Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
1998-06-22
2001-05-29
Bui, Phuong T. (Department: 1638)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C435S007200, C435S007100, C435S070300, C435S371000, C436S064000, C530S350000, C530S828000, C536S023500
Reexamination Certificate
active
06238876
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to the diagnosis and treatment of pathologies involving tumor formation and neoplasia, and more particularly to the detection of a condition of skin cancer known as sporadic basal cell carcinoma (BCC), and to the identification of relevant therapeutic agents based on their effect on the level of expression and/or activity of the gene Gli1, as well as to the preparation of therapeutic compositions and methods of use.
BACKGROUND OF THE INVENTION
Inductive signaling plays a critical role in both normal and disease development as developmental pathways that become unregulated in the adult can lead to abnormal patterning, overproliferation and neoplasia. One signaling pathway that is involved in several patterning events during embryogenesis is that triggered by secreted sonic hedgehog (Shh
1-4
). Shh binding to the membrane patched (ptc)-smoothened (smo) receptor complex elicits a cascade of cytoplasmic signal transduction events, including the inhibition of protein kinase A (PKA
5-12
) that leads to the transcription of the zinc finger transcription factor gene Gli1
11,13
. Gli1 is a proto-oncogene first isolated as an amplified gene in a glioma
14
that can transform fibroblasts in cooperation with E1A
15
. Gli1 is a member of a family comprising two other related genes: Gli2 and Gli3
16,17
. However, only Gli1 has been shown to be a target of Shh and mimic its effects
13
. In Drosophila, hedgehog signaling
18
similarly leads to the action of cubitus interruptus (ci), a Gli homolog that activates transcription of hedgehog-target genes
19-23
.
One of the processes in which Shh signaling is involved is the differentiation of ventral neural tube cell types acting as a notochord and floor plate-derived signal
1,4,24-27
. Previous work by the applicants herein on the role of sonic hedgehog signaling during neural plate patterning in frog (
Xenopus laevis
) embryos demonstrated that cells becoming floor plate respond to Shh by expressing Gli1, Pintallavis and HNF-3&bgr;, critical transcription factors that themselves can induce the differentiation of floor plate cells
13,25,28,29
.
In addition to effects on neural tissue, it has been found that ectopic expression of Shh and Gli1 also leads to the activation of Shh signaling target genes in epidermal non-neural ectoderm. Injected Shh induced the ectopic expression of Gli1, HNF-3&bgr; and Shh
25
, and ectopic expression of Gli1 induced the ectopic expression of HNF-3&bgr; and Shh
13
. Together, these results indicated that both neural and epidermal cells have functional reception and transduction mechanisms for Shh and can respond by activating the expression of Shh/Gli1 target genes even though epidermal cells do not normally receive the Shh signal at this stage.
The citation of any reference herein should not be construed as an admission that such reference is available as “Prior Art” to the instant application.
SUMMARY OF THE INVENTION
In accordance with the present invention, methods and corresponding materials, including reagents and kits, are disclosed for use in the diagnosis of basal cell carcinoma (BCC), and particularly, sporadic BCC, which are based, at least in part, on the observation that there is a relationship between the ectopic expression of the gene Gli1 and the development onset or presence of BCC.
Accordingly, the invention in an initial aspect extends to a method for the diagnosis and detection of BCC in mammals, including humans, which comprises measuring the presence and level of ectopic expression of Gli1.
In a further aspect, the invention extends to an assay for the examination and diagnosis of the presence and extent of basal cell carcinoma in an animal, which comprises an observable test colony which exhibits a demonstrable development of tumor formation and/or neoplasia upon contact with ectopically expressed Gli1A-
1
J from a biological sample taken from the animal.
Still further, the invention includes the development of therapeutic agents that are capable of controlling the expression and/or activity/function and expression of Gli1, and are thereby able to inhibit the development and/or treat sporadic basal cell carcinoma in animals, and particularly in humans. Such agents may include small molecules, ligands, and other agents that would function as Gli1 antagonists or would otherwise interrupt Gli1 expression and activity. Suitable pharmaceutical compositions could be administered by a variety of routes, including topical, oral, parenteral, intrathecal, intranasal, and the like, at a dosage level and schedule that may be determined by the clinician in accordance with the particular condition of the patient.
Accordingly, it is a principal object of the present invention to provide a method for the detection and diagnosis of basal cell carcinoma and particularly, sporadic basal cell carcinoma, that is efficient and accurate.
It is a further object of the present invention to provide a method as aforesaid that involves the observation and measurement of the level of expression of the gene Gli1 and/or its protein product.
It is a still further object of the present invention to provide assays for the performance of the methods as aforesaid that include an observable test colony capable of eliciting and exhibiting a demonstrable tumorigenic response upon stimulation with Gli1.
It is a still further object of the present invention to provide assays as aforesaid that may be used to screen for candidate inhibitors of basal cell carcinoma.
It is a yet further object of the present invention to provide therapeutic agents, compositions containing them, and corresponding methods of administration, that result from the identification and development of agents that act to modulate or control the activity or expression of Gli1 in animals, and particularly humans.
Other objects and advantages will become apparent to those skilled in the art from a consideration of the ensuing detailed description that proceeds with reference to the following illustrative drawings.
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Bui Phuong T.
Klauber & Jackson
New York University
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