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|Ref Type||Journal Article|
|Authors||Soler A, Figueiredo AM, Castel P, Martin L, Monelli E, Angulo-Urarte A, Milà-Guasch M, Viñals F, Baselga J, Casanovas O, Graupera M|
|Title||Therapeutic Benefit of Selective Inhibition of p110α PI3-Kinase in Pancreatic Neuroendocrine Tumors.|
|Journal||Clinical cancer research : an official journal of the American Association for Cancer Research|
|Date||2016 Dec 01|
|Abstract Text||Mutations in the PI3K pathway occur in 16% of patients with pancreatic neuroendocrine tumors (PanNETs), which suggests that these tumors are an exciting setting for PI3K/AKT/mTOR pharmacologic intervention. Everolimus, an mTOR inhibitor, is being used to treat patients with advanced PanNETs. However, resistance to mTOR-targeted therapy is emerging partially due to the loss of mTOR-dependent feedback inhibition of AKT. In contrast, the response to PI3K inhibitors in PanNETs is unknown.In the current study, we assessed the frequency of PI3K pathway activation in human PanNETs and in RIP1-Tag2 mice, a preclinical tumor model of PanNETs, and we investigated the therapeutic efficacy of inhibiting PI3K in RIP1-Tag2 mice using a combination of pan (GDC-0941) and p110α-selective (GDC-0326) inhibitors and isoform-specific PI3K kinase-dead-mutant mice.Human and mouse PanNETs showed enhanced pAKT, pPRAS40, and pS6 positivity compared with normal tissue. Although treatment of RIP1-Tag2 mice with GDC-0941 led to reduced tumor growth with no impact on tumor vessels, the selective inactivation of the p110α PI3K isoform, either genetically or pharmacologically, reduced tumor growth as well as vascular area. Furthermore, GDC-0326 reduced the incidence of liver and lymph node metastasis compared with vehicle-treated mice. We also demonstrated that tumor and stromal cells are implicated in the antitumor activity of GDC-0326 in RIP1-Tag2 tumors.Our data provide a rationale for p110α-selective intervention in PanNETs and unravel a new function of this kinase in cancer biology through its role in promoting metastasis. Clin Cancer Res; 22(23); 5805-17. ©2016 AACR.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|GDC-0326||PIK3CA inhibitor 16||GDC-0326 is a small molecule that inhibits PIK3CA, resulting in decreased downstream signaling and potentially leading to reduced tumor growth (PMID: 27225693, PMID: 26741947).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||islet cell tumor||not applicable||GDC-0326||Preclinical||Actionable||In a preclinical study, GDC-0326 inhibited AKT activation, decreased tumor growth, metastasis, and angiogenesis and increased lifespan in a transgenic mouse model of pancreatic neuroendocrine tumor (PMID: 27225693).||27225693|
|Unknown unknown||islet cell tumor||not applicable||Pictilisib||Preclinical||Actionable||In a preclinical study, Pictilisib (GDC-0941) inhibited AKT activation, reduced tumor burden, and increased lifespan in a transgenic mouse model of pancreatic neuroendocrine tumor (PMID: 27225693).||27225693|