dexamethasone
With current treatment regimes, the
Glucocorticoids
have been
anlong
important
majority of patients
will be
term
component
of the treatment
acute of
survivors, however,
almost of
one‐third
lymphoblastic
leukemia
(ALL)
forofmore
ALL patients relapse
and
most
those die
than
However, it of
is still
due50
toyears.
the development
drugunknown
what
specific factors affect sensitivity and
resistance.
resistance to these drugs.
With current treatment regimes, the
majority of patients will be long term
The development
of resistance
chemotherapy
survivors, however,
almosttoone‐third
of
agents
poses
a major
clinical
Manydie
cells
ALL
patients
relapse
andproblem.
most of those
develop
not only toof
the
selecting agent
dueresistance
to the development
drug
but also
exhibit cross‐resistance to other
resistance.
structurally unrelated compounds.
Looking for better ways to deal with this problem researchers
from an multi‐institutional collaboration led by Scott Armstrong
created a 100‐gene wide gene signature of glucocorticoid
resistance (Wei et al, Cancer Cell, 10, 4, 331)
Glucocorticoid
sensitive resistant
Glucocorticoid
sensitive
resistant
The CMAP shows that the drug sirolimus,
also known as rapamycin, is a top match
Rapamycin instances
Multiple instances of
rapamycin score high
when the leukemia
resistance/sensitivity
signature is used to
query the CMAP.
Good hit, but, What is Rapamycin…?
It is a natural product from Rapa Nui
Also known as Easter Island
It was isolated in the
1960s from a bacteria
and known
developed
into Island
Also
as Easter
an antifungal drug
It was isolated in the
1960s from a bacteria
and developed into
an antifungal drug
It was also found to have immunosuppressant
properties and in 1999 became an FDA approved
drug for preventing the rejection of kidney
transplants
Rapamycin regulates one of
the critical nodes in
mammalian cell circuitry:
the mTOR/Akt pathway.
It was also found to have immunosuppressant
properties and in 1999 became an FDA approved
drug for preventing the rejection of kidney
transplants
Following up the CMAP discovery Broad Institute researchers
were able to confirm that rapamycin decreases glucocorticoid
resistance in acute lymphoblastic leukemia cells.
Cell survival (resistance)
Without rapamycyin
resistant cells remain
resistant
With rapamycyin
Resistant cells become
sensitive
Higher glucocorticoid concentration
Rapamycin is currently the subject of
multiple clinical trials in leukemia and
other cancers.
This and other examples have
demonstrated that the CMAP has real
potential for accelerating drug
discovery.
Could we do it the other way?
Disease X
signature
Top
genes up
Score disease
samples
using the
drug
signatures
Top
genes
down
564 (5774 v2) drug
instances
……
~22,000
genes
CMAP queries “in reverse”
Are the genes in the
down drug signature
enriched on this side?
Disease x
More formally:
V ( j ) j − 1
−
b = max 

j =1
tdown 
 n
More formally:
tdown
tdown = size of down signature
n = number of genes
Kdown =
a if a > b
Are the genes in the up
drug signature enriched
on this side?
 j V ( j) 
a = max  −

j =1
n 
 tup
tup
Disease
signature
disease effect on genes
down
up
tup = size of up signature
n = number of genes
‐b if b > a
Connectivity score Sx =
Kup =
a if a > b
‐b if b > a
0 if sign(Kup) ≠ sign(Kdown)
Kup – Kdown otherwise
CML Armstrong et al 2006
Class 1
Sensitive
Resistant
RAPA LATE
P-value= 0.001
Part IV:
Demonstration of the
CMAP web interface
The Leukemia
example
Part V:
Future plans and
conclusions
Future plans
The CMAP will represent about 1,000 drugs in its next
release. This is already a significant fraction of all FDA
approved drugs.
It will eventually include several additional libraries
of experimental drugs and small molecules.
It will also contain other types of “perturbagens”
such as those produced by silencing every gene is
the genome.
Conclusions
The CMAP has demonstrated the potential of using gene
expression profiles of particular disease states as a tool for drug
screening.
The CMAP allows rapid in silico, assessment of molecules and
their ability to reverse signatures associated with specific disease
states or drug resistance profiles. It is a virtual biomedical
laboratory.
The CMAP is a very useful tool to rapidly assess for potential
activity of thousands of drugs and is an approach
complementary and synergistic with other drug screening
methods.
Postscript:
What can we learn from
the CMAP from a
database perspective?
The CMAP represents a type of database where the process
of information retrieval is deeply integrated with an
analytical component, in the case of the CMAP, an
statistical test.
This synergy between databases and analytics is also
becoming more common in other databases where
analytics are at the core of retrieval operations that involve
pattern matching, clustering, regression, forecasting or
prediction.
Since the late 1990’s Oracle has incorporated analytical
functions, e.g. statistics and data mining, in the core stack of
database technology. The challenge is now how to combine
and integrate them with more traditional information
retrieval patterns.
At present with a few hundred drugs the CMAP does not push
database technology to the limit… however, once it contains a
few hundred thousand perturbagens and many more online
users worldwide it will.
Using advanced analytic database technology the entire
connectivity score of the CMAP could be computed inside the
database, for example by multiple calls to Oracle’s SQL
Kolmogorov‐Smirnov test:
SELECT stats_ks_test(signature, drug_order,
'STATISTIC') ks_statistic, FROM cmap_drugs
This is a current subject of research at Oracle Data Mining
technologies.
Comments to the author can be sent to tamayo@broad.mit.edu.
For additional information about the CMAP or the Broad Institute
please contact Nicole Davies (ndavis@broad.mit.edu).
The End
For additional information about Oracle corporation and Oracle
products please contact Charlie Berger (charlie.berger@oracle.com)
Acknowledgements:
Eli and Edythe Broad Institute: Bang Wong, Matt Wrobel, Nicole Davis, Justin Lamb,
Todd Golub and Jill Mesirov.
Oracle Corporation: Jacek Myczkowski, Charlie Berger, Jodi Greenberg and Paul
Salinger.
Cell animations from “Inner Life of the Cell", provided by Robert Lue and Alain Viel,
Harvard University (c) (2007) and created by Alain Viel and Robert Lue in collaboration
with XVIVO, LLC. John Liebler, Lead Animator, and under generous support from the
Howard Hughes Medical Institution's Undergraduate Science Education Program.”
Music by:
Part I: “A Dream in the Evening, “ DJ Saryon.
Part II:” L'arrivée,” Ehma ‐ La plage de Blâne‐est. Music from the “Inner Life of the
Cell“.
Part III: “Medieval Acoustic,” Vincent Bernay ‐ Etincelle
Part IV: “A Dream in the Evening, “ DJ Saryon.
Part V: Music from the “Inner Life of the Cell“.
Postscript: “Spoir,” Vincent Bernay – Etincelle
Public domain images from wikipedia.org
Art work by Daniel Kohn (www.kohnworkshop.com)