Neoadjuvant Therapy in Rectal Cancer - Biobanking of Preoperative Tumor Biopsies

Jo, Peter; Nietert, M.; Gusky, Linda; Kitz, Julia; Conradi, LC; Müller-Dornieden, Annegret; Schüler, P.; Wolff, Hendrik A.; Rüschoff, Josef; Ströbel, Philipp; Grade, Marian; Liersch, Torsten; Beißbarth, Tim; Ghadimi, Michael; Sax, Ulrich; Gaedcke, Jochen

doi:10.1038/srep35589

Cited by 8 publications

(6 citation statements)

References 25 publications

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“…Furthermore, normalization effects or sample quality could also influence a change of miRNA expression. In this context, we have to emphasize that each plasma sample was taken, stored and processed under stringent biobanking Standard Operating Procedures [ 7 ] since translational research relies on high-quality biospecimens.…”

Section: Discussionmentioning

confidence: 99%

“…Especially in the case of rectal cancer, beyond intratumoral heterogeneity, tumor biopsies are in general accompanied by normal, adenomatous or stromal tissue. This contamination may affect results of molecular analyses [ 6 , 7 ]. Resorting to bloodstream bypasses those problems: blood samples are a source of fresh DNA and RNA, without modifications due to preservatives.…”

Section: Introductionmentioning

confidence: 99%

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Changes of Microrna Levels in Plasma of Patients with Rectal Cancer during Chemoradiotherapy

Azizian

Salendo

et al. 2017

IJMS

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Since the response to chemoradiotherapy in patients with locally advanced rectal cancer is heterogeneous, valid biomarkers are needed to monitor tumor response. Circulating microRNAs are promising candidates, however analyses of circulating microRNAs in rectal cancer are still rare. 111 patients with rectal cancer and 46 age-matched normal controls were enrolled. The expression levels of 30 microRNAs were analyzed in 17 pre-treatment patients’ plasma samples. Differentially regulated microRNAs were validated in 94 independent patients. For 52 of the 94 patients a paired comparison between pre-treatment and post-treatment samples was performed. miR-17, miR-18b, miR-20a, miR-31, and miR-193a_3p, were significantly downregulated in pre-treatment plasma samples of patients with rectal cancer (p < 0.05). miR-29c, miR-30c, and miR-195 showed a trend of differential regulation. After validation, miR-31 and miR-30c were significantly deregulated by a decrease of expression. In 52 patients expression analyses of the 8 microRNAs in matched pre-treatment and post-treatment samples showed a significant decrease for all microRNAs (p < 0.05) after treatment. Expression levels of miR-31 and miR-30c could serve as valid biomarkers if validated in a prospective study. Plasma microRNA expression levels do not necessarily represent miRNA expression levels in tumor tissue. Also, expression levels of microRNAs change during multimodal therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Changes of Microrna Levels in Plasma of Patients with Rectal Cancer during Chemoradiotherapy

Azizian

Salendo

et al. 2017

IJMS

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“…Tissue collection and gene expression profiling have been already described for the rectal cancer cohort [ 72 , 73 , 74 ]. Briefly, tissue samples were obtained from patients with locally advanced rectal cancer patients.…”

Section: Methodsmentioning

confidence: 99%

Effects of the Novel PFKFB3 Inhibitor KAN0438757 on Colorectal Cancer Cells and Its Systemic Toxicity Evaluation In Vivo

Oliveira

Goldhardt

Edelmann

et al. 2021

Cancers

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Background: Despite substantial progress made in the last decades in colorectal cancer (CRC) research, new treatment approaches are still needed to improve patients’ long-term survival. To date, the promising strategy to target tumor angiogenesis metabolically together with a sensitization of CRC to chemo- and/or radiotherapy by PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-3) inhibition has never been tested. Therefore, initial evaluation and validation of newly developed compounds such as KAN0438757 and their effects on CRC cells are crucial steps preceding to in vivo preclinical studies, which in turn may consolidate new therapeutic targets. Materials and Methods: The efficiency of KAN0438757 to block PFKFB3 expression and translation in human CRC cells was evaluated by immunoblotting and real-time PCR. Functional in vitro assays assessed the effects of KAN0438757 on cell viability, proliferation, survival, adhesion, migration and invasion. Additionally, we evaluated the effects of KAN0438757 on matched patient-derived normal and tumor organoids and its systemic toxicity in vivo in C57BL6/N mice. Results: High PFKFB3 expression is correlated with a worse survival in CRC patients. KAN0438757 reduces PFKFB3 protein expression without affecting its transcriptional regulation. Additionally, a concentration-dependent anti-proliferative effect was observed. The migration and invasion capacity of cancer cells were significantly reduced, independent of the anti-proliferative effect. When treating colonic patient-derived organoids with KAN0438757 an impressive effect on tumor organoids growth was apparent, surprisingly sparing normal colonic organoids. No high-grade toxicity was observed in vivo. Conclusion: The PFKFB3 inhibitor KAN0438757 significantly reduced CRC cell migration, invasion and survival. Moreover, on patient-derived cancer organoids KAN0438757 showed significant effects on growth, without being overly toxic in normal colon organoids and healthy mice. Our findings strongly encourage further translational studies to evaluate KAN0438757 in CRC therapy.

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“…Tumor biopsies were collected prior to preoperative CRT during diagnostic procedures. After surgery, residual tumor was taken for analyses from the resected specimens [ 12 , 22 ]. Patients presenting metastases or local recurrence during follow-up were subjected to needle biopsy or surgical biopsy and resulting tumor tissue was referred to histopathological confirmation and KRAS mutation analysis.…”

Section: Methodsmentioning

confidence: 99%

KRAS mutation status concordance between the primary tumor and the corresponding metastasis in patients with rectal cancer

Jo¹,

Bernhardt²,

Nietert³

et al. 2020

PLoS ONE

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Introduction Oncogenic mutation within the KRAS gene represents a negative predictor for treatment response to anti-epidermal growth factor receptor (EGFR) in patients with colorectal cancer. Recently, we have shown no relevant heterogeneity for KRAS mutation status within and between pre-and posttherapeutic samples from the primary tumor in patients with locally advanced rectal cancer. The aim of this study was to evaluate the intertumoral heterogeneity of KRAS mutation status between the primary tumor and the corresponding metastasis or local recurrence in the similar cohort and to evaluate the ideal representative tissue for KRAS mutation testing. Materials and methods KRAS mutation status was analyzed from 47 patients with locally advanced rectal cancer, which were enrolled in the CAO/ARO/AIO-94 or CAO/ARO/AIO-04 trial. Mutations in KRAS codons 12, 13, and 61 were analyzed by using the KRAS RGQ PCR Kit (therascreen® KRAS test). Six patients needed to be excluded due to incomplete follow up data. 11 patients showed a relapse of the disease during the follow up presented by distant metastases or local recurrence. DNA from representative areas of metastatic tissue was obtained from formalin-fixed paraffin-embedded specimens. Results The mean patient age was 64.13 ± 10.64 years. In total, 19 patients showed a KRAS mutation (46.34%) in the primary tumor. Of the eleven patients with a metastatic disease or local recurrence, five patients showed a KRAS mutation whereas six patients had a KRAS wildtype status. Metastatic localizations included the liver (n = 2), lung (n = 4), local recurrence

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Neoadjuvant Therapy in Rectal Cancer - Biobanking of Preoperative Tumor Biopsies

Cited by 8 publications

References 25 publications

Changes of Microrna Levels in Plasma of Patients with Rectal Cancer during Chemoradiotherapy

Changes of Microrna Levels in Plasma of Patients with Rectal Cancer during Chemoradiotherapy

Effects of the Novel PFKFB3 Inhibitor KAN0438757 on Colorectal Cancer Cells and Its Systemic Toxicity Evaluation In Vivo

KRAS mutation status concordance between the primary tumor and the corresponding metastasis in patients with rectal cancer

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