Optimising Translation of Pleiotropic Research into Clinical Applications: Low Molecular Weight Heparin Treatment in Cancer
The concept of pleiotropy is derived from genetics whereby a locus can influence multiple traits. Applied to pharmacology, pleiotropic effects may be regarded as the multiple influences that a molecule or group of molecules have on biological systems. One class of molecules with an extensive but disparate range of publications over the last forty years reporting clinically relevant pleiotropic effects are the Low Molecular Weight Heparins (LMWH). As clinical practice with regards to use of LMWH in thromboprophylaxis changes and other anticoagulants are adopted, there is a risk of this pleiotropic research becoming obsolete and the full clinical potential of LMWH failing to be realised. To avoid this, the efficient and timely translation of pleiotropic research into clinical applications is vital so patients may benefit from these novel therapeutic avenues of agents whose safety and toxicity profiles are well defined via many years of robust clinical evidence.
To overcome this ‘translation barrier’ a number of carefully designed clinical trials are underway, informed by the new science, with endpoints designed to demonstrate the clinical value of LMWH beyond their licensed anticoagulant effects. Results from earlier studies indicate that whereas some pleiotropic effects are a class effect of LMWHs, others are influenced by the specific LMWH molecule. In cancer, for example, LMWHs have anti-metastatic, anti-angiogenic and immune modulatory effects, but the potency varies by molecule. A recent study in pancreatic cancer, based on current scientific rationale and involving a particular LMWH–tinzaparin - demonstrated an improvement in Progression-Free Survival (PFS); follow-up studies are planned.
To translate researched pleiotropic effects of LMWH into clinical practice, a robust methodology is required to filter, prioritise, and clinically study those that are likely to have clinical impact, such as measurable improvements in progression free survival (PFS) and overall survival (OS) of cancer patients receiving LMWH. For pleiotropic research to be translated into clinical care, this methodology would need to overcome key challenges such as heterogeneity of patients and lack of reliable biomarkers to guide patient selection. This paper outlines the findings from a recently convened scientific exchange panel to review pleiotropic effects of LMWHs on cancer outcomes, and the lessons for pleiotropic research translation into real world clinical practice, culminating in the drafting of a ‘Pleiotropic-to-Practice’ (P2P) method.
Gerd Bendas, Ismail Elalamy, Anna Falanga, Frank Gieseler, Michalis V Karamouzis, Utz Krug, Jamie MO’Sullivan