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Temsirolimus - Crossref

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Last Updated: 05 July 2022

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Abstract 5654: Docetaxel followed by temsirolimus suppresses mTOR pathway and can overcome PI3K / AKT over activation mechanism of resistance in lung cancer cell line.

BACKGROUNDING: rapamycin, a mammalian target of the PI3K/AKT signal transduction pathway, is a downstream regulatory protein of the PI3K/AKT signal transduction pathway. MTOR inhibition may be a promising new treatment of lung cancer. Docetaxel is a common treatment for lung cancer treatment. Previously, we showed that the combination of D and mTOR inhibitor temsirolimus in lung cancer cell lines had improved cell proliferation inhibition as compared to the reverse sequence of T2192D. We hypothesized that the D192T sequence would delay the deactivation of the PI3K/AKT mechanism of resistance's over-activation. In lung cancer cell lines treated with different sequences of D and T and at various time points, we investigated the expression of pmTOR, AKT, and PI3K genes. In both LCCL and prepared cell lysate at 24, 48 and 72h time points, we then treated both LCCL with D exposed for 24h, addition of T, and the reverse sequence. In the H1437, the sequence of Du2192T suppressed expression of pmTOR and reduced the expression of pAKT and PI3K at 48 and 72 h. When using D in combination with a mTOR inhibitor in lung cancer treatment, it appears that a sequence of D2192T may be the optimal treatment sequence. Docetaxel is the first in a lung cancer cell line and can bypass PI3K / AKT because of the activation mechanism of resistance in lung cancer cells.

Source link: https://doi.org/10.1158/1538-7445.am2013-5654


Abstract 4647: Tie2-expressing monocytes (TEMs) as potential biomarkers of angiopoietin-Tie2 (Ang/Tie2) directed therapies: correlative analysis of a phase I study of AMG386 + temsirolimus (T).

In a phase I study of AMG386 + T in patients with solid tumors, we used flow cytometry to analyze TEMs. For phase I of the study pts, blood was collected on Cycle 1 Day 1, D3 and D8. Tie2 staining was present on all M in healthy controls and cancer pts, as shown by no discrete Tie2+/- populations. An association has been found between increase in TP D1 to D3 and tumor response in Preliminary results. With tumor shrinkage, TP M/L decreased in all pts, but with tumor formation, it increased in the pt with tumor formation. In cancer pts and healthy volunteers, Tie2 and TP staining are similar. In pts receiving AMG386+T, there is a correlation between an initial decrease in TP and tumor shrinkage. 8. 87 % - 8. 10 7. 7% -5. 7% M2D7 M/T 6. 6 8. 8 5. 73 5. 85 5. 71 6. 58 5. 30 5. 19 6. 86 5. 76 5. 6 4. 1 5. 14 6. 35 6. 74 5. 76 6. 41 5. 86 5. 40 5. 6 5. 6 7. 95 2. 8. 4. 2 5. 79 5. 80 5. 46 4. 05 4. 2 5. 92 5. 69 8. 85 6. 3 5. 6 4. 7 4. 2 3. 2 4. 2 3. 7 5. 69 5. 42 5. 89 4. 6 6. 5 5. 6 5. 7 2. 6 2. 8 3. 6 5. 6 4. 9 5. 6 5. 6 5. 6 4. 7 7. 0 2. 8 5. 6 6. 2 2. 8 4. 7 5. 7 4. 7 4. 2 5. 6 6. 68 6. 78 5. 3 3. 7 4. 7 5. 6 5. 6 6. 57 6. 67 5. 6 4. 2 4. 7 5. 6 5. 3 4. 2 7. 2 5. 3 4. 7 5. 4 6. 2 6. 4 5. 7 6. 2 5. 4 5. 4 6. 7 6. 2 6. 7 5. 6 5. 6 7. 0 5. 6 6. 6 8. 67 6. 54 7. 61 5. 43 4. 8 5. 6 7. 90 7. 69 5. 6 5. 6 5. 6 5. 7 5. 6 7. 2 6. 2 6. 2.

Source link: https://doi.org/10.1158/1538-7445.am2013-4647


Abstract 2761: Temsirolimus is effective as a single agent and in combination with cisplatin or bevacizumab in preclinical osteosarcoma models.

Abstract Abstract: Osteosarcoma is the most commonly diagnosed primary malignant bone tumor that occurs in children and teens. We investigated the effects of the mTOR-inhibitor temsirolimus on human osteosarcoma xenografts in vivo, with and without chemotherapy or a VEGF inhibitor. Methods: BALB/C nude mice were s. c. implanted with human osteosarcoma xenografts and treated with temsirolimus, cisplatin, bevacizumab, ramie, to temsirolimus + bevacizumab for 4 weeks; s. c. Implanted with human osteosarcoma xenografts and treated with xeno c. To compare tumor formation in the groups, relative tumor volumes were used. At the end of the trial, tumor volumes were reduced by percentage reduction relative to tumors in control mice. Results: As compared to controls, Temsirolimus monotherapy greatly reduced the growth of OS-1 and OS-33 tumors. Compared to each monotherapy in mice with OS-1 tumors and OS-33 tumors, TC treatment resulted in significant tumor growth inhibition. In both OS-1 and OS-33 models, also in TB-treated mice, significant anti-tumor responses were seen. Conclusion: Temsirolimus is highly effective as a single agent in OS-1 and OS-33 osteosarcoma models, but the combination with cisplatin or bevacizumab produced a good anti-tumor response in comparison to all monotherapies. In preclinical osteosarcoma models, Temsirolimus is both a single agent and in combination with cisplatin or bevacizumab.

Source link: https://doi.org/10.1158/1538-7445.am2013-2761


Abstract 28: Phase I trial of combined temsirolimus, erlotinib, and cisplatin in advanced solid tumors.

Abstract A large number of triple negative breast cancers are fueled in part by a combination of stimulated growth factor signaling and downstream constitutive stimulation of the PI3K pathway. We've hypothesized that simultaneously with the EGFR inhibitor erlotinib, TNBC inhibitor erlotinib, and DNA damage pathways, as well as cisplatin, may have therapeutic value in a definable subset of TNBC patients. While the starting doses of erlotinib and temsirolimus were 100 mg and 15 mg, respectively, Cisplatin was administered at a dose of 30 mg/m2, respectively. For at least the first six weeks of therapy, the trial included a standard anti-emetic regimen, rejected prn scripts for loperamide at the outset, and employed a prophylactic rash therapy program with doxycycline 100 mg bid for at least the first six weeks of therapy. Within the first week of therapy, two of the six patients on dose level one developed a DLT. Three new patients were then accrued at the de-escalated dose level, in which erlotinib was dose-reduced to 75 mg without a DLT. Frequent dose delays due to thrombocytopenia occurred in one patient at dose level one and one patient at the de-escalated dose level. One PR was seen in a patient with TNBC being treated on the de-escalated dose level, but the reaction was short lived due to skin problems. Given the known genetic abnormalities in TNBC, this novel drug combination may be safe to use in a select-the-winner phase 2 random trial with embedded futility testing.

Source link: https://doi.org/10.1158/1538-7445.am2013-28


PD09-08: Combined Inhibition of mTORC1 with Temsirolimus and HER2 with Neratinib: A Phase I/II Study in Patients with Metastatic HER2−Amplified or Triple-Negative Breast Cancer.

HER1 overexpression has been found in triple-negative breast cancer, and models display sensitivity to combined HER1 and mTOR inhibition. We hypothesize that dual inhibition of the PI3K pathway, HER1/2, and induced HER3 may be especially helpful in patients with HER2+ or TN breast cancer. Patients with trastuzumab-refractory, HER2+, or TN BC are among the patients on this phase I/II trial to determine the adherence and potential safety of the mTOR inhibitor nemegratinib plus the HER1/2 inhibitor neratinib. Since it relates to responses to the T-N combination, we will also investigate mutational activation of the PI3K pathway in trastuzumab-refractory tumors. Methods: T plus N was assessed in patients with metastatic HER2+ or TN BC, according to the phase I dose-escalation study. The phase II research examines the HER2+ and TN patients separately as a result of Simon two-stage construction. The phase I trial included 8 HER2+ patients who underwent a median of 5 cycles of therapy. Ib's MTD is 8 mg IV/week. For a RR of 67%, six patients treated at MTD were evaluable for response; four patients had PR, and one had SD for a RR of 67%. In 4/6 tumors tested, P3K pathway activation, not limited to temsirolimus and neratinib, was found through PIK3CA mutational activation or PTEN loss, but did not exclude reaction to temsirolib and neratinib. Temsirolimus plus neratinib is also used in trastuzumab-refractory HER2+ patients. The phase II research is ongoing, and additional efficacy and safety data for both HER2u2212amplified and triple-negative breast cancer patients will be reported.

Source link: https://doi.org/10.1158/0008-5472.sabcs11-pd09-08


OT3-01-13: Phase One Trial of Combined Temsirolimus, Erlotinib, and Cisplatin in Advanced Solid Tumors.

Abstract Background: A large number of triple negative breast cancers are largely triggered by a combination of stimulated growth factor signaling and downstream constitutive activation of the PI3K pathway. In a TNBC subpoena, there is a strong correlation between PTEN loss and both expression of EGFR and mutation of p53. In part, single agent trials in breast cancer targeting EGFR have been a disappointment, owing to constitutive downstream activation of PI3K, AKT, and mTOR signals, largely due to the lack of PTEN expression. 2 that resistance to an EGFR-targeted therapy in the context of an activated PI3K pathway can be overcome with rapamycin, which reduces the TORC1 mTOR complex, and 2 that a subset of TNBC cells with p53 mutations are particularly sensitive to DNA damaging agent cisplatin due to their high expression of p63 and p73. In advanced solid tumor patients, a single institution phase one dose escalation trial of combined temsirolimus, erlotinib, and cisplatin is a pilot study.

Source link: https://doi.org/10.1158/0008-5472.sabcs11-ot3-01-13


Abstract 723: Beyond temsirolimus: Discovery of PKI-587 a highly efficacious dual PI3K/mTOR inhibitor

Abstract Temsirolimus, a rapamycin derivative, is a selective mTor inhibitor that has been used in the clinic for renal cancer treatment. paraphosphate's phosphatidylinositol diphosphate is one of these, among them is Phosphatidylitol diphosphate, which phosphatidylinositol diphosphate to phosphatidyliphosphate. Several pre-clinical and clinical studies have found that PI3K-u03b1 plays a key role in human cancer's biology. Therefore, it is likely that a small molecule inhibitor of both PI3K and mTOR would have therapeutic value. In vitro, PKI-587 reduces tumor cell survival and proliferation. When used as a single agent, PKI-587 has demonstrated elective mouse xenograft models such as MDA 361, U87, H1975, A549 in nude mice.

Source link: https://doi.org/10.1158/1538-7445.am10-723


Abstract 4480: Preclinical evaluation of the mTOR inhibitor, temsirolimus, in combination with the epothilone B analog, ixabepilone

In vitro, we tested the possibility that introducing Ixa to Tem would improve its anti-tumor activity. Tem doses varied from 0. 125 [nM] to 5 [nM] and Ixa doses varied from 2. 5 [nM] to 100 [nM]. In all tested cell lines as single agents in dose-dependent manners, both Tem and Ixa inhibited cell growth. In addition, the combination of Tem and Ixa increased cytotoxicity in all tested cell lines, according to Cell LineED50 [nM]: Conclusion: The combination of Ixa and Tem showed promising results in all tested cell lines.

Source link: https://doi.org/10.1158/1538-7445.am10-4480


Abstract 3482: Combination of temsirolimus, a mTOR targeting drug, with the association of EGFR-targeting drug cetuximab, VEGF-targeting drug bevacizumab, and irradiation: A pre-clinical study on head and neck tumour

Abstract - Background : AKT initiation and progression by constitutive activation of PTEN following PTEN inactivation is a well-known mechanism involved in tumor formation and progression. Since mTOR is one of the key AKT-related messengers, mTOR inhibitors such as temsirolimus are also promising anticancer drugs. Tumor regrowth was followed by tumor regrowth, according to our group's earlier reports that the tumor regression caused by the combination of radiotherapy with anti-EGFR and anti-angiogenic drugs was followed by tumor regrowth. This tumour re-growth was accompanied by a dramatic decrease in PTEN expression and an increase in phospho-AKT expression, which were both important. The aim of this research was to provide a mTOR blocking drug to a tri-therapy consisting of RT + anti-EGFR + anti-angiogenic drugs in order to prolong anti-tumor effects. CAL33, the human head and neck cancer cell line, was xenografted in the flank of nude mice. Once a week, Tumor volume and mouse weight were determined. Comparisons : The time to reach a tumor volume of 2000 mm3 in the four treatment groups was significantly different among the four treatment groups, with a median of 29. 5, 44. 5, 67. 0, and 70. 0 days for control, temsirolimus, tri-therapy, and combination groups. Figure shows that temsirolimus and combination treatments had no significant interactions between temsirolimus and combination therapy, meaning that temsirolimus on one hand and RT-cetuximab-bevacizumab on the other hand have additive effects on tumor formation inhibition. Conclusion : These experimental findings show that temsirolimus may be a promising drug for testing in conjunction with irradiation, anti-EGFR, and anti-angiogenic therapies in head and neck cancer patients.

Source link: https://doi.org/10.1158/1538-7445.am10-3482


Abstract 2175: Genomic and transcriptional profiling characterizes the molecular basis for response to cediranib and temsirolimus in endometrial cancer cells

In four endometrial cancer cell lines, these studies report a genome-wide SNP and copy number variation analysis as well as expression array profiling to fully identify how the genomic changes present are shown in the level of gene expression of key cancer-associated transcripts. Hec50co cells in the Ishikawa cells are poor-distinguished adenocarcinoma with serous subdifferentiation; RL95-2 and KLE are moderately differentiated adenocarcinoma, respectively; and Ishikawa H cells have been found to have somewhat distinct hormone response endometrial adenocarcinoma. For each cell line, Affymetrix genome wide microarray SNP6. 0 and gene expression microarray U133 experiments were carried out. With 132 chromosomal locations showing changes, RL95-2 cells had the fewest number of copy number variants with the fewest number of copy number variants, with only 132 chromosomal locations showing changes. Several extra copies of chromosomal fragments were used in dozens of publications, 119 show increases resulting in three or four copies, while 13 chromosomal segments had only one copy. With a total of 857 cells, KLE cells had the most chromosomal abnormalities. The second fewest chromosome copy number changes observed in Ishikawa H cells was the second fewest chromosome copy number changes, and Hec50co cells had the second most anomalies. One of the most unexpected results was the strong correlation between copy number and relative mRNA expression levels. There was a clear connection between increased copy number and an elevated level of gene expression for several genes. When compared to Ishikawa H cells with the same copy number of two, all three genes within the amplified region showed a high degree of mRNA expression. In conclusion, genomic and transcriptional studies that were correlated with drug sensitivity provide a molecular characterization predictive of drug response.

Source link: https://doi.org/10.1158/1538-7445.am10-2175

* Please keep in mind that all text is summarized by machine, we do not bear any responsibility, and you should always check original source before taking any actions

* Please keep in mind that all text is summarized by machine, we do not bear any responsibility, and you should always check original source before taking any actions