Nessa Carey The Challenges in Turning Epigenetic Hope into

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Nessa Carey

The Challenges in Turning Epigenetic Hope into Clinical Reality

Confidential and Internal to Pfizer - subject to works council and/or union consultations and other legal requirements.

“Today we are learning the language in which God created life”

“The outstanding achievement .. in terms of human history”

All Hail The Double Helix


But There Must Be More


How Do We Know?

EYE OF SCIENCE / SPL / BARCROFT MEDIA

Where genetic identity ≠ phenotypic identity…..EPIGENETICS


DNA Is Not A Lonely Molecule

Lodish et al., 2000










Licensed Epigenetic Drugs (1)DNA Methyltransferase Inhibitors

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N

NH

N

NH2

O


Licensed Epigenetic Drugs (2)Histone Deacetylase Inhibitors

14

NH

O

NH

O

OH



Reassuring

Clinical trials

PubMed

www.clinical trials.gov Search on “epigenetic” n=101


Breaking It Down

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Clinical trials Clinical trials


Not So Reassuring

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How Hard Can It Be?

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The Hero Who Will Save Us....

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The Thought Experiment

• Generate a straightforward question

• Generate a huge amount of data relevant to the question

• Feed into the Systems Biology “machine”

• Do we get a useful answer?

• Two questions for the price of one

• DNMTi and MDS?

• HDACi and CTCL?

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Not Without Hope

• EZH2• DOT1L

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An Embarrassment of Riches?

Richon et al., Chem Biol Drug Des 2011; 78: 199–210


And It’s Not Getting Any Easier......

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A Return To Tradition?

Biased Phenotypic Screening

• siRNA

• Tool compounds

Random Phenotypic Screening

• Random compounds

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Playing Nicely Together.....

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From Little Acorns....

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Orphan Diseases

• Potentially very powerful test beds for epigenetic therapies

• The disease need not be caused by a defect in an epigenetic pathway per se

• May generate data that can be expanded from the orphan disease to the wider population e.g. HD into more general neurodegenerative disorders

• Address many of the dosing issues that are possibly key to the success of epigenetic therapies

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Learning More From Clinical Trials

• Pulsatile dosing• Selectivity – how big an issue really?• Toxicity• Off-target• Biomarkers• Sub-MTD dosing in cancer• Drug combinations• PK/PD relationships

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Toxicity Of Epigenetic Drugs

• Nausea• Anaemia• Thrombocytopaenia• Neutropaenia• Leukopaenia

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Not All DNA Is Created Equal

• Impossible to create mammals by fusing two sperm nuclei or two egg nuclei in an enucleate egg

• Seems odd, given that two sperm or two eggs would have exactly the same DNA as an egg and a sperm

• Mammalian DNA is marked with its parent-of-origin• Only occurs at a relatively small number of specific genes• Process known as imprinting• Probably evolved as a mechanism to balance out the competing drivers from

maternal and paternal developmental agendas• The information on parent-of-origin is not transmitted in the DNA sequence• It is transmitted by chromatin modifications, usually DNA methylation, that

regulate expression of genes from specific chromosomal loci

• Shows that epigenetic information can be transmitted from one generation to the next

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Alcohol And Epigenetics

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Exposure of a dark agouti mother to alcohol led to a greater proportion of dark offspring, with increased DNA methylation at the agouti-associated retrotransposon.

Environmental agents can alter the transmission of epigenetically-mediated traits.

╬

Kaminen-Ahola et al., PLoS Genet. 2010


Fathers And Food And Epigenetics

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These effects, just like those found in the alcohol-treated agouti mice, occur at too high a rate to be due to mutation.


Hmmm

• Most of the compounds known to have epigenetic effects are not direct inhibitors of epigenetic proteins

• In some cases they are probably working by altering the availability of e.g. methyl donors

• In other cases we have no real idea how they cause epigenetic alterations

• There are hints from human systems that we may be susceptible to similar effects Foetal alcohol syndrome Dutch hunger winter Overkalix feast or famine

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Here To Stay

• Publications• Clinical Trials• Investment Funding• Pharma Funding• Government Funding• Charity Funding• CROs

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Rationally, What Do We Need?

• Better and more standardised model systems• Greater availability of tool compounds• A way of changing data into information• Increased use of pre-competitive collaborations • Integrated patient data sets• Dialogue with regulatory authorities• Avoidance of group-think

• What’s the most important lesson from the history of epigenetic drug discovery?

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With Thanks To

PfizerMark BunnageAnne PhelanCaroline BennRob RollinsValeria FantinDenis PatrickSally JohnKevin LeeRachel Grimley

AcademiaHarvardMGHUniversity of CambridgeUniversity of EdinburghUniversity of PennsylvaniaUSCBabraham Institute

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Nessa Carey The Challenges in Turning Epigenetic Hope into