Phase 2 trial of everolimus and letrozole in relapsed estrogen receptor-positive high-grade ovarian cancers

Colón‐Otero, Gerardo; Weroha, S. John; Foster, Nathan R.; Haluska, Paul; Hou, Xiaonan; Wahner-Hendrickson, Andrea E.; Jatoi, Aminah; Block, Matthew S.; Dinh, Tri A.; Robertson, Matthew; Copland, John A.

doi:10.1016/j.ygyno.2017.04.020

Cited by 42 publications

(31 citation statements)

References 33 publications

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“…So, some studies turned to reveal the clinical usage of drugs that affect Ras downstream signaling. For instance, temsirolimus (CCI-779) and everolimus (RAD-001), the drugs for inhibiting PI3K/AKT/mTOR signaling [35,36], are in trials at present. A better understanding of Ras-AKT signaling will be helpful for the development of antitumor drugs.…”

Section: Discussionmentioning

confidence: 99%

Ras-AKT signaling represses the phosphorylation of histone H1.5 at threonine 10 via GSK3 to promote the progression of glioma

Sang

Sun

Yang

et al. 2019

Artificial Cells, Nanomedicine, and Biotechnology

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Section: Discussionmentioning

confidence: 99%

Ras-AKT signaling represses the phosphorylation of histone H1.5 at threonine 10 via GSK3 to promote the progression of glioma

Sang

Sun

Yang

et al. 2019

Artificial Cells, Nanomedicine, and Biotechnology

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“…Our study also demonstrates a relatively high rate of successful PDX models from biopsy specimens (47%), confirming our previous findings in OC and extending them to EC. 35 The success of engraftment is determined largely by the amount of tissue available; therefore, it is higher when tissue is obtained from surgical procedures (74%). 21 Coclinical trials with PDX models have been proposed as a tool to discover mechanisms of resistance to therapies that could be used to adjust therapy for the patient from whom the PDX was derived.…”

Section: Discussionmentioning

confidence: 99%

Phase II trial of ribociclib and letrozole in patients with relapsed oestrogen receptor-positive ovarian or endometrial cancers

et al. 2020

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ObjectiveWe describe a phase II clinical trial of the combination of ribociclib and letrozole for treatment of relapsed oestrogen receptor (ER)-positive ovarian cancer (OC) and endometrial cancer (EC). The primary endpoint was the proportion of patients alive, progression-free survival (PFS), and still on treatment at 12 weeks (PFS12), with 45% or greater considered positive.MethodsPatients with measurable, relapsed ER-positive OC or EC (platinum-sensitive or resistant) were eligible and treated with 400 mg of oral ribociclib and 2.5 mg of oral letrozole daily. Patient-derived xenografts (PDXs) were created from imaging-guided tumour biopsies.ResultsForty patients (20 OC and 20 EC) were enrolled. A PFS12 of 55% was observed in the EC cohort and 50% in the OC cohort. A PFS greater or equal to 24 weeks (PFS24) was seen in 20% (4/20) of the OC cohort and 35% (7/20) of the EC cohort. The greatest benefit was seen in low-grade serous OC (LGSOC) (3/3, 100% PFS24) and grades 1 and 2 EC (5/11, 45% PFS24). All three LGSOC patients obtained at least a partial response lasting for over 2 years, with two of the three patients still on treatment. PDX tumour engraftment was feasible in 45% of patients. Positive survival effects of the combination of ribociclib and letrozole were observed in two of three EC PDX models.ConclusionRibociclib and letrozole have promising clinical activity in relapsed ER-positive OC and EC, particularly in LGSOC and relapsed ER-positive grade 1 and 2 EC. Generation of PDX models is feasible with positive survival effects observed in EC models.Trial registration numberClinicalTrials.gov registry (NCT02657928).

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“…In vitro, sirolimus inhibits cancer cell growth, promotes G1 cell cycle arrest, and enhances cytotoxic effects in combination with other agents [228][229][230][231]. Sirolimus is clinically often used in renal transplantations and for the treatment of a rare lung disease called lymphangioleiomyomatosis (LAM) but has also been investigated for the treatment of solid tumors and hematological malignancies [184,[232][233][234][235].…”

Section: Sirolimusmentioning

confidence: 99%

Targeting PI3K/Akt/mTOR in AML: Rationale and Clinical Evidence

Darici

Alkhaldi

Horne

et al. 2020

JCM

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Acute myeloid leukemia (AML) is a highly heterogeneous hematopoietic malignancy characterized by excessive proliferation and accumulation of immature myeloid blasts in the bone marrow. AML has a very poor 5-year survival rate of just 16% in the UK; hence, more efficacious, tolerable, and targeted therapy is required. Persistent leukemia stem cell (LSC) populations underlie patient relapse and development of resistance to therapy. Identification of critical oncogenic signaling pathways in AML LSC may provide new avenues for novel therapeutic strategies. The phosphatidylinositol-3-kinase (PI3K)/Akt and the mammalian target of rapamycin (mTOR) signaling pathway, is often hyperactivated in AML, required to sustain the oncogenic potential of LSCs. Growing evidence suggests that targeting key components of this pathway may represent an effective treatment to kill AML LSCs. Despite this, accruing significant body of scientific knowledge, PI3K/Akt/mTOR inhibitors have not translated into clinical practice. In this article, we review the laboratory-based evidence of the critical role of PI3K/Akt/mTOR pathway in AML, and outcomes from current clinical studies using PI3K/Akt/mTOR inhibitors. Based on these results, we discuss the putative mechanisms of resistance to PI3K/Akt/mTOR inhibition, offering rationale for potential candidate combination therapies incorporating PI3K/Akt/mTOR inhibitors for precision medicine in AML.

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Phase 2 trial of everolimus and letrozole in relapsed estrogen receptor-positive high-grade ovarian cancers

Cited by 42 publications

References 33 publications

Ras-AKT signaling represses the phosphorylation of histone H1.5 at threonine 10 via GSK3 to promote the progression of glioma

Ras-AKT signaling represses the phosphorylation of histone H1.5 at threonine 10 via GSK3 to promote the progression of glioma

Phase II trial of ribociclib and letrozole in patients with relapsed oestrogen receptor-positive ovarian or endometrial cancers

Targeting PI3K/Akt/mTOR in AML: Rationale and Clinical Evidence

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