Multicellular living organisms and unmodified parts thereof and – Nonhuman animal – The nonhuman animal is a model for human disease
Reexamination Certificate
2000-07-19
2003-10-28
Crouch, Deborah (Department: 1632)
Multicellular living organisms and unmodified parts thereof and
Nonhuman animal
The nonhuman animal is a model for human disease
C800S003000, C800S008000, C800S009000, C800S018000, C435S455000, C435S325000, C435S320100
Reexamination Certificate
active
06639121
ABSTRACT:
BACKGROUND OF THE INVENTION
Advanced malignancy represents the phenotypic end-point of successive genetic lesions that impact on the function and regulation of oncogenes and tumor suppressor genes
1
. The established tumor is maintained through complex and poorly understood host-tumor interactions guiding processes such as angiogenesis and immune sequestration. The numerous and diverse genetic alterations that accompany tumor-ogenesis raises questions as to whether experimental cancer-promoting mutations remain relevant to tumor maintenance.
SUMMARY OF INVENTION
Melanoma genesis and maintenance were shown to be strictly dependent upon H-RAS
V12G
expression in a novel doxycycline-inducible H-RAS
V12G
INK4a null mouse melanoma model. Withdrawal of doxycycline and H-RAS
V12G
down-regulation resulted in clinical and histological regression of primary and explanted tumors. The initial stages of regression were highlighted by dramatic activation of apoptosis in the tumor cell and host-derived endothelial cells. Although the regulation of VEGF was found to be RAS-dependent in vitro, the failure of persistent endogenous and enforced VEGF expression to sustain tumor viability indicated that the tumor maintenance actions of activated RAS extend beyond the regulation of VEGF gene expression in vivo. Together these data provide genetic evidence that H-RAS
V12G
plays a critical role in both the genesis and maintenance of solid tumors.
Accordingly, the invention features a non-human mammal having incorporated into its genome an expression construct including nucleic acid encoding an oncogene operably linked to an inducible promoter, the mammal further having a genetic mutation that causes it to have a greater susceptibility to cancer than a mammal not having that mutation.
In preferred embodiments: the mammal is a mouse; the oncogene is ras; the ras gene has an activating mutation; the inducible promoter can be induced by doxycycline; and the mutation is in DNA encoding a tumor suppressor such as INK4.
In a second, related aspect, the invention features a non-human mammal having incorporated into its genome: (i) a first expression construct in which a reverse tetracycline transactivator is operably linked to a tissue-specific promoter; and (ii) a second expression construct in which nucleic acid encoding an oncogene is operably linked to a promoter that can be regulated by the reverse tetracycline transactivator; the mammal further has a genetic mutation that causes it to have greater susceptibility to cancer than a mammal that does not have the mutation. In preferred embodiments of this aspect of the invention, the tissue-specific promoter is a tyrosine promoter, and expression of the oncogene results in the mammal having greater susceptibility to cancer than a mammal having the mutation but not expressing the oncogene.
In a third, related aspect, the invention features a non-human mammal having incorporated into its genome: (i) a first expression construct in which a reverse tetracycline transactivator is operably linked to a tyrosinase promoter; and (ii) a second expression construct in which nucleic acid encoding ras is operably linked to a promoter than can be regulated by the reverse tetracycline transactivator.
The invention can be used as a model for any cancer, and in particular solid tumors such as melanoma. The oncogene linked to the inducible promoter and/or the mutation in the genome of the mammal are chosen to direct development of the desired tumor type.
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Chin Lynda
DePinho Ronald A.
Crouch Deborah
Dana-Farber Cancer Institute Inc.
Fish & Richardson P.C.
Ton Thai-an N.
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