Aspirin prevents cancer, but no one knows exactly how—and that ignorance is blocking its widespread use. This project aims to pin down the mechanism by testing whether aspirin’s cancer-fighting power comes from suppressing platelet activation, and whether the immune system plays a key role. The problem is practical. Doctors cannot tell patients how long to take aspirin, at what dose, or which cancers it prevents. Without a clear mechanism, clinical trials have tested aspirin in unselected populations, producing muddy results. This research uses genetically modified mice, patient urine samples, and existing trial data to connect the dots between platelets, immune cells, and tumour immunogenicity. If successful, the work could transform aspirin from a blunt, one-size-fits-all preventive into a precision tool. A simple urine test might identify people whose platelet activation levels make them likely to benefit. The findings could also open the door to other anti-platelet drugs—such as ADP-P2Y12 antagonists—for cancer prevention, expanding the toolkit beyond aspirin alone. A patient forum will help communicate the risks and benefits, making implementation more realistic.
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Background: Pre-clinical, epidemiological and randomised evidence show that once daily low-dose aspirin (75-100mg) prevents cancer, but the underlying mechanism(s) are not understood. Consequently, aspirin for cancer prevention has mainly been evaluated in unselected populations with limited information to guide decisions on dose, duration of treatment, relevance of previous aspirin exposure, or types of cancer to target (anatomically or molecularly.) Daily low-dose aspirin inhibits thromboxane (TX)A2-dependent platelet activation by permanently inactivating cyclooxygenase (COX1). We have demonstrated: i) the role of platelet COX1 in early carcinogenesis using pPtgs1-/- mice ii) that TXA2 limits T-cell immunity to cancer metastasis by activating the immunosuppressive functions of a guanine exchange factor, Arhgef1 in T-cells; iii) persistently increased TXA2-dependent platelet activation (reflected by urinary 11-dehydro-TXB2 (U-TXM)) in recently diagnosed cancer patients and iv) aspirin reduces the highly immunogenic Lynch syndrome cancers and is recommended in NICE guidelines. Together these results suggest that the anticancer effects of aspirin are mediated through suppression of platelet activation and modulated by the immune system. Aims: i) to provide further mechanistic insights into how aspirin (and potentially other anti-platelet) drugs prevent cancer ii) to investigate the potential of U-TXM to identify and monitor individuals likely to benefit from aspirin and iii) to utilise the mechanistic knowledge to aid the interpretation of accumulating clinical trial data, specifically to investigate the relationship between tumour immunogenicity and aspirin response, and develop a precision medicine/patient centric approach to employing aspirin for cancer prevention. Methods: We will: i) use genetically defined mouse models to a) compare TXA2 signalling and anti-tumour immunity during progression and metastasis of neoantigen-rich and neoantigen-sparse tumours and b) investigate whether inhibition of platelet activation through the adenosine diphosphate (ADP)-P2Y12 receptor pathway also reduces cancer; ii) explore U-TXM levels in Lynch syndrome carriers and a wider set of cancer patients correlated with demographic and clinical outcome data; iii) use accumulating trial data and associated biorepositories to a) explore tumour mutational burden, immunogenicity and aspirin response b) meta-analyse adjuvant aspirin colorectal trials informed by the trial biorepositories and c) develop a patient/participant forum to inform the research and implementation particularly around communication of the potential benefits-to-risks. How the results will be used: They will i) provide mechanistic insights into cancer-related pathways associated with abnormal platelet activation; ii) aid the interpretation of several aspirin clinical trials iii) inform recommendations for the use of aspirin for cancer prevention and iv) potentially stimulate research into (ADP)-P2Y12 antagonists
Prevention and Population Research Committee - Programme
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