Phase 2 study of LY3023414 in patients with advanced endometrial cancer harboring activating mutations in the PI3K pathway

Rubinstein, Maria M.; Hyman, David M.; Caird, Imogen; Won, Helen; Soldan, Krysten; Seier, Kenneth; Iasonos, Alexia; Tew, William P.; O’Cearbhaill, Roisin E.; Grisham, Rachel N.; Hensley, Martee L.; Troso-Sandoval, Tiffany A.; Sabbatini, Paul; Guillen, Joyce; Selcuklu, S. Duygu; Zimel, Catherine; Torrisi, Jean; Aghajanian, Carol; Makker, Vicky

doi:10.1002/cncr.32677

Cited by 52 publications

(31 citation statements)

References 33 publications

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“…LY3023414 is a novel oral PI3K/mTOR dual inhibitor designed for advanced cancer. It has recently completed a phase II clinical trial, 10 which demonstrated modest single-agent activity and a manageable safety profile in treating advanced endometrial cancer. However, little is known about its effect on bone modelling/remodelling, which will help to understand its potential effect on the skeletal system.…”

Section: Discussionmentioning

confidence: 99%

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LY3023414 inhibits both osteogenesis and osteoclastogenesis through the PI3K/Akt/GSK3 signalling pathway

Chen

Aung

et al. 2021

Bone & Joint Research

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Aims LY3023414 is a novel oral phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) dual inhibitor designed for advanced cancers, for which a phase II clinical study was completed in March 2020; however, little is known about its effect on bone modelling/remodelling. In this study, we aimed to explore the function of LY3023414 in bone modelling/remodelling. Methods The function of LY3023414 was explored in the context of osteogenesis (bone formation by osteoblasts) and osteoclastogenesis (osteoclast formation and bone resorption). Murine preosteoblast MC3T3-E1 cell line and murine bone marrow-derived macrophage cells (BMMs) were subjected to different treatments. An MTS cell proliferation assay was used to examine the cytotoxicity. Thereafter, different induction conditions were applied, such as MCSF and RANKL for osteoclastogenesis and osteogenic media for osteogenesis. Specific staining, a bone resorption assay, and quantitative real-time polymerase chain reaction (qRT-PCR) were subsequently used to evaluate the effect of LY3023414. Moreover, small interfering RNA (siRNA) was applied to knockdown Akt1 or Akt2 for further validation. Lastly, western blot was used to examine the exact mechanism of action. Results LY3023414 attenuated PI3K/protein kinase B (Akt)/GSK3-dependent activation of β-catenin and nuclear factor-activated T cell 1 (NFATc1) during osteogenesis and osteoclastogenesis, respectively. LY3023414 mainly inhibited osteoclast formation instead of mature osteoclast function. Moreover, it suppressed osteogenesis both in the early stage of differentiation and late stage of calcification. Similarly, gene knockdown of Akt isoforms by siRNA downregulated osteogenic and osteoclastogenic processes, indicating that Akt1 and Akt2 acted synergistically. Conclusion LY3023414 can suppress osteogenesis and osteoclastogenesis through inhibition of the PI3K/Akt/GSK3 signalling pathway, which highlights the potential benefits and side effects of LY3023414 for future clinical applications. Cite this article: Bone Joint Res 2021;10(4):237–249.

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Section: Discussionmentioning

confidence: 99%

“… 9 LY3023414 subsequently showed modest single-agent activity and a manageable safety profile in treating advanced endometrial cancer in a phase II clinical study in March 2020. 10 Nevertheless, little is known about the function of LY3023414 in bone modelling/remodelling.…”

Section: Introductionmentioning

confidence: 99%

LY3023414 inhibits both osteogenesis and osteoclastogenesis through the PI3K/Akt/GSK3 signalling pathway

Chen

Aung

et al. 2021

Bone & Joint Research

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“…1), and it is an important signaling pathway for MDR in a variety of cancers, such as breast cancer, leukemia, lung cancer, ovarian cancer, hepatocellular carcinoma, and melanoma [7][8][9][10][11][12] . Many types of tumors often carry at least one change in PI3K [13][14][15][16][17] ( Table 1). The MDR phenotype often accompanies activation of the PI3K/AKT pathway, which renders a survival signal to withstand cytotoxic anticancer drugs and enhances cancer stem cell (CSC) characteristics.…”

Section: Introductionmentioning

confidence: 99%

PI3K/AKT pathway as a key link modulates the multidrug resistance of cancers

et al. 2020

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Multidrug resistance (MDR) is the dominant challenge in the failure of chemotherapy in cancers. Phosphatidylinositol 3-kinase (PI3K) is a lipid kinase that spreads intracellular signal cascades and regulates a variety of cellular processes. PI3Ks are considered significant causes of chemoresistance in cancer therapy. Protein kinase B (AKT) is also a significant downstream effecter of PI3K signaling, and it modulates several pathways, including inhibition of apoptosis, stimulation of cell growth, and modulation of cellular metabolism. This review highlights the aberrant activation of PI3K/AKT as a key link that modulates MDR. We summarize the regulation of numerous major targets correlated with the PI3K/AKT pathway, which is further related to MDR, including the expression of apoptosis-related protein, ABC transport and glycogen synthase kinase-3 beta (GSK-3β), synergism with nuclear factor kappa beta (NF-κB) and mammalian target of rapamycin (mTOR), and the regulation of glycolysis.

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“…Stable disease in 58% of patients was the best response reached and the pro-drug was found to be well tolerated [100] . XL765 (SAR245409) was tested in a first-in-human clinical trial to evaluate safety, maximum tolerated dose, PK, PD and efficacy; stable disease was achieved in 48% of patients with evaluable disease, supporting further development of XL765 [132] . Other Phase I clinical trials have since been completed with XL765 in solid tumors, including ovarian cancer, and lymphoma, as a monotherapy (NCT01587040; NCT01596270) or in combination with other agents, e.g., erlotinib (NCT00777699), and letrozole (NCT01082068).…”

Section: Dual Pi3k/mtor Inhibitorsmentioning

confidence: 99%

Targeting the PI3K/AKT/mTOR pathway in epithelial ovarian cancer, therapeutic treatment options for platinum-resistant ovarian cancer

Rinne¹,

Christie²,

Ardasheva³

et al. 2021

CDR

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The survival rates for women with ovarian cancer have shown scant improvement in recent years, with a 5-year survival rate of less than 40% for women diagnosed with advanced ovarian cancer. High-grade serous ovarian cancer (HGSOC) is the most lethal subtype where the majority of women develop recurrent disease and chemotherapy resistance, despite over 70%-80% of patients initially responding to platinum-based chemotherapy. The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway regulates many vital processes such as cell growth, survival and metabolism. However, this pathway is frequently dysregulated in cancers including different subtypes of ovarian cancer, through amplification or somatic mutations of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), amplification of AKT isoforms, or deletion or inactivation of PTEN. Further evidence indicates a role for the PI3K/AKT/mTOR pathway in the development of chemotherapy resistance in ovarian cancer. Thus, targeting key nodes of the PI3K/AKT/mTOR pathway is a potential therapeutic prospect. In this review, we outline dysregulation of PI3K signaling in ovarian cancer, with a particular emphasis on HGSOC and platinum-resistant disease. We review preclinical evidence for inhibitors of the main components of the PI3K pathway and highlight past, current and upcoming trials in ovarian cancers for different inhibitors of the pathway. Whilst no inhibitors of the PI3K/AKT/mTOR pathway have thus far advanced to the clinic for the treatment of ovarian cancer, several

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Phase 2 study of LY3023414 in patients with advanced endometrial cancer harboring activating mutations in the PI3K pathway

Cited by 52 publications

References 33 publications

LY3023414 inhibits both osteogenesis and osteoclastogenesis through the PI3K/Akt/GSK3 signalling pathway

LY3023414 inhibits both osteogenesis and osteoclastogenesis through the PI3K/Akt/GSK3 signalling pathway

PI3K/AKT pathway as a key link modulates the multidrug resistance of cancers

Targeting the PI3K/AKT/mTOR pathway in epithelial ovarian cancer, therapeutic treatment options for platinum-resistant ovarian cancer

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