US 7,254,487 B2Granted

Methods for determining therapeutic index from gene expression profiles

AssigneeRosetta Inpharmatics LLC

InventorsMatthew Marton, Roland Stoughton

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Abstract

This invention provides methods for determining drug specificity, therapeutic index and effective doses for individual patients. According to the methods of the invention, graded levels of drug are applied to a biological sample or a patient. A plurality of cellular constituents are measured to determine the activity of the drug on a target pathway and at least one off-target pathway. A drug specificity is determined by comparing the target and off target activities of the drug. A therapeutic concentration (or dose) is defined as a concentration (or dose) of the drug that induces certain response in the target pathway. A toxic concentration (or dose) is defined as a concentration (or dose) of the drug that induces certain response in the off target pathway. Therapeutic index is the ratio of the toxic concentration over therapeutic concentration. Methods are also provided to determine an effective dose of a drug for a patient by measuring the activity of the drug on the particular patient.

Claims35

Dependent claims

A method for evaluating specificity of a drug comprising:

a) comparing activity of a drug against its target pathway (Dtarget) in a biological sample and activity of said drug against at least one of its off-target pathways (Doff-target) in said biological sample, wherein said Dtarget and Doff-target are represented by quantities selected from the group consisting of
(
i
)
D
target
=
R
target
,
k
⁡
(
α
target
,
t
l
)
⁢
⁢
and
D
off
-
target
=
R
off
-
target
,
k
⁡
(
α
off
-
target
,
t
l
)
,
respectively
;
(
ii
)
D
target
=
∑
k
⁢
β
k
⁢
R
target
,
k
⁡
(
α
target
,
t
l
)
⁢
⁢
and
D
off
-
target
=
∑
k
⁢
β
k
⁢
R
off
-
target
,
k
⁡
(
α
off
-
target
,
t
l
)
,
respectively
;
and
⁢
(
iii
)
D
target
=
C
target
⁢
⁢
and
⁢
⁢
D
off
-
target
=
C
off
-
target
,
respectively
;
wherein αtarget is a scaling constant of a scaling transformation of said target pathway, αoff-target is a scaling constant of a scaling transformation of said at least one of its off-target pathways, Rtarget, k (αtarget,tl) is a scaled response of cellular constituent k in said target pathway and Roff-target, k (αoff-target,tl) is a scaled response of cellular constituent k in said at least one of its off-target pathways, tl is a drug exposure level, βk is a constant for cellular constituent k, Ctarget is the minimal level of said drug to achieve a threshold response in said target pathway, and Coff-target is the minimal level of said drug to achieve a threshold response in said at least one of its off-target pathways;
thereby evaluating specificity of said drug;
and
b) displaying or outputting a result of said comparing step a) to a user, a computer readable storage medium, a monitor, or a computer that is part of a network.

131 more elements

A method for evaluating specificity of a drug comprising:

a) measuring activity of a drug against its target pathway to obtain a target activity (Dtarget);
b) measuring activity of said drug against at least one pathway other than said target pathway to obtain at least one off-target activity (Doff-target)
c) determining said specificity by comparing said Dtarget and said Doff-target;
wherein said Dtarget and Doff-target are represented by quantities selected from the group consisting of
(
i
)
D
target
=
R
target
,
k
⁡
(
α
target
,
t
l
)
⁢
⁢
and
D
off
-
target
=
R
off
-
target
,
k
⁡
(
α
off
-
target
,
t
l
)
,
respectively
;
(
ii
)
D
target
=
∑
k
⁢
β
k
⁢
R
target
,
k
⁡
(
α
target
,
t
l
)
⁢
⁢
and
D
off
-
target
=
∑
k
⁢
β
k
⁢
R
off
-
target
,
k
⁡
(
α
off
-
target
,
t
l
)
,
respectively
;
and
⁢
(
iii
)
D
target
=
C
target
⁢
⁢
and
⁢
⁢
D
off
-
target
=
C
off
-
target
,
respectively
;
wherein αtarget is a scaling constant of a scaling transformation of said target pathway, αoff-target is a scaling constant of a scaling transformation of said at least one of its off-target pathways, Rtarget, k (αtarget,tl) is a scaled response of cellular constituent k in said target pathway and Roff-target,k (αoff-target, tl) is a scaled response of cellular constituent k in said at least one of its off-target pathways, tl is a drug exposure level, βk is a constant for cellular constituent k, Ctarget is the minimal level of said drug to achieve a threshold response in said target pathway and Coff-target is the minimal level of said drug to achieve a threshold response in said at least one of its off-target pathways;
and
d) displaying or outputting a result of said determining step c) to a user, a computer readable storage medium, a monitor, or a computer that is part of a network.

133 more elements

A method for evaluating specificity of a drug, said method comprising:

(a) decomposing a drug response profile into one or a combination of pathway response profiles, wherein said drug response profile comprises measurements of a plurality of cellular constituents in a biological sample in response to said drug over a plurality of levels of drug exposure, and each said pathway response profile comprises measurements of said plurality of cellular constituents at a plurality of levels of perturbation to a biological pathway, said decomposing comprising representing said drug response profile in terms of said one or a combination of pathway response profiles according to equation
D
k
⁡
(
t
l
)
≅
∑
i
⁢
R
i
,
k
⁡
(
α
i
,
t
l
)
wherein tl is a level of the drug, αi is a scaling constant of a scaling transformation of pathway i, Dk(tl) is the measurement of cellular constituent k in said drug response profile at the drug exposure level of t1, Ri,k (αi,tl) is the measurement of cellular constituent k in pathway i at the drug exposure level of tl;
and
(b) comparing, among said one or a combination of pathway response profiles, the pathway response profiles for the one or more biological pathways associated with therapeutic effects of the drug with the pathway response profiles for the one or more biological pathways that are associated with one or more non-therapeutic effects of the drug, thereby evaluating specificity of said;
and
c) displaying or outputting a result of said comparing step b) to a user, a computer readable storage medium, a monitor, or a computer that is part of a network.

26 more elements

A method for evaluating specificity of a drug, said method comprising:

a) decomposing a drug response profile into one or a combination of pathway response profiles, wherein said drug response profile comprises measurements of a plurality of cellular constituents in a biological sample in response to said drug over a plurality of levels of drug dosage, and each said pathway response profile comprises measurements of said plurality of cellular constituents at a plurality of levels of perturbation to a biological pathway, said decomposing comprising representing said drug response profile in terms of said one or a combination of pathway response profiles according to equation
D
k
⁡
(
t
l
)
≅
∑
i
⁢
R
i
,
k
⁡
(
α
i
,
t
l
)
wherein tl is a level of the drug, αi is a scaling constant of a scaling transformation of pathway i, Dk(tl) is the measurement of cellular constituent k in said drug response profile at the drug exposure level of tl, Ri,k(αi,t,l) is the measurement of cellular constituent k in pathway i at the drug exposure level of tl;
b) comparing among said one or a combination of pathway response profiles, the pathway response profiles for the one or more biological pathways associated with therapeutic effects of the drug with the pathway response profiles for the one or more biological pathways that are associated with one or more non-therapeutic effects of the drug, thereby evaluating specificity of said drug;
and
c) displaying or outputting a result of said comparing step b) to a user, a computer readable storage medium, a monitor, or a computer that is part of a network.

25 more elements

Dependencies are inferred from the claim text.

Facts

Application: 09/823,322Filed 2 Apr 2001 · division
Priority: 28 Dec 1998
Published: US 2001/0012983 A19 Aug 2001
Granted: 7 Aug 2007
Term ends: Not estimatedThe source records don’t support an estimate.

Classification15 codes

C12Q 1/6883
Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes: for diseases caused by alterations of genetic material
C12Q 1/025
Involving viable microorganisms: for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
C12Q 1/18
Involving viable microorganisms: testing for antimicrobial activity of a material
G01N 33/5005
Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing:…