MTAP

CHICAGO — A new type of targeted cancer drug that blocks a “DNA caretaker” protein called Werner helicase has captured the attention of several big pharma companies in recent years, and the first data appear to reinforce its potential. Cells are typically equipped with critical redundancies for important proteins, but when they mutate in cancer patients, a single protein can become the key to a cell’s life or death. By finding the proteins that aberrant cancer cells need to function and then blocking them, drug developers are building the next generation of targeted cancer treatments. Roche now has the first data for its experimental drug, which takes advantage of what’s known as synthetic lethality, in gynecologic and colon cancers. It was shared this week at the American Association for Cancer Research’s annual meeting in Chicago. In the span of six years, scientists and physicians took a promising drug target identified via CRISPR screening and created a handful of experimental treatments for cancer patients. There are now four different Werner helicase-targeting agents in early-stage clinical trials from Roche, Novartis, GSK and Nimbus Therapeutics — a private drug developer with a track record of doing big deals. “Werner helicase really and truly represents a synthetic lethal vulnerability and therefore a therapeutic opportunity in MSI cancers,” said Timothy Yap, a physician-scientist with the University of Texas MD Anderson Cancer Center, referring to cancers with a specific DNA signature. “That’s really the crux of it and why it was so exciting.” Synthetic lethality is a phenomenon that scientists are exploiting to develop new targeted cancer treatments. Their inspiration is PARP inhibitors (such as AstraZeneca’s Lynparza), a class of drugs used to treat a wide range of cancers including breast and ovarian. PARP inhibitors are a synthetic lethal therapy for cancers with BRCA mutations. In the Phase 1 study, Roche’s experimental drug led to four confirmed responses — two in endometrial cancer, one in colorectal cancer, and one in ovarian cancer — in 35 patients. There was also a fifth unconfirmed response in endometrial cancer. Yap presented the data Sunday at the AACR meeting. The responses mean the drug, which came from Roche’s partnership with Vividion Therapeutics in 2020, shrank the tumors in these patients at least 30%. It’s the first time that researchers have shown the effect of a Werner helicase blocker in people. Many of the patients in the study had gone through several previous treatment regimens. While their cancers were found in a wide range of locations, most of the tumors were considered microsatellite instable, which is a sign of DNA misrepair that physicians frequently look for in cancer diagnoses. The initial science that identified Werner helicase as a potential target showed that knocking it out was lethal to the microsatellite instable cells, and this piqued the interest of drug developers. Microsatellite instability-high cancers make up around 3% of all cancer cases, according to some estimates. The responses to Roche’s drug occurred at a range of doses, from 150 mg a day to 1,000 mg twice a day. In an interview, Ryan Corcoran, director of the gastrointestinal cancer center program at the Massachusetts General Hospital Cancer Center, said there’s not a clear correlation between the responses and dose levels. Researchers typically look for dose dependency (more drug equals better efficacy) in clinical studies as a green flag the treatment is working as intended. Corcoran, who chaired the session where Roche’s clinical trial results were presented, consults for Roche but not on the Werner helicase project. The primary side effects related to the drug were nausea, vomiting and diarrhea. There were no dose-limiting toxicities. Like Novartis had already reported, both GSK and Nimbus disclosed at the meeting that their molecules were non-covalent, meaning they do not permanently bind Werner helicase. This leaves Roche as the lone company developing a covalent, or permanently binding, agent in clinical trials. GSK suggested in its presentation that its drug could work in tumors that acquired resistance to Roche or Novartis’ compounds, but that’s based on animal model data and has not been shown in humans. GSK’s drug comes from a partnership with Ideaya Biosciences, a biotech company that’s focused on developing drugs against synthetic lethalities. In 2019, four papers were published showing Werner helicase could be a promising target for treating microsatellite instable cancers. These cancers tend to respond well to immunotherapy, but patients have few other options beyond those treatments. Of the two studies published in Nature on the same day, one was from Mathew Garnett’s lab at the Wellcome Sanger Institute, while the other was led by Adam Bass, who at the time was at the Dana-Farber Cancer Institute and now leads translational cancer research at Novartis. Using CRISPR screening, researchers from both groups found that Werner helicase was needed in microsatellite instable cancer models but dispensable in models that were microsatellite stable. “When you knock out Werner helicase, in 48 hours, the cells are dead,” Garnett said. “All their DNA is just shattered, and it’s really phenomenal. You had this sense when you saw this genome shattering, that there was something really profound happening to these cells.” There are several other synthetic lethality programs in early-stage trials. Corcoran said he has yet to see results from another class of synthetic lethal drugs that matches the success of PARP inhibitors, though many of these efforts are still early and have yet to report clinical data. One closely-watched effort to leverage synthetic lethality is targeting a protein called PRMT5 in cancers with mutations known as MTAP deletions. This is an area in which Bristol Myers Squibb, Amgen, Ideaya and others are all working on early-stage programs, though readouts so far have been mixed . Eli Lilly and Foghorn Therapeutics last year began a Phase 1 trial for a SMARCA2 inhibitor, which they are studying in patients with SMARCA4-mutated cancers. “Imagine you’re riding a bicycle — it’s a bicycle with two wheels — and one of the wheels is lost, and now you’re riding a unicycle,” Foghorn CEO Adrian Gottschalk said. And so giving a SMARCA2 inhibitor to one of these patients is like taking a stick to the cancer cell’s remaining wheel, he said.

Mesothelioma is a type of cancer that develops in the lining that covers the outer surface of some of the body’s organs and is usually linked to asbestos exposure. Image credit: Shutterstock / Wirestock Creators. GSK’s Zejula (niraparib) has reduced the risk of death or progression by 27% in patients with mesothelioma in an investigator-led Phase II trial. The NERO study (NCT05455424) investigated the efficacy of Zejula in 88 mesothelioma patients who relapsed after previously receiving platinum-based systemic therapy. The study is sponsored by the University Hospital Southampton NHS Foundation Trust and funded by Asthma + Lung UK, with support from Mesothelioma UK and the Mavis Nye Foundation. Mesothelioma is a highly aggressive cancer that forms in the protective lining surrounding certain internal organs, most commonly the lungs, and is usually linked to asbestos exposure. Treatments are limited, and the standard of care (SOC) includes surgery, chemotherapy, radiation therapy, and immunotherapy. Those treated with Zejula benefited from an average of 1.5 months progression-free survival (PFS) compared to SOC – marking a 27% reduction in the risk of the cancer progressing or death. Professor Gareth Griffiths, director of the Southampton Clinical Trials Unit and co-lead of the trial, said: “Although this increase may seem small, for this group of patients who have very few treatment options and a generally poor prognosis, this is a significant step forward. GlobalData Strategic Intelligence US Tariffs are shifting - will you react or anticipate? Don’t let policy changes catch you off guard. Stay proactive with real-time data and expert analysis. By GlobalData Learn more about Strategic Intelligence “We have shown for the first time that this kind of drug can improve progression-free survival for mesothelioma patients compared with their usual treatment in the NHS. This gives enormous hope to those patients and their families and means we can now carry out further research to find out more about how these treatments could be tailored and enhanced to stimulate an even better response in more people.” The data was presented at the American Association of Cancer Research (AACR) Annual Meeting 2025 in Chicago, US, on 29 April. The University Hospital Southampton NHS Foundation Trust is now keen to initiate a new study, SELECTmeso, which will be a Phase II platform trial in patients with confirmed histological diagnosis of mesothelioma with evidence of MTAP loss on immunohistochemistry, and evidence of disease progression following prior standard systemic therapy on CT scan. Griffiths added: “This trial will see patients tested for certain biomarkers, or genetic signals, in their tumours and then given the drug that is most likely to work for them. We really hope this step into more personalised medicine could further help these patients who desperately need better treatment options.” Other PARP inhibitors being investigated in mesothelioma Zejula is an oral poly-ADP ribose polymerase (PARP) inhibitor that was approved on 27 March 2017 by the US Food and Drug Administration (FDA) for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer. Other PARP inhibitors being investigated in patients with mesothelioma include AstraZeneca’s Lynparza (olaparib), which is currently in a Phase II trial (NCT04515836); and Pfizer’s Talzenna (talazoparib), which is also in a Phase II study (NCT04462809). AstraZeneca is also studying volrustomig , a bispecific antibody immunotherapy that targets and blocks PD-1 and CTLA-4. The drug is currently being evaluated in a Phase III trial for malignant pleural mesothelioma (NCT06097728). In September 2024, the FDA approved MSD’s Keytruda in combination with chemotherapy as a treatment for unresectable advanced or metastatic malignant pleural mesothelioma, based on data from the KEYNOTE-483 (NCT02784171) study.

SHANGHAI, April 27, 2025 /PRNewswire/ -- Abbisko Therapeutics Co., Ltd. (Abbisko Therapeutics 02256.HK) today announced that it has presented four late-breaking pre-clinical research posters at the 2025 AACR conference held in Chicago, Illinois (USA) from April 25 to April 30. Results were shared for ABSK112 (EGFR exon20ins inhibitor), ABSK131 (PRMT5*MTA inhibitor), and ABK-KRAS-1 (pan-KRAS inhibitor), as well as results from a study investigating potential resistance mechanisms to KRAS G12C inhibitors. Abbisko presented the following posters at the 2025 AACR: Title1: Preclinical Evaluation of ABSK112, a Selective and CNS-penetrant Compound with Strong HER2 Inhibitory Activity for Treating HER2-Driven Solid Tumors Session Category: Late-Breaking Research: Experimental and Molecular Therapeutics 2 Session Date and Time: April 28, 2025, 2:00 PM - 5:00 PM (CDT) Location: Poster Section 54 Poster Board Number: 14 Poster Number: LB240 Conclusion: Our findings establish ABSK112 as a potent, selective and CNS-penetrant HER2 inhibitor, warranting further clinical evaluation of it as a monotherapy or in combination with HER2-targeted ADCs for the treatment of HER2+ cancers with brain metastases. Title 2: Loss-of-Function (LoF) of KEAP1 promotes cell survival through multiple mechanisms, leading to resistance to KRAS G12C inhibitors Session Title: Late-Breaking Research: Experimental and Molecular Therapeutics 3 Session Date and Time: April 29, 2025 9: 00AM – 12: 00 PM (CDT) Location: Poster Section 52 Poster Board Number: 1 Poster Number: LB278 Conclusion: KEAP1 LoF mutant NSCLCs develop resistance to KRAS G12C inhibitors through reduced drug-induced ROS accumulation, metabolic adaptation, and sustained activation of MAPK and AKT signaling. Combination therapies targeting glutamine metabolism (e.g., GLS1 inhibitors), MAPK (e.g., MEK inhibitors), and PI3K-AKT-mTOR pathways (e.g., BEZ235) reverse resistance and improve therapeutic efficacy in KEAP1-mutant cell lines. These strategies may restore sensitivity to KRAS G12C inhibitors and enhance clinical outcomes. Title 3: The MTA-Cooperative PRMT5 Inhibitor ABSK131 Exhibits Potent Activity and Broad Synergistic Potential in MTAP-Deleted Cancer Models Session Category: Late-Breaking Research: Experimental and Molecular Therapeutics 4 Session Date and Time: April 30, 2025 9:00 AM - 12:00 PM (CDT) Location: Poster Section 51 Poster Board Number: 9 Poster Number: LB427 Conclusion: ABSK131 exhibits strong anti-tumor activity in MTAP-deleted lung and pancreatic cancer models and synergizes effectively with multiple therapeutic agents. These findings support the continued clinical development of ABSK131 as both a monotherapy and in combination regimens for MTAP-deleted cancers. Title 4: Discovery and characterization of a highly potent and orally available small-molecule inhibitor for diverse KRAS mutations Session Category: Late-Breaking Research: Experimental and Molecular Therapeutics 4 Session Date and Time: April 30, 2025 9:00 AM - 12:00 PM (CDT) Location: Poster Section 51 Poster Board Number: 13 Poster Number: LB431 Conclusion: Taken together, ABK-KRAS-1 exhibits broad in vitro activity against different KRAS mutations and induces dose-dependent tumor regression in KRAS mutated xenograft models. Moreover, ABK-KRAS-1 possesses favorable drug-like properties. Here, ABK-KRAS-1 is presented as a promising therapeutic candidate for the treatment of cancers harboring KRAS mutations. About Abbisko Therapeutics Founded in April 2016, Abbisko Therapeutics Co., Ltd. (HKEX: 02256.HK), is an oncology-focused biopharmaceutical company based in Shanghai that is dedicated to the discovery and development of innovative medicines to treat unmet medical needs in China and globally. The Company was established by a group of seasoned drug hunters with rich research & development and managerial expertise from top multinational pharmaceutical companies. Since its founding, Abbisko Therapeutics has built an extensive pipeline of innovative programs focused on precision oncology and immuno-oncology. Please visit for more information. SOURCE Abbisko WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED