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.

Alternative phospholipase D/mTOR survival signal in human breast cancer cells

“…Many cells undergo apoptosis in the absence of growth factors that stimulate survival signals. The MDA-MB-231 and MCF-7 breast cancer cell lines have frequently been used to represent highly malignant and relatively benign cancer cells, respectively (Yu et al, 2002). Consistent with this paradigm, the MCF-7 cells undergo apoptosis when subjected to serum withdrawal, whereas the MDA-MB-231 cells are resistant to this stress (Figure 1).…”

PTEN mutations are common in sporadic microsatellite stable colorectal cancer

“…If subsequent in vitro functional studies confirm cellular dysfunction, PTEN may become a potential therapeutic target in CRC. In vitro and in vivo demonstration of enhanced sensitivity of PTEN-deficient tumours to inhibition of the FRAP/ RAFT/TOR component of the P13K intracellular pathway by the rapamycin analogue CCI-779 has led to the postulate that such drugs may have clinical efficacy in human PTEN-deficient cancers (Neshat et al, 2001;Yu et al, 2001). Data presented here provide a molecular basis for the inclusion of patients with CRC in clinical trials of such novel anticancer agents.…”

Phorbol 12-myristate 13-acetate and serum synergize to promote rapamycin-insensitive cell proliferation via protein kinase C-eta

“…Rapamycin prevents glioblastoma cell proliferation in vitro and xenograft cell growth in vivo (Yu et al, 2001). Rapamycin also increases the effectiveness of radiation in U-87MG glioblastoma cells (Eshleman et al, 2002).…”