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European Endocrinology Mar 2013Hormonal therapies such as progestins have only modest activity in the treatment of advanced endometrial cancer. Mechanisms of resistance to progestin therapy are not... (Review)
Review
Hormonal therapies such as progestins have only modest activity in the treatment of advanced endometrial cancer. Mechanisms of resistance to progestin therapy are not well understood. However, activation of the PI3K/AKT/mammalian target of rapamycin (mTOR) pathway has been associated with resistance to hormonal therapy and alterations in components of the PI3K/AKT/mTOR pathway, including inactivating mutations in PTEN, activating mutations in PIK3CA and mutations in PIK3R1, are very common in endometrial carcinomas. mTOR inhibitors, including temsirolimus, everolimus and ridaforolimus, are also known to be active against endometrial cancer, and interest has been stimulated in combinations of hormonal treatment with mTOR inhibitors, as both therapies have single-agent activity, and it is hypothesised that mTOR inhibition would enhance sensitivity to hormonal therapy.
PubMed: 30349605
DOI: 10.17925/EE.2013.09.01.18 -
British Journal of Cancer Mar 2013This open-label, multicentre, phase 2 trial evaluated the efficacy and tolerability of the mammalian target of rapamycin inhibitor ridaforolimus in women with advanced...
BACKGROUND
This open-label, multicentre, phase 2 trial evaluated the efficacy and tolerability of the mammalian target of rapamycin inhibitor ridaforolimus in women with advanced endometrial cancer.
METHODS
Women with measurable recurrent or persistent endometrial cancer and documented disease progression were treated with ridaforolimus 12.5 mg intravenously once daily for 5 consecutive days every 2 weeks in a 4-week cycle. The primary end point was clinical benefit response, defined as an objective response or prolonged stable disease of 16 weeks or more.
RESULTS
In all, 45 patients were treated with single-agent ridaforolimus. Clinical benefit was achieved by 13 patients (29%), including 5 (11%) with confirmed partial responses and 8 (18%) with prolonged stable disease. All patients with clinical benefit response received ridaforolimus for more than 4 months. In this heavily pretreated population, the 6-month progression-free survival was 18%. Ridaforolimus was generally well tolerated: adverse events were predictable and manageable, consistent with prior studies in other malignancies. Overall, the most common adverse events were diarrhoea (58%) and mouth sores (56%); most common grade 3 or higher adverse events were anaemia (27%) and hyperglycaemia (11%).
CONCLUSION
Single-agent ridaforolimus has antitumor activity and acceptable tolerability in advanced endometrial cancer patients. Further clinical evaluation of ridaforolimus is warranted.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Disease-Free Survival; Drug Administration Schedule; Endometrial Neoplasms; Female; Humans; Middle Aged; Retreatment; Sirolimus; TOR Serine-Threonine Kinases
PubMed: 23403817
DOI: 10.1038/bjc.2013.59 -
Translational Oncology Dec 2012Activation of the phosphoinositide 3-kinase pathway is commonly observed in human prostate cancer. Loss of function of phosphatase and tensin homolog (PTEN) is...
Activation of the phosphoinositide 3-kinase pathway is commonly observed in human prostate cancer. Loss of function of phosphatase and tensin homolog (PTEN) is associated with the activation of AKT and mammalian target of rapamycin (mTOR) in many cancer cell lines as well as in other model systems. However, activation of mTOR is also dependent of kinases other than AKT. Here, we show that activation of mTOR is not dependent on AKT in a prostate-specific PTEN-deficient mouse model of prostate cancer. Pathway bifurcation of AKT and mTOR was noted in both mouse and human prostate tumors. We demonstrated for the first time that cotargeting mTOR and AKT with ridaforolimus/MK-8669 and M1K-2206, respectively, delivers additive antitumor effects in vivo when compared to single agents. Our preclinical data suggest that the combination of AKT and mTOR inhibitors might be more effective in treating prostate cancer patients than current treatment regimens or either treatment alone.
PubMed: 23323157
DOI: 10.1593/tlo.12241 -
Oncology & Hematology Review 2013Hormonal therapies such as progestins have only modest activity in the treatment of advanced endometrial cancer. Mechanisms of resistance to progestin therapy are not...
Hormonal therapies such as progestins have only modest activity in the treatment of advanced endometrial cancer. Mechanisms of resistance to progestin therapy are not well understood. However, activation of the PI3K/AKT/mTOR pathway has been associated with resistance to hormonal therapy and alterations in components of the PI3K/AKT/mTOR pathway, including inactivating mutations in PTEN, activating mutations in PIK3CA, and mutations in PIK3R1, are very common in endometrial carcinomas. mTOR inhibitors, including temsirolimus, everolimus, and ridaforolimus, are also known to be active against endometrial cancer, and interest has been stimulated in combinations of hormonal treatment with mTOR inhibitors, as both therapies have single-agent activity, and it is hypothesized that mTOR inhibition would enhance sensitivity to hormonal therapy.
PubMed: 25431800
DOI: 10.17925/ohr.2013.09.1.41 -
Annals of Oncology : Official Journal... Apr 2013Ridaforolimus is an inhibitor of mTOR with evidence of antitumor activity in an I.V. formulation. This multicenter, open-label, 3 + 3 design nonrandomized,...
Phase I/IIa trial of the mammalian target of rapamycin inhibitor ridaforolimus (AP23573; MK-8669) administered orally in patients with refractory or advanced malignancies and sarcoma.
BACKGROUND
Ridaforolimus is an inhibitor of mTOR with evidence of antitumor activity in an I.V. formulation. This multicenter, open-label, 3 + 3 design nonrandomized, dose-escalation, phase I/IIa trial was conducted to determine the safety, pharmacokinetic (PK) and pharmacodynamic parameters, maximum tolerated dose, and antitumor activity of oral ridaforolimus.
PATIENTS AND METHODS
Patients with metastatic or unresectable solid tumors refractory to therapy were eligible. Seven different continuous and intermittent dosing regimens were examined.
RESULTS
One hundred and forty-seven patients were enrolled in this study among which 85 were patients with sarcoma. Stomatitis was the most common DLT observed. The dosing regimen, 40 mg QD × 5 days/week, provided the best combination of cumulative dose, dose density, and cumulative exposure, and was the recommended dosing regimen for subsequent clinical development. PK was nonlinear, with less than proportional increases in day-1 blood AUC0-∞ and Cmax, particularly with doses >40 mg. The terminal half-life estimate of ridaforolimus (QD × 5 40 mg) was 42.0 h, and the mean half-life ∼30-60 h. The clinical benefit rate, (complete response, partial response, or stable disease for ≥4 months was 24.5% for all patients and 27.1% for patients with sarcoma.
CONCLUSION
Oral ridaforolimus had an acceptable safety profile and exhibited antitumor activity in patients with sarcoma and other malignancies. ClinicalTrials.gov Identifier NCT00112372.
Topics: Adult; Aged; Aged, 80 and over; Animals; Drug Administration Schedule; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Neoplasms; Sarcoma; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome
PubMed: 23211938
DOI: 10.1093/annonc/mds602 -
OncoTargets and Therapy 2012Sarcomas of soft tissue and bone are a rare group of cancers hallmarked by relative insensitivity to cytotoxic chemotherapy. The development of targeted therapies in the...
Sarcomas of soft tissue and bone are a rare group of cancers hallmarked by relative insensitivity to cytotoxic chemotherapy. The development of targeted therapies in the treatment of sarcoma has been difficult due to the significant heterogeneity and rarity of these diseases. Inhibition of the mammalian target of rapamycin (mTOR) has emerged as an exciting treatment approach and is being studied extensively in sarcoma patients. Ridaforolimus is a second generation mTOR inhibitor that has shown potential benefit in the treatment of sarcoma. Recently a Phase III study demonstrated an improvement in progression-free survival when patients with at least stable disease after treatment with standard chemotherapy received maintenance ridaforolimus compared to placebo. The results of this study show that mTOR is an important pathway in soft tissue and bone sarcomas and represents an exciting opportunity for the improvement in the treatment of our patients.
PubMed: 22942649
DOI: 10.2147/OTT.S19055 -
Cancer Chemotherapy and Pharmacology Oct 2012This dedicated QTc study was designed to evaluate the effect of the mammalian target of rapamycin inhibitor, ridaforolimus, on the QTc interval in patients with advanced...
PURPOSE
This dedicated QTc study was designed to evaluate the effect of the mammalian target of rapamycin inhibitor, ridaforolimus, on the QTc interval in patients with advanced malignancies.
METHODS
We conducted a fixed-sequence, single-blind, placebo-controlled study. Patients (n = 23) received placebo on day 1 and a single 100-mg oral dose of ridaforolimus on day 2 in the fasted state. Holter electrocardiogram (ECG) monitoring was performed for 24 h after each treatment, and blood ridaforolimus concentrations were measured for 24 h after dosing. The ECGs were interpreted in a blinded fashion, and the QT interval was corrected using Fridericia's formula (QTcF). After a washout of at least 5 days, 22 patients went on to receive a therapeutic regimen of ridaforolimus (40 mg orally once daily for 5 days per week).
RESULTS
The upper limit of the two-sided 90 % confidence interval for the placebo-adjusted mean change from baseline in QTcF was <10 ms at each time point. No patient had a QTcF change from baseline >30 ms or QTcF interval >480 ms. Geometric mean exposure to ridaforolimus after the single 100-mg dose was comparable to previous experience with the therapeutic regimen. There appeared to be no clear relationship between individual QTcF change from baseline and ridaforolimus blood concentrations. Ridaforolimus was generally well tolerated, with adverse events consistent with prior studies.
CONCLUSIONS
Administration of the single 100-mg dose of ridaforolimus did not cause a clinically meaningful prolongation of QTcF, suggesting that patients treated with ridaforolimus have a low likelihood of delayed ventricular repolarization.
Topics: Adult; Aged; Electrocardiography; Female; Humans; Male; Middle Aged; Neoplasms; Single-Blind Method; Sirolimus; TOR Serine-Threonine Kinases
PubMed: 22878520
DOI: 10.1007/s00280-012-1942-7 -
Cancer Research Sep 2012Although the prognosis for clinically localized prostate cancer is now favorable, there are still no curative treatments for castration-resistant prostate cancer (CRPC)...
Although the prognosis for clinically localized prostate cancer is now favorable, there are still no curative treatments for castration-resistant prostate cancer (CRPC) and, therefore, it remains fatal. In this study, we investigate a new therapeutic approach for treatment of CRPC, which involves dual targeting of a major signaling pathway that is frequently deregulated in the disease. We found that dual targeting of the Akt and mTOR signaling pathways with their respective inhibitors, MK-2206 and ridaforolimus (MK-8669), is highly effective for inhibiting CRPC in preclinical studies in vivo using a refined genetically engineered mouse model of the disease. The efficacy of the combination treatment contrasts with their limited efficacy as single agents, since delivery of MK-2206 or MK-8669 individually had a modest impact in vivo on the overall tumor phenotype. In human prostate cancer cell lines, although not in the mouse model, the synergistic actions of MK-2206 and ridaforolimus (MK-8669) are due in part to limiting the mTORC2 feedback activation of Akt. Moreover, the effects of these drugs are mediated by inhibition of cellular proliferation via the retinoblastoma (Rb) pathway. Our findings suggest that dual targeting of the Akt and mTOR signaling pathways using MK-2206 and ridaforolimus (MK-8669) may be effective for treatment of CRPC, particularly for patients with deregulated Rb pathway activity.
Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cluster Analysis; Disease Models, Animal; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Heterocyclic Compounds, 3-Ring; Humans; Male; Mice; Mice, Transgenic; Orchiectomy; Phenotype; Prostatic Neoplasms; Proto-Oncogene Proteins c-akt; Retinoblastoma Protein; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Tumor Burden; Xenograft Model Antitumor Assays
PubMed: 22815528
DOI: 10.1158/0008-5472.CAN-12-0283 -
Clinical Genitourinary Cancer Dec 2012Few options are available after taxane-based therapy in men with CRPC. Genetic alterations involving the mTOR pathway have been associated with CRPC development, raising...
BACKGROUND
Few options are available after taxane-based therapy in men with CRPC. Genetic alterations involving the mTOR pathway have been associated with CRPC development, raising the hypothesis that blocking mTOR signaling may be an effective targeted approach to treatment.
PATIENTS AND METHODS
In this open-label phase II study, the mTOR inhibitor Ridaforolimus was administered at a dose of 50 mg intravenous once weekly to 38 patients with taxane-treated CRPC. The primary end point was best overall response according to modified Response Evaluation Criteria in Solid Tumors guidelines. Serum prostate-specific antigen levels were prospectively monitored as a biomarker for cancer activity.
RESULTS
No objective responses were observed, but 18 patients (47.4%) had stable disease as their best response. Based on progression-free survival analysis, median time to progression with Ridaforolimus was 28 days (95% confidence interval, 27-29). Eight patients (21.1%) had stable disease as their best overall prostate-specific antigen response. The median number of days from first to last dose was 109.5 days (range, 1-442 days). Ridaforolimus was generally well tolerated, with a safety profile similar to that observed in patients with advanced malignancies. The most common side effects were typically mild or moderate in severity.
CONCLUSIONS
Ridaforolimus was generally well tolerated. Treatment did not produce objective responses, but stable disease was observed in some patients with taxane-treated CRPC. Alternative treatment regimens, such as combination therapy with a taxane or in a maintenance treatment paradigm, should be considered for further evaluation in this patient population.
Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Disease-Free Survival; Drug Administration Schedule; Gonadotropin-Releasing Hormone; Humans; Male; Middle Aged; Orchiectomy; Prostate-Specific Antigen; Prostatic Neoplasms; Sirolimus; TOR Serine-Threonine Kinases; Taxoids; Treatment Outcome
PubMed: 22695254
DOI: 10.1016/j.clgc.2012.05.001 -
International Journal of Oncology Aug 2012Although androgen ablation therapy is the foundation of current prostate cancer treatment, most patients ultimately develop castration-resistant disease. One proposed...
Although androgen ablation therapy is the foundation of current prostate cancer treatment, most patients ultimately develop castration-resistant disease. One proposed mechanism to account for androgen receptor (AR) activity in the castrate environment is via crosstalk with other signaling pathways. Specifically, reciprocal interactions between the AKT/mTOR and AR pathways have been implicated in prostate cancer progression. Here, we used the potent inhibitor ridaforolimus to target mTOR signaling alone and in combination with AR blockade by bicalutamide to examine the effect of abrogating these signaling pathways. Ridaforolimus treatment inhibited the proliferation of all six prostate cancer cell lines examined with the greatest sensitivity associated with loss of PTEN and elevated AKT/mTOR pathway activity. Dual inhibition of the AR and mTOR signaling pathways provided further benefit with the ridaforolimus-bicalutamide combination producing synergistic antiproliferative effects in prostate cancer cells in vitro when compared with each agent alone. Pharmacodynamic analysis confirmed that combination treatment resulted in full inhibition of each of the respective pathways. Importantly, the ridaforolimus-bicalutamide combination exhibited potent antitumor activity with parallel reductions in plasma PSA levels in vivo. Taken together, ridaforolimus exhibited potent antiproliferative and antitumor activity in prostate cancer models and the addition of bicalutamide represents a potentially effective combination strategy for patient therapy.
Topics: Androgen Receptor Antagonists; Anilides; Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Drug Synergism; Humans; Male; Mice; Mice, Nude; Nitriles; PTEN Phosphohydrolase; Prostate-Specific Antigen; Prostatic Neoplasms; Receptors, Androgen; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Tosyl Compounds; Tumor Burden; Xenograft Model Antitumor Assays
PubMed: 22614157
DOI: 10.3892/ijo.2012.1487