scholarly journals Combination therapy for treating breast cancer using antiestrogen, ERA-923, and the mammalian target of rapamycin inhibitor, temsirolimus

2006 ◽  
Vol 13 (3) ◽  
pp. 863-873 ◽  
Author(s):  
T M Sadler ◽  
M Gavriil ◽  
T Annable ◽  
P Frost ◽  
L M Greenberger ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Mammalian Target Of Rapamycin ◽  
Xenograft Model ◽  
Metastatic Breast ◽  
Estrogen Receptor Α ◽  
Phase Iii ◽  
Target Of Rapamycin ◽  
G1 Arrest ◽  
Wide Range

The effect of combinations of a mammalian target of rapamycin (mTOR) inhibitor, temsirolimus, and an estrogen receptor-α (ERα) antagonist, ERA-923, on breast carcinoma in culture and in a xenograft model has been studied. Phase III trials are underway using temsirolimus for several cancers. ERA-923 was studied in a phase I trial for tamoxifen refractory metastatic breast cancer and was shown to have good safety profiles. Combination of noninhibitory doses of temsirolimus with suboptimal doses of ERA-923 synergistically inhibited the growth of MCF-7 cells. Synergy was found across a wide range of doses and could also be achieved by combining temsirolimus with other antiestrogens such as raloxifene and 4-hydroxytamoxifen. In vivo combination of temsirolimus and ERA-923 at certain doses and schedules completely inhibited tumor growth, while individual agents were only partially effective. Although the mechanism underlying the synergism remains to be understood, the results were associated with the ability of temsirolimus to block the transcriptional activity mediated by ERα as well as an increase in G1 arrest when it was combined with ERA-923. Results demonstrated for the first time that the combination of temsirolimus and a pure antiestrogen has excellent anticancer activity in preclinical models and, therefore, may have clinical use in treating hormone-dependent tumors.

Current perspectives on aromatase inhibitors in breast cancer.

1994 ◽  
Vol 12 (11) ◽  
pp. 2460-2470 ◽  
Author(s):  
P E Goss ◽  
K M Gwyn
Keyword(s):  
Breast Cancer ◽  
Aromatase Inhibitors ◽  
Metastatic Breast ◽  
Phase Iii ◽  
Future Application ◽  
In Vivo Experiments ◽  
Estrogen Production ◽  
New Generation

PURPOSE AND DESIGN: One way to deprive hormone-dependent breast cancer of estrogen is to prevent its synthesis. This is achievable by inhibiting the aromatase cytochrome P-450 (P-450arom) enzyme complex responsible for the ultimate step in estrogen production. A new generation of specific and selective aromatase inhibitors is currently under investigation. The purpose of this review is to outline the preclinical test systems for screening these inhibitors, to summarize the preclinical and clinical data published to date, and to discuss the future application of these inhibitors in the management of breast cancer. RESULTS AND CONCLUSION: Disadvantages to the use of earlier inhibitors are described. In vitro and in vivo experiments that reflect the potency and selectivity of new inhibitors are highlighted. From preliminary clinical trials, these inhibitors appear to have excellent pharmacokinetic profiles and produce few side effects when administered orally. Activity against postmenopausal metastatic breast cancer has been demonstrated for the agents reviewed. They are all now in phase III testing to determine their relative efficacy in this setting. Their application in combination with both hormone therapy and chemotherapy, in premenopausal metastatic disease, and in the adjuvant setting in both premenopausal and postmenopausal women remains to be defined.

scholarly journals Managing advanced HR-positive, HER2-negative breast cancer with CDK4/6 inhibitors in post-menopausal patients: is there a best sequence?

2018 ◽  
Vol 10 ◽  
pp. 175883591881559 ◽  
Author(s):  
Lorenzo Rossi ◽  
Amelia McCartney ◽  
Emanuela Risi ◽  
Luca Malorni ◽  
Laura Biganzoli ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Mammalian Target Of Rapamycin ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Therapeutic Landscape ◽  
Wide Range ◽  
Epidermal Growth ◽  
Post Menopausal ◽  
Complex Scenario

The current therapeutic landscape of luminal human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (mBC) is fundamentally evolving, particularly in the advent of molecularly targeted therapies, such as inhibitors of mammalian target of rapamycin and cyclin-dependent kinase 4/6 (CDK4/6). In the context of CDK4/6 inhibitors, landmark clinical trials for palbociclib (PALOMA-1, PALOMA-2, PALOMA-3), ribociclib (MONALEESA-2, MONALEESA-3, MONALEESA-7) and abemaciclib (MONARCH-1, MONARCH-2, MONARCH-3) have provided solid data regarding progression-free survival and overall response rate, justifying the introduction of this class of drugs into our therapeutic armoury. However, several clinical questions remain open. One of the most relevant issues faced in practice is that of the optimum sequencing of CDK4/6 inhibitors, particularly given the wide range of therapeutic options open to clinicians treating luminal mBC. In this brief commentary, we would like to focus on the best sequence for CDK4/6 inhibitors and their place in this growing, complex scenario.

Phase III Study of N,N-Diethyl-2-[4-(Phenylmethyl) Phenoxy]Ethanamine (BMS-217380-01) Combined With Doxorubicin Versus Doxorubicin Alone in Metastatic/Recurrent Breast Cancer: National Cancer Institute of Canada Clinical Trials Group Study MA.19

2004 ◽  
Vol 22 (2) ◽  
pp. 269-276 ◽  
Author(s):  
Leonard Reyno ◽  
Lesley Seymour ◽  
Dongsheng Tu ◽  
Susan Dent ◽  
Karen Gelmon ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Recurrent Breast Cancer ◽  
Phase Iii ◽  
Metastatic Breast Carcinoma ◽  
Significant Difference ◽  
Recurrent Breast

Purpose N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine (DPPE; tesmilifene) is a novel agent that augments chemotherapy cytotoxicity in vitro and in vivo. A phase II trial combining DPPE and doxorubicin (DOX) in metastatic breast carcinoma showed increased response over that expected with DOX. We report a phase III trial comparing DOX with DPPE plus DOX in metastatic or recurrent breast cancer. Patients and Methods Anthracycline-naive women with measurable metastatic disease were randomly assigned to receive, every 21 days, either DOX 60 mg/m2 intravenously or DOX during the last 20 minutes of an 80-minute infusion of DPPE (5.3 mg/kg), in both cases to cumulative DOX doses of 450 mg/m2. Patients receiving DPPE were aggressively premedicated to ameliorate toxicity. End points included progression-free survival (PFS), response rate (RR), and response duration (RD), quality of life (QOL), toxicity, and overall survival (OS). Results A planned interim analysis failed to detect an RR difference more than 5%. The study was closed to additional accrual and all DPPE was discontinued. The final analysis was conducted as planned after 256 progression events (median follow-up, 20.5 months). There was no significant difference in RR, RD, or PFS between arms. DPPE plus DOX was statistically superior to DOX in OS (hazard ratio, 0.66; 95% CI, 0.48 to 0.91; P = .021). DPPE plus DOX was associated with more gastrointestinal and CNS toxicity. No consistent influence on QOL was detected. Conclusion This study demonstrated no advantage in RR, RD, or PFS but significantly superior OS for DPPE plus DOX. Additional studies of DPPE are warranted.

scholarly journals Therapy options after CDK4/6 inhibitors for HR+, HER2- postmenopausal metastatic/recurrent breast cancer in Japan: a role for mammalian target of rapamycin inhibitors?

2020 ◽  
Author(s):  
Takahiro Nakayama ◽  
Fumie Fujisawa
Keyword(s):  
Breast Cancer ◽  
Large Scale ◽  
Current Knowledge ◽  
Treatment Options ◽  
Mammalian Target Of Rapamycin ◽  
Metastatic Breast ◽  
Basic Research ◽  
Target Of Rapamycin ◽  
Real World Data ◽  
Randomized Controlled Studies

Despite advances in the treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer, the disease is rarely curable. In this review, we focus on the use of cyclin-dependent kinase (CDK) 4/6 inhibitors, examining clinical experience and the mechanisms underlying the development of resistance, and evaluating treatment options after failure to respond to CDK4/6 inhibitors. Current basic research supports the use of mammalian target of rapamycin inhibitors after CDK4/6 inhibitor failure; however, more data are needed, particularly regarding treatment sequencing. Real-world data studies may help to fill the current knowledge gap, particularly where large-scale randomized controlled studies are not feasible.

scholarly journals Bnip3 Mediates the Hypoxia-induced Inhibition on Mammalian Target of Rapamycin by Interacting with Rheb

2007 ◽  
Vol 282 (49) ◽  
pp. 35803-35813 ◽  
Author(s):  
Yong Li ◽  
Yian Wang ◽  
Eunjung Kim ◽  
Peter Beemiller ◽  
Cun-Yu Wang ◽  
...  
Keyword(s):  
Cell Growth ◽  
Energy Levels ◽  
Mammalian Target Of Rapamycin ◽  
Small Gtpase ◽  
Mtor Pathway ◽  
Target Of Rapamycin ◽  
Intracellular Signals ◽  
Central Controller ◽  
Wide Range

The mammalian target of rapamycin (mTOR) is a central controller of cell growth, and it regulates translation, cell size, cell viability, and cell morphology. mTOR integrates a wide range of extracellular and intracellular signals, including growth factors, nutrients, energy levels, and stress conditions. Rheb, a Ras-related small GTPase, is a key upstream activator of mTOR. In this study, we found that Bnip3, a hypoxia-inducible Bcl-2 homology 3 domain-containing protein, directly binds Rheb and inhibits the mTOR pathway. Bnip3 decreases Rheb GTP levels in a manner depending on the binding to Rheb and the presence of the N-terminal domain. Both knockdown and overexpression experiments show that Bnip3 plays an important role in mTOR inactivation in response to hypoxia. Moreover, Bnip3 inhibits cell growth in vivo by suppressing the mTOR pathway. These observations demonstrate that Bnip3 mediates the inhibition of the mTOR pathway in response to hypoxia.

scholarly journals Edelfosine nanoemulsions inhibit tumor growth of triple negative breast cancer in zebrafish xenograft model

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sofia M. Saraiva ◽  
Carlha Gutiérrez-Lovera ◽  
Jeannette Martínez-Val ◽  
Sainza Lores ◽  
Belén L. Bouzo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Xenograft Model ◽  
Skin Barrier ◽  
Zebrafish Embryos ◽  
Biorelevant Media

AbstractTriple negative breast cancer (TNBC) is known for being very aggressive, heterogeneous and highly metastatic. The standard of care treatment is still chemotherapy, with adjacent toxicity and low efficacy, highlighting the need for alternative and more effective therapeutic strategies. Edelfosine, an alkyl-lysophospholipid, has proved to be a promising therapy for several cancer types, upon delivery in lipid nanoparticles. Therefore, the objective of this work was to explore the potential of edelfosine for the treatment of TNBC. Edelfosine nanoemulsions (ET-NEs) composed by edelfosine, Miglyol 812 and phosphatidylcholine as excipients, due to their good safety profile, presented an average size of about 120 nm and a neutral zeta potential, and were stable in biorelevant media. The ability of ET-NEs to interrupt tumor growth in TNBC was demonstrated both in vitro, using a highly aggressive and invasive TNBC cell line, and in vivo, using zebrafish embryos. Importantly, ET-NEs were able to penetrate through the skin barrier of MDA-MB 231 xenografted zebrafish embryos, into the yolk sac, leading to an effective decrease of highly aggressive and invasive tumoral cells’ proliferation. Altogether the results demonstrate the potential of ET-NEs for the development of new therapeutic approaches for TNBC.

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