sirolimus and 17-hydroxywortmannin

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.

Topics: Androstadienes; Animals; Antibiotics, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Carcinoma, Non-Small-Cell Lung; Carcinoma, Renal Cell; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Female; Glioma; Humans; Interferon-alpha; Kidney Neoplasms; Lung Neoplasms; Mice; Mice, Nude; Molecular Structure; Molecular Weight; Neoplasm Transplantation; Neoplasms; Paclitaxel; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Proto-Oncogene Proteins c-akt; Signal Transduction; Sirolimus; Transplantation, Heterologous; Xenograft Model Antitumor Assays

Topics: Androstadienes; Animals; Antibiotics, Antineoplastic; Antineoplastic Agents; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Glioma; Humans; Interferon alpha-2; Interferon-alpha; Mice; Mice, Nude; Neoplasm Transplantation; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Proto-Oncogene Proteins c-akt; Recombinant Proteins; Signal Transduction; Sirolimus; Transplantation, Heterologous; Xenograft Model Antitumor Assays