Dual Inhibition of PI3Kα and mTOR as an Alternative Treatment for Kaposi's Sarcoma

Chaisuparat, Risa; Hu, Jiadi; Jham, Bruno Correia; Knight, Zachary A.; Shokat, Kevan M.; Montaner, Silvia

doi:10.1158/0008-5472.can-08-0878

Cited by 51 publications

(45 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…A novel pyridinylfuranopyrimidine inhibitor, PI-103, has been shown to dually inhibit PI3K and mTOR and block cell proliferation in several cancer cell lines including gliomas (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(31)(32)(33)(34). In this study, we show that PI-103 inhibits cell proliferation in a dose-and time-dependent manner.…”

Section: Discussionmentioning

confidence: 60%

A Dual PI3K/mTOR Inhibitor, PI-103, Cooperates with Stem Cell–Delivered TRAIL in Experimental Glioma Models

et al. 2011

View full text Add to dashboard Cite

The resistance of glioma cells to a number of antitumor agents and the highly invasive nature of glioma cells that escape the primary tumor mass are key impediments to the eradication of tumors in glioma patients. In this study, we evaluated the therapeutic efficacy of a novel PI3-kinase/mTOR inhibitor, PI-103, in established glioma lines and primary CD133 þ glioma-initiating cells and explored the potential of combining PI-103 with stem celldelivered secretable tumor necrosis factor apoptosis-inducing ligand (S-TRAIL) both in vitro and in orthotopic mouse models of gliomas. We show that PI-103 inhibits proliferation and invasion, causes G 0 -G 1 arrest in cell cycle, and results in significant attenuation of orthotopic tumor growth in vivo. Establishing cocultures of neural stem cells (NSC) and glioma cells, we show that PI-103 augments the response of glioma cells to stem celldelivered S-TRAIL. Using bimodal optical imaging, we show that when different regimens of systemic PI-103 delivery are combined with NSC-derived S-TRAIL, a significant reduction in tumor volumes is observed compared with PI-103 treatment alone. To our knowledge, this is the first study that reveals the antitumor effect of PI-103 in intracranial gliomas. Our findings offer a preclinical rationale for application of mechanismbased systemically delivered antiproliferative agents and novel stem cell-based proapoptotic therapies to improve treatment of malignant gliomas. Cancer Res; 71(1); 154-63. Ó2010 AACR.

show abstract

Section: Discussionmentioning

confidence: 60%

A Dual PI3K/mTOR Inhibitor, PI-103, Cooperates with Stem Cell–Delivered TRAIL in Experimental Glioma Models

et al. 2011

View full text Add to dashboard Cite

show abstract

“…For example, drugs that inhibit the PI(3)K/Akt/mTOR (mammalian target of rapamycin) pathway hamper KS development and, in certain cases, induce tumor regression (Sodhi et al, 2004bStallone et al, 2005;Chaisuparat et al, 2008). Importantly, we show that the PI(3)K/Akt nexus is activated in human KS.…”

Section: Discussionmentioning

confidence: 68%

“…Importantly, we show that the PI(3)K/Akt nexus is activated in human KS. To this regard, PI-103, a dual PI(3)K and mTOR inhibitor could lead to a reduction in tumor growth in mice implanted with vGPCR-expressing endothelial cells (Chaisuparat et al, 2008). In addition, our results suggest that blocking the PI(3)Kg by AS 605402 can effectively interfere with loss of endothelial barrier function provoked by vGPCR, therefore placing PI(3)Kg activity as a multi-functional molecular target for the treatment of patients with KS.…”

Section: Discussionmentioning

confidence: 99%

Remodeling of VE-cadherin junctions by the human herpes virus 8 G-protein coupled receptor

et al. 2010

View full text Add to dashboard Cite

Kaposi Sarcoma (KS) are opportunistic tumors, associated with human herpes virus 8 (HHV8) infection. KS development is highly favored by immune-depression and remains the second most frequent tumor in acquired immune deficiency syndrome patients. Although it has been shown that experimental expression of the HHV8 G-proteincoupled receptor (vGPCR) in the endothelial compartment is alone sufficient to recapitulate the formation and progression of KS-like lesions, its functional effects on endothelial homeostasis are not fully understood. Here we show that vGPCR expression in endothelial cells induces an increase in paracellular permeability both in vivo and in vitro. By using pharmacological inhibitors and small interference RNA-based knockdown, we demonstrate an essential role for the PI(3)Kinase-c/Rac nexus in vGPCRmediated permeability. This was further accompanied by dramatic remodeling of VE-cadherin-dependent cell-cell junctions. Importantly, this in vitro vGPCR-initiated signaling signature was observed in a large panel of human KS. Altogether, our results support the hypothesis that endothelial vGPCR signaling is co-opted in KS, and unveil new key cellular targets for therapeutic intervention.

show abstract

“…25 Similarly, PI103 induced a G1 arrest but no apoptosis in glioma 10,11 and in acute myeloid leukaemia, 26 whereas a combined G0/G1 cell cycle arrest and apoptosis have been observed in T-cell acute lymphoblastic leukaemia and Kaposi's sarcoma. 27 PI103 has also been shown to induce autophagy of therapy resistant glioma cells and to synergize with various chemotherapeutic drugs to trigger apoptosis of neuroblastoma cells. 14,28 Despite the different growth inhibitory actions of OSU03012 and PI103, both compounds impaired the protein expression of cyclin D1 and Mycn in neuroblastoma cells and MYCN-amplified neuroblastoma cells were more sensitive to OSU03012 or PI103 compared with nonamplified cells (Fig.…”

Section: Discussionmentioning

confidence: 99%

Effects of small molecule inhibitors of PI3K/Akt/mTOR signaling on neuroblastoma growth in vitro and in vivo

Segerström

Baryawno

Sveinbjørnsson

et al. 2011

Intl Journal of Cancer

View full text Add to dashboard Cite

Activation of the PI3K/Akt signaling pathway is correlated with poor prognosis in neuroblastoma, the most common and deadly extracranial tumor of childhood. In this study, we show that the small-molecule inhibitors of phosphoinositidedependent protein kinase-1 (PDK1) OSU03012 and the dual class I PI3K/mTOR inhibitor PI103 have profound effects on neuroblastoma survival in vitro and in vivo. Both OSU03012 and PI103 inhibited neuroblastoma growth in vitro. In treated cells, OSU03012 induced apoptosis and an S phase cell cycle arrest, whereas only minor apoptosis was detected in PI103 treated cells together with a G1 arrest. Both OSU03012 and PI103 downregulated phosphorylation of Akt and inhibited the downstream targets glycogen synthase kinase-3b (GSK3b) and p70 S6 kinase-1 (S6K1), as well as downregulated the expression of cyclin D1 and Mycn protein. Neuroblastoma cells expressing high levels of Mycn were more sensitive to OSU03012 or PI103 compared with cells expressing low Mycn levels. Both compounds significantly inhibited the growth of established, subcutaneous MYCN-amplified neuroblastoma xenografts in nude NMRI nu/nu mice. These results suggest that inhibition of the PI3K/Akt signaling pathway represent a clinical relevant target for the treatment of patients with high-risk MYCN-amplified neuroblastoma.Neuroblastomas are peripheral nervous system tumors that originate in the neural crest and are most commonly found in the adrenal medulla or along the sympathetic chain. 1 These tumors show heterogeneous biological and clinical features, in which a subset is prone to regress through spontaneous apoptosis with little or no therapy while another subset differentiates over time to benign ganglioneuromas. However, the majority of neuroblastomas are malignant with metastatic spread that is difficult to cure with current treatment modalities.2 Amplification of the MYCN gene, which occurs in 40-50% of the high-risk neuroblastoma cases, remains the major key predictor of poor outcome and is associated with advanced-stage disease, rapid tumor progression and low survival.3 Advanced-stage tumors and those with MYCN gene amplification typically show emergence of treatment resistance and new treatment alternatives for these patients are highly warranted.Abnormal activation of the PI3K/Akt signaling pathway is a common event in human cancers and has been validated through epidemiological and experimental studies as being essential for several human tumors, including neuroblastoma.4-6 PI3K is a family of lipid kinases, heterodimeric proteins composed of one catalytic and one regulatory subunit. In the class IA PI3Ks, there are currently three isoforms of the catalytic (p110a, b, and d) and five of the regulatory (p50a, p55a, p85a, p85b, and p55c) subunits, where p50a and p55a are splice variants of p85a. PI3Ks functions as signal transducers downstream of cell-surface receptors, such as receptor tyrosine kinases. Activated PI3Ks phosphorylate the lipid phosphatidyl-inositol 4,5-biphosphate (PIP2) to generate phosphatidyl-...

show abstract

Dual Inhibition of PI3Kα and mTOR as an Alternative Treatment for Kaposi's Sarcoma

Cited by 51 publications

References 42 publications

A Dual PI3K/mTOR Inhibitor, PI-103, Cooperates with Stem Cell–Delivered TRAIL in Experimental Glioma Models

A Dual PI3K/mTOR Inhibitor, PI-103, Cooperates with Stem Cell–Delivered TRAIL in Experimental Glioma Models

Remodeling of VE-cadherin junctions by the human herpes virus 8 G-protein coupled receptor

Effects of small molecule inhibitors of PI3K/Akt/mTOR signaling on neuroblastoma growth in vitro and in vivo

Contact Info

Product

Resources

About