Phase II trial of temsirolimus alone and in combination with irinotecan for<i>KRAS</i>mutant metastatic colorectal cancer: Outcome and results of<i>KRAS</i>mutational analysis in plasma

Spindler, Karen Lise Garm; Sørensen, Morten; Pallisgaard, Niels; Andersen, Rikke Fredslund; Havelund, Birgitte Mayland; Pløen, John; Lassen, Ulrik; Jakobsen, Anders

doi:10.3109/0284186x.2013.776175

Cited by 54 publications

(20 citation statements)

References 20 publications

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“…KRAS mutations were detected in 41 patients with primary or metastatic tumors and the levels of the plasma mutant KRAS (pmKRAS) were lower than 75%. Similar results were observed in another study by the same group [97] when examining 64 patients who were treated with temsirolimus, either alone or in combination with irinotecan. Additionally, the use of a biomarker panel consisting of three genes ( KRAS , TP53 , and APC ) enabled the detection of at least one gene mutation from approximately 75% of CRC tissues [98].…”

Section: Plasma Ctdna In the Clinicsupporting

confidence: 87%

Circulating Tumor DNA as Biomarkers for Cancer Detection

Han

Wang

Sun

2017

Genomics, Proteomics &Amp; Bioinformatics

200

163

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Detection of circulating tumor DNAs (ctDNAs) in cancer patients is an important component of cancer precision medicine ctDNAs. Compared to the traditional physical and biochemical methods, blood-based ctDNA detection offers a non-invasive and easily accessible way for cancer diagnosis, prognostic determination, and guidance for treatment. While studies on this topic are currently underway, clinical translation of ctDNA detection in various types of cancers has been attracting much attention, due to the great potential of ctDNA as blood-based biomarkers for early diagnosis and treatment of cancers. ctDNAs are detected and tracked primarily based on tumor-related genetic and epigenetic alterations. In this article, we reviewed the available studies on ctDNA detection and described the representative methods. We also discussed the current understanding of ctDNAs in cancer patients and their availability as potential biomarkers for clinical purposes. Considering the progress made and challenges involved in accurate detection of specific cell-free nucleic acids, ctDNAs hold promise to serve as biomarkers for cancer patients, and further validation is needed prior to their broad clinical use.

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Section: Plasma Ctdna In the Clinicsupporting

confidence: 87%

Circulating Tumor DNA as Biomarkers for Cancer Detection

Han

Wang

Sun

2017

Genomics, Proteomics &Amp; Bioinformatics

200

163

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“…When the patient progressed on PCE therapy, he was changed to a multiagent regimen that included a topoisomerase I inhibitor (irinotecan) in combination with mTOR inhibition which has been used for the treatment of various solid tumors [11, 61–64] and based on findings from our genomic and preclinical studies. The patient rapidly progressed, suggesting that the combinatorial strategy may not have produced the desired additive effect.…”

Section: Resultsmentioning

confidence: 99%

A case study of an integrative genomic and experimental therapeutic approach for rare tumors: identification of vulnerabilities in a pediatric poorly differentiated carcinoma

et al. 2016

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BackgroundPrecision medicine approaches are ideally suited for rare tumors where comprehensive characterization may have diagnostic, prognostic, and therapeutic value. We describe the clinical case and molecular characterization of an adolescent with metastatic poorly differentiated carcinoma (PDC). Given the rarity and poor prognosis associated with PDC in children, we utilized genomic analysis and preclinical models to validate oncogenic drivers and identify molecular vulnerabilities.MethodsWe utilized whole exome sequencing (WES) and transcriptome analysis to identify germline and somatic alterations in the patient’s tumor. In silico and in vitro studies were used to determine the functional consequences of genomic alterations. Primary tumor was used to generate a patient-derived xenograft (PDX) model, which was used for in vivo assessment of predicted therapeutic options.ResultsWES revealed a novel germline frameshift variant (p.E1554fs) in APC, establishing a diagnosis of Gardner syndrome, along with a somatic nonsense (p.R790*) APC mutation in the tumor. Somatic mutations in TP53, MAX, BRAF, ROS1, and RPTOR were also identified and transcriptome and immunohistochemical analyses suggested hyperactivation of the Wnt/ß-catenin and AKT/mTOR pathways. In silico and biochemical assays demonstrated that the MAX p.R60Q and BRAF p.K483E mutations were activating mutations, whereas the ROS1 and RPTOR mutations were of lower utility for therapeutic targeting. Utilizing a patient-specific PDX model, we demonstrated in vivo activity of mTOR inhibition with temsirolimus and partial response to inhibition of MEK.ConclusionsThis clinical case illustrates the depth of investigation necessary to fully characterize the functional significance of the breadth of alterations identified through genomic analysis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-016-0366-0) contains supplementary material, which is available to authorized users.

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“…Since rapamycin has poor water solubility and stability in aqueous solutions, we used the rapamycin ester temsirolimus. This drug has more favorable pharmaceutical properties and only induces mild side effects in humans, and it is undergoing evaluation through phase II and phase III clinical trials for treating certain types of cancer [ 79 , 81 ] (NCT01026792, NCT00827684). Thus, we treated 10-month-old Abcd1 − mice with temsirolimus or a vehicle (control) administered through intraperitoneal injection over a 4.5-month period as described above (see the “ Materials and methods ” section) [ 52 , 67 ].…”

Section: Resultsmentioning

confidence: 99%

Autophagy induction halts axonal degeneration in a mouse model of X-adrenoleukodystrophy

et al. 2014

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X-linked adrenoleukodystrophy (X-ALD) is a rare neurometabolic disease characterized by the accumulation of very long chain fatty acids (VLCFAs) due to a loss of function of the peroxisomal transporter ABCD1. Here, using in vivo and in vitro models, we demonstrate that autophagic flux was impaired due to elevated mammalian target of rapamycin (mTOR) signaling, which contributed to X-ALD pathogenesis. We also show that excess VLCFAs downregulated autophagy in human fibroblasts. Furthermore, mTOR inhibition by a rapamycin derivative (temsirolimus) restored autophagic flux and inhibited the axonal degenerative process as well as the associated locomotor impairment in the Abcd1−/Abcd2−/− mouse model. This process was mediated through the restoration of proteasome function and redox as well as metabolic homeostasis. These findings provide the first evidence that links impaired autophagy to X-ALD, which may yield a therapy based on autophagy activators for adrenomyeloneuropathy patients.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-014-1378-8) contains supplementary material, which is available to authorized users.

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Phase II trial of temsirolimus alone and in combination with irinotecan forKRASmutant metastatic colorectal cancer: Outcome and results ofKRASmutational analysis in plasma

Abstract: Phase II trial of temsirolimus alone and in combination with irinotecan for KRAS mutant metastatic colorectal cancer: Outcome and results of KRAS mutational analysis in plasma, Acta Oncologica, 52:5,[963][964][965][966][967][968][969][970]

Cited by 54 publications

References 20 publications

Circulating Tumor DNA as Biomarkers for Cancer Detection

Circulating Tumor DNA as Biomarkers for Cancer Detection

A case study of an integrative genomic and experimental therapeutic approach for rare tumors: identification of vulnerabilities in a pediatric poorly differentiated carcinoma

Autophagy induction halts axonal degeneration in a mouse model of X-adrenoleukodystrophy

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