Suppressing Platelet Activation to Reduce Cancer (SPARC): A New Approach to Cancer Prevention

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.