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Frontiers in Oncology 2014The phosphatidylinositol-3-kinase (PI3K)/Akt and the mammalian target of rapamycin (mTOR) signaling pathways are two pathways crucial to many aspects of cell growth and... (Review)
Review
The phosphatidylinositol-3-kinase (PI3K)/Akt and the mammalian target of rapamycin (mTOR) signaling pathways are two pathways crucial to many aspects of cell growth and survival, in physiological as well as in pathological conditions (e.g., cancer). Indeed, they are so interconnected that, in a certain sense, they could be regarded as a single, unique pathway. In this paper, after a general overview of the biological significance and the main components of these pathways, we address the present status of the development of specific PI3K, Akt, and mTOR inhibitors, from already registered medicines to novel compounds that are just leaving the laboratory bench.
PubMed: 24782981
DOI: 10.3389/fonc.2014.00064 -
Blood Oct 2022Relapse and refractory T-cell acute lymphoblastic leukemia (T-ALL) has a poor prognosis, and new combination therapies are sorely needed. Here, we used an ex vivo...
Relapse and refractory T-cell acute lymphoblastic leukemia (T-ALL) has a poor prognosis, and new combination therapies are sorely needed. Here, we used an ex vivo high-throughput screening platform to identify drug combinations that kill zebrafish T-ALL and then validated top drug combinations for preclinical efficacy in human disease. This work uncovered potent drug synergies between AKT/mTORC1 (mammalian target of rapamycin complex 1) inhibitors and the general tyrosine kinase inhibitor dasatinib. Importantly, these same drug combinations effectively killed a subset of relapse and dexamethasone-resistant zebrafish T-ALL. Clinical trials are currently underway using the combination of mTORC1 inhibitor temsirolimus and dasatinib in other pediatric cancer indications, leading us to prioritize this therapy for preclinical testing. This combination effectively curbed T-ALL growth in human cell lines and primary human T-ALL and was well tolerated and effective in suppressing leukemia growth in patient-derived xenografts (PDX) grown in mice. Mechanistically, dasatinib inhibited phosphorylation and activation of the lymphocyte-specific protein tyrosine kinase (LCK) to blunt the T-cell receptor (TCR) signaling pathway, and when complexed with mTORC1 inhibition, induced potent T-ALL cell killing through reducing MCL-1 protein expression. In total, our work uncovered unexpected roles for the LCK kinase and its regulation of downstream TCR signaling in suppressing apoptosis and driving continued leukemia growth. Analysis of a wide array of primary human T-ALLs and PDXs grown in mice suggest that combination of temsirolimus and dasatinib treatment will be efficacious for a large fraction of human T-ALLs.
Topics: Child; Humans; Mice; Animals; Lymphocyte Specific Protein Tyrosine Kinase p56(lck); Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Dasatinib; Zebrafish; Tyrosine; Cell Line, Tumor; Signal Transduction; Protein Kinase Inhibitors; Mechanistic Target of Rapamycin Complex 1; Receptors, Antigen, T-Cell; T-Lymphocytes; Recurrence; Mammals
PubMed: 35544598
DOI: 10.1182/blood.2021015106 -
Journal of Clinical Oncology : Official... Oct 2022The status of p53 in a tumor can be inferred by next-generation sequencing (NGS) or by immunohistochemistry (IHC). We examined the association between p53 IHC and... (Randomized Controlled Trial)
Randomized Controlled Trial
Sequencing and p53 Immunohistochemistry Predict Outcomes When Bevacizumab Is Added to Frontline Chemotherapy in Endometrial Cancer: An NRG Oncology/Gynecologic Oncology Group Study.
PURPOSE
The status of p53 in a tumor can be inferred by next-generation sequencing (NGS) or by immunohistochemistry (IHC). We examined the association between p53 IHC and sequence and whether p53 IHC alone, or integrated with NGS, predicts the outcome.
METHODS
From GOG-86P, a randomized phase II study of chemotherapy combined with either bevacizumab or temsirolimus in advanced endometrial cancer, 213 cases had p53 protein expression data measured by IHC and NGS data. An analysis was designed to integrate p53 expression by IHC with the presence or absence of a mutation. These variables were further correlated with progression-free survival (PFS) and overall survival (OS) in the chemotherapy plus bevacizumab arms versus the chemotherapy plus temsirolimus arm.
RESULTS
In the analysis of p53 IHC, the most striking treatment effect favoring bevacizumab was in cases where p53 was overexpressed (PFS hazard ratio [HR]: 0.46, 95% CI, 0.26 to 0.88; OS HR: 0.31, 95% CI, 0.16 to 0.62). On integrated analysis, patients with missense mutations and p53 protein overexpression had a similar treatment effect on PFS (HR: 0.41, 95% CI, 0.22 to 0.83) and OS (HR: 0.28, 95% CI, 0.14 to 0.59) favoring bevacizumab plus chemotherapy relative to temsirolimus plus chemotherapy. Concordance between NGS and p53 IHC was 88%. Concordance was 92% when cases with mutations and mutations or mismatch repair deficiency were removed.
CONCLUSION
IHC for p53 alone or when integrated with sequencing for identifies a specific, high-risk tumor genotype/phenotype for which bevacizumab is particularly beneficial in improving outcomes when combined with chemotherapy.
Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Endometrial Neoplasms; Female; Humans; Immunohistochemistry; Mutation; Sirolimus; Tumor Suppressor Protein p53
PubMed: 35658479
DOI: 10.1200/JCO.21.02506 -
Gynecologic Oncology Aug 2018Paclitaxel and carboplatin (PC) is a standard initial therapy for advanced endometrial cancer. We evaluated the efficacy and tolerability of incorporating three novel... (Randomized Controlled Trial)
Randomized Controlled Trial
A phase II study of frontline paclitaxel/carboplatin/bevacizumab, paclitaxel/carboplatin/temsirolimus, or ixabepilone/carboplatin/bevacizumab in advanced/recurrent endometrial cancer.
OBJECTIVE
Paclitaxel and carboplatin (PC) is a standard initial therapy for advanced endometrial cancer. We evaluated the efficacy and tolerability of incorporating three novel agents into initial therapy.
METHODS
In this randomized phase II trial, patients with chemotherapy-naïve stage III/IVA (with measurable disease) and stage IVB or recurrent (with or without measurable disease) endometrial cancer were randomly assigned to treatment with PC plus bevacizumab (Arm 1), PC plus temsirolimus (Arm 2) or ixabepilone and carboplatin (IC) plus bevacizumab (Arm 3). The primary endpoint was progression-free survival (PFS). Comparable patients on the PC Arm of trial GOG209 were used as historical controls. Secondary endpoints were response rate, overall survival (OS), and safety.
RESULTS
Overall, 349 patients were randomized. PFS duration was not significantly increased in any experimental arm compared with historical controls (p > 0.039). Treatment HRs (92% CI) for Arms 1, 2, and 3 relative to controls were 0.81 (0.63-1.02), 1.22 (0.96-1.55) and 0.87 (0.68-1.11), respectively. Response rates were similar across arms (60%, 55% and 53%, respectively). Relative to controls, OS duration (with censoring at 36 months), was significantly increased in Arm 1 (p < 0.039) but not in Arms 2 and 3; the HRs (92% CIs) were 0.71 (0.55-0.91), 0.99 (0.78-1.26), and 0.97 (0.77-1.23), respectively. No new safety signals were identified. Common mutations and rates of mismatch repair protein loss are described by histotype. Potential predictive biomarkers for temsirolimus and bevacizumab were identified.
CONCLUSION
PFS was not significantly increased in any experimental arm compared to historical controls. NRG Oncology/Gynecologic Oncology Group Study GOG-86P.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carboplatin; Endometrial Neoplasms; Epothilones; Female; Humans; Middle Aged; Neoplasm Recurrence, Local; Paclitaxel; Sirolimus
PubMed: 29804638
DOI: 10.1016/j.ygyno.2018.05.018 -
The Lancet. Oncology Jul 2017Outcomes for children with relapsed and refractory neuroblastoma are dismal. The combination of irinotecan and temozolomide has activity in these patients, and its... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Outcomes for children with relapsed and refractory neuroblastoma are dismal. The combination of irinotecan and temozolomide has activity in these patients, and its acceptable toxicity profile makes it an excellent backbone for study of new agents. We aimed to test the addition of temsirolimus or dinutuximab to irinotecan-temozolomide in patients with relapsed or refractory neuroblastoma.
METHODS
For this open-label, randomised, phase 2 selection design trial of the Children's Oncology Group (COG; ANBL1221), patients had to have histological verification of neuroblastoma or ganglioneuroblastoma at diagnosis or have tumour cells in bone marrow with increased urinary catecholamine concentrations at diagnosis. Patients of any age were eligible at first designation of relapse or progression, or first designation of refractory disease, provided organ function requirements were met. Patients previously treated for refractory or relapsed disease were ineligible. Computer-based randomisation with sequence generation defined by permuted block randomisation (block size two) was used to randomly assign patients (1:1) to irinotecan and temozolomide plus either temsirolimus or dinutuximab, stratified by disease category, previous exposure to anti-GD2 antibody therapy, and tumour MYCN amplification status. Patients in both groups received oral temozolomide (100 mg/m per dose) and intravenous irinotecan (50 mg/m per dose) on days 1-5 of 21-day cycles. Patients in the temsirolimus group also received intravenous temsirolimus (35 mg/m per dose) on days 1 and 8, whereas those in the dinutuximab group received intravenous dinutuximab (17·5 mg/m per day or 25 mg/m per day) on days 2-5 plus granulocyte macrophage colony-stimulating factor (250 μg/m per dose) subcutaneously on days 6-12. Patients were given up to a maximum of 17 cycles of treatment. The primary endpoint was the proportion of patients achieving an objective (complete or partial) response by central review after six cycles of treatment, analysed by intention to treat. Patients, families, and those administering treatment were aware of group assignment. This study is registered with ClinicalTrials.gov, number NCT01767194, and follow-up of the initial cohort is ongoing.
FINDINGS
Between Feb 22, 2013, and March 23, 2015, 36 patients from 27 COG member institutions were enrolled on this groupwide study. One patient was ineligible (alanine aminotransferase concentration was above the required range). Of the remaining 35 patients, 18 were randomly assigned to irinotecan-temozolomide-temsirolimus and 17 to irinotecan-temozolomide-dinutuximab. Median follow-up was 1·26 years (IQR 0·68-1·61) among all eligible participants. Of the 18 patients assigned to irinotecan-temozolomide-temsirolimus, one patient (6%; 95% CI 0·0-16·1) achieved a partial response. Of the 17 patients assigned to irinotecan-temozolomide-dinutuximab, nine (53%; 95% CI 29·2-76·7) had objective responses, including four partial responses and five complete responses. The most common grade 3 or worse adverse events in the temsirolimus group were neutropenia (eight [44%] of 18 patients), anaemia (six [33%]), thrombocytopenia (five [28%]), increased alanine aminotransferase (five [28%]), and hypokalaemia (four [22%]). One of the 17 patients assigned to the dinutuximab group refused treatment after randomisation; the most common grade 3 or worse adverse events in the remaining 16 patients evaluable for safety were pain (seven [44%] of 16), hypokalaemia (six [38%]), neutropenia (four [25%]), thrombocytopenia (four [25%]), anaemia (four [25%]), fever and infection (four [25%]), and hypoxia (four [25%]); one patient had grade 4 hypoxia related to therapy that met protocol-defined criteria for unacceptable toxicity. No deaths attributed to protocol therapy occurred.
INTERPRETATION
Irinotecan-temozolomide-dinutuximab met protocol-defined criteria for selection as the combination meriting further study whereas irinotecan-temozolomide-temsirolimus did not. Irinotecan-temozolomide-dinutuximab shows notable anti-tumour activity in patients with relapsed or refractory neuroblastoma. Further evaluation of biomarkers in a larger cohort of patients might identify those most likely to respond to this chemoimmunotherapeutic regimen.
FUNDING
National Cancer Institute.
Topics: Adolescent; Alanine Transaminase; Anemia; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Child; Child, Preschool; Dacarbazine; Disease-Free Survival; Fever; Ganglioneuroblastoma; Gene Amplification; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Hypokalemia; Hypoxia; Infant; Infections; Irinotecan; N-Myc Proto-Oncogene Protein; Neoplasm Recurrence, Local; Neuroblastoma; Neutropenia; Pain; Response Evaluation Criteria in Solid Tumors; Retreatment; Sirolimus; Survival Rate; Temozolomide; Thrombocytopenia
PubMed: 28549783
DOI: 10.1016/S1470-2045(17)30355-8 -
A phase II study of bevacizumab and temsirolimus in advanced extra-pancreatic neuroendocrine tumors.Endocrine-related Cancer Nov 2023We assessed the efficacy and safety of combining bevacizumab with temsirolimus in patients with advanced extra-pancreatic neuroendocrine tumors. This NCI-sponsored...
We assessed the efficacy and safety of combining bevacizumab with temsirolimus in patients with advanced extra-pancreatic neuroendocrine tumors. This NCI-sponsored multicenter, open-label, phase II study (NCT01010126) enrolled patients with advanced, recurrent, or metastatic extra-pancreatic neuroendocrine tumors. All patients were treated with temsirolimus and bevacizumab until disease progression or unacceptable toxicity. Temsirolimus 25 mg was administered i.v. on days 1, 8, 15, and 22 and bevacizumab 10 mg/kg i.v. on days 1 and 15 of a 4-week cycle. Discontinuation of temsirolimus or bevacizumab did not require discontinuation of the other agent. The primary endpoints were objective response rate and 6-month progression-free survival rate. Fifty-nine patients were enrolled in this study, and 54 were evaluated for efficacy and adverse events. While median progression-free survival was 7.1 months, the median duration of treatment with temsirolimus was 3.9 months and that with bevacizumab was 3.5 months. The objective response rate of combination therapy was 2%, and 6-month progression-free survival was 48%. The most frequently reported grade 3-4 adverse events included fatigue (13%), hypertension (13%), and bleeding (13%). Close to 54% of the patients discontinued treatment due to adverse events, refusal of further treatment, or treatment delays. Three deaths occurred in the study, of which two were due to treatment-related bowel perforations. Given the minimal efficacy and increased toxicity seen with the combination of bevacizumab and temsirolimus, we do not recommend the use of this regimen in patients with advanced extra-pancreatic neuroendocrine tumors.
Topics: Humans; Bevacizumab; Neuroendocrine Tumors; Combined Modality Therapy; Neoplasms, Second Primary; Pancreatic Neoplasms
PubMed: 37702588
DOI: 10.1530/ERC-22-0301 -
Cost Effectiveness and Resource... Jan 2023Renal cell carcinoma (RCC) is the most common type of kidney cancer. VEGF inhibitors and mTORs are the most common therapeutic options among the different classes of... (Review)
Review
OBJECTIVE
Renal cell carcinoma (RCC) is the most common type of kidney cancer. VEGF inhibitors and mTORs are the most common therapeutic options among the different classes of available treatments. In this study, the effectiveness of Everolimus was compared to Temsirolimus, and Everolimus plusLenvatinib in renal cell carcinoma patients by review of the international clinical evidence.
MATERIALS AND METHODS
A systematic review was conducted and all relevant published clinical studies on the efficacy and cost-effectiveness of Everolimus, Temsirolimus, and Lenvatinib plus Everolimus were searched comprehensively in electronic databases including Pubmed, Scopus, Medline, Cochrane Library, and ISI web of science. The Q score and I2 test checked the Heterogeneity and publication bias test, respectively. Egger's test and Begg's test were used to checking publication bias. The hazard ratio (HR) of included studies and subclass analysis were estimated by fixed and random effect models.
RESULTS
Out of 1816 found studies, ultimately, were included considering inclusion and exclusion criteria. None of these studies evaluated all three treatment strategies together and each study was about one strategy. Only one study was found for Everolimus plus Lenvatinib, so it was excluded from meta-analysis. Overall, data from 526 patients on Temsirolimus and 648 patients on Everolimus were included in Meta-Analysis. Accordingly, the efficacy of Everolimus and Temsirolimus was not statistically significant in assessed outcomes (PFS, TTSF, and death). However, Everlimus is superior to Temsirolimus in OS (Q = 3.61, p-value: 0.462, I2 = 0%). No heterogeneity or bias was detected.
CONCLUSION
According to the results of this study, Everolimus could be related to an increase of OS versus Temsirolimus as a second line treatment of ORCC patients.
PubMed: 36703202
DOI: 10.1186/s12962-023-00420-4 -
World Journal of Urology Feb 2017Current systemic treatment of targeted therapies, namely the vascular endothelial growth factor-antibody (VEGF-AB), VEGF receptor tyrosine kinase inhibitor (TKI) and... (Review)
Review
PURPOSE
Current systemic treatment of targeted therapies, namely the vascular endothelial growth factor-antibody (VEGF-AB), VEGF receptor tyrosine kinase inhibitor (TKI) and mammalian target of rapamycin (mTOR) inhibitors, have improved progression-free survival and replaced non-specific immunotherapy with cytokines in metastatic renal cell carcinoma (mRCC).
METHODS
A panel of experts convened to review currently available phase 3 data for mRCC treatment of approved agents, in addition to available EAU guideline data for a collaborative review as the plurality of substances offers different options of first-, second- and third-line treatment with potential sequencing.
RESULTS
Sunitinib and pazopanib are approved treatments in first-line therapy for patients with favorable- or intermediate-risk clear cell RCC (ccRCC). Temsirolimus has proven benefit over interferon-alfa (IFN-α) in patients with non-clear cell RCC (non-ccRCC). In the second-line treatment TKIs or mTOR inhibitors are treatment choices. Therapy options after TKI failure consist of everolimus and axitinib. Available third-line options consist of everolimus and sorafenib. Recently, nivolumab, a programmed death-1 (PD1) checkpoint inhibitor, improved overall survival benefit compared to everolimus after failure of one or two VEGFR-targeted therapies, which is likely to become the first established checkpoint inhibitor in mRCC. Data for the sequencing of agents remain limited.
CONCLUSIONS
Despite the high level of evidence for first and second-line treatment in mRCC, data for third-line therapy are limited. Possible sequences include TKI-mTOR-TKI or TKI-TKI-mTOR with the upcoming checkpoint inhibitors in perspective, which might settle a new standard of care after previous TKI therapy.
Topics: Antibodies, Monoclonal; Antineoplastic Agents; Axitinib; Carcinoma, Renal Cell; Decision Trees; Everolimus; Humans; Imidazoles; Indazoles; Indoles; Niacinamide; Nivolumab; Phenylurea Compounds; Pyrimidines; Pyrroles; Sirolimus; Sorafenib; Sulfonamides; Sunitinib
PubMed: 27277600
DOI: 10.1007/s00345-016-1868-5