Compositions and methods for identifying agents which modulate PTEN function and PI-3 kinase pathways

• US 20050032727A1
• Filed: 11/13/2003
• Published: 02/10/2005
• Est. Priority Date: 05/30/2000
• Status: Active Grant

• Current Assignee: Donald L. Durden
• Original Assignee: Donald L. Durden
• Inventors: Durden, Donald L.
• Granted Patent: US 7,470,721 B2
• Time in Patent Office: Days
• US Class Current: 514/44.R
• CPC Class Codes: A61K 38/1709 from mammals
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: G01N 2500/04 Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)
• CPC Class Codes: G01N 33/5011 for testing antineoplastic activity

Abstract

Methods are provided for the identification, biochemical characterization and therapeutic use of agents which impact PTEN, p53, PI-kinase and AKT mediated cellular signaling.

Claims

1-90. -90. (Cancelled)

91. A method for the treatment of cancer in a patient in need thereof, comprising the administration of an effective amount of at least one PTEN agonist, wherein said PTEN agonist effectively inhibits aberrant tumor-associated angiogenesis.

92. The method as claimed in claim 91, wherein said PTEN agonist effectively inhibits cancer cell metastasis.

93. The method as claimed in claim 91, further comprising the administration of at least one additional chemotherapeutic agent.

94. The method as claimed in claim 93, wherein said at least one additional chemotherapeutic agent is selected from the group consisting of alkylating agents, antimetabolites, asparaginase, vincristine, vinblastine, anthracyclines, microtubule disrupting agents, taxol, herceptin, and etoposides.

95. The method as claimed in claim 91, further comprising the administration of an inhibitor of PI3 kinase.

96. The method as claimed in claim 95, wherein said PI-kinase inhibitor is LY294002.

97. The method as claimed in claim 91, further comprising the administration of an inhibitor of AKT.

98. The method of claim 91, wherein said cancer is chemoresistant and administration of said at least one agonist is effective to enhance the chemosensitivity of cells in said cancer.

99. The method as claimed in claim 98, further comprising the administration of at least one additional chemotherapeutic agent.

100. The method as claimed in claim 99, wherein said at least one additional chemotherapeutic agent is selected from the group consisting of alkylating agents, antimetabolites, asparaginase, vincristine, vinblastine, anthracyclines, microtubule disrupting agents, taxol, herceptin, and etoposides.

101. The method as claimed in claim 99, further comprising the administration of an inhibitor of PI3 kinase.

102. The method as claimed in claim 101, wherein said PI-kinase inhibitor is LY294002.

103. The method as claimed in claim 98, further comprising the administration of an inhibitor of AKT.

104. The method of claim 91, wherein said cancer is radioresistant and administration of said at least one PTEN agonist is effective to enhance the radiosensitivity of cells in said cancer.

105. The method as claimed in claim 104, further comprising the administration of at least one additional chemotherapeutic agent.

106. The method as claimed in claim 105, wherein said at least one additional chemotherapeutic agent is selected from the group consisting of alkylating agents, antimetabolites, asparaginase, vincristine, vinblastine, anthracyclines, microtubule disrupting agents, taxol, herceptin, and etoposides.

107. The method as claimed in claim 105, further comprising the administration of an inhibitor of PI3 kinase.

108. The method as claimed in claim 107, wherein said PI-kinase inhibitor is LY294002.

109. The method as claimed in claim 104, further comprising the administration of an inhibitor of AKT.

110. The method as claimed in claim 91 comprising the targeted administration of said PTEN agonist to cancer tissues to induce stress induced apoptosis thereof and inhibit tumor-associated angiogenesis, wherein said PTEN agonist inhibits a kinase activity selected from the group consisting of AKT kinase activity and PI3 kinase activity.

111. The method as claimed in claim 110, wherein said apoptosis is p53 mediated.

112. The method as claimed in claim 110, wherein said agonist is the PI3 kinase inhibitor LY294002.

113. The method as claimed in claim 92, wherein said PTEN agonist is selected from the group consisting of a PI3 kinase inhibitor and an AKT inhibitor.

114. The method as claimed in claim 113, wherein said PI3 kinase inhibitor is LY294002.

115. A method for the treatment of cancer in a patient in need thereof, comprising the administration of an effective amount of at least one PTEN antagonist.

116. The method of claim 115, wherein said PTEN antagonist inhibits p53 mediated programmed cell death.

117. The method as claimed in claim 116, comprising the targeted administration of said PTEN inhibitor to normal tissues to inhibit stress induced apoptosis thereof, wherein said patient is in need of such treatment due to deleterious cytotoxic effects of anticancer treatment.

118. The method as claimed in claim 115, wherein said PTEN antagonist inhibits cellular senescence thereby promoting survival of normal cells.

119. The method as claimed in claim 118, wherein said normal cells are selected from the group consisting of brain cells, heart cells, blood cells, T cells, B cells and skin cells.