Research Foundation, the Twisted Pink Foundation, Hope Scarves, the Jayne Koskinas Ted Giovanis Foundation, the Cindy Rosencrans Fund for Triple Negative Breast Cancer Research and the National Institutes of Health's National Cancer Institute (U01CA217846, U54CA268083, 3P30CA006973, U01CA212007, U01CA253403).

Findings provide key insights into ATYR2810’s potential mechanism of action, including ability to modulate key immune cells involved in tumor progression, metastasis and therapy resistance. Data will support the clinical development of ATYR2810, including a Phase 1 study in cancer next year. SAN DIEGO, Nov. 09, 2021 (GLOBE NEWSWIRE) -- aTyr Pharma, Inc. (Nasdaq: LIFE), a biotherapeutics company engaged in the discovery and development of innovative medicines based on novel biological pathways, today announced a poster presentation at the Society for Immunotherapy of Cancer (SITC) Annual Meeting, which is being held November 10 – 14, 2021 in Washington, DC, and virtually. The full text of the corresponding abstract is available on the SITC website. The poster will be available for browsing on the SITC website starting Friday, November 12 at 7:00 a.m. ET through Sunday, November 14 at 5:00 p.m. ET. The poster presents preclinical findings for ATYR2810, providing key insights into its mechanism of action that will help support the clinical development of ATYR2810, including a Phase 1 study in cancer next year. ATYR2810, an anti-Neuropilin-2 (NRP2) monoclonal antibody that blocks NRP2’s VEGF-induced signaling axis, was developed from aTyr’s research platform focused on targeting human disease pathways associated with extracellular tRNA synthetases. This work details the effects of ATYR2810 on tumor associated macrophages (TAMs) differentiated from human triple-negative breast cancer tumor cells. Treatment with ATYR2810 was shown to decrease the suppressive capabilities of TAMs against T cells compared to untreated TAMs. Furthermore, TAMs treated with ATYR2810 showed a decrease in ZEB1 gene expression, which is a master transcription factor regulating epithelial-mesenchymal transition (EMT), a process that is of great importance in regulating tumor growth, progression and metastatic cascade as well as being implicated in tumor evasion of the immune system. These results suggest that ATYR2810 may be able to treat cancer by targeting tumor immune avoidance mechanisms as well as regulating EMT. Details of the poster and corresponding abstract are as follows: Title: ATYR2810, an anti-NRP2 monoclonal antibody, targets tumor associated macrophages Authors: Samantha Tyler, Michaela Ferrer, Erik Escobedo, Kaitlyn Rauch, Sofia Klopp-Savino, Justin Rahman, Zhiwen Xu, Esther Chong, Suzanne Paz, Leslie Nangle. aTyr Pharma, San Diego, CA. Abstract Number: 699 Date and Time: November 12 – 14, 2021 from 7:00AM – 5:00PM ET “We are pleased to demonstrate, for the first time, modulation of key cells associated with suppressing T cell-mediated anti-tumor responses in the tumor microenvironment as a result of treatment with ATYR2810, aTyr’s IND candidate in preclinical development for aggressive solid tumors where NRP2 is implicated,” said Leslie Nangle, Ph.D., Vice President, Research at aTyr. “It is well known that TAMs suppress T cell activity and play an important role in the induction of EMT, contributing to therapy resistance and metastasis. As we and others have shown, these highly suppressive TAMs express high levels of NRP2. The ability of ATYR2810 to regulate EMT-related genes like ZEB1 in human TAMs and reduce their suppressive nature provides insight into the role of NRP2/VEGF signaling in TAMs. These findings advance our understanding of ATYR2810’s mechanism of action and the process by which it may inhibit tumor progression and disrupt immune evasion.” About ATYR2810 aTyr is developing ATYR2810 as a potential therapeutic for certain aggressive tumors where Neuropilin-2 (NRP2) is implicated. ATYR2810 is a fully humanized monoclonal antibody that is designed to specifically and functionally block the interaction between NRP2 and one of its primary ligands, VEGF. ATYR2810 is the first Investigational New Drug (IND) candidate to arise from aTyr’s in-house research program designing monoclonal antibodies to selectively target the NRP2 receptor and its associated signaling pathways. NRP2 is a cell surface receptor that is highly expressed in certain tumors, in the lymphatic system and on key immune cells implicated in cancer progression. Increased NRP2 expression is associated with worse outcomes in many cancers. Preclinical data suggest that ATYR2810 could be effective against certain types of solid tumors. ATYR2810 is currently undergoing IND-enabling studies. About aTyr aTyr is a biotherapeutics company engaged in the discovery and development of innovative medicines based on novel biological pathways. aTyr’s research and development efforts are concentrated on a newly discovered area of biology, the extracellular functionality and signaling pathways of tRNA synthetases. aTyr has built a global intellectual property estate directed to a potential pipeline of protein compositions derived from 20 tRNA synthetase genes and their extracellular targets. aTyr’s primary focus is ATYR1923, a clinical-stage product candidate which binds to the Neuropilin-2 receptor and is designed to down-regulate immune engagement in inflammatory lung diseases. For more information, please visit . Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements are usually identified by the use of words such as “anticipates,” “believes,” “estimates,” “expects,” “intends,” “may,” “plans,” “projects,” “seeks,” “should,” “will,” and variations of such words or similar expressions. We intend these forward-looking statements to be covered by such safe harbor provisions for forward-looking statements and are making this statement for purposes of complying with those safe harbor provisions. These forward-looking statements include statements regarding the potential therapeutic benefits and applications of NRP2 antibodies, including ATYR2810; timelines and plans with respect to certain development activities; and certain development goals. These forward-looking statements also reflect our current views about our plans, intentions, expectations, strategies and prospects, which are based on the information currently available to us and on assumptions we have made. Although we believe that our plans, intentions, expectations, strategies and prospects, as reflected in or suggested by these forward-looking statements, are reasonable, we can give no assurance that the plans, intentions, expectations or strategies will be attained or achieved. All forward-looking statements are based on estimates and assumptions by our management that, although we believe to be reasonable, are inherently uncertain. Furthermore, actual results may differ materially from those described in these forward-looking statements and will be affected by a variety of risks and factors that are beyond our control including, without limitation, uncertainty regarding the COVID-19 pandemic, risks associated with the discovery, development and regulation of our product candidates, the risk that we or our partners may cease or delay preclinical or clinical development activities for any of our existing or future product candidates for a variety of reasons (including difficulties or delays in patient enrollment in planned clinical trials), the possibility that existing collaborations could be terminated early, and the risk that we may not be able to raise the additional funding required for our business and product development plans, as well as those risks set forth in our most recent Annual Report on Form 10-K, Quarterly Reports on Form 10-Q and in our other SEC filings. Except as required by law, we assume no obligation to update publicly any forward-looking statements, whether as a result of new information, future events or otherwise. Contact: Ashlee Dunston Director, Investor Relations and Corporate Communications adunston@atyrpharma.com