Phase Ib study of gedatolisib in combination with palbociclib and endocrine therapy (ET) in women with estrogen receptor (ER) positive (+) metastatic breast cancer (MBC) (B2151009).

Forero‐Torres, Andres; Han, Heather; Dees, Elizabeth Claire; Wesolowski, Robert; Bardia, Aditya; Kabos, Peter; Layman, Rachel M.; Lu, Janice; Kern, Kenneth A.; Perea, Rachelle; Pierce, Kristen J.; Houk, Brett E.; Pathan, Nuzhat; Rugo, Hope S.

doi:10.1200/jco.2018.36.15_suppl.1040

Cited by 12 publications

(10 citation statements)

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“…There are some ongoing clinical trials to evaluate the safety and efficacy of CDK4/6 and PI3K/AKT dual inhibition. Palbociclib with PI3K/mTOR inhibitor PF-05212384 in patients with estrogen receptor positive (ER+) metastatic breast cancer reported promising preliminary anti-tumor activity with manageable toxicities [ 39 ]. Palbociclib and PI3K inhibitor, taselisib, combination treatment in patients with PIK3CA mutated advanced breast cancer revealed clinical benefit with tolerable toxicities [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

PI3K p110α Blockade Enhances Anti-Tumor Efficacy of Abemaciclib in Human Colorectal Cancer Cells

Lee

Kim

Sung

et al. 2020

Cancers

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Targeting cell cycle regulation in colorectal cancer has not been fully evaluated. We investigated the efficacy of the CDK4/6 inhibitor, abemaciclib, and confirmed a synergistic interaction for PI3K p110α and CDK dual inhibition in colorectal cancer cell lines. Caco-2 and SNU-C4 cell lines were selected to explore the mechanism of action for and resistance to abemaciclib. In vitro and in vivo models were used to validate the anti-tumor activity of abemaciclib monotherapy and BYL719 combination therapy. Abemaciclib monotherapy inhibited cell cycle progression and proliferation in Caco-2 and SNU-C4 cells. CDK2-mediated Rb phosphorylation and AKT phosphorylation appeared to be potential resistance mechanisms to abemaciclib monotherapy. Abemaciclib/BYL719 combination therapy demonstrated synergistic effects regardless of PIK3CA mutation status but showed greater efficacy in the PIK3CA mutated SNU-C4 cell line. Growth inhibition, cell cycle arrest, and migration inhibition were confirmed as mechanisms of action for this combination. In an SNU-C4 mouse xenograft model, abemaciclib/BYL719 combination resulted in tumor growth inhibition and apoptosis with tolerable toxicity. Dual blockade of PI3K p110α and CDK4/6 showed synergistic anti-tumor effects in vivo and in vitro in human colorectal cancer cell lines. This combination could be a promising candidate for the treatment of patients with advanced colorectal cancer.

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Section: Discussionmentioning

confidence: 99%

PI3K p110α Blockade Enhances Anti-Tumor Efficacy of Abemaciclib in Human Colorectal Cancer Cells

Lee

Kim

Sung

et al. 2020

Cancers

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“…Gedatolisib combined with either palbociclib/letrozole or palbociclib/fulvestrant showed manageable toxicity and promising antitumor activity. Further analysis on dose escalation is being completed and dose expansion is ongoing [ 135 ]. Whether the effect of this class of agents in combination with immunotherapy can lead to further clinical benefit is an open issue.…”

Section: Currently Available Inhibitors Acting On Akt and Mtor In Breast Cancermentioning

confidence: 99%

Targeting PI3K/AKT/mTOR Signaling Pathway in Breast Cancer

Prever

Hirsch

et al. 2021

Cancers

103

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Breast cancer is the most frequently diagnosed cancer and the primary cause of cancer death in women worldwide. Although early diagnosis and cancer growth inhibition has significantly improved breast cancer survival rate over the years, there is a current need to develop more effective systemic treatments to prevent metastasis. One of the most commonly altered pathways driving breast cancer cell growth, survival, and motility is the PI3K/AKT/mTOR signaling cascade. In the past 30 years, a great surge of inhibitors targeting these key players has been developed at a rapid pace, leading to effective preclinical studies for cancer therapeutics. However, the central role of PI3K/AKT/mTOR signaling varies among diverse biological processes, suggesting the need for more specific and sophisticated strategies for their use in cancer therapy. In this review, we provide a perspective on the role of the PI3K signaling pathway and the most recently developed PI3K-targeting breast cancer therapies.

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“…Several clinical studies are ongoing to explore their efficacy in breast cancer. Gedatolisib is being tested in treatment for metastatic TNBC and ER + patients (Forero-Torres et al, 2018;Radovich et al, 2018).…”

Section: The Clinical Development Of Pi3k Inhibitors: Efficacy Resistance and Toxicitymentioning

confidence: 99%

The Role of PI3K Inhibition in the Treatment of Breast Cancer, Alone or Combined With Immune Checkpoint Inhibitors

Zhang

Richmond

2021

Front. Mol. Biosci.

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Dysregulation of phosphoinositide 3-kinase (PI3K) signaling is highly implicated in tumorigenesis, disease progression, and the development of resistance to the current standard of care treatments in breast cancer patients. This review discusses the role of PI3K pathway in breast cancer and evaluates the clinical development of PI3K inhibitors in both early and metastatic breast cancer settings. Further, this review examines the evidence for the potential synergistic benefit for the combination treatment of PI3K inhibition and immunotherapy in breast cancer treatment.

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Phase Ib study of gedatolisib in combination with palbociclib and endocrine therapy (ET) in women with estrogen receptor (ER) positive (+) metastatic breast cancer (MBC) (B2151009).

Cited by 12 publications

References 0 publications

PI3K p110α Blockade Enhances Anti-Tumor Efficacy of Abemaciclib in Human Colorectal Cancer Cells

PI3K p110α Blockade Enhances Anti-Tumor Efficacy of Abemaciclib in Human Colorectal Cancer Cells

Targeting PI3K/AKT/mTOR Signaling Pathway in Breast Cancer

The Role of PI3K Inhibition in the Treatment of Breast Cancer, Alone or Combined With Immune Checkpoint Inhibitors

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