PTEN, PIK3CA, p-AKT, and p-p70S6K Status

Esteva, Francisco J.; Guo, Hua; Zhang, Siyuan; Santa-Maria, Cesar A.; Stone, Steven; Lanchbury, Jerry S.; Şahin, Ayşegül; Hortobágyi, Gabriel N.; Yu, Dihua

doi:10.2353/ajpath.2010.090885

Cited by 263 publications

(125 citation statements)

References 39 publications

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“…It has been previously reported that the aptamer AS1411 displays a decoy activity on NCL, preventing its binding to specific mRNAs (Bates et al, 2009a,b), and here our data demonstrated that AS1411 is able to modulate NCL binding to the microprocessor complex, affecting the processing of a specific group of miRNAs. We are also reporting that AS1411 affects cell motility and invasive properties of breast cancer cells both in vitro and in vivo by modulating the expression of several well-established targets of NCL-dependent miRNAs, including PTEN, DICER, and PDCD4 (Esteva et al, 2010;Martello et al, 2010;Chang et al, 2011). In our experimental set, we did not observe, after short-term NCL impairment (siRNAs or aptamers), differences in BCL-2 mRNA expression involved in cancer (Mercatelli et al, 2008;Zhang et al, 2012).…”

Section: Discussionmentioning

confidence: 95%

In vivo NCL targeting affects breast cancer aggressiveness through miRNA regulation

Pichiorri¹,

Palmieri²,

Luca³

et al. 2013

J Cell Biol

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Numerous studies have described the altered expression and the causal role of microRNAs (miRNAs) in human cancer. However, to date, efforts to modulate miRNA levels for therapeutic purposes have been challenging to implement. Here we find that nucleolin (NCL), a major nucleolar protein, posttranscriptionally regulates the expression of a specific subset of miRNAs, including miR-21, miR-221, miR-222, and miR-103, that are causally involved in breast cancer initiation, progression, and drug resistance. We also show that NCL is commonly overexpressed in human breast tumors and that its expression correlates with that of NCL-dependent miRNAs. Finally, inhibition of NCL using guanosine-rich aptamers reduces the levels of NCL-dependent miRNAs and their target genes, thus reducing breast cancer cell aggressiveness both in vitro and in vivo. These findings illuminate a path to novel therapeutic approaches based on NCLtargeting aptamers for the modulation of miRNA expression in the treatment of breast cancer.

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Section: Discussionmentioning

confidence: 95%

In vivo NCL targeting affects breast cancer aggressiveness through miRNA regulation

Pichiorri¹,

Palmieri²,

Luca³

et al. 2013

J Cell Biol

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“…Blood samples for PK analysis were taken on days 1 (predose then 1.5, 3, 6 and 12 h after infusion start), 2 (24 h after infusion start), 3,5,8,15,22,29,50 and 71. Noncompartmental trastuzumab serum PK parameters were b Safety population: all randomised subjects who received a complete or partial dose of either CT-P6 or reference trastuzumab.…”

Section: Primary Endpointsmentioning

confidence: 99%

“…HER2 over-expression occurs in up to 30% of all breast cancers [3] and at a similar rate in gastric cancers [4]. Over-expression is associated with decreased time to recurrence and poorer prognosis in breast cancer [3,5], and may be linked to worse prognosis and increased recurrence in gastric cancer [4,6].…”

Section: Introductionmentioning

confidence: 99%

A randomised trial comparing the pharmacokinetics and safety of the biosimilar CT-P6 with reference trastuzumab

Esteva¹,

Stebbing

Wood-Horrall³

et al. 2018

Cancer Chemother Pharmacol

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Purpose Access to trastuzumab, a valuable anti-cancer treatment, can be limited by cost. The primary aim of this study was to evaluate and compare the PK profiles of CT-P6, a biosimilar of trastuzumab, and US-licensed reference trastuzumab (Herceptin ® ) in healthy subjects. Secondary study aims included comparison of the safety and immunogenicity of CT-P6 and reference trastuzumab in these subjects. Methods We performed a single-dose, randomised, double-blind, parallel group study (NCT02665637) comparing CT-P6 with reference trastuzumab (6 mg/kg, 90 min intravenous infusion) in 70 healthy adult males. Pharmacokinetics, safety and immunogenicity were evaluated up to 10 weeks post-dose. Primary endpoints were area under the serum concentration-time curve (AUC) from time 0 to infinity (AUC inf ); AUC from time 0 to last quantifiable concentration (AUC last ); and observed maximum serum concentration (C max ). The pre-determined equivalence criterion was a 90% confidence interval of 80-125% for ratios of geometric least squares (LS) means. Results Equivalence of CT-P6 and reference trastuzumab was demonstrated. Ratios (CT-P6/reference trastuzumab) of geometric LS means (90% confidence interval) were: AUC inf 99.05 (93.00, 105.51); AUC last 99.30 (92.85, 106.20); C max 96.58 (90.93, 102.59). Safety profiles were similar; treatment-emergent adverse events occurred in ten subjects (28.6%) in the CT-P6 group and 11 (31.4%) in the reference trastuzumab group. No serious adverse events or deaths occurred. No subjects tested positive for anti-drug antibodies. Conclusions These data add to the totality of evidence required to demonstrate biosimilarity. A phase III study of CT-P6-in which equivalent neoadjuvant efficacy to reference trastuzumab has been demonstrated-is ongoing.

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“…by PIK3CA mutations) [70]; and 328 altered signalling via non-HER family RTKs [71,72]. 329 P95HER2, which lacks an extracellular domain but retains 330 kinase activity, has been proposed as a mechanism of 331 resistance [73].…”

Section: U N C O R R E C T E D P R O O Fmentioning

confidence: 99%

HER2-family signalling mechanisms, clinical implications and targeting in breast cancer

Elster

Collins

Toomey

et al. 2014

Breast Cancer Res Treat

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8 Abstract Approximately 20 % of human breast cancers 9 (BC) overexpress HER2 protein, and HER2-positivity is 10 associated with a worse prognosis. Although HER2-tar-11 geted therapies have significantly improved outcomes for 12 HER2-positive BC patients, resistance to trastuzumab-13 based therapy remains a clinical problem. In order to better 14 understand resistance to HER2-targeted therapies in HER2-15 positive BC, it is necessary to examine HER family sig-16 nalling as a whole. An extensive literature search was 17 carried out to critically assess the current knowledge of 18 HER family signalling in HER2-positive BC and response 19 to HER2-targeted therapy. Known mechanisms of trast-20 uzumab resistance include reduced receptor-antibody 21 binding (MUC4, p95HER2), increased signalling through 22 alternative HER family receptor tyrosine kinases 23 (RTK), altered intracellular signalling involving loss of 24 PTEN, reduced p27kip1, or increased PI3 K/AKT activity 25 and altered signalling via non-HER family RTKs such as 26 IGF1R. Emerging strategies to circumvent resistance to 27 HER2-targeted therapies in HER2-positive BC include co-28 targeting HER2/PI3 K, pan-HER family inhibition, and 29 novel therapies such as T-DM1. There is evidence that 30 immunity plays a key role in the efficacy of HER-targeted 31 therapy, and efforts are being made to exploit the immune 32 system in order to improve the efficacy of current anti-HER 33 therapies. With our rapidly expanding understanding of 34 HER2 signalling mechanisms along with the repertoire of 35 HER family and other targeted therapies, it is likely that the 36 near future holds further dramatic improvements to the 37 prognosis of women with HER2-positive BC. 38 39 Keywords Trastuzumab · HER2 · Breast cancer · 40 PI3 K 41 Introduction 42 BC is the second most common cancer in the world, and the 43 fifth highest cause of cancer mortality worldwide [1]. 20 % of 44 human BC's overexpress HER2, and HER2-positivity is 45 associated with a significantly worse prognosis. HER2 first 46 became targetable in patients with trastuzumab (Herceptin, 47 ™ Genentech/Roche), a monoclonal antibody that has sig-48 nificantly improved outcomes for patients with HER2-49 positive BC, but the efficacy of trastuzumab is limited in 50 some patients by acquired and de novo resistance [2]. 51 HER family signalling 52There are 20 known RTK families: since members of over 53 half of these have been found to be mutated or overex-54 pressed in diseases marked by abnormal proliferation, 55 RTK's have been considered potential targets for cancer 56 therapy. HER2, a type 1 transmembrane protein RTK, and 57 an oncogenic driver of the growth of HER2-positive BC, is 58 associated with a shorter time to relapse and decreased 59 overall survival (OS 44Author Proof 26] evidence shows that lapatinib is effective against 151 trastuzumab-resistant HER2-positive BC, and it is cur-152 rently used as subsequent therapy for patients with disease 153 that has progressed on trastuzumab. Lapatinib inhibits 15...

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PTEN, PIK3CA, p-AKT, and p-p70S6K Status

Cited by 263 publications

References 39 publications

In vivo NCL targeting affects breast cancer aggressiveness through miRNA regulation

In vivo NCL targeting affects breast cancer aggressiveness through miRNA regulation

A randomised trial comparing the pharmacokinetics and safety of the biosimilar CT-P6 with reference trastuzumab

HER2-family signalling mechanisms, clinical implications and targeting in breast cancer

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