作为PI3Kα抑制剂和降解剂,Inavolisib可以与FGFR2合作,以增强PIK3CA突变固体瘤患者和临床前模型中的反应
Dejan Juric1, Kyung Song2, Radia M Johnson2
1Department of Medicine, Mass General Cancer Center, Harvard Medical School, Boston, Massachusetts.
概括
伊纳沃利西布对PIK3CA突变的癌症,特别是乳腺癌有前途. 将其与FGFR2抑制剂结合使用可能会改善同时发生突变的患者的治疗结果.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 药理学 药理学是指药理学的学科.
背景情况:
- PIK3CA突变是固体瘤的关键驱动因素,特别是激素受体阳性乳腺癌.
- 一种p110α抑制剂Inavolisib针对这些突变,并促进p110α降解.
- 现有的PI3K抑制剂在单剂疗效和安全性方面存在局限性.
研究的目的:
- 评估在PIK3CA突变固体瘤患者的第一阶段试验中inavolisib的安全性和耐受性.
- 为了确定口服伊纳沃利西布的最大耐受剂量 (MTD).
- 探索药物的药理动力学和药理动力学影响,包括与ctDNA的相关性.
主要方法:
- 一项首次在人身上进行的第一阶段研究 (NCT03006172) 评估了口服不可抗药性.
- 纳入了患有PIK3CA突变固体瘤的患者.
- 相对分析包括循环瘤DNA (ctDNA) 和临床前异种移植模型.
主要成果:
- MTD是每天9毫克,可控的副作用如高血糖和腹.
- 伊纳沃利西布在HR+/PIK3CA突变乳腺癌 (26%ORR,45%CBR) 中表现出线性药理动力学,药理动力学调制和抗瘤活性.
- 在ctDNA中的FGFR2突变与临床益处相关;临床前数据显示,FGFR2信号通过HER3/RAS/p85β增强了无可转化敏感性,促进了p110α降解.
结论:
- 在FGFR2和p110α之间存在一种新的协同作用,增强了inavolisib的疗效.
- 精密瘤学应该考虑复杂的协同发生变化的算法,而不仅仅是单个生物标志物.
- 将inavolisib与FGFR2抑制剂结合使用可能会在PIK3CA/FGFR2改变的瘤中产生优异和持续的反应.
相关概念视频
PI3K/mTOR/AKT Signaling Pathway
5.3K
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast, mTORC2 consists of a...
5.3K
Inhibition of Cdk Activity
5.5K
The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
5.5K
The JAK-STAT Signaling Pathway
11.9K
Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as SH2...
11.9K
Phosphoinositides and PIPs
10.1K
Phosphoinositides are a group of phospholipids containing a glycerol backbone with two fatty acid chains and a phosphate attached to a myoinositol sugar ring. The inositol head group extends into the cytoplasm, where it is modified by adding phosphate groups to form phosphatidylinositol phosphates or PIPs.
Different phosphoinositides are synthesized and recruited on the cytosolic face of the plasma membrane. The localization of specific phosphoinositides concentrated in separate membrane...
Different phosphoinositides are synthesized and recruited on the cytosolic face of the plasma membrane. The localization of specific phosphoinositides concentrated in separate membrane...
10.1K
Dipeptidyl Peptidase 4 Inhibitors
575
Dipeptidyl peptidase 4 (DPP-4) is a serine protease widely distributed in the body. It's involved in the inactivation of GLP-1 and GIP hormones, which are crucial for insulin regulation. DPP-4 inhibitors, such as sitagliptin (Januvia), saxagliptin (Onglyza), linagliptin (Tradjenta), alogliptin (Nesina), and vildagliptin (Galvus), help increase the proportion of active GLP-1, enhancing insulin secretion. These inhibitors work by competitively binding to DPP-4. This binding causes a...
575
mTOR Signaling and Cancer Progression
4.6K
The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
The mTOR pathway or the...
4.6K

