YTHDF1

The cGAS-STING signaling pathway is a cytoplasmic DNA sensing pathway that plays a critical role in innate immune responses. Understanding this signaling pathway is extremely important for studying drug targets and treatment strategies. When tumor DNA is sensed by cGAS in the cytoplasm, cGAS catalyses the linkage of nucleotides to form CDNs, which then binds to and activates STING. This process triggers a series of immune responses, including the activation of interferon pathways and mobilization of other important signaling pathways. The activated STING translocates to various locations within the cell, recruiting other key molecules such as TBK1 and IRF3, further activating interferon pathways and other vital immune response pathways. These responses assist the body in resisting the invasion of pathogens such as viruses and tumors. In addition to tumor DNA, STING can also sense cyclic dinucleotide natural ligands produced by bacteria to activate downstream signaling pathways. This reveals the essential role of the cGAS-STING pathway in immune surveillance of the organism. As of now, 87 drugs targeting STING have been discovered, covering 35 different indications. There are 72 organizations involved in the development of these drugs. Clinical trial data shows that there have been 53 clinical trials related to drugs targeting STING. Furthermore, the development of drugs targeting STING has received widespread attention and protection, with 12,480 patent applications related to drugs targeting STING. To support the progress of research on drugs targeting STING, 5,586 papers have been published. This reflects the scientific activity and knowledge accumulation in this field. Key DrugsThe first generation of STING agonists are derivatives of CDNs. However, their range of actions is limited due to their rapid clearance in vivo, poor membrane permeability, and their requirement for administration directly into tumors. In order to address these issues, the focus of research and development for a new generation of STING agonists is to achieve systemic administration, increase drug concentration distribution within tumors, and thus improve the drug treatment window. F-star Therapeutics' SB11285 is a new generation of STING agonists, which can specifically target the hard-to-reach tumor cells and induce the activated immune cells to migrate from the periphery to the tumor lesions. In a phase I clinical trial of treatment for advanced solid tumors with SB11285 either alone or in combination with the PD-L1 antibody Atezolizumab (trade name: Tecentriq), SB11285 demonstrated good tolerability and efficacy. Merck's MSA-2 is a stable type of STING agonist, which binds to STING in a non-covalent dimeric form, inducing it to assume a closed conformation. Efficacy studies showed that MSA-2, administered intratumorally, subcutaneously or orally, demonstrated good tolerability in a mouse model of colorectal cancer and resulted in complete tumor regression in 80% to 100% of the treated mice. Furthermore, MSA-2 only interacts with STING when it forms a dimer, and the acidic conditions of the tumor microenvironment are more conducive to the dimerization of MSA-2. Therefore, despite MSA-2 being administered systemically, it has potential tumor specificity, showing good safety and tolerability. Takeda's TAK-676 is a novel synthetic STING agonist optimized to reduce serum degradation and enhance permeability compared to intratumoral STING agonists. It can be utilized through systemic venous administration. Furthermore, the addition of TAK-676 post-radiation therapy can intensify immune response by increasing STING mediated IFN inhibitor release and further stimulating T-cell mediated anti-tumor immune responses. Ongoing studies are aimed at evaluating the safety and preliminary anti-tumor activity of TAK-676 combined with pembrolizumab post-radiation. Eisai's E7766 is a macrocyclic bridged STING agonist. In a mouse model of hepatic tumors, a single injection of E7766 caused 90% of tumors to regress with no relapses over eight months. Currently, E7766 is undergoing phase I/Ib clinical trials aiming to evaluate its efficacy as a monotherapy in patients with advanced solid tumors and lymphomas. Scripps Research Institute's SR-717 is a non-nucleotide small molecule STING agonist that can be orally or systemically administered. In an aggressive melanoma animal model, SR-717 significantly inhibited the growth and metastasis of tumors and promoted tumor antigen presentation to the immune system, substantially increasing the levels of peritumoral CD8+ T cells and natural killer (NK) cells. GSK's GSK37417, a non-CDN small molecule STING agonist with a diamino-benzimidazole scaffold, is currently in phase I dose-escalation study, examining GSK37417 as a monotherapy or in combination with dostarlimab (trade name: Jemperli) for treating refractory/recurrent solid cancer patients. GSK37417 is administered via an intravenous injection, with the study expected to conclude in 2025. Synlogic's SYNB1891 represents an E.coli strain expressing the dacA protein, which catalyzes the conversion of two ATP molecules into a cyclic AMP dimer, thereby activating STING protein to trigger type I interferon responses and enhance tumor-specific T Cell responses. Roche has partnered with Synlogic to explore the efficacy of its PD-L1 inhibitor atezolizumab in combination with SYNB1891 in treating patients with advanced solid tumors.

The roles and mechanisms of the m6A reader protein YTHDF1 in tumor biologyHepatocellular carcinoma (HCC) is the sixth most commonly diagnosed cancer and the third leading cause of cancer-related deaths worldwide. The development of HCC is influenced by both viral and non-viral factors. Non-alcoholic steatohepatitis (NASH) has emerged as a growing risk factor for HCC, as the prevalence of diabetes and metabolic syndrome increases. NASH is a progressive liver disease characterized by the accumulation of excessive triglycerides and is not caused by alcohol consumption. Although NASH is linked to the development of HCC, the molecular mechanisms underlying these diseases are not fully understood, which has hindered the development of effective treatments. Handicapping anti-PD1 therapyCurrently, there are no approved drugs or biological therapies specifically targeting NASH-related HCC (NASH-HCC). This deadly disease urgently requires new treatment methods. Immune checkpoint blockade (ICB) using monoclonal antibodies that target programmed cell death protein-1 (PD-1), programmed cell death-ligand 1 (PD-L1), or cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) has recently become a treatment option for HCC.  However, NASH-HCC's poor response to ICB treatment is due to NASH-related immune changes in the liver. Therefore, identifying potential therapeutic targets is critical to overcoming resistance to ICB treatment in NASH-HCC. YTHDF1, a m6A reader, is upregulated in human NASH-HCC tumors compared to peri-tumor tissues.N6-methyladenosine (m6A) is the most prevalent chemical modification in eukaryotic mRNA and is known to play a crucial role in post-transcriptional regulation. m6A modification regulates RNA fate by controlling RNA stability, processing, transport, localization, translation, and RNA-protein interactions. YTH domain-containing family protein 1 (YTHDF1) is a translation-promoting m6A reader that targets mRNAs in the cytoplasm and contributes to tumor progression by regulating cell proliferation, DNA damage, and immunity.  YTHDF1 deficiency in mice enhances antigen-specific CD8+ T cell-mediated anti-tumor responses in colorectal and gastric cancers, making it a potential therapeutic target for cancer immunotherapy. However, the role of YTHDF1 in the pathogenesis of HCC, particularly NASH-HCC, and its regulation of the tumor immune microenvironment are currently not well understood. A recent study published in Journal of Hepatology provides valuable insights into YTHDF1’s role in the progression of NASH-HCC. It is the first to demonstrate that tumor-intrinsic YTHDF1 is linked to the accumulation of myeloid-derived suppressor cells (MDSCs) in the NASH-HCC microenvironment. In transgenic mice with liver-specific YTHDF1 overexpression, YTHDF1 induces MDSC infiltration and accelerates spontaneous NASH-HCC.  Ythdf1 recruits MDSCs via IL-6 in NASH-HCC.The signaling cascade of YTHDF1 activates the EZH2-IL-6 signaling pathway to recruit MDSCs, resulting in T cell dysfunction and promoting tumor growth. Conversely, targeting YTHDF1 with lipid nanoparticle (LNP)-siRNA can significantly enhance the anti-PD-1 blockade effect in NASH-HCC mouse models, suggesting that YTHDF1 is a new target for enhancing the efficacy of immune checkpoint blockade therapy in NASH-HCC.  Targeting the accomplice: YTHDF1 According to the Synapse database, there are currently four patent applications targeting YTHDF1 for cancer therapy. Three of these applications are for the novel use of already existing drugs, while one is for a new formula: This is not the first time YTHDF1's role in cancer pathology has been elucidated. Last year, a study reported that YTHDF1 promotes breast cancer cell growth in both in vitro and in vivo environments and plays a crucial role in DNA damage repair and chemoresistance. And it seems that YTHDF1 modulates E2F8 mRNA stability and DNA damage repair in a METTL14-dependent manner. METTL14 is involved in DNA replication, DNA damage repair and chemoresistance.On the other hand, YTHDF1 knockdown has been shown to sensitize breast cancer cells to Adriamycin and Cisplatin, as well as Olaparib, a PARP inhibitor. During the experiments, researchers observed that the knockdown of YTHDF1 in MDA-MB-231 cells resulted in a reduction of S-phase fraction and an increased G1-phase fraction. The YTHDF1 knockdown also downregulated CDK2 and Cyclin E2, while upregulating P21, a CDK inhibitor involved in S-phase.   YTHDF1’s roles in other types of cancer have been revealed as well. A study published earlier this year has suggested that YTHDF1 may play an important role in shaping the immune microenvironment of colorectal cancer (CRC).  In their study, the team of researchers revealed that removing YTHDF1 from mouse CRC cells (both microsatellite stable (MSS) and microsatellite instable-high (MSI-H) varieties) results in an accumulation of myeloid-derived suppressor cells (MDSCs). This accumulation subsequently inhibits the infiltration of T cells in both mouse CRC models and humanized mouse models, demonstrating a deep interconnectedness. The investigation led to the identification of p65/Rela as a target of YTHDF1. The researchers observed that YTHDF1 encouraged the production of p65 protein, which in turn escalated the regulation of CXCL1. This process amplified the migration of MDSCs through the CXCL1-CXCR2 pathway, resulting in an increased number of MDSCs. These MDSCs then countered the function of CD8+ T cells within the tumor immune microenvironment (TIME). This intricate research, along with the others discussed here, suggest that the strategic targeting of YTHDF1, potentially using techniques such as CRISPR or VNPs-siYTHDF1, could enhance the efficacy of anti-PD1 therapy in a variety of cancers. References: 1.Wang L. et al., Targeting N6-methyladenosine reader YTHDF1 with siRNA boosts anti-tumor immunity in NASH-HCC by inhibiting EZH2-IL-6 axis 2, Journal of Hepatology, Available online 17 July 2023. 2.Sun, Y., Dong, D., Xia, Y. et al. YTHDF1 promotes breast cancer cell growth, DNA damage repair and chemoresistance. Cell Death Dis 13, 230 (2022). 3.Bao Y, Zhai J, Chen H, et al, Targeting m6A reader YTHDF1 augments antitumour immunity and boosts anti-PD-1 efficacy in colorectal cancer, Gut 2023;72:1497-1509. 

University of Cambridge researchers published the first preclinical validation for a novel therapeutic strategy targeting epitranscriptomic modifiers of RNA, opening the door for spinout STORM Therapeutics’ acute myeloid leukemia therapy (AML)–and potentially much more. Tony Kouzarides, cofounder and director of Milner Therapeutics Institute at Cambridge and a Storm co-founder, led the team that published the paper in Nature in April, which was the first published data showing the efficacy of a catalytic METTL3 inhibitor in mouse models of AML. Consistent with earlier findings on METTL3’s role in regulating disease, Storm’s STM2457 decreased AML engraftment and increased survival. Last year the company nominated a related compound as its lead clinical candidate, and Kouzarides said Storm expects it will reach clinical testing early next year. This is the first published in vivo data for a small molecule inhibiting an epitranscriptomic disease target, but the approach has been brewing for years. Just as epigenetic modifications to DNA can directly control gene expression, epitranscriptomic modifications control RNA gene expression indirectly via RNA translation, making them potential therapeutic targets. While the first epigenetic therapy was approved in 2004, the connection between epitranscriptomic modifiers and disease pathways have only begun to be characterized. METTL3 is an epigenetic writer of N6-methyladenosine (m6A) modifications, the most prevalent reversable epitranscriptomic modification in human cells. METTL3 and other writers form m6A modifications via methylation of certain RNA sequences, which is key for numerous processes in normal cells. This would seem to make it an unlikely therapeutic target. But in 2017, two key publications began to elucidate the role of m6A in AML and demonstrate the possibility of targeting the pathway without toxicity in healthy cells. Kouzarides and colleagues published findings showing the role of METTL3 in both establishing disease and in leukemia cell differentiation. Separately, a team from Weill Cornell Medicine and Memorial Sloan Kettering Cancer Center showed in a Nature Medicine paper that leukemia cells were more dependent on METTL3 than normal hematopoietic cells. Samie Jaffrey, an author on the paper and a professor of pharmacology at Weill Cornell, said that the abnormal differentiation seen in leukemia cells was abrogated by only mild inhibition of METTL3–important because a complete METTL3 inhibitor delivered systemically would be highly toxic. The new paper from the Cambridge researchers was therefore a proof-of-concept for Jaffrey’s approach as well. “I think a lot of other people were cautious because they felt it was a fool’s errand to go after METTL3,” he said. “I think this makes the METTL3 target seem much more validated.” Researchers from both groups founded companies to exploit the therapeutic pathway in leukemia. Kouzarides and fellow Cambridge professor Eric Miska co-founded Storm Therapeutics in 2015 to develop first-in-class therapies against RNA epigenetic targets. Jaffrey co-founded Gotham Therapeutics in 2017. Storm has raised £42 million ($59.4 million) seed and Series A rounds, while Gotham raised $54 million in a Series A. At least one other company appears to be chasing METTL3: Accent Therapeutics, which last year raised a $63 million B round and announced a co-development deal with AstraZeneca utilizing its RNA-modifying protein platform, has presented in vitro data in AML for its inhibitors of METTL3 and METTL14, another m6A writer. Additional publications have shown more therapeutic possibilities for targeting the m6A pathway, suggesting it may be possible to increase sensitivity to existing therapies in pancreatic and ovarian cancer, for example. m6A methylation has also been linked to a suppressed immune response in infectious diseases like Zika and HIV, and in April a team led by University of California San Diego School of Medicine professor Tariq Rana published in vitro data showing METTL3 inhibition could suppress SARS-CoV-2 replication. Rana’s team has previously shown that the inhibition of ALKBH5, an m6A eraser, can improve the efficacy of cancer immunotherapies in mice, and Rana has spun out ViRx Pharmaceuticals with plans to license intellectual property from the university around RNA therapeutics for broad-spectrum antivirals. But Storm, Accent and Gotham are starting in AML for a reason. Optimizing compounds for AML is an easier task because unlike other cancers, “when you inhibit the METTL3 pathway, you can see the cells differentiating with your eyes,” Jaffrey said. “In most cancers, you can inhibit METTL3 and they will die but you’re inhibiting it to such a degree that probably normal cells will die too. it all comes down to one thing: therapeutic index.” Gotham has identified several solid tumor types with comparable “m6A addictions” it is looking at closely, he added. Several other companies are likely targeting different epitranscriptomic targets. Academic work by an Accent scientific cofounder, Chuan He, has focused on YTHDF1, an RNA reader that could function as an immune system control switch for modulating the response to cancer immunotherapy. He is also a chemistry professor at the University of Chicago. Accent is also pursuing ADAR1 inhibitors for cancer. Silicon Therapeutics, which uses a physics-based approach to drug design for intractable protein targets, is developing an ADAR1 antagonist for cancer. The company said inhibiting ADAR1 can both activate innate antitumor immune cells and directly kill tumors. Gotham is also looking into additional epitranscriptomic regulators that are much less prevalent than m6A, Jaffrey says, using its screening platform to identify and analyze RNA modifiers. Kouzarides envisions a lot more opportunities ahead for the burgeoning space. “These enzymes can potentially regulate many different processes in many different diseases,” he said. He declined to specify which other epitranscriptomic targets Storm is chasing, but the company is currently raising a Series B round to support its anticipated clinical testing for a METTL3 inhibitor in 2022.