Development of a Signature of Aberrant Myc Transcription has Prognostic Value in Evaluating Novel Myc-Targeted Therapies

Altered expression of transcription factors are key indicators in cancer progression in functions such as proliferation and differentiation, angiogenesis and apoptosis. A significant proportion of cancers are driven by mutations in these networks, including Wnt/β-catenin, Ras/MAPK and Myc.

Myc is a nuclear phosphoprotein implicated in a number of malignancies, for example Burkitt’s lymphoma, neuroblastoma, and medullablastoma. Myc is a promising target for novel cancer therapies, and a number of clinical trials are ongoing evaluating novel therapies including PI3k/HDAC dual inhibitors, small interfering RNA (siRNA), and biologics, as well as evaluating new indications for existing medication. A recent publication by Jung et al discusses the unmet need for a clinically relevant prognostic tool for effective use in the drug discovery pipeline.

This paper identifies the following:

A selection of genes as candidate members of the signature, derived from analyzing publicly available microarray datasets studying neuroblastoma, breast cancer, DLBCL, medullablastoma, and ovarian cancer. Candidates were refined by subtype classification and filtering by examining overlapping studies, resulting in a total of 75 genes. This was refined to 18 genes to fit into the limited space afforded by TaqMan Low Density Arrays (TLDAs).

RT-qPCR assays were selected for these 18 genes to allow economical assaying of test samples, in this study 35 cancer cell lines to validate the signature performance prior to use on clinical samples. Use of TLDAs allows up to 8 samples and 23 targets to be analysed per run. Higher throughput or a more complex signature may be run using alternative instrumentation like the Fluidigm Biomark, which also allows full customization of assay design or the selection of commercially available pre-validated assays.

Analysis of 42 primary neuroblastoma samples. Although this dataset was small, high signature scores derived from the PCR data were associated with poor prognosis in the patient, indicating a clinically relevant tool that is potentially useful in evaluating Myc-targeted therapies in early phase clinical trials.

The authors have proposed a Myc signature as a solution to an unmet need in evaluating the performance of Myc-targeted therapies in cancer research. A multi-member signature as a biomarker is a powerful tool to accelerate or streamline pre-clinical research, reducing attrition in pre-and early-phase clinical trials. This approach is relevant in a number of cancer paradigms and similar approaches can prove invaluable as a biomarker toolkit to facilitate drug development programs, ultimately accompanying regulatory submissions.

At Epistem we offer preclinical services using animal models (including xenografts), cell-based assays, and culture of plucked human anagen hair cells, all of which are suitable for exposing to candidate drugs and generating custom datasets for analysis and subsequent development of powerful signature based biomarkers. We have extensive experience in genomic analysis of low RNA input and analytics to generate signatures from a few genes to scores of genes, using custom datasets and optionally high quality relevant public datasets. This results in the demonstrated ability to provide powerful analyses for preclinical studies leading to relevant use in early phase clinical studies in our GCLP accredited laboratories.

Jung et al. “A Myc Activity Signature Predicts Poor Clinical Outcomes in Myc‑Associated Cancers.” doi: 10.1158/0008-5472.CAN-15-2906

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