Evaluating Temsirolimus Activity in Multiple Tumors: A Review of Clinical Trials
Section snippets
Temsirolimus Activity in Preclinical Tumor Models
mTOR activity is enhanced by genetic alterations and aberrant activity of oncogenes, tumor-suppressor genes, and growth factors that are characteristic of a number of solid and hematologic malignancies (eg, PI3K/Akt pathway activation, PTEN inactivation, cyclin D1 overexpression, and c-myc).1, 2, 3, 4 Numerous preclinical studies have shown anti-tumor activity of temsirolimus in a variety of human solid tumor types. These include RCC,5, 6 breast cancer,7, 8, 9 lung cancer,10, 11, 12, 13
Renal Cell Carcinoma
The results of phase II and III trials of temsirolimus for patients with advanced RCC, which led to its approval for this indication, are reviewed in detail in this supplement by Hudes et al. Briefly, a phase II study characterized safety, pharmacokinetics, and anti-tumor activity of temsirolimus at three flat doses (25 mg, 75 mg, or 250 mg weekly) in patients with cytokine-refractory advanced RCC.40 The objective response rate was 7% (one complete response, seven partial responses) and minor
Mantle Cell Lymphoma
MCL is a subset of non-Hodgkin lymphoma that is characterized by a chromosomal translocation, t(11;14)(q13;q32). This translocation results in overexpression of cyclin D, which is regulated at the translational level by mTOR, suggesting the potential for mTOR inhibition as a novel treatment approach.82 Temsirolimus was shown to have significant anti-tumor activity in relapsed or refractory MCL in two phase II studies83, 84 and in a subsequent phase III randomized study,85 which are reviewed in
Conclusions
mTOR is now well recognized as a therapeutic target for many solid and hematologic malignancies. As the first mTOR inhibitor approved for an oncology indication, temsirolimus has demonstrated significant overall survival and progression-free survival benefits in patients with advanced RCC. More recently, temsirolimus treatment led to improved progression-free survival compared with investigator's choice of therapy in patients with relapsed and/or refractory MCL. Temsirolimus monotherapy
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2022, Tumour Virus ResearchCitation Excerpt :The rationale for this is that radiotherapy induces high levels of DNA damage and the DNA damage response (DDR) is compromised in cervical cancer cells and therefore they have impaired ability to repair this DNA damage and consequently they undergo cell death by apoptosis [125,126]. Indeed, the common site of HPV integration is in RAD51B, a well characterised DDR gene, and the E6 and E7 oncoproteins inactivate p53 and pRb which are key mediators of the DDR [112–116]. Additional mechanisms to inhibit cervical cancer have also involved targeting other cell cycle checkpoint regulators and DDR factors such as Poly ADP-ribose polymerases (PARP) [96,130,131].
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2015, International Journal of Biochemistry and Cell BiologyCitation Excerpt :This category of compounds include primarily mTOR inhibitors as temsirolimus (CCI-779) and everolimus (RAD001), which are clinically approved drugs (Unwith et al., 2014). Upon activation of the PI3K/AKT pathway, mTOR phosphorylates eIF4F-binding proteins that serve as negative regulators of the eIF4F translation initiation complex, resulting in its release from inhibition with concomitant translation of proteins involved in cell cycle progression, in addition to increased translation of HIF (Subbiah et al., 2010; Dancey et al., 2009). Among the first preclinical studies that reported observations along this line is a 2006 work by Del Bufalo et al. (2006) who showed that in BT474, a human breast cancer cell line that harbors HER2 amplification, temsirolimus inhibited VEGF production under both normoxic and hypoxic conditions through inhibition of HIF-1α expression and transcriptional activation.
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2015, Advances in Biological RegulationCitation Excerpt :However, a phase II trial with this particular drug combination showed only minor effects as demonstrated by a progression-free survival rate of 3.1% (Reardon et al., 2010). Temsirolimus is an analog of rapamycin, which also inhibits mTOR, and has demonstrated clinical efficacy in the treatment of non-CNS cancers including renal cell carcinoma and mantle cell lymphoma (Dancey et al., 2009). Several other phase II clinical trials have investigated the efficacy of temsirolimus as a novel chemotherapeutic agent for GBM.
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2013, Advances in Biological RegulationIncidence and management of mtor inhibitor-associated pneumonitis in patients with metastatic renal cell carcinoma
2012, Annals of OncologyCitation Excerpt :Everolimus, used either as a single agent or in combination, has led to meaningful increases in median progression-free survival (PFS) in recent placebo-controlled phase III trials in patients with neuroendocrine (carcinoid and pancreatic) tumours who have failed cytotoxic chemotherapy [22, 23]. Both products are under investigation in the phase II and III settings for a wide variety of other malignancies ([24], see also clinicaltrials.gov). A fourth mTOR inhibitor, ridaforolimus (formerly deforolimus, AP23573, MK-8669; Ariad Pharmaceuticals Inc., Cambridge, MA) has recently met the primary end point of improved PFS compared with placebo in a phase III trial conducted in patients with metastatic soft-tissue or bone sarcomas who previously had a favourable response to chemotherapy.
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STATEMENT OF CONFLICT OF INTEREST: Dr Dancey is a Consultant and has received past honoraria from Wyeth*; at the time this supplement was prepared, Drs Curiel and Purvis were employees of Wyeth Research.* (*Wyeth was acquired by Pfizer Inc in October 2009.)