Phase II study of everolimus and bevacizumab in recurrent ovarian, peritoneal, and fallopian tube cancer

Taylor, S.E.; Chu, Tianjiao; Elvin, Julia A.; Edwards, Robert P.; Zorn, Kristin K.

doi:10.1016/j.ygyno.2019.10.029

Cited by 19 publications

(20 citation statements)

References 31 publications

(18 reference statements)

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“…Currently, several clinical trials, including those testing the combination of everolimus and the VEGF inhibitor bevacizumab, 42,43 are targeting the PI3K/Akt/mTOR pathway. To evaluate the effectiveness of the combined inhibition of Akt/mTOR and MDM2 against CCCs, we evaluated everolimus as a concomitant drug with DS‐3032b.…”

Section: Discussionmentioning

confidence: 99%

Effect of murine double‐minute 2 inhibitors in preclinical models of advanced clear cell carcinomas originating from ovaries and kidneys

et al. 2020

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Section: Discussionmentioning

confidence: 99%

Effect of murine double‐minute 2 inhibitors in preclinical models of advanced clear cell carcinomas originating from ovaries and kidneys

et al. 2020

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“…More recently capivasertib has been tested in a Phase I trial in combination with the PARP inhibitor olaparib for multiple solid tumors (NCT02338622) based on preclinical studies demonstrating synergy between PARP and PI3K/AKT pathway inhibitors in BRCA1/2 deficient and proficient tumors. In the 64 patients enrolled (n = 25 ovarian) capivasertib was well tolerated, overall 44.6% of patients achieved clinical benefit (RECIST1.1 complete response/partial response or stable disease > 4 months), 44% of ovarian patients had a median duration of response of 26.6 weeks (11.3-115), and 8/11 platinum resistant ovarian cancer patients showed clinical benefit [72] . In general, several AKT inhibitors are well tolerated and continue to be investigated both in vitro and in clinical trials in multiple advanced solid tumors.…”

Section: Akt Inhibitorsmentioning

confidence: 97%

“…A greater understanding of the effects of PI3K pathway inhibitors on the different aspects of the tumor microenvironment is also required, which could open up new avenues for combination treatments with immunotherapies. Positive findings have been observed for PI3Kα or AKT inhibitors in combination with olaparib treatment for recurrent and platinum-resistant ovarian cancer patients [72,93] , and further combinations with DDR therapeutics warrant investigation in these patient cohorts. It is becoming increasingly evident that PI3K/AKT/mTOR pathway inhibitors, particularly in combination with other chemotherapeutic and/or targeted therapies, may hold significant promise for the future treatment and outcomes of women with chemotherapy-resistant ovarian cancer.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 98%

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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“…Three other responders had serous ovarian cancer with mutations in the homologous recombination pathway. It was noted that the two OCCC were among the patients staying on treatment for the longest with 11 and 15 cycles of treatment respectively (141). Although the combination of bevacizumab plus everolimus, compared to bevacizumab alone, did not improve PFS or OS in recurrent or persistent ovarian, fallopian tube or peritoneal carcinoma in a randomized Phase II trial (142), these observations indicate a possible benefit in certain subgroups such as ARID1A mutated OCCC.…”

Section: Current Clinical Trialsmentioning

confidence: 99%

Endometriosis-associated ovarian carcinomas: insights into pathogenesis, diagnostics, and therapeutic targets—a narrative review

Samartzis¹,

Labidi-Galy²,

Moschetta³

et al. 2020

Ann Transl Med

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Endometriosis is a benign gynecologic condition affecting up to one woman out of ten of reproductive age. It is defined by the presence of endometrial-like tissue in localizations outside of the uterine cavity. It often causes symptoms such as chronic pain, most frequently associated with the menstrual cycle, and infertility, but may also be oligo-or asymptomatic. There is evidence that some ovarian carcinoma (OC) histotypes, mainly the ovarian clear cell (OCCC) and endometrioid (EnOC) carcinoma, may arise from endometriosis. The most frequent genomic alterations in these carcinomas are mutations in the AT-rich interacting domain containing protein 1A (ARID1A) gene, a subunit of the SWI/SNF chromatin remodeling complex, and alterations in the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway, which frequently co-occur. In ARID1A deficient cancers preclinical experimental data suggest different targetable mechanisms including epigenetic regulation, cell cycle, genomic instability, the PI3K/AKT/mTOR pathway, inflammatory pathways, immune modulation, or metabolic alterations as potential precision oncology approaches. Most of these strategies are relying on the concept of synthetic lethality in which tumors deficient in ARID1A are more sensitive to the different compounds. Some of these approaches are currently being or have recently been investigated in early clinical trials. The remarkably frequent occurrence of these mutations in endometriosisassociated ovarian cancer, the occurrence in a relatively young population, and the high proportion of platinumresistant disease certainly warrants further investigation of precision oncology opportunities in this population. Furthermore, advanced knowledge about oncogenic mutations involved in endometriosis-associated ovarian carcinomas may be potentially useful for early cancer detection. However, this approach may be complicated by the frequent occurrence of somatic mutations in benign endometriotic tissue as recent studies suggest. In this narrative review of the current literature, we will discuss the data available on endometriosis-associated ovarian carcinoma, with special emphasis on epidemiology, diagnosis and molecular changes that could have therapeutic implications and clinical applicability in the future.

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Phase II study of everolimus and bevacizumab in recurrent ovarian, peritoneal, and fallopian tube cancer

Cited by 19 publications

References 31 publications

Effect of murine double‐minute 2 inhibitors in preclinical models of advanced clear cell carcinomas originating from ovaries and kidneys

Effect of murine double‐minute 2 inhibitors in preclinical models of advanced clear cell carcinomas originating from ovaries and kidneys

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

Endometriosis-associated ovarian carcinomas: insights into pathogenesis, diagnostics, and therapeutic targets—a narrative review

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