更新于：2024-11-01

PI3Kδ x PI3Kα x PI3K family x BRAF

更新于：2024-11-01

基本信息

关联

项与 PI3Kδ x PI3Kα x PI3K family x BRAF 相关的药物

ASN-003

靶点

BRAF x PI3K family x PI3Kα x PI3Kδ

作用机制

BRAF抑制剂 [+3]

在研机构

Asana BioSciences LLC初创企业

原研机构

Asana BioSciences LLC初创企业

在研适应症

结直肠癌 [+2]

非在研适应症

晚期恶性实体瘤

最高研发阶段临床2期

首次获批国家/地区-

首次获批日期1800-01-20

项与 PI3Kδ x PI3Kα x PI3K family x BRAF 相关的临床试验

NCT02961283 / Terminated临床1期

A Phase 1, Open-label, Dose-finding and Cohort Expansion Study of ASN003 in Subjects With Advanced Solid Tumors

The study is divided into two parts. The first part of the study will test various doses of ASN003 to find out the highest safe dose to test in three specific groups.
The second part of the study will test how well ASN003 can control cancer. Subjects will be enrolled into one of three groups.
Group 1: metastatic or recurrent melanoma with documented BRAFV600 mutation (n=20 evaluable patients) Group 2: metastatic colorectal cancer (CRC), or advanced non-small cell lung cancer (NSCLC) with documented BRAFV600 mutation (n=14 evaluable patients) Group 3: advanced solid tumors with documented PI3K pathway alterations (PIK3CA mutation or PTEN loss) (n=14 evaluable patients)

开始日期2016-10-01

申办/合作机构

Asana BioSciences LLC初创企业

100 项与 PI3Kδ x PI3Kα x PI3K family x BRAF 相关的临床结果

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100 项与 PI3Kδ x PI3Kα x PI3K family x BRAF 相关的转化医学

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0 项与 PI3Kδ x PI3Kα x PI3K family x BRAF 相关的专利（医药）

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项与 PI3Kδ x PI3Kα x PI3K family x BRAF 相关的文献（医药）

2021-12-01·BMC Cancer2区 · 医学

Diverse mechanisms activate the PI 3-kinase/mTOR pathway in melanomas: implications for the use of PI 3-kinase inhibitors to overcome resistance to inhibitors of BRAF and MEK

2区 · 医学

ArticleOA

作者: Baguley, Bruce C ; Rewcastle, Gordon W ; Wang, Qian ; Kolekar, Sharada ; Jaynes, Patrick ; Tran, Khanh B ; Flanagan, Jack U ; Shih, Jen-Hsing ; Jabed, Anower ; Shepherd, Peter R

AbstractBackgroundThe PI 3-kinase (PI3K) pathway has been implicated as a target for melanoma therapy.MethodsGiven the high degree of genetic heterogeneity in melanoma, we sought to understand the breadth of variation in PI3K signalling in the large NZM panel of early passage cell lines developed from metastatic melanomas.ResultsWe find the vast majority of lines show upregulation of this pathway, and this upregulation is achieved by a wide range of mechanisms. Expression of all class-IA PI3K isoforms was readily detected in these cell lines. A range of genetic changes in different components of the PI3K pathway was seen in different lines. Coding variants or amplification were identified in the PIK3CA gene, and amplification of the PK3CG gene was common. Deletions in the PIK3R1 and PIK3R2 regulatory subunits were also relatively common. Notably, no genetic variants were seen in the PIK3CD gene despite p110δ being expressed in many of the lines. Genetic variants were detected in a number of genes that encode phosphatases regulating the PI3K signalling, with reductions in copy number common in PTEN, INPP4B, INPP5J, PHLLP1 and PHLLP2 genes. While the pan-PI3K inhibitor ZSTK474 attenuated cell growth in all the lines tested, isoform-selective inhibition of p110α and p110δ inhibited cell growth in only a subset of the lines and the inhibition was only partial. This suggests that functional redundancy exists between PI3K isoforms. Furthermore, while ZSTK474 was initially effective in melanoma cells with induced resistance to vemurafenib, a subset of these cell lines concurrently developed partial resistance to PI3K inhibition. Importantly, mTOR-selective or mTOR/PI3K dual inhibitors effectively inhibited cell growth in all the lines, including those already resistant to BRAF inhibitors and ZSTK474.ConclusionsOverall, this indicates a high degree of diversity in the way the PI3K pathway is activated in different melanoma cell lines and that mTOR is the most effective point for targeting the growth via the PI3K pathway across all of these cell lines.

2015-02-01·Cancer Discovery1区 · 医学

PI3′-Kinase Inhibition Forestalls the Onset of MEK1/2 Inhibitor Resistance in BRAF-Mutated Melanoma

1区 · 医学

Article

作者: McMahon, Martin ; Marsh Durban, Victoria ; Deuker, Marian M. ; Phillips, Wayne A.

AbstractPhosphatidylinositide 3′ (PI3′)-lipid signaling cooperates with oncogenic BRAFV600E to promote melanomagenesis. Sustained PI3′-lipid production commonly occurs via silencing of the PI3′-lipid phosphatase PTEN or, less commonly, through mutational activation of PIK3CA, encoding the 110-kDa catalytic subunit of PI3′-kinase-α (PI3Kα). To define the PI3K catalytic isoform dependency of BRAF-mutated melanoma, we used pharmacologic, isoform-selective PI3K inhibitors in conjunction with melanoma-derived cell lines and genetically engineered mouse (GEM) models. Although BRAFV600E/PIK3CAH1047R melanomas were sensitive to the antiproliferative effects of selective PI3Kα blockade, inhibition of BRAFV600E/PTENNull melanoma proliferation required combined blockade of PI3Kα, PI3Kδ, and PI3Kγ, and was insensitive to PI3Kβ blockade. In GEM models, isoform-selective PI3K inhibition elicited cytostatic effects, but significantly potentiated melanoma regression in response to BRAFV600E pathway–targeted inhibition. Interestingly, PI3K inhibition forestalled the onset of MEK inhibitor resistance in two independent GEM models of BRAFV600E-driven melanoma. These results suggest that combination therapy with PI3K inhibitors may be a useful strategy to extend the duration of clinical response of patients with BRAF-mutated melanoma to BRAFV600E pathway–targeted therapies.Significance: Although BRAFV600E pathway–targeted therapies elicit melanoma regression, the onset of drug resistance limits the durability of response. Here, we show that combined treatment with PI3K inhibitors significantly forestalled the onset of MEK1/2 inhibitor–resistant disease in BRAF-mutated GEM melanoma models. These results provide a conceptual framework for the combined deployment of BRAFV600E plus PI3K pathway–targeted inhibitors in the treatment of a subset of patients with BRAF-mutated melanoma. Cancer Discov; 5(2); 143–53. ©2014 AACR.This article is highlighted in the In This Issue feature, p. 97