Publications by authors named "Vicky M Coyle"

Article Synopsis
  • NUC-3373 is an experimental drug designed to improve the treatment of advanced solid tumors by being a more effective alternative to 5-fluorouracil (5-FU), which has drawbacks like poor conversion to active form and high toxicity.
  • The drug was tested on patients with persistent tumors, administered through IV, and aimed to determine the maximum tolerated dose (MTD) and assess its effectiveness and safety.
  • Results showed NUC-3373 was generally well-tolerated, had a favorable pharmacokinetic profile, and provided stable disease responses in patients previously treated with traditional therapies, with the MTD established at 2500 mg/m weekly.
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Purpose: Immune checkpoint blockade (ICB) has become a standard of care in the treatment of recurrent/metastatic head and neck squamous cell cancer (R/M HNSCC). However, only a subset of patients benefit from treatment. Quantification of plasma circulating tumour DNA (ctDNA) levels and on-treatment kinetics may permit real-time assessment of disease burden under selective pressures of treatment.

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Article Synopsis
  • Scientists wanted to see if a new drug called ALM201 was safe and how it worked for patients with certain types of cancer.!
  • They gave the drug to 20 patients for a few weeks and found that most people handled it well, with only mild side effects like injection pain and tiredness.!
  • There were no major safety issues, and they think the drug could be tested more to see how well it works in specific cancer types.!
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Inhibitors of apoptosis proteins (IAPs) are intracellular proteins, with important roles in regulating cell death, inflammation, and immunity. Here, we examined the clinical and therapeutic relevance of IAPs in colorectal cancer. We found that elevated expression of cIAP1 and cIAP2 (but not XIAP) significantly correlated with poor prognosis in patients with microsatellite stable (MSS) stage III colorectal cancer treated with 5-fluorouracil (5FU)-based adjuvant chemotherapy, suggesting their involvement in promoting chemoresistance.

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p53 is the most frequently mutated, well-studied tumor-suppressor gene, yet the molecular basis of the switch from p53-induced cell-cycle arrest to apoptosis remains poorly understood. Using a combination of transcriptomics and functional genomics, we unexpectedly identified a nodal role for the caspase-8 paralog and only human pseudo-caspase, FLIP(L), in regulating this switch. Moreover, we identify FLIP(L) as a direct p53 transcriptional target gene that is rapidly up-regulated in response to Nutlin-3A, an MDM2 inhibitor that potently activates p53.

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Article Synopsis
  • Src is linked to cancer invasion and metastasis, and the oral inhibitor AZD0424 has shown promise against tumors in earlier studies.
  • A phase Ia study tested the safety of AZD0424 in patients with advanced solid tumors, revealing that 41% of participants experienced significant adverse effects, especially at higher doses.
  • Despite showing some pharmacodynamic effects, AZD0424 did not demonstrate efficacy as a standalone treatment, leading to the conclusion that further testing of this monotherapy is not recommended.
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Around 12-15% of patients with locally advanced rectal cancer undergo a pathologically complete response (tumor regression grade 4) to long-course preoperative chemoradiotherapy; the remainder exhibit a spectrum of tumor regression (tumor regression grade 1-3). Understanding therapy-related transcriptional alterations may enable better prediction of response as measured by progression-free and overall survival, in addition to aiding the development of improved strategies based on the underlying biology of the disease. To this end, we performed high-throughput gene expression profiling in 40 pairs of formalin-fixed paraffin-embedded rectal cancer biopsies and matched resections following long-course preoperative chemoradiotherapy (discovery cohort).

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Article Synopsis
  • Colorectal cancer develops through various pathways influenced by genetic mutations, but effective treatment options targeting these mutations are still limited.
  • As research progresses, there is a shift towards broader genomic testing and collaborative efforts to create adaptive clinical trials for better treatment results.
  • Recent advancements include the routine use of extensive mutational testing before targeted therapy and emerging potential for immunotherapy, highlighting the importance of biomarkers for personalized treatment strategies.
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Aims And Background: . The incidence of malignant melanoma has risen steadily over recent decades. NCI data from 2005-2007 have suggested that 1.

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Article Synopsis
  • * Research revealed that the absence of p53 significantly alters gene expression and activates certain pathways related to cell movement in colorectal cancer cells after treatment with irinotecan's active form, SN38.
  • * Treatment with SN38 enhances the migratory ability of p53-null and p53-mutant cancer cells, suggesting a potential for metastasis, which can be reduced by inhibiting the MAPK pathway.
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Chemotherapy response rates for advanced colorectal cancer remain disappointingly low, primarily because of drug resistance, so there is an urgent need to improve current treatment strategies. To identify novel determinants of resistance to the clinically relevant drugs 5-fluorouracil (5-FU) and SN38 (the active metabolite of irinotecan), transcriptional profiling experiments were carried out on pretreatment metastatic colorectal cancer biopsies and HCT116 parental and chemotherapy-resistant cell line models using a disease-specific DNA microarray. To enrich for potential chemoresistance-determining genes, an unsupervised bioinformatics approach was used, and 50 genes were selected and then functionally assessed using custom-designed short interfering RNA (siRNA) screens.

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Article Synopsis
  • Novel genomic technologies allow researchers to simultaneously evaluate multiple genomic markers in solid tumors, shifting from traditional methods that focus on single alterations.
  • This change presents challenges related to clinical study design, result reproducibility, and the interpretation of findings, particularly highlighted in microarray-based gene-expression profiling.
  • To successfully integrate genomic markers into clinical practice, a focused evaluation and validation approach using adaptive clinical trials is necessary, improving the tailored application of cancer therapies to individual patients.
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Purpose: In an attempt to identify genes that are involved in resistance to SN38, the active metabolite of irinotecan (also known as CPT-11), we carried out DNA microarray profiling of matched HCT116 human colon cancer parental cell lines and SN38-resistant cell lines following treatment with SN38 over time.

Experimental Design: Data analysis identified a list of genes that were acutely altered in the parental cells following SN38 treatment as well as constitutively altered in the SN38-resistant cells.

Results: Independent validation of 20% of these genes by quantitative reverse transcription-PCR revealed a strong correlation with the microarray results: Pearson's correlation was 0.

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Article Synopsis
  • Colorectal cancer remains a significant health issue, being the second leading cause of cancer deaths in the Western world, highlighting the need for better treatment strategies and new therapies.
  • Pharmacogenomic studies indicate that genetic differences can affect how patients respond to treatments and their likelihood of adverse effects or survival.
  • Advances in gene-expression profiling are enabling researchers to identify specific gene sets that can help predict treatment response and recurrence, paving the way for more personalized cancer care in the future.
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Colorectal cancer is the second leading cause of cancer-related deaths in the Western world. Recently, improvements have been made in treating patients with advanced colorectal cancer; however, response rates still remain low at only 40-50% following combination therapy. The major limitation in treating these patients is the development of drug resistance.

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