title: PWT-458, a novel pegylated-17-hydroxywortmannin, inhibits phosphatidylinositol 3-kinase signaling and suppresses growth of solid tumors.
abstract: Deregulated phosphatidylinositol 3-kinase (PI3K) signaling pathway is widely implicated in tumor growth and resistance to chemotherapy. While a strong rationale exists for pharmacological targeting of PI3K, only a few proof-of-principle in vivo efficacy studies are currently available. PWT-458, pegylated-17-hydroxywortmannin, is a novel and highly potent inhibitor of PI3K in animal models. Upon in vivo cleavage of its poly(ethyleneglycol) (PEG), PWT-458 releases its active moiety 17-hydroxywortmannin (17-HWT), the most potent inhibitor in its class. Here we show that a single intravenous injection of PWT-458 rapidly inhibited PI3K signaling, as measured by a complete loss of AKT (Ser-473) phosphorylation in xenograft tumors grown in nude mice. Following a daily X5 dosing regimen, PWT-458 demonstrated single-agent antitumor activity in nude mouse xenograft models of U87MG glioma, nonsmall cell lung cancer (NSCLC) A549, and renal cell carcinoma (RCC) A498. Efficacious doses ranged from 0.5 mg/kg to 10 mg/kg, achieving a superior therapeutic index over 17-HWT. PWT-458 augmented anticancer efficacy of a suboptimal dose of paclitaxel against A549 and U87MG tumors. Combination treatment of PWT-458 and an mTOR inhibitor, Pegylated-Rapamycin (Peg-Rapa), resulted in an enhanced antitumor efficacy in U87MG. Finally, PWT-458 in combination with interferon-alpha (Intron-A) caused a dramatic regression of RCC A498, which was not achieved by either agent alone. These studies identify PWT-458 as an effective anticancer agent and provide strong proof-of-principle for targeting the PI3K pathway as novel anticancer therapy.
authors.affiliation: Department of Oncology Research, Wyeth Research, Pearl River, NY, USA. yuk@wyeth.com
authors.forename: Ker
authors.initials: K
authors.lastname: Yu
authors.forename: Judy
authors.initials: J
authors.lastname: Lucas
authors.forename: Tianmin
authors.initials: T
authors.lastname: Zhu
authors.forename: Arie
authors.initials: A
authors.lastname: Zask
authors.forename: Christine
authors.initials: C
authors.lastname: Gaydos
authors.forename: Lourdes
authors.initials: L
authors.lastname: Toral-Barza
authors.forename: Jianxin
authors.initials: J
authors.lastname: Gu
authors.forename: Fangbiao
authors.initials: F
authors.lastname: Li
authors.forename: Inder
authors.initials: I
authors.lastname: Chaudhary
authors.forename: Ping
authors.initials: P
authors.lastname: Cai
authors.forename: Jason
authors.initials: J
authors.lastname: Lotvin
authors.forename: Roseann
authors.initials: R
authors.lastname: Petersen
authors.forename: Mark
authors.initials: M
authors.lastname: Ruppen
authors.forename: Mahdi
authors.initials: M
authors.lastname: Fawzi
authors.forename: Semiramis
authors.initials: S
authors.lastname: Ayral-Kaloustian
authors.forename: Jerauld
authors.initials: J
authors.lastname: Skotnicki
authors.forename: Tarek
authors.initials: T
authors.lastname: Mansour
authors.forename: Philip
authors.initials: P
authors.lastname: Frost
authors.forename: James
authors.initials: J
authors.lastname: Gibbons
mesh_terms: D000730:Androstadienes / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D008970:Molecular Weight; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000494:pharmacology; D014183:Transplantation, Heterologous; D023041:Xenograft Model Antitumor Assays
chemical_list: D000730:Androstadienes; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D016898:Interferon-alpha; D000081082:Phosphoinositide-3 Kinase Inhibitors; C053480:17-hydroxywortmannin; D051057:Proto-Oncogene Proteins c-akt; D017239:Paclitaxel; D020123:Sirolimus