How Do We Accelerate the Discovery of New Medicines for Patients?
Abstract: The discovery of new medicines is too risky, too slow and too costly. There is massive duplication and wastage in biomedical research, there are questions being raised about the reproducibility of published work, and for many increasingly important therapeutic areas we are simply not producing what society and patients want. In my lecture I will discuss, how we are trying to address these challenges.
The validation of pioneer targets for drug discovery, remains a major challenge. We are therefore:
- working with a large number of pharmaceutical companies, to develop high quality small molecule inhibitors, using structure based drug design
- focussing only on novel targets, or those deemed to be ‘difficult’ or intractable
- and giving these inhibitors to a large and growing international network of academic collaborators, to crowd source new biology, disease understanding and ‘target discovery’
We have already facilitated proprietary efforts in pharma, catalysed the creation of new biotechs, and accelerated numerous clinical studies.
We are now
- generating ‘Target Enabling Packages’ (comprising purified proteins, biophysical or biochemical assays to assess function, three dimensional X ray structures and chemical starting points) for novel, high priority, disease linked genes
- building platforms of primary human cells, for screening novel inhibitors, in order to identify new ‘better’ targets for drug discovery
- building major collaborations with patient groups and hospitals, in order to catalyse these studies and enhance dissemination into the best disease labs across the world
Together, we are creating a new ecosystem for drug discovery. One which we believe will accelerate the generation of more novel medicines, more quickly. We hope these medicines will also be more affordable.
Biography: Prof. Bountra is a Professor of Translational Medicine in the Nuffield Department of Clinical Medicine and Associate Member of the Department of Pharmacology at the University of Oxford. He is also a Visiting Professor in Neuroscience and Mental Health at Imperial College, London. Prof. Chas is an invited expert on several government and charitable research funding bodies, and an advisor for many academic, biotech and pharma drug discovery programmes. His research focus is elucidation of 3D structures of therapeutically relevant human proteins and chemical probe identification for epigenetic proteins and clinical target discovery. He has given over 300 invited lectures. In 2012 he was voted one of the “top innovators in the industry”.
Professor of Clinical Pharmacology
Population Pharmacokinetic and Pharmacodynamic Modelling of Antimalarial Drugs
Abstract: Malaria is still the most important parasitic disease of humans with an estimated 216 million new cases per year. Approximately 1,200 people die every day from malaria, mainly young children under the age of five.
We rely on effective antimalarial drug therapy to control and treat malaria. Artemisinin-based combination therapy is the recommended first-line therapy worldwide. These therapies comprise a short acting but potent artemisinin derivative, and a partner drug with a longer elimination half-life (e.g. piperaquine or lumefantrine). The artemisinins reduce the majority of the parasite biomass during the first three days of treatment and the slower acting partner drug eliminates residual parasites in order to prevent recrudescent malaria. However, many of the antimalarial drugs used today were introduced at the wrong doses, especially in young children, and it is therefore crucial to optimise dosing regimens to reduce treatment failures and the risk of resistance development.
Well controlled antimalarial drug trials in patients with malaria, including special risk groups, can provide the data needed to optimise treatments through pharmacometric modelling. Here we present different trial data used in pharmacokinetic-pharmacodynamic modelling of antimalarial drugs, e.g. time-to-recrudescence, time-to-reinfection, microscopy-based parasite counts, and/or PCR-based parasite counts. These developed pharmacometric models have been used to optimise antimalarial treatments in young children and can provide a rational framework for dose-finding in antimalarial drug development.
Biography: Prof. Tarning is the head of the Clinical Pharmacology group focusing on bioanlytical method development, drug measurements in biological fluids and pharmacometric research. His research interest includes dose-optimisation using novel pharmacometric modelling approaches. His particular research interest includes antimalarial treatment in children and pregnant women. Prof. Joel received the biennial Giorgio Segré Prize from EUFEPS in 2014 for his research on the pharmacokinetic and pharmacodynamic properties of antimalarial drugs in vulnerable populations, such as pregnant women and young children.
Professor Dr. Goh Boon Cher, MBBS, MRCP, MMed (Int Med), FAMS, Fellow of the Royal College of Physicians (Edinburgh)
Deputy Director of Cancer Science Institute of Singapore
National University of Singapore, Singapore
Oncology Drug Development in the Era of Precision Medicine
Abstract: The ultimate aim of precision oncology is to select treatments and doses for patients according to a priori information on tumour and patient characteristics. Technological advancements in next generation sequencing and bioinformatics has allowed us unprecedented insights into the molecular biology of cancers. These have uncovered somatic mutational events that regulate molecular pathways that drive individual cancers, and a fraction of these are pathways that can be targeted for drug discovery and validation of biomarkers. Some of these pathways are tumour specific, some are general oncogenic drivers across different cancer types. Clinical trials have to be designed differently to address the complexity of these molecular based drugs. Enrichment designs like basket studies where patients are stratified to specific drugs according to the molecular profile of their tumour regardless of their tumour type, and umbrella studies where patients with a particular tumor type are stratified to different drugs according to their molecular characteristics, have allowed efficient clinical drug development to achieve proof of concept. However, the number of actionable mutations which can be inhibited by the current repertoire of drugs is still limited, and by and large, most of the oncogenic mutations in cancers lack a potential therapeutic agent. Furthermore, exome sequencing has yielded rare mutations that are not functionally understood; these pose a conundrum to drug development, as it is difficult to achieve sufficient statistical events on these rare mutations with the current clinical trial designs. In this situation, sharing of data on n=1 studies would help with therapeutic development against these genetic events. Finally, application of artificial intelligence to dose-decision platforms may allow more precise real time dosing of patients to achieve therapeutic targets.
Biography: Dr. Goh is principal investigator of the Experimental therapeutics group at the Cancer Science Institute, Singapore focused on evaluating novel treatments for cancer. As a clinician, he is well established in the fields of head and neck/lung cancer. As a senior clinician and scientist, he has mentored many clinical oncology and pharmacology fellows, and has been awarded senior clinician scientist from the Biomedical Research Council and the National Medical Research Council since 2005. In addition, he has been competitive in being awarded research grants as principal investigator of both individual project grants and infrastructure grants. Beyond cancer therapeutics, he is also widely published in pharmacogenetics, studying how human genetics affect drug response. Internationally, as a key opinion leader, he has served on advisory boards of several pharmaceutical companies advising on drug development of very novel drugs, and has served on editorial boards of important journals like the Journal of Clinical Oncology and Annals of Oncology.
Professor Dr. Balram Chowbay, B.Pharm, PhD
Principal Investigator of Clinical Pharmacology Laboratory
National Cancer Centre, Singapore
Understanding the Genetic Basis of Heterogeneity in Endoxifen Pharmacokinetics and Pharmacodynamics in Breast Cancer Patients
Abstract: The selective estrogen receptor modulator tamoxifen represents the standard-of-care adjuvant treatment for patients with estrogen receptor-positive breast cancer. However, there exists wide inter-patient and inter-ethnic variability in tamoxifen disposition, which may in turn influence treatment outcomes. Tamoxifen has a highly complex metabolic fate and undergoes extensive metabolism that is mediated by several phase I and II enzymes, including CYP2D6, CYP2C9, CYP2C19, CYP3A4/5, UGT1A4, UGT2B7 and UGT2B15, to yield multiple primary and secondary metabolites that exhibit variable potencies towards estrogen receptors. Its pharmacological activity is attributed mainly to its principal active metabolite, endoxifen, for which extremely high variability in steady-state concentrations have been observed. Indeed, maintenance of endoxifen levels above certain therapeutic thresholds has been suggested to be of crucial importance in achieving optimal treatment outcomes.
We investigated the associations between polymorphisms in the candidate genes encoding tamoxifen metabolizing enzymes with steady-state concentrations of tamoxifen and its metabolites in Asian breast cancer patients and found that CYP2D6 variants (*5 and *10) were associated with significantly lower endoxifen concentrations. In addition, genetic variants in CYP2C19 and UGT1A4 were also observed to significantly influence plasma norendoxifen and tamoxifen-N-glucuronide levels, respectively, while polymorphisms in other candidate genes appeared to be of minor relevance. However, polymorphisms in these candidate genes only partially accounted for the inter-patient variability in tamoxifen pharmacokinetics. We subsequently conducted a multi-ethnic genome-wide association study to delineate the key controlling locus for serum endoxifen levels and identified a very strong evidence of association between the rs932376 marker mapping to TCF20 on chromosome 22 with steady-state endoxifen concentrations, with no evidence of heterogeneity between patient collections from Singapore, Germany, Lebanon and the United Kingdom. This marker was found to be much more informative and consistent than any of the candidate genes, including the canonical CYP2D6 gene, in accounting for variability in endoxifen concentrations. We also observed a trend towards increased risk (hazard ratio for relapse-free survival =1.24, P=0.015) between TCF20 rs932376 and strictly defined 5-year relapse-free survival in the meta-analysis of five longitudinal cohorts (PGSNPS, POSH, Germany, SASBAC and TIGER) of European descent totalling 1,677 breast cancer patients with 200 events occurring. Previous reports did not show association between activity score and relapse free survival (P>0.2). These findings provide important new insights informing patient stratification into low, intermediate and high endoxifen groups across all ethnic cohorts, and may potentially influence tamoxifen treatment outcomes.
Biography: Prof. Chowbay is a Principal Investigator of the Clinical Pharmacology Laboratory in National Cancer Centre Singapore, and Director of the SingHealth Clinical Pharmacology Core. Prof. Balram has been actively involved in clinical pharmacology research and early-phase clinical trials of anti-cancer agents. His research has largely focused on the application of pharmacokinetic (PK) and pharmacodynamic (PD) principles to optimise individualised dosage regimens. He has published extensively in international peer-reviewed journals, particularly in the field of pharmacogenomics and its influence on inter-individual and inter-ethnic variabilities in PK and PD outcomes. His contributions are particularly important in the context of Asian populations. He currently serves on several review panels and editorial boards.
Professor Emeritus Dr. Yukio Yoneda, PhD
Former Chairman Professor of Pharmacology (1999-2015)
Kanazawa University, Japan
Beneficial Pharmacology of a Green Tea Amino Acid for Brain Health
Abstract: Neural progenitor cells (NPCs) are a primitive cell capable of proliferating for self-replication and differentiating into neuronal, astroglial and oligodendroglial lineages in embryonic, developing and adult brains. We have shown drastic modulation by glutamatergic and GABAergic signals of properties of embryonic NPCs. Theanine is an amino acid ingredient more abundant in green tea than black and oolong tea, with a structural analogy to glutamine. We thus evaluated pharmacological profiles of this exogenous green tea amino acid in modulating mechanisms of NPCs. Undifferentiated NPCs were prepared from embryonic rat and mouse neocortex, adult mouse hippocampus and embryonic carcinoma cells, followed by culture with theanine in the presence of growth factors for the formation of round neurospheres composed of clustered proliferating cells. Neurospheres were then dispersed for subsequent further culture in the absence of theanine and growth factors toward differentiation. In cultured NPCs from embryonic rodent neocortex, theanine promoted both proliferation and subsequent neuronal differentiation with suppressed astroglial differentiation. In cultured NPCs from adult nestin-GFP mouse hippocampus, theanine significantly increased the size of neurospheres formed. In murine embryonic carcinoma P19 cells, marked promotion was similarly seen in proliferation and neuronal differentiation after exposure to theanine. Exposure to theanine up-regulated the particular glutamine transporter isoform Slc38a1 transcript in rat and mouse NPCs, whereas theanine failed to further promote both proliferation and neuronal differentiation activities already facilitated in P19 cells stably overexpressing Slc38a1. The exogenous amino acid theanine would promote embryonic and adult neurogenesis through activation of NPCs in a manner relevant to upregulation of the glutamine transporter Slc38a1 in rodent brains. As a return of laboratory experimental results, we have made several dietary supplement products enriched of theanine expected to be beneficial for the improvement of particular brain dysfunctions.
Biography: Prof. Emeritus Dr. Yoneda is serving as an Associate Editor in several international journals such as Neurochemistry International, Neurochemical Research and Journal of Neuroscience Research, in addition to acting on the Editorial Board in other international scientific journals. His research interests have been lying on pharmacological profiling of amino acid signaling in neuronal and non-neuronal cells using molecular biological techniques. As a return of laboratory experimental results to the community, he is now attempting to develop several dietary supplements beneficial for the prophylaxis of different diseases besides the bench work with colleagues in domestic and foreign universities.
Professor Dr. Kam Y. Zhang, PhD
Leader of Structural Bioinformatics Team
Exploiting Ligand 3D Shape Similarity for Computational Structure Based Drug Design
Abstract: To predict the binding pose of a ligand in a target protein is a key step in virtual screening and computational structure based drug design. Both sufficient conformational sampling and accurate scoring function are required for successful pose prediction. To improve the accuracy of pose prediction by tackling the sampling problem, we have sought to exploit the ever-increasing amount of small molecule ligand and protein complexes in Protein Data Bank. We have developed a method of pose prediction using 3D shape similarity. It first places a ligand conformation of the highest 3D shape similarity with known crystal structure ligands into protein binding site and then refines the pose by various strategies. We have prospectively assessed our methods in several D3R Grand Challenges. Overall, our results demonstrated that ligand 3D shape similarity with the crystal ligand is sufficient to predict binding poses of new ligands with acceptable accuracy.
Biography: Dr. Kam Zhang is currently a Team Leader at the Center for Biosystems Dynamics Research, RIKEN, Japan. His main research interests are on protein design and drug design. His lab develops and uses computational tools in the structure-based drug discovery for various protein targets. His lab has discovered small molecular inhibitors for sumoylation enzymes, epigenetic regulators, denitrification enzymes, chitinases and DNA methyltransferases. Prior to joining RIKEN, he was the Director of Structural Biology at Plexxikon Inc. in Berkeley, USA, where he established the scaffold-based drug discovery platform. He has contributed to the discovery of several drug candidates that are currently in various stages of clinical trials. One of them, Zelboraf, has been approved by FDA for the treatment of metastatic melanoma. He was a faculty member at the Fred Hutchinson Cancer Research Center, and University of Washington, Seattle, USA. He obtained a BS in Chemistry, and a MSc in Structural Chemistry from Peking University, China and a PhD in Physics from the University of York, UK. He carried out his postdoctoral training at the Molecular Biology Institute, UCLA, USA.
Professor Dr. Ian Charles Paterson, B.Sc (Hons), PhD
Professor in Department of Oral & Craniofacial Sciences
University of Malaya, Malaysia
The Role of Sphingosine 1-Phosphate in Cancer
Abstract: Sphingosine 1-phosphate (S1P) is a small bioactive lipid that is formed when sphingosine is phosphorylated by sphingosine kinase 1 and 2 (SK1/2). S1P exerts its effects following binding to a family of five G protein-coupled receptors, known as S1P1–5. Following receptor activation, multiple signalling cascades are activated, allowing S1P to regulate a range of cellular processes, such as proliferation, apoptosis, migration and angiogenesis. There is strong evidence implicating the involvement of sphingosine kinases and S1P receptors in cancer progression and the oncogenic effects of S1P can result from alterations in the expression of one or more of the S1PRs and/or the enzymes that regulate the levels of S1P. Sphingosine kinases and S1P receptors represent targets for potential therapeutic intervention in the treatment of cancer. Their role in cancer and opportunities for novel drug discovery will be discussed.
Biography: Prof. Paterson current interests are in mechanisms of epithelial carcinogenesis (tumour progression, metastasis, tissue homeostasis), cancer drug design (structure-based design, molecular docking, TGF-beta, GPCR) and molecular pathology of head and neck cancer (oncogenes, tumour suppressor genes, epigenetics, HPV). He is a member of British Association for Cancer Research (1995) and Editorial Board Member of Frontiers in Cancer Endocrinology and Oncology (2014).
Professor Dr. Hj. Hamidon Hj. Basri, BSc (Med), MD, MMed, AM
Head of the Department of Medicine
Universiti Putra Malaysia, Malaysia
Potential Benefits of Palm Vitamin E Tocotrienols in Stroke and Neurodegenerative Diseases
Abstract: Palm oil is an important agriculture-based industry in Malaysia. It occupies 77% of agricultural land or about 15% of total land area in Malaysia. Palm tocotrienol is an active ingredient which belongs to the family of vitamin E. Vitamin E consists of 4 tocopherols (alpha, beta, gamma, delta) and 4 tocotrienols (alpha, beta, gamma, delta). Vitamin E is commonly found in plant and seed oils. However, only crude palm oil extracted from the fruits of oil palm (is the richest source of tocotrienols (up to 800 mg/kg). Tocotrienols only occur at very low levels in nature. Several in vitro and in vivo studies have been done to show the potential benefits of tocotrienol in stroke and neurodegenerative diseases. However, there are limited information whether tocotrienol is of benefit in humans. This lecture will discuss on a few human trials in relation to stroke and other neurodegenerative disease. This include several local clinical trials like SATURN, NUTRITION, VENUS and effects on cerebral white matter.
Biography: Prof. Dr. Hamidon has authored and co-authored multiple peer-reviewed scientific papers and presented works at many national and international conferences. His contributions have acclaimed recognition from honourable subject experts around the world. He is actively associated with different societies and academics. His academic career is decorated with several reputed awards and funding. His main area of research interest is in stroke, and he is one of the pioneer Neurologists to promote advance management of stroke in Malaysia.
Associate Professor Dr. Ulvi Bayraktutan, BVMS, PhD
Associate Professor in Division of Clinical Neuroscience (Stroke Group)
University of Nottingham, UK.
Abstract: Stroke continues to be one of the leading causes of morbidity and mortality in the World. There are two main types of stroke, haemorrhagic and ischaemic. Haemorrhagic strokes stem from the leak or rupture of an artery within or on the surface of the brain tissue. Ischaemic strokes constitute ~85% of all strokes in the Western World and derive from the occlusion of a blood vessel leading to or within the brain due to formation of an embolus (embolic strokes) or a thrombus (thrombotic strokes).
Despite being the leading cause of human brain damage, there is currently no medical therapy for haemorrhagic strokes and there is only a single pharmacotherapy with recombinant tissue plasminogen activator for ischaemic stroke. However, given the short therapeutic window (within 4.5 h of stroke onset) and elevated risk of haemorrhage beyond this time window, each year only a small percentage of patients receive this therapy worldwide. Although new therapeutic strategies including novel fibrinolytics, glycoprotein IIb/IIIa antagonists and interventional approaches including mechanical thrombectomy may somewhat enhance the number of patients receiving reperfusive treatment, alternative treatments capable of repairing damaged neurovasculature beyond (sub)acute phase of the disease are desperately required.
In this context, accumulating recent evidence suggest endothelial progenitor cells (EPCs) as potential therapeutics. EPCs are released into peripheral circulation by bone marrow to negate the deleterious effect of an ischaemic attack. Unlike other neuroprotectants, EPCs can simultaneously target several mechanisms implicated in stroke pathogenesis e.g. inflammation and apoptosis, demonstrate long-term effects, repair damaged endothelium and help maintain neurogenic potential through release of various growth factors. However, the definition of EPCs remain ambiguous. Since outgrowth endothelial cells, obtained by EPC culture, are morphologically closer to mature endothelial cells and possess higher proliferative, migrational and tubulogenic capacities, they may represent the only EPC type that display therapeutic potential.
Biography: A/Prof Dr Bayraktutan’s current research focuses on the investigation of the mechanisms that account for the breakdown and recovery of the blood-brain barrier under ischaemic and hyperglycaemic versus their respective control conditions; endothelial progenitor cells; neurovascular dysfunction; ischaemic and haemorrhagic stroke pathophysiology and clinical biomarkers for stroke.
Associate Professor Dr. Wong Wai-Shiu Fred , B.Pharm (cum laude), PhD
Head of the Department of Pharmacology
National University of Singapore, Singapore
Vitamin E Isoform γ-Tocotrienol: A Potential Remedy for Asthma and COPD
Abstract: Inflammation and oxidative damage contribute to the pathogenesis of asthma and COPD. As vitamin E isoform γ-tocotrienol possesses both anti-oxidative and anti-inflammatory properties, we aimed to establish the therapeutic potential of γ-tocotrienol in a house dust mite (HDM)-induced mouse asthma model and a cigarette smoke-induced COPD models. Methods: For asthma, BALB/c mice were sensitized and challenged with HDM. For COPD, BALB/c mice were exposed to cigarette smoke (CS) daily for 2 months. Bronchoalveolar lavage (BAL) fluid and lung tissues were assessed for cell infiltration and mucus hypersecretion, oxidative damage, and regulation of transcription factor activities. Airway hyperresponsiveness (AHR) in response to methacholine, and lung function parameters were measured. Main Results: γ-Tocotrienol displayed better free radical-neutralizing activity in vitro and inhibition of BAL fluid total, eosinophil and neutrophil counts in HDM mouse asthma in vivo. γ-Tocotrienol abated HDM-induced elevation of BAL fluid cytokines and chemokines, total reactive oxygen species and oxidative damage biomarkers, and of serum IgE levels, but promoted lung endogenous antioxidant activities. γ-Tocotrienol markedly suppressed methacholine-induced AHR in mouse asthma. On the other hand, γ-tocotrienol reduced CS-induced BAL fluid neutrophil count and levels of cytokines, chemokines and oxidative damage biomarkers, and restored lung endogenous antioxidant activities. Mechanistically, γ-tocotrienol blocked nuclear STAT3 and NF-kB levels and enhanced nuclear Nrf2 levels in the lungs. γ-Tocotrienol ameliorated bronchial epithelium thickening and destruction of alveolar sacs in lungs, and improved lung functions. Conclusions: We revealed for the first time the anti-inflammatory and antioxidant efficacies of vitamin E isoform γ-tocotrienol in allergic asthma and COPD models. In addition, γ-tocotrienol was able to attenuate emphysematous lesions and improve lung function in COPD. γ-Tocotrienol may have therapeutic potential for the treatment of asthma and COPD.
Biography: A/Prof Dr Wong’s research focuses on drug discovery and development for asthma and COPD. He has published over 70-peer reviewed journal articles including Nature Medicine, American Journal of Respiratory and Critical Care Medicine, Journal of Allergy and Clinical Immunology and Journal of Immunology. He has also filed or obtained four patent applications. In collaboration with NUH doctors and the Investigational Medicine Unit, A/Prof Dr Wong has successfully translated his pre-clinical findings from bench to bedside by treating asthmatic patients with the anti-malarial drug artesunate. This clinical trial is still ongoing, and he aims to introduce a new drug therapy for asthma in the next five to 10 years.
Associate Professor Dr. Brian P. Kirby, BSc (Pharm), PhD, MSc(LMD), Dip QC, MPSI.
Associate Professor of Pharmacology
Royal College Surgeons in Ireland, Ireland
Modelling Neurodegenerative Diseases in Rodents: Simply Complex
Abstract: Rodent models of human diseases accurately and reproducibly capturing their pathology are key tools in furthering our understanding of the mechanisms behind these diseases and in the development of novel treatment approaches. However, pre-clinical studies in rodents are often criticised for the relative lack of replication and success upon translation to humans. Animal models of neurodegenerative diseases (and other CNS conditions) are very complex, often with multifactorial inputs into their development and progression. This complexity is a significant challenge and, consequently, there are relatively few neurodegenerative rodent models for pre-clinical testing and their use is particularly challenging. In addition to this, there are often concerns raised about the conduct, analysis and interpretation of the model results. This talk will focus on disease model end-points and, in particular, behavioural phenotyping which, while appearing relatively straightforward, has the potential to be poorly conducted and the results misconstrued.
Biography: Prof. Kirby undertook post-doctoral research in the University of Oxford, investigating novel treatments for Alzheimer’s and Parkinson’s diseases with Prof JNP Rawlins (Experimental Psychology) and Prof S Greenfield (Pharmacology). He joined RCSI in 2003 and established the pharmacology teaching within the School of Pharmacy and following this he developed, with Prof Kelly and the School of Nursing, the pharmacology component of the Nurse Prescribing course.He also has close links with the Addiction Services Department of the HSE and has worked in the areas of addiction treatment for many years. Prof. Kirby has extensive research links and collaborations with Malaysia and was recently appointed as a visiting Associate Professor of Pharmacology in Universiti Putra Malaysia (UPM).
Associate Professor Dr. Ho Gwo Fuang, BSc (Medical Science), MBBS, MRCP, FRCS
University Malaya, Malaysia
Updates on Immunotherapy for Lung Cancers
Abstract: Most lung cancers are diagnosed at advanced stage. It is now known that immune system plays a key role in surveillance and eradication of lung cancers, and cancer cells evolve ways to elude the immune system. Checkpoint inhibitor, with or without concurrent chemotherapy, has become the new standard of care for treatment of advanced lung cancers in recent years.
Keynote 024 demonstrated that in patients with advanced NSCLC and PD-L1 expression on at least 50% of tumor cells, pembrolizumab was associated with significantly longer progression-free and overall survival than chemotherapy. Median progression-free survival was 10.3 months in the pembrolizumab group versus 6.0 months in the chemotherapy group (HR 0.50; P<0.001).
Keynote 189 demonstrated that in patients with previously untreated metastatic nonsquamous NSCLC without EGFR or ALK mutations, pembrolizumab and pemetrexed/platinum combination was significantly more effective than placebo and chemotherapy. Overall survival at 12 months a 69.2% in the pembrolizumab-combination group versus 49.4% in the placebo-combination group (HR 0.49; P<0.001). Improvement in overall survival was seen across all PD-L1 categories that were evaluated.
Checkmate 227 study demonstrated that progression-free survival among patients with a high tumor mutational burden was significantly longer with nivolumab plus ipilimumab than with chemotherapy. The 1-year progression-free survival rate was 42.6% with nivolumab plus ipilimumab versus 13.2% with chemotherapy. The objective response rate was 45.3% with nivolumab plus ipilimumab and 26.9% with chemotherapy.
PACIFIC study demonstrated that in patients with stage III NSCLC who did not have disease progression after chemoradiotherapy, additional consolidation treatment with durvalumab for one year resulted in significantly better survival. The median progression-free survival from randomization was 16.8 months with durvalumab versus 5.6 months with placebo (HR, 0.52; P<0.001).
Biography: Dr. Ho began his career at the Royal Albert Edward Infirmary in 1998. He is the oncology lead for CIGMIT stereotactic radiosurgery project at the University, as well as sub-investigators for UM High Impact Research (HIR) Grant projects. His research interests involve breast, gastrointestinal and gynaecological cancers. He is involved in many national and international collaborative research work. Being a council member of Malaysian Oncological Society (MOS), he heads the MOS Cancer Healthcare Advocacy Committee (CHAC), championing cancer patients’ rights in Malaysia.
Associate Professor Dr. Amin Malik Shah Abdul Majid, BSc (Chem), PGDip Sci (Pharm & Tox), MSc (Biopharmaceuticals), PhD (Molec. Pharm & Tox)
Associate Professor in Department of Pharmacology
Universiti Sains Malaysia, Malaysia
Canssufive Nuvastatic TM, A Botanical Drug Based on Orthosiphon stamineus extract for Cancer Therapy
Abstract: Angiogenesis is a process of new blood vessel formation which plays an important role in large proportion of human diseases. Cancer cells growth and metastasis is highly dependent on angiogenesis from which it is able to obtain vital nutrients and oxygen. Hence inhibiting angiogenesis is a useful strategy in cancer therapy. Canssufive NuvastaticTM is a botanical drug made from solvent extract of Orthosiphon stamineus leaves, a common herb found in Malaysia. The extract is standardised to rosmarinic acid and has been found to inhibit angiogenesis. Preclinical studies show that the extract has potent activity towards a variety of cancer including colon, lung, breast and ovarian. GLP toxicology studies in beagle dogs and rats shows that Canssufive Nuvastatic TM formulation has good safety profile. Similarly, in phase 1 clinical studies on healthy volunteers, Canssufive Nuvastatic TM formulation did not show any drug related toxicity. Rosmarinic acid, the key active ingredient was detectable in the patient’s plasma within 30 minutes of oral ingestion. Canssufive NuvastaticTM is currently undergoing phase 2 clinical studies in breast and colon cancer patients and is expected to commence phase 3 clinical studies by end of 2019.
Biography: Dr. Amin Malik Shah is a lecturer at Department of Pharmacology, School of Pharmaceutical Sciences, Universiti Sains Malaysia (USM). Currently he is being seconded to NatureCeuticals Sdn Bhd a botanical pharmaceutical company which he founded serving as the group CEO. He is also a Visiting Associate Professor in John Curtins School of Medical Research at Australian National University. He is the chairman of EMAN Biodiscoveries Sdn Bhd which is a technology company that focuses on botanical drug research and development and recently founded Eman Research Ltd, an international a not-for-profit research organization based in Australia that was established to promote better pharmaceutical product research in developing and underdeveloped countries His laboratories and manufacturing facilities are established on the platform of lowering the cost of drug discovery and manufacturing that will translate into cheaper medicine. The facilities provide services for many researchers and companies in Malaysia and internationally.
Most of Amin’s research interest focuses on development of natural products that target angiogenesis for the treatment of cancer. His main work is based on Cat Whiskers herb (Orthosiphon stamineus) which is currently in phase 2 clinical studies for breast and colon cancer.
Dr. Joseph Standing, MSc (Statistics), Ph.D
Principal Research Associate
University College London, UK.
The Role of Pharmacometrics in Paediatric Drug Development: Application to antimicrobial agents
Abstract: Mathematical and statistical modelling of pharmacokinetics (PK) and pharmacodynamics (PD) plays a key role in understanding the dose-concentration-effect relationship at all stages of drug development. This pharmacometric approach differs somewhat from traditional empirical statistical analysis in that a restricted class of biologically informed models tend to be used. Incorporation of this “biological prior” information is potentially useful when using models for extrapolation, for example when seeking to use results derived in adult clinical trials to aid the design of paediatric studies. Antimicrobial resistance is a global problem meaning there is a need to develop new agents, and to develop optimised combinations of existing agents. Clinical trials of such agents are fraught with difficulties since identifying and then recruiting patients infected with resistant organisms is a significant challenge. However, it is only these patients who are likely to derive clinical benefits of a new agent over standard of care. Pharmacometric approaches to support and in some cases replace traditional comparative trials are therefore crucial in antimicrobial drug development. In this talk I will briefly introduce pharmacometric approaches and how models are scaled in children, and then go on to present antimicrobial pre-clinical and clinical trial results from work in our group. I will conclude with a suggested approach to antimicrobial drug development in children.
Biography: Dr. Standing’s current projects include: Modelling HIV viral load and CD4 counts in adults and children, and investigating the role of antiretroviral treatment on long-term viral suppression and immune reconstitution; PK/PD studies of antimicrobial and antiviral agents in pre-term and term neonates; Models for immune reconstitution following bone marrow transplantation in children and personalised pre-transplant conditioning; Investigating novel treatments for Polycystic Kidney Disease using PK/PD modelling; PK/PD modelling to support antimicrobial stewardship.
Dr. Sri Ganesh Muthiah, MBBS (AIMST), MPH (UPM), DrPH (UPM)
Senior Lecturer in Department of Community Health
University Putra Malaysia, Malaysia
Quality of Life Among Oncology Patients in Malaysia
Abstract: The diagnosis of cancer does not only lead to adverse effects on patients’ physical and mental health, but also on their financial independence. Poor financial stability denotes poor quality of life (QOL). Materials and Methods: This is a cross sectional study conducted between May to July 2018 among cancer patients at Institut Kanser Negara (IKN), Malaysia. Systematic random sampling was used to recruit patients. The Quality of Life was assessed by using the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Questionnaire, measuring the functional scale, symptom scale, and the Global Health Status (GHS) scores. Result: A total 324 respondents’ were recruited in this study. The mean age of respondents were 53.7 years old (95% CI = 52.4 55.0, SD = 12.3). Majority of respondents were Malays (69.4%), female participants (72.2%), married (87.4%) and have received secondary school education (48.8%). More than 50% of respondents have been diagnosed with breast cancer (54.2%). A total of 24.8% of respondents were retrenched from employment after the diagnosis of cancer. The mean scores from the QLQ-C30 questionnaires were 63.9 (SD= 19.1) for the GHS, 73.6 (SD= 18.0) for functional scale, and 25.1 (SD= 18.5) for symptom scale. Significant predictors for poorer GHS scores were age above 50 years, retrenchment from employment, and post-diagnosis period during the treatment and follow-up phase. Conclusion: This study found that factors associated with poorer quality of life are age above 50 years, retrenchment from employment, and post-diagnosis period during the treatment and follow-up phase.
Biography: Dr. Sri Ganesh is a Public Health Specialist and a Medical Lecturer (Epidemiology), at the Faculty of Medicine & Health Sciences, University Putra Malaysia (UPM). He established the Cancerfly Employment Portal, www.cancerfly.com, a social innovation to provide better quality of life to cancer patients through employment and business opportunities. This social innovation was awarded the ‘Best Invention of Malaysia’ and the ‘Romanian Inventors Forum Special Award’ at the International Invention Innovation Competition Canada (ICAN 2016).
Dr Aaron Hiew, MD (UKM), MRCP (UK)
Palliative Medicine Physician
Kuala Lumpur Hospital, Malaysia
Translational Research – Implication in Palliative Care
Abstract: The need for palliative care in today’s world is ever growing and increasing at a rapid pace. Increase in the world’s ageing population and also incidences of cancer contributes significantly to this need. The importance of good and relevant research in palliative care is ever more important as diseases develop and become more complex.
This talk with briefly go through the challenges faced in research in palliative care and also some of the efforts that has contributed to the growing evidence base of this field that has made an impact to patient’s symptom control and end of life care.
Biography: Dr Aaron Hiew is currently a Palliative Medicine Physician based in Hospital Kuala Lumpur. He was trained initially in Internal Medicine before pursuing his fellowship training in Palliative Medicine under the Ministry of Health Malaysia. Part of this training included work in both inpatient and community palliative care services. His interest include training and education of healthcare professionals in the field of palliative care.
Dr. Tim Hammonds, B.Pharm, Ph.D
CRUK Therapeutic Discovery Laboratories, UK.
Collaborative Oncology Drug Discovery at Cancer Research UK
Abstract: Working together is critical in drug discovery and industry is now engaging with academia at the earliest stages of drug discovery. In this talk I will outline how at CRUK we are using our unique access to hundreds of cancer scientists to pioneer multi-PI themed drug discovery alliances in key areas of oncology. Alliances are successfully built and run despite the differing structures, rewards and drivers that exist within each partner organisation and examples of team science, including new targets and new discoveries, will be presented.
Biography: Tim is Deputy Director of Drug Discovery at CRUK Therapeutic Discovery Laboratories (TDL), an in-house CRUK drug discovery unit with a principal focus on establishing and prosecuting themed multi-project alliances with industry. Tim has strategic responsibility for the design, planning, negotiation and management of multi-site academia-industry alliances. During his 18 years at CRT, Tim has been central to establishing and managing the small molecule drug discovery capabilities, including building and running HTS, compound management, compound profiling and protein production. Tim joined CRT-DL after 5 years postdoctoral enzymology research at the University of Leicester. He has a degree in Pharmacy and a PhD in pharmaceutical chemistry and microbiology from the University of Nottingham.
Dr. Peter John Bond, BSc, Ph.D
Bioinformatics Institute A*STAR, Singapore
A Multiscale Simulation Approach to Endotoxin Recognition and Neutralization
Abstract: The Gram-negative bacterial outer membrane contains lipopolysaccharide, an endotoxin which potently stimulates the mammalian innate immune response. This response involves a relay of specialized complexes, culminating in transfer of lipopolysaccharide from the CD14 receptor to Toll-like receptor 4 (TLR4) at the plasma membrane, leading to activation of downstream inflammatory responses. This pathway is key in host defense against pathogenic infections, and is also a leading cause of sepsis. The transient nature of these complexes has hampered elucidation of their molecular details. To tackle this, we have developed structurally-detailed computational models for the TLR4 cascade, and leveraged this to establish the modes of action of novel anti-endotoxic peptides found in wounds. We first derived a multiscale simulation platform allowing us to trace in near-atomic resolution each component of the TLR4 cascade. We demonstrate that lipopolysaccharide molecules traversing the receptor cascade are progressively funnelled along an affinity gradient, favoring transfer to the terminal receptor-signalling complex at the plasma membrane surface. Subsequently, we focused on multi-functional peptides that occur naturally as part of the clotting pathway in wounds, where they play anti-bacterial and anti-endotoxic roles. By integrating diverse structural, biophysical, and cellular data with simulation, we determine the bound conformations of these peptides with lipopolysaccharide, and also identify a previously undisclosed pH-dependent inhibitory interaction with CD14 that blocks TLR4-induced inflammation. Collectively, this work helps to unravel the key structural determinants governing endotoxin recognition in the innate immune pathway, and provides novel therapeutic routes to targeting bacterial sepsis and endotoxic shock.
Biography: Dr. Bond has 12 years of experience in the development and application of multiscale modelling and simulation approaches to understand biomolecular recognition and assembly. As well as gaining fundamental insights into the mechanisms of action of biomolecules, for example, in the areas of immunological signalling or membrane transport. He helps to develop new approaches for pharmaceutical intervention in disease states and new applications in (bio)nanotechnology.