Opinion on pharmacology research and new drug development from precision medicine

Michael SPEDDING＊,James BARRETT＊,Ying ZHAO

(1.International Union of Pharmacology,IUPHAR;2.Chinese Pharmacological Society,CNPHARS)

Michael SPEDDING,Secretary General of International Union of Pharmacology(IUPHAR),President of Spedding Research Solutions SAS(Paris).Dr.Spedding obtained his B.Sc.,Ph.D.and lectured at Sunderland,then joined Merrell Dow Research Institute in Strasbourg in 1978 where he became the project leader for cardiovascular drugs,assisting in the discovery of D,L-α-difluoromethylornithine and an international reputation on calcium channels,defining allosteric mechanisms of drugs at channels,multiple different drug binding sites and the first effects of calcium channel modulators in the brain.In 1985,he was appointed the pharmacology director and therapeutic area director for preclinical and clinical central nervous system drugs in the Edinburgh labs of Syntex—the group

Michael SPEDDING Secretary General,IUPHAR

Dr.Spedding has been elected to the French Academy of Pharmacy and as a Fellow of the British Pharmacological Society.In addition,he has a long history with IUPHAR.He was secretary or chair of NC-IUPHAR from 1990-2015,growing this to 90 subcommittees of 860 expert scientists contributing to the IUPHAR/BPS guide to pharmacology.org,a freely available knowledge base on all drug targets.In 2014,he was elected IUPHAR Secretary General.

James E.BARRETT Councilor,IUPHAR

James E.BARRETT,Councilor of International Union of Pharmacology(IUPHAR),is professor and chair of Pharmacology and Physiology and founding director of the Drug Discovery and Development Program at Drexel University College of Medicine and Founding Director of the Clinical and Translational Research Institute,Drexel University.He received his Ph.D.from Pennsylvania State University followed by postdoctoral training in neuropsy?chopharmacology at the Worcester Foundation for Experimental Biology.He has served on the faculty at the University of Maryland and at the Uniformed Services University of the Health Sciences(USUHS)where he was professor in the Department of Psychiatry.Dr.Barrett joined Wyeth as vice president of Neuroscience Discovery Research following the merger with Lederle Laboratories where he had been director of Central Nervous System Research.Prior to his current position at Drexel University College of Medicine,he was senior vice president,chief scientific officer,and president over research at Adolor Corporation,a company focused on pain pharma?ceuticals.He moved to Adolor after serving as president of Research and Development at Memory Pharmaceuticals,a biopharmaceutical company founded by the Nobel Laureate Eric Kandel dedicated to the development of drugs for the treatment of debilitating central nervous system disorders.

He has published more than 275 scientific articles,books and abstracts in the areas of neuropharmacology,neurobi?ology,behavioral pharmacology,translational research and neuroscience and serves on several editorial boards.He has served as president of the Behavioral Pharmacology Society and of the American Society for Pharmacology and Experimental Therapeutics(ASPET).Dr.Barrett was chair of the Board of Publication Trustees for ASPET and has served on the Board of Directors for the Federation of American Societies for Experimental Biology(FASEB),where he was a member of the Science Policy Committee and the Public Affairs Committee as well as chair of the"Breakthrough Series in Science"and"Horizons in Bioscience"Series.Dr.Barrett is the editor-in-chief of the Handbook of Experimental Pharmacology.He has received the Solvay-Duphar Award for Research on Affective Disorders,the George B.Koelle Award from the Mid-Atlantic Pharmacology Society for contributions to teaching and research and is the recipient of the Torald Sollmann Award in Pharmacology for significant contributions to the advancement and extension of knowledge in the field of pharmacology.Most recently,he received the P.B.Dews Lifetime Achievement Award for Research in Behavioral Pharmacology.

In addition to being a member of ASPET,he is also a member of AAAS,the American Pain Society and a fellow of the American College of Neuropsychopharmacology.His current research emphasis is in the area of pain,its co-morbid pathologies,and on basic mechanisms and new therapeutics.

Since President Obama announced the Pre?cision Medicine Initiative from a national strategy perspective in his State of the Union address,precision medicine has rapidly become a worldwide hotspot and drawn global attention in the medical field.Precision medicine aims at applying geneticinformation ofindividualdiseasesto guide his or her diagnosis and treatment.The keynote of precision medicine is to develop person?alized therapeutic regimen,on the basis of precise classification and diagnosis of diseases.The Chinese government and medical scientists also pay close attention to precision medicine and its development.So far,precision medicine research has been listed in National Key Research and Development(R&D)Plans in the 13thFive-Year Plan of China.Please talk about your viewpoints and suggestions about precision medicine issue.

Question 1:What impacts would the development of precision medicine bring about to pharmacology(eg,new drug development and clinical medication)?

Dr.SPEDDING：Precision medicine has always been a great goal and was foreseen in Ehrlich′s"Magic Bullet".However,with the possible excep?tion of clinical immunopharmacology that goal has not been realised.Certainly,certain tumours are exquisitely sensitive to some therapies and the immunological therapies open new avenues.But these are not always due to single mutations which can be targeted.

First,however,we have to define precision medicine.①The tightest definition would be that drugs are precisely administered based on the genetic information from the patient,perhaps even based on single nucleotide polymorphisms(SNPs)in the drug target,ideally in the protein causing the disease,or in enzymes metabolising the drug.My view is that this type of precision medicine is a worthy goal but can only be addressed for a small percentage of the popula?tion.This definition is of course much supported and touted by scientists with interests in genetic screening.②A wider definition would be based on coupling drug administration with predictive surrogate tests of any kind which were powerful enough to discriminate patient subpopulations who are more sensitive to the drug,or who have less side-effects?

Why is the tightest definition of more limited interest to China?

First,many of these causes of death in China(Fig.1)have lifestyle and epigenetic causes,or in the cancers there are multiple catastrophic muta?tions,such as in oesophageal cancer.Few are linked to SNPs.

Fig.1 Causes of death in China.Blue:non-communicable;red:communicable;green:injuries.（http://vizhub.healthdata.org/gbdcompare/）

Stroke is a leading cause of death,yet it has proven almostimpossible to develop drugs which reduce ischaemic damage in the 6 hours post-stroke,apart from rapid reperfusion after a CT scan.Ischaemic heart disease is best treated by coronary stenting.

However,I agree that cancer genetic profiling is important vis-à-vis finding drug selectivity.Gastric cancer is among the most common cancers worldwide,and endoscopic or surgical removal remains treatment of choice.However,R?cken[1]has proposed profiling four molecular types of gastric cancer：Epstein-Barr virus-associated,micro?satellite instable,chromosomal instable and genomi?cally stable carcinomas,but here the low prevelance of therapeutic targets remains a difficulty.Indeed,even with such remarkable successes such as rituximab,the exact molecular epitope for ritux?imab within the B-cell antigen CD20 is largely unknown and Klein et al[2]have reviewed the interactions of all the CD20 antibodies with consid?erable variability in binding sites,but no predictive capacity yet.

However,for melanoma,targeting drugs for distinct molecular cohorts of patients with advanced melanoma as in BRAF V600-mutant melanoma,combination of BRAF and MEK inhibition leads to important synergies,whereas in non-V500 Braf tumours MEK-inhibitor monotherapy may be opti?mal[3].In contrast to this,two thirds of aggressive pancreatic tumours harbour very complex rear?rangements with such massive genetic changes that it is difficult to envisage targeted chemotherapy[4].

Second,even when we have clear single gene causes,therapies have been slow to develop.Orphan diseases are a case in point,where multiple mutations contribute to many diseases.In a land?mark review Shendure and Akey[5]show how the human mutation rate is underestimated and with a population of seven billion people,homo sapiens is exploring every possible non-lethal mutation in hundreds of people,leading to many orphan diseases,but where we do not have the resources to explore them all.Indeed,many diseases,or pharmacokinetic susceptibilities to drug metabo?lism,are the sum from many rare mutations rather than a few causative mutations.

Thus,there are multiple mutations in,for example,the genes associated with autophagy.Neefjs and Van der Kant[6]reviewed 42 proteins associated with the late endosomes/lysosomes affecting autophagy and mutated in neuronal diseases which can result in neurologic conse?quences,but there are almost too many muta?tions leading to different disease outcomes to be targeted by drugs acting on the autophagy.However,CD244 is a marker of sensitivity to rapamycininduced autophagy in human populations[7]and this may be a marker for the use of drugs affecting autophagy in rheumatoid arthritis and systemic lupus erythematosus.

Laboratory Developed Tests(LDTs)are often crucial providing innovative and tailored treatment to patients linking rapidly developing diagnostic tools,where the FDA is already providing guide?lines(https://www.aamc.org/download/472876/data/laboratorydevelopedtests.pdf).

Dr.BARRETT：Among the more significant challenges facing the discovery and development of new drugs are the many costly failures that follow the extensive investment of resources and time.Many of the failures in clinical development are related to a lack of clinical efficacy.Although there are a number of reasons that might account for this,such as the failure to pharmacologically engage the target,the development of unantici?pated toxicology,or poorly predictive animal models,a significant factor likely underlying many of these failures is the variability of human responses to drugs.Undoubtedly,this is partly based on the fact that the phenotypic expression of the disease or disorder,ie,the clinical presentation,may be very similar,but the underlying pathophysiology as well as other factors specific to a given individu?al,may differ substantially.It has become clear that,despite common diagnostic similarities,many diseases are more heterogeneous than believed and disorders such as pain,cancer,and several neuropsychiatric and neurodegenerative disorders have diverse and sometimes overlap?ping pathophysiology.The absence of a clear understanding of the many factors governing an individual′s response to a drug necessarily results in frequent drug failures in clinical development and also in inadequate treatments even for approved drugs.

Precision medicine,sometimes referred to as"personalized medicine",has the potential to address many of these issues and to have a signif?icant and long-lasting impact on drug discovery and on the development of therapeutics for a wide variety of diseases and disorders.Preci?sion medicine has been defined as the right drug,administered at the right dose,for the right patient and at the right time.A major emphasis underlying precision medicine is that of delivering the most appropriate therapy to a patient on the basis of a clear and detailed understanding of the clinical and molecular features of their disease.The discipline of pharmacology should be a central participant in these developments as the funda?mental principles of pharmacology,ranging from basic drug action,to drug metabolism and clinical pharmacology,together with its subdisciplines such as pharmacogenomics,pharmacoepidemi?ology and metabolomics,are an integral part of the drug development process and of the appli?cation of clinical therapeutics.The discipline of pharmacology is appropriately poised to have a major impact on the"precise"application of preci?sion medicine.

It is inevitable and encouraging that the devel?opments in pharmacology and allied subdisci?plines will further impact precision medicine and drug development in a variety of beneficial ways.For example,the goal of developing drugs that act at a single target-a long-standing effort to discovery the"magic bullet"——as enticing and enduring as it has been,has not proven to be a uniformly successful endeavor.Most complex disorders,including those in oncology,as well as neurology and neuropsychiatry,whether in their initial stages or in their progression,are typically not mediated by a single protein target and are multifactorial,involving differentreceptors or signaling pathways that require drugs that engage multiple targets,leading to a growing interest in polypharmacology.While the development of a single drug addressing an optimal array of targets poses several challenges,informed drug combi?nations have the potential to hit multi-sensitive nodes belonging to a network of both static and emerging targets.New computational approaches that combine structural information,molecular modeling,genomics,and an understanding of the target have already contributed significantly to identifying new uses for old drugs(repurposing)that permit polypharmacological approaches to genetic variants of certain diseases that have been otherwise difficult to treat.

Further developments in precision medicine will open new avenues for pharmacology and pharmacologists as it is increasingly recognized that the mechanisms associated with effective therapeutics need to incorporate genetic,epigenetic and environmental variables making it necessary to understand and embrace the principles and approaches associated with metabolomics.The integration of this information requires a deep under?standing of quantitative and systems pharmacology,along with basic principles of drug metabolism,pharmacogenetics,and biochemical pathways associated with pathophysiology,and ever-increas?ingly,the reliance on computational approaches to be able to compile and analyze this complex array of data.

The long-term objective of precision medi?cine,to combine comprehensive data collected over time about an individual′s genetics,the en?vironment and lifestyle,to advance our under?standing of disease and appropriate therapeutic intervention,while also providing new founda?tions for drug discovery is daunting.It will require increasing sophistication on the part of pharma?cologists to be versed in a wide variety of related disciplines but this expansion of the discipline and the necessity to integrate this information will be opportunities for the discipline to grow in its sophistication and impact on the delivery of effective,targeted therapeutics.

Question 2:Considering precise clinical medication,what aspects do you think that pharmacology should focus on?Whats your opinion about pharmacological research contents?

Dr.SPEDDING：Pharmacology can and does play a critical role.First,in simple mutations where SNPs are causative,then use of transgenic animals is crucial,although much validation is required to show that the human condition resem?bles that shown in animals.Human evolution has massively driven increases in oxidative metabo?lism,compared with other primates[8]and these changes have to be taken into account,particu?larly for aging-related diseases.

As even single mutations can have complex effects depending on cellular metabolism and epigenetic changes,then phenotypical screening of drugs in well-chosen pathophysiological models is critical in selecting the right agent.This is not a new concept,because it was actually the way in which the early Glaxo group,led by Roy Brittain in the 1970s-1980s,discovered drugs for a total cumulative value of ～650 billion￡.This shows that phenotypical screening in pathophysiological models which mimic the patient population can be critical in drug selection.

Now however,the susceptibility of different patient populations,either based on different molec?ular mechanisms of disease,or on different patient populations,must be taken into account in drug testing,but that is the fundamental basis of phar?macology,which is critical to modern science.

Dr.BARRETT：The foundation of precision medicine and its approach to clinical medication must consist first and fundamentally of a deep understanding of human pathophysiology that spans the gap from the molecular level to the whole organism.It is certainly the case that many of the disorders for which there is insuffi?cient treatment are complex.Several lines of evidence indicate that complex pathologies are often polygenic in nature and tend to involve the deregulation of complex and extended networks of proteins.A robust and integrated platform incorporating molecular diagnostics is an essen?tial component of precision medicine.In addition,it has become clear that the ability,as well as the need,to collect more information from initiatives in pharmacogenomics and metabolomics within the context of clinical pharmacology will require a merger of systems biology and pharmacology.The emergence of entirely new disciplines such as quantitative and systems pharmacology will enable the further development and application of precision medicine.In addition to these devel?opments and essential components within the field of precision medicine,there is also a clearly recog?nized need to incorporate molecular imaging,particularly in the field of oncology but,increas?ingly so,in other areas to ensure appropriate target engagement.

Perhaps one of the more significant compo?nents of precision medicine will be the further devel?opment of metabolomics.As has been pointed out,the concept that a person′s metabolic state provides not only a representation of the overall health of that individual but also that which has been encoded by the genome and epigenome,modified by environmental factors,diet and,as pointed out previously,the gut microbiome.The signatures from the integration ofthis vast amount of data necessarily will be incorporated into computational analyses and will provide much needed insight into guiding clinical pharma?cology and therapeutics.

These comments,while generally quite posi?tive aboutthe future ofprecision medicine,should be tempered somewhat by concerns raised in attempting to incorporate precision medicine into targeted cancer therapies.Significant advances in the molecular characterization of tumors have led to an increased understanding of the molecular and genomic pathways that underlie cancer.The population of cells in a tumor can be geneti?cally diverse,requiring the need to understand the cellular topography of the tumor.It also has become increasingly apparent that a therapeutic agent,alone or in combination,needs to address these issues when more than a single target has been identified for the failure to do so may lead to only a partial inhibition of the tumor,or to the acti?vation of an alternate signaling pathway.Precision medicine,based on attempting to match genetic information with a targeted therapy,requires appro?priate agents that target the specific molecular pathologies that address the heterogeneity and evolving nature of the tumor.

Finally,given the apparent complexity of precision medicine,and of the complexity of most diseases,there is and will continue to be a significant need for educational programs not only within pharmacology but with related disci?plines that are coupled to progressive insights derived from research.Training of the next gen?eration of scientists and clinicians will need to be expanded to embrace new technologies and allied disciplines that will necessarily intersect with pharmacology.

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［2］ Klein C，Lammens A，Sch?fer W，Georges G，Schwaiger M，M?ssner E，et al.Epitope interac?tions of monoclonal antibodies targeting CD20 and their relationship to functional properties［J］.MAbs，2013，5（1）：22-33.

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［5］ Shendure J，Akey JM.The origins，determinants，and consequences of human mutations［J］.Science，2015，349（6255）：1478-1483.

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FURTHER READING:

［1］Beger RD，Dunn W，Schmidt MA，Gross SS，Kirwan JA，Cascante M，et al.Metabolomics enables precision medicine："A White Paper，Community Perspective"［J］.Metabolomics，2016，12（10）：149.

［2］ Everett JR.Pharmacometabonomics in humans：a new tool for personalized medicine［J］.Pharma?cogenomics，2015，16（7）：737-754.

［3］ Huang BE，Mulyasasmita W，Rajagopal G.The path from big data to precision medicine［J］.Expert Rev.Precis Med Drug Dev，2016，1（2）：129-143.

［4］ Ghasemi M，Nabipour I，Omrani A，Alipour Z，AssadiM.Precision medicine and molecular imaging：new targeted approaches toward cancer therapeutic and diagnosis［J］.Am J Nucl Med Mol Imaging，2016，6（6）：310-327.

［5］ Kaddurah-Daouk R，Weinshilboum R.Pharmaco?metabolomics Research Network.Metabolomic signa?tures for drug response phenotypes：pharmacome?tabolomics enables precision medicine［J］.Clin Pharmacol Ther，2015，98（1）：71-75.

［6］ Tan L，Jiang T，Tan L，Yu JT.Toward precision medicine in neurological diseases［J］.Ann Transl Med，2016，4（6）：104.

［7］ Tannock IF，Hickman JA.Limits to personalized cancer medicine［J］.N Engl J Med，2016，375（13）：1289-1294.

［8］ Wishart DS.Emerging applications of metabolo?mics in drug discovery and precision medicine［J］.Nat Rev Drug Discov，2016，15（7）：473-484.

［9］ Woodcock J."Precision"drug development？［J］.Clin Pharmacol Ther，2016，99（2）：152-154.