Connectivity Map

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Connectivity Map

An introduction

Speaker Roger Yang 楊伍隆

Advisors Prof. Kun-Mao Chao 趙坤茂

Prof. Chi-Ying Huang 黃奇英

May 14, 2012

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References

Science 313(5795): 1929-1935.

Nature Reviews Cancer 7(1): 54-60.

Cited in Scopus: 489 (as Oct 10, 2011)

Cited in Scopus: 73 (as Oct 10, 2011)

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Goals

‣ Create a large drug- response profile

database.

‣ Use microarray profiles to query best matching or mismatching drugs

‣ Drug repurposing

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Goals

Control Treatment

Cell Cell + Drug

Gene Control Treatme

nt Fold Change

A 1 5 5/1

B 1 1 1/1

C 5 1 1/5

...

measurement of

mRNA

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Drug 1 Drug 2 Drug 3 Drug ... Drug N Gene 1

Gene 2 Gene 3 Gene 4 Gene 5 Gene 6 Gene ...

Gene M

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Drug Similarity

Compare

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Drug Repurposing

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Drug Development Process

http://www.msd.com.hk/health_info/drug_education/e_ddp_introduction.html

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Ashburn, Ted T, and Karl B Thor. 2004. “Drug repositioning: identifying and developing new uses for existing drugs.” Nature Reviews Drug

Discovery 3(8): 673–683.

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- 2007: 69 drugs, but 16 are new drugs

- average 15 years and US$800 million for a new drug to market

- New drugs approved by FDA each year remain at 20~30 compounds.

Hughes, Bethan. 2010. “2009 FDA drug approvals.” Nature Reviews Drug Discovery 9(2): 89–92.

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New uses for old drugs

Nobel laureate James Black

Nature 448, 645-646 (2007)

"The most fruitful basis for the discovery of a new drug is to start with an old drug"

“The most fruitful basis for the discovery of a new drug is to start with an old drug”

-- Nobel laureate James Black

Chong, Curtis R, and David J Sullivan. 2007. “New uses for old drugs.” Nature 448(7154): 645–646.

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Drug repurposing examples

• Nelfinavir for cancer

• Tamoxifen for bipolar disorder

• Gleevec for rheumatoid arthiritis

• Pentylenetetrazole for Down Syndrome

• Astemizole for malaria

• Lipitor for alzhemimers

• Lipitor for influenza mortality

• Metformin for cancer CDD Community Group Meeting, SFO,

Oct 1, 2009

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Database

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Drugs

‣ 1309 small molecules

‣ 680 drugs have been

conducted 4 times each.

‣ 6100 instances

‣ 7056 microarrays

0 175

350 525 700

49 43

162

680

226

87 13 17 3

1 2 3 4 5 6 7 8 9

Num of Instances

Drug Co unt

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Drug dosage

‣ Most drugs are tested between 1µM and 20µM

0.01 0.10.01<x<1 1<x<5 1 5≤x<6 6≤x<7 7≤x<8 8≤x<9 9≤x<10 10 10<x<11 11≤x<12 12≤x<13 13≤x<14 14≤x<15 15≤x<16 16≤x<17 17≤x<18 18≤x<19 19≤x<20 20≤x<21 21≤x<22 22≤x<23 23≤x<24 24≤x<25 25≤x<26 26≤x<27 27≤x<28 28≤x<29 29≤x<30 30≤x<31 31≤x<32 32≤x<40 50≤x<100 100100<x<1000) 10001000<x<10000

≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤

Drug concentration (µM)

Co unt

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Dose count

0 375 750 1125 1500

Number of doses

6 5 4 3 2 1

1225

10 72 1

0 1

Instance Count v.s. Number of Doses

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Duration

‣ Most drugs are

conducted for 6 hours.

• Primary effects, not second effects

0 1750 3500 5250 7000

6 Hours 12 Hours

4 6096

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Cell Type

0 1000 2000 3000 4000

MCF7 PC3 HL60 ssMCF7 SKMEL5

17 18

1229 1741

3095

MCF7 Breast cancer PC3 Prostate Cancer

HL60 Leukemia

ssMCF7 Breast cancer

charcoal-stripped serum

SKMEL5 Skin Cancer

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Fold Change

‣ 64% of 6100 instances have less than 2% of probes having 2-Fold change.

0 750 1500 2250 3000

<1%

1%~2%

2%~3%

3%~4%

4%~5%

5%~6%

6%~7%

7%~8%

8%~9%

>10%

128 197 80 70

219 132 381

1005 1967 2021

Percentage of probes with 2-Fold change

Co unt

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Instances

‣ Each instance is defined as one drug treatment over a sample of controls.

• e.g. cells treated with vorinostat versus untreated ones.

‣ Instance = Drug type x Cell type x Duration x Dose

• e.g. 10µM vorinostat on MCF7 for 6 hours

‣ 6100 instances over 1309 drugs

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Cel l T ype

Drug

Do sag e

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Lamb, Justin. 2007. “The Connectivity Map: a new tool for biomedical research.” Nature Reviews Cancer 7(1): 54–60.

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Drug-Drug similarity

Input: 13 HDAC gene signature

Lamb, J et al. 2006. “The Connectivity Map: using gene-expression signatures to connect small

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Drug-disease

Sirolimus reverses gluco-corticoid resistance in acute lymphoblastic leukemia.

Lamb, J et al. 2006. “The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease.” Science 313(5795): 1929–1935.