Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1997-03-12
2001-08-07
Guzo, David (Department: 1636)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C435S320100
Reexamination Certificate
active
06271205
ABSTRACT:
The technical field of this invention is gene therapy of brain tumors. More particularly, this invention relates to inhibition of or reduction in tumorigenicity of cells within neural tumors by transferring a nucleic acid encoding a tyrosine kinase receptor for a differentiation-inducing factor into such cells and inducing expression of the nucleic acid.
BACKGROUND OF THE INVENTION
The nervous system is derived from multipotential precursor cells that maintain a closely regulated inverse relationship between cell proliferation and differentiation, as demonstrated in
FIG. 1
, which employs tissue culture of a neural tumor cell line. In the central nervous system, these precursor cells commit to a specific differentiation pathway shortly after their last mitosis. In the peripheral nervous system, sensory neurons differentiate following withdrawal from the cell cycle, but sympathetic neuroblasts begin to differentiate while still mitotically active. The molecular basis of the coupling between neuronal differentiation and cell proliferation is a problem of current interest which has been extensively studied using cell lines derived from neural tumors. The coupling between neuronal differentiation and cell proliferation is highly relevant to the etiology of neural tumors, in which the regulation of these two cell processes is disrupted.
Neuronal differentiation is induced and maintained by proteinaceous growth factors known as the neurotropins. Several neurotropins are known at this time: nerve growth factor (NGF), brain derived growth factor (BDNF) and neurotrophin-3 (NT-3). Neurotrophins mediate differentiation by binding to and activating high-affinity (K
d
≈10
−11
M) receptor tyrosine kinases called Trk receptors which appear to transduce most of their biological actions (Chao (1992)
Neuron
9:583-93; Hosang et al. (1985)
J. Biol. Chem
. 260:655-62; Schecter et al. (1981)
Cell
24:867-74; and Sutter et al. (1979)
J. Biol. Chem
. 254:5972-82; Kaplan et al. (1991)
Science
252:554-558; Klein et al. (1991)
Cell
65:189-197). Activated TrkA is critical for initiating NGF signal transduction, while BDNF binds to a closely related TrkB receptor and NT-3 binds to the TrkC receptor.
Transmembrane receptor tyrosine kinases (RTKs) such as the Trk receptors generally function as molecular switches for transduction of signals from a cell's extracellular milieu, across the cell membrane, into the cytoplasm, and ultimately into the nucleus. Extracellular binding of a cognate ligand to its RTK results in receptor dimerization and autophosphorylation, followed by tyrosine phosphorylation of a specific subset of cellular protein substrates. Ultimately DNA synthesis and cell proliferation or differentiation results from signal transduction via an RTK. A large number of RTKs are known, for example, the epidermal growth factor receptor (EGFR), the platelet derived growth factor receptor (PDGFR), the macrophage colony stimulating factor receptor (CSF-1R), the various fibroblast growth factor receptors (FGFR), the insulin receptor, and the like. The EGFR and PDGFR are known to be involved in glioma growth and progression (see, e.g., Agosti et al. (1992)
Virchows Archiv. A. Pathol. Anat
. 420:321-5; Torp et al. (1991)
Cancer Immunol. Immunother
. 33:61-4; Fleming et al. (1992)
Cancer Res
. 52:4550-3. Additionally both EGF and PDGF tend to promote motility in in vitro assays (compared to NGF which tends to inhibit motility) (Chicoine et al. (1995)
Neurosurg
. 36:1165-71). Chimeric receptors of EGF and PDGF extracellular domains with the TrkA intracellular domain have been reported (Obermeier et al. (1993)
EMBO J
12:933-41) and shown to autophosphorylate and initiate signal transduction in response to EGF and PDGF, respectively.
Recent clinical studies suggest that the TrkA receptor plays a critical role in neuroblastoma, one of the most common pediatric solid tumors. Patients whose tumors express significant levels of TrkA have a good chance for survival, while patients whose tumors lack TrkA respond poorly to therapy (Kogner et al. (1993)
Cancer Res
. 53:2044-2050; Nakagawara et al. (1993)
New Engl. J. Med
. 328:847-854; Suzuki et al. (1993)
J. Natl. Cancer Inst
. 85:377-384). Neuroblastoma frequently occurs during infancy, with the primary lesion in the adrenals and sympathetic chain and metastases to lymph nodes, liver, skin, and bone marrow. This tumor is difficult to treat as common modes of chemotherapy have harsh side effects on normal infant tissue. A variety of modalities have been used to treat neuroblastoma, such as surgery, radiotherapy, and chemotherapy, with varying degrees of success. For many patients, neuroblastoma continues to be fatal.
Cells within neuroblastoma tumors resemble those found in normally developing tissue of the sympathetic nervous system. Neuroblastomas may contain undifferentiated, closely packed spheroidal cells that closely resemble migrating neural crest cells of early embryos (neuroblasts), along with more differentiated cells whose immature nerve fibers tangle, thereby forming a rosette which is the first recognizable sign of neuronal differentiation. Some neuroblastomas undergo spontaneous regression or maturation to benign ganglioneuromas. The similarity of neuroblastoma cells to neuroblasts and the ability of neuroblastoma cells to spontaneously mature to a more benign form indicate that the disease may originate as the result of a block of differentiation of a sympathetic precursor cell.
Another neural tumor, glioma, is a family of cancers comprising the most common adult-onset neurological neoplasms such as malignant astrocytoma (or glioblastoma or malignant glioma), oligodendroglioma, and ependymoma, along with the juvenile onset neoplasms such as juvenile pilocystic astrocytoma (JPA) and the uncommon gangliogliomas. Expression of functional Trk receptors has not been reported for gliomas (Oelmann et al. (1995)
Cancer Res
. 55:2212-9), though neurotrophin production occurs with fairly high frequency. NGF is secreted by many glioma cell lines (Arnason et al. (1974)
J. Clin. Invest
. 53:2a; Longo et al. (1974)
Proc. Natl. Acad. Sci. USA
71:2347-9; and Reynolds et al. (1981)
J. Neurosci. Res
. 6:319-25).
While most gliomas are difficult to treat and are ultimately untreatable, there are a few uncommon forms of glioma which are neither aggressive nor invasive. In fact, some patients with these rare gliomas can be followed without treatment for years; others can be effectively treated and even cured with surgery alone. Two types of glioma that behave in such a benign fashion are the uncommon gangliogliomas and JPA. The former tumor, composed of both neoplastic astrocytes and neurons, tends to occur in the temporal lobe of children and behaves very indolently. JPA, characteristically identified histologically by the presence of Rosenthal fibers and microcystic changes, can present as a large cystic mass that often produces symptoms by compressing neighboring structures and causing hydrocephalus. Nevertheless, they are curable by surgery alone, even when they attain significant size. JPA appears to be incapable of invading surrounding tissues.
In contrast, malignant glioma cells produce very invasive brain tumors with infiltration of both white and grey matter (Bjerkvig et al. (1986)
Cancer Res
. 46:4071-912). At the time of diagnosis, microscopic extension through much of the neural axis by malignant glioma is the rule (Burger et al. (1980)
Cancer
46:1179-86; Kelly et al. (1987)
J. Neurosurg
. 66:865-74; Moser (1988)
Cancer
62:381-90; and Salazar et al. (1976)
Int. J. Radiat. Oncol. Biol. Phys
. 1:627-37). Extension by motile invading cells underlies the incurability by surgery of most gliomas, even when they appear small and restricted in nature. Because gliomas are believed to arise from transformed astrocytes or their immediate precursors, glioma differentiation therapy has been primarily directed at increasing astrocytic differentiation, despite the observation that increasing glial fibrillary acidic protein (GFAP)
Lachyankar Mahesh B.
Recht Lawrence D.
Ross Alonzo H.
Fish & Richardson P.C.
Guzo David
University of Massachusetts Medical Center
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