LRIG1

A team of scientists and physicians have discovered that the immune checkpoint protein VISTA can directly turn off tumor-fighting T-cells during immunotherapy and resist treatment. The study explains that VISTA can bind to a protein called LRIG1 in T cells, which was previously only thought to promote bone and fat development. When VISTA binds to LRIG1, the researchers found, LRIG1 sends signals that suppress T cell replication, survival and function. This interaction can happen between molecules on tumor cells and on T cells, molecules on healthy cells and T cells and even between molecules on the same T cell. A Cleveland Clinic-led team of scientists and physicians have discovered that the immune checkpoint protein VISTA can directly turn off tumor-fighting T-cells during immunotherapy and resist treatment. The study, published in Science Immunology, explains that VISTA can bind to a protein called LRIG1 in T cells, which was previously only thought to promote bone and fat development. When VISTA binds to LRIG1, the researchers found, LRIG1 sends signals that suppress T cell replication, survival and function. This interaction can happen between molecules on tumor cells and on T cells, molecules on healthy cells and T cells and even between molecules on the same T cell. Their preclinical work suggests that blocking LRIG1 function can halt tumor growth in many cancers. In human melanoma and endometrial cancer, LRIG1 expression in tumor-associated T cells was correlated with resistance to immunotherapy. VISTA modulates the immune responses of healthy cells to keep them from attacking our own bodies, protecting us from autoimmune issues. However, studies from a group led by Li Lily Wang, PhD, of Cleveland Clinic, have shown that during immunotherapy, VISTA impairs immune activation and prevents T cells from attacking cancer cells. Pharmeceutical companies have tried to make therapeutics to block VISTA from working during immunotherapy. Success has been limited, because the field still does not know exactly how VISTA works. The findings from this study follow another discovery from the laboratory of Dr. Wang, Translational Hematology and Oncology that showed VISTA indirectly suppresses our immune systems by promoting cells called myeloid-derived suppressor cells (MDSCs) that are well known to block T-cell function. "Our two discoveries combined create a paradigm that explains how VISTA can act as a 'super villain' that uses many different weapons to impair antitumor responses during cancer treatments," says Dr. Wang. "This is an insight that drug developers need to consider if they want to boost treatment response rates to their full potential." Immunotherapies and immune checkpoint therapies were a huge breakthrough in cancer treatments, providing hope for individuals affected by previously incurable cancers. But with response rates of only 20% -- 30% and high recurrence rates, Dr. Wang says there is still much room to improve. "Studying the molecular aspect of how LRIG1 functions as VISTA's receptor on T cells can provide insights on how to successfully block VISTA and improve the clinical outcomes of the patients who don't respond to existing immune therapies" says lead first author Hieu Minh Ta, PhD. This project was a collaboration between labs led by Dr. Wang and Timothy Chan, MD, PhD, Chair of Cleveland Clinic's Center for Immunotherapy & Precision Immuno-Oncology, Director of the Global Center for Immunotherapy and Sheikha Fatima bint Mubarak Endowed Chair in Immunotherapy. The paper has four co-first authors: postdoctoral fellows Dr. Ta and Dia Roy, PhD; research associate Keman Zhang, PhD; and project staff Tyler Alban, PhD. The scientists worked closely with physicians including Brian Gastman, MD, Cleveland Clinic surgical oncologist, and Case Western Reserve University cancer pathologist Stefanie Avril, MD. Drs. Gastman and Avril provided the research team with melanoma and endometrial samples for studying the expression of LRIG1. The results were striking. Patients who had been more resistant to immunotherapy had higher levels of LRIG1 in their tumor-fighting T cells. "Our findings in human cancer samples inform and support the decision to go after LRIG1 as a potential drug target for new immune checkpoint therapies," says study co-first author Dia Roy, PhD.

BOSTON, March 05, 2024 (GLOBE NEWSWIRE) -- Tango Therapeutics, Inc. (NASDAQ: TNGX), a clinical-stage biotechnology company committed to discovering and delivering the next generation of precision cancer medicines, today announced that one abstract has been selected for an oral minisymposium and seven abstracts have been accepted as poster presentations at the American Association for Cancer Research (AACR) Annual Meeting 2024, taking place April 5-10, 2024, in San Diego, California. Abstract accepted for oral minisymposium Title: TNG260, a small molecule CoREST inhibitor, sensitizes STK11-mutant NSCLC to anti-PD1 immunotherapyAbstract #: 3916Session Title: Immune Targets and Therapies Presenter: Ayushi Patel, Ph.D., NYU Langone Health Date and Time: Monday April 8, 2024, 2:30 – 4:30 p.m. PT Abstracts accepted for poster presentation Title: Genome-wide drug anchor screens identify CAAP1 and AKAP17A as regulators of PRMT5 inhibitor sensitivityAbstract #: 4636Presenter: Satoshi Yoda, M.D., Ph.D., Principal Scientist, Tango TherapeuticsDate and Time: April 9, 2024, 9:00 a.m. – 12:30 p.m. PT Title: Evaluation of the impact of homozygous MTAP truncations on the activity and selectivity of MTA-cooperative PRMT5 inhibitorsAbstract #: 4631Presenter: Kimberly Briggs, Ph.D., Director, Tango TherapeuticsDate and Time: April 9, 2024, 9:00 a.m. – 12:30 p.m. PT Title: TNG348 is synergistic with PARP inhibitors in tumor models with elevated replication stressAbstract #: 4527Presenter: Antoine Simoneau, Ph.D., Senior Scientist, Tango TherapeuticsDate and Time: April 9, 2024, 9:00 a.m. – 12:30 p.m. PT Title: TNG917 is a clinical-grade, potent and selective inhibitor of EHMT1/2 for the treatment of immune cold tumorsAbstract #: 3242Presenter: Yingnan Chen, Ph.D., Senior Director, Tango TherapeuticsDate and Time: April 8, 2024, 1:30 – 5:00 p.m. PT Title: Experimental ‘loss-of function’ annotation of STK11 mutations with prognostic and therapeutic implicationsAbstract #: 5584Presenters: Silvia Fenoglio, Ph.D., Principal Scientist, Tango Therapeutics and Brian Haines, Ph.D., Vice President, Tango Therapeutics Date and Time: April 9, 2024, 1:30 – 5:00 p.m. PT Title: LIG1 inactivation selectively inhibits growth of BRCA1 mutant cells in vitro and in vivoAbstract #: 3363Presenter: Hilary Nicholson, Ph.D., Principal Scientist, Tango TherapeuticsDate and Time: April 8, 2024, 1:30 – 5:00 p.m. PT Title: Stearoyl-CoA desaturase is a synthetic lethal target in SMAD4-deficient cancersAbstract #: 558Presenter: Alvin Lu, Ph.D., Principal Scientist, Tango TherapeuticsDate and Time: April 7, 2024, 1:30 – 5:00 p.m. PT About Tango Therapeutics Tango Therapeutics is a clinical-stage biotechnology company dedicated to discovering novel drug targets and delivering the next generation of precision medicine for the treatment of cancer. Using an approach that starts and ends with patients, Tango leverages the genetic principle of synthetic lethality to discover and develop therapies that take aim at critical targets in cancer. This includes expanding the universe of precision oncology targets into novel areas such as tumor suppressor gene loss and their contribution to the ability of cancer cells to evade immune cell killing. For more information, please visit www.tangotx.com. Forward-Looking Statements Certain statements in this press release may be considered forward-looking statements. Forward-looking statements generally relate to future events, Tango’s future operating performance and goals, the anticipated benefits of therapies and combination therapies (that include a Tango pipeline product), expectations, beliefs and development objectives for Tango’s product pipeline and clinical trials. In some cases, you can identify forward-looking statements by terminology such as “may”, “should”, “expect”, “intend”, “will”, “goal”, “estimate”, “anticipate”, “believe”, “committed” “predict”, “designed,” “potential” or “continue”, or the negatives of these terms or variations of them or similar terminology. For example, implicit or explicit statements concerning the following include or constitute forward-looking statements: the Company is committed to discovering and delivering the next generation of precision cancer medicines; the expected timing of: (i) development candidate declaration for certain targets, (ii) initiating IND-enabling studies; (iii) filing INDs; (iv) clinical trial initiation and (v) disclosing preliminary, interim and final clinical trial results; the expected therapeutic impact of the Company’s pre-clinical compounds; and the expected benefits of the Company's pre-clinical programs, pre-clinical compounds, development candidates and other product candidates. Such forward-looking statements are subject to risks, uncertainties, and other factors which could cause actual results to differ materially from those expressed or implied by such forward-looking statements. These forward-looking statements are based upon estimates and assumptions that, while considered reasonable by Tango and its management, are inherently uncertain. New risks and uncertainties may emerge from time to time, and it is not possible to predict all risks and uncertainties. Factors that may cause actual results to differ materially from current expectations include, but are not limited to: benefits of product candidates seen in preclinical analyses may not be evident when tested in later pre-clinical studies or in clinical trials or when used in broader patient populations (if approved for commercial sale); Tango has limited experience conducting clinical trials (and will rely on a third party to operate its clinical trials) and may not be able to commence the clinical trial (including opening clinical trial sites and enrolling and dosing an adequate number of clinical trial participants) when expected, may not be able to continue dose escalation on anticipated timelines, and may not generate results (including final or initial safety, efficacy data and proof-of-mechanism and proof-of-concept) in the anticipated timeframe (or at all); Tango’s pipeline products and pre-clinical products may not be safe and/or effective in humans; Tango has a limited operating history and has not generated any revenue to date from product sales, and may never become profitable; other companies may be able to identify and develop product candidates more quickly than the Company and commercially introduce the product prior to the Company; the Company’s proprietary discovery platform is novel and may not identify any synthetic lethal targets for future development; the Company may not be able to identify development candidates on the schedule it anticipates due to technical, financial or other reasons; the Company may not be able to file INDs for development candidates on time, or at all, due to technical or financial reasons or otherwise; the Company may utilize cash resources more quickly than anticipated; Tango will need to raise capital in the future and if we are unable to raise capital when needed or on attractive terms, we would be forced to delay, scale back or discontinue some of our development programs or future commercialization efforts (which may delay filing of INDs, dosing patients, reporting clinical trial results and filing new drug applications); Tango’s approach to the discovery and development of product candidates is novel and unproven, which makes it difficult to predict the time, cost of development, and likelihood of successfully developing any products; Tango may not identify or discover additional product candidates or may expend limited resources to pursue a particular product candidate or indication and fail to capitalize on product candidates or indications that may be more profitable or for which there is a greater likelihood of success; the Company’s product candidates may cause adverse or other undesirable side effects (or may not show requisite efficacy) that could, among other things, delay or prevent regulatory approval; our dependence on third parties for conducting clinical trials and producing drug product; our ability to obtain and maintain patent and other intellectual property protection for our technology and product candidates or the scope of intellectual property protection obtained is not sufficiently broad; and delays and other impacts on product development and clinical trials from the COVID-19 pandemic. Additional information concerning risks, uncertainties and assumptions can be found in Tango’s filings with the SEC, including the risk factors referenced in Tango’s Annual Report on Form 10-K for the fiscal year ended December 31, 2022, as supplemented and/or modified by its most recent Quarterly Report on Form 10-Q. You should not place undue reliance on forward-looking statements in this presentation, which speak only as of the date they are made and are qualified in their entirety by reference to the cautionary statements herein. Tango specifically disclaims any duty to update these forward-looking statements. Investor Contact:Sam Martin/Andrew VulisArgot Partnerstango@argotpartners.com Media Contact:Amanda Brown GalgaySVP, Corporate Communications, Tango Therapeuticsmedia@tangotx.com

Researchers have identified biological markers in triple negative breast cancer that are associated with resistance to chemotherapy treatment. Researchers at Baylor College of Medicine and the Broad Institute of MIT and Harvard and clinicians at Washington University in St. Louis have identified biological markers in triple negative breast cancer (TNBC) that are associated with resistance to chemotherapy treatment. The study is published in the journal Cancer Discovery and was funded by the National Cancer Institute's Clinical Proteomics Tumor Analysis Consortium (CPTAC). "TNBC is the most difficult to treat form of breast cancer, with standard treatment requiring multiple chemotherapy drugs that unfortunately often fail to cure the patient," said first and co-corresponding author Dr. Meenakshi Anurag, assistant professor of medicine at the Lester and Sue Smith Breast Center at Baylor. "It is imperative that we develop approaches to predict response so that only effective treatments are given. Furthermore, patients who don't respond to standard drugs need entirely new treatment approaches. The discovery of therapeutic alternatives will depend on new insights into how TNBC arises." The research team used an innovative analytic approach called "microscaled proteogenomics" that they previously developed (Satpathy et al, 2020) to analyze tumor biopsies taken from TNBC patients prior to treatment with carboplatin and docetaxel combination chemotherapy. Data from standard DNA and RNA sequencing approaches were integrated with mass spectrometry-based proteomics and phosphoproteomic analyses to derive more complete molecular portraits of treatment-responsive versus treatment-resistant tumors. "The proteomic analysis of pretreatment biopsies uniquely revealed metabolic pathways that were associated with resistance to treatment, including fatty acid metabolism," said Anurag, also a member of Baylor's Dan L Duncan Comprehensive Cancer Center. When the team considered both proteomics and gene expression data together, they observed that sensitivity to chemotherapy was marked by higher DNA repair signatures, interferon gamma signaling and immune checkpoint components. These data suggest a multi-omics predictor for chemotherapy response is within reach. The team then conducted analyses that triangulated treatment response, chromosomal deletion or gain and concordant decreases or increases in mRNA and protein expression. This led the team to determine that a deletion on chromosome 19, located in a region called 19q13.31-33, was associated with resistance to chemotherapy treatment. Of the hundreds of genes deleted in this location, expression of the DNA ligase gene LIG1 was one of the mostly consistently suppressed genes at both the mRNA and protein level. In model systems, and in other TNBC data sets, loss of expression and/or deletion of LIG1 was associated with selective carboplatin resistance and poor clinical outcome. "LIG1 loss was also associated with poor prognosis in other cancer types, showing that this deletion has broader clinical significance," Anurag said. The researchers are currently working on clinical grade assays to confirm that LIG1 loss can be safely used to direct carboplatin chemotherapy in TNBC. Dr. Matthew Ellis, a McNair Scholar at Baylor and director of the Lester and Sue Smith Breast Center at the time of this research, and Dr. Steve Carr, senior director of the Proteomics Platform and an institute scientist at Broad, who together orchestrated the analysis, said, "This groundbreaking study clearly reveals the power of combining microscaled proteogenomic analyses with careful clinical research to produce new insights into the nature of cancer." LIG1 is a critical component of lagging strand DNA synthesis that connects Okazaki fragments (small DNA segments that must be connected to complete the synthesis reaction). Interestingly, the lagging stand DNA polymerase POLD1 is frequently co-deleted with LIG1, suggesting a multigenic mechanism is in play. Lagging-strand synthesis components are generally considered essential to cellular survival but here reductions in the levels of these enzymes are associated with marked chromosomal instability in multiple cancer types and selective carboplatin resistance in TNBC. Mechanistic studies are underway to determine how the genome is destabilized and how tumors with LIG1 deletion can be more effectively treated. "This is an exciting result that is a testament to the remarkably close collaboration between patients, oncology care teams and laboratory scientists. In our view, proteogenomic analyses should be routine in clinical trials to discover clinically useful biomarkers, new biological insight and therapeutic hypotheses," said Dr. Shankha Satpathy, co-corresponding author of the study and senior group leader at in the Proteomics Platform at Broad.