Repurposing therapies in AML Ken Mills 5 th World Hematologist Congress 18 th August 2016
Drug Repurposing Repurposing, Repositioning or Rescue –the discovery of new indications for approved or failed drugs –“renewing failed drugs or expanding successful ones” (Barrett & Friel, 2012)
*Adsorption, Distribution, Metabolism, Elimination & Toxicology Pipeline for new agents 7-12 years Formulation / Manufacturing 1-2 years Approval Laboratory studies Pre-clinical studies Medicinal chemical optimisation 3-5 years 1-2 years2-3 years ADMET* 2-3 years ??? ?? Clinical Trials Development of a new drug is lengthy Laboratory studies Pre-clinical studies Clinical Trials Novel activity identified Pre-clinical studies 1-3 years years Drug Repurposing Novel activity identified Pre-clinical studies Average cost to develop and gain marketing approval for a new -$2.558 billion Tufts Center for the Study of Drug Development 2016
Drug repurposing, repositioning or rescue Bromocriptine cMAP Mebendasole In vitro drug screen Using a combination of approaches: computational biology in vivo/in vitro studies to develop and confirm hypothesis
Unmet need for new therapies Cytotoxics Cytarabine (Cytosar-U) –First synthesized in 1959 –Approved by FDA in June 1969! Daunorubicin (Cerubidine) –Identified in 1950s –Isolated from soil-based microbes near a 13th- century castle in Italy Idarubicin (Idamycin) –More potent than Daunorubicin –Developed in 1980’s. Epigenetic agents Decitabine (Dacogen) Azacitidine (Vidaza)
Myelodysplastic Syndrome (MDS) Acute Myeloid Leukaemia (AML) NBM MDS AML Normal Bone Marrow (NBM) ~ 1 / 3 transform
Prognostic Classification via microarray of MDS patients Mills et al. 2009
1,311 probe sets (genes) whose expression consistently increases or decreases with development and progression in mononuclear samples NBM MDS AML Identifying genes that change during development and progression
Connectivity Mapping Lamb et al Gene X Gene Y Gene X DISEASE DEVELOPMENT PERTURBAGEN TREATMENT Gene Y
QUADrATiC
statistically-significant Connectivity Mapping Five signatures were tested –Top 50/40/30/20/10 up or down genes by p-value 3738 connection scores ×5 ~1000 perturbagens 8 statistically significant connections for 4 drugs –3 drugs >1 significant connection –ATRA – currently used in some MDS/AML subtypes –A number of dopamine/serotonin agonists were or approached significance –Buspirone – no detected effect –Bromocriptine – cytotoxic against MDS/AML
Bromocriptine Ergot derivative Potent dopamine receptor agonist Indicated for: –Hyperprolactinaemia-associated dysfunctions –Acromegaly –Parkinson’s disease Not currently used in haematological malignancy
D1D2D3D4D5 Sumanirole Pramipexole Lisuride BC Dihydrexidine Dopamine receptors Cabergoline Buspirone
5-HT 2B 5-HT 2C BC BW 723C86 EAAT m-CPP Serotonin receptors Excitatory amino acid transporters DL-TBOACabergoline Buspirone 5-HT 1A
Bromocriptine
Synergy with cytarabine (standard genotoxic agent) Bromocriptine shows synergy at a range of doses in both cell lines –CI < 1 synergy –CI = 1 additive –CI > 1 antagonism
Bromocriptine FDA and EMA-approved drug Currently widely prescribed –Correlation neuroleptics and reduced cancer risk Novel potential in high-risk MDS and sAML treatment Exhibits synergy with existing therapies
Repurposing vignettes Bromocriptine –cMAP Mebendasole –In vitro drug screen Dr Kyle Matchett Dr Ivan Grishagin
Acute Myeloid Leukaemia (AML) and 11q23 Mixed Lineage Leukaemia (MLL) have particularly poor outcomes. AML is characterised by the over-production of immature myeloid blast cells and has a median onset of 64 years, and an overall 5- year survival of 24%. MLL is an aggressive paediatric leukaemia, defined by the presence of MLL fusion proteins. 5-year survival of children diagnosed with MLL is <40%. Novel treatments are therefore required that provide efficacy but also reduced toxicity, especially for patients in these age ranges. AML and 11q23 MLL
Scripts written in XML, compiled using Vialink interface Provides high throughput and reproducibility In vitro drug screen FDA Drug Screen –786 drugs –FDA approved drugs Screened using –AML normal karotype model –MLL model –3 drug concentrations
FDA library – examples of drugs
9,120 data points (760 drugs, 3 concentrations, 2 time points, 2 cell lines) Primary Screen – normalized mean values
Candidate drugs 70% survival = 55 drugs (7.2%) 60% survival = 42 drugs (5.5%) 50% survival = 38 drugs (5%) 40% survival = 24 drugs (3.2%) 30% survival = 6 drugs (0.8%)
Primary Mouse Cells AB C D NBM MLL AML Candidate validation
Repurposing Different approaches –In silico –In vitro Candidate drugs for –MDS to AML progression –Normal AML –11q23 MLL