The Pan-Cancer Atlas: “The End of the Beginning”

Yesterday, a series of 27 papers representing the most comprehensive genomic analysis of human cancers to date was published in Cell Press journals.

The collection constitutes the final outputs from the Cancer Genome Atlas (TCGA) project, a collaboration between the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI) involving analysis of over 11,000 tumors representing 33 different cancers. The many research teams involved analyzed tumor DNA, mRNA, miRNA and chromatin, comparing them to matched normal cellular genomes to perform a complete molecular characterization of cancer-specific changes. The results have been presented with much hope that open access to this type of comprehensive analysis will build on recent advances in understanding tumor biology and spur further progress in developing new approaches to treatment. (See this news item for more detail).

The Pan-Cancer Atlas results are collected on a portal, where they are presented in three collections grouped by topic: Cell of Origin, Oncogenic Processes and Signaling Pathways. Each collection is accompanied by a “Flagship” paper introducing the topic and summarizing the findings. It seems fitting that these findings have been published in #HumanGenomeMonth. This comprehensive analysis of the genomic and metagenomic profiles of tumors illustrates one powerful application of the type of genomic analysis pioneered by the original Human Genome Project, and shows just how much has been made possible since the initial publication of the human genome fifteen years ago. Continue reading

HaloTag® Research Application: Detection of Cancer Biomarkers

10242TAAntibodies labelled with radioisotopes or the sequential administrationof an antibody and a radioactive secondary agent facilitate the in vivo detection and/or characterisation of cancers by positron emission tomography (PET) or by single-photon emission computed tomography (SPECT) imaging.

There are drawbacks to both methods, including prolonged exposure to radiation and  ensuring that both the antibody and the radiolabelled secondary agent are suitably designed so that they bind rapidly upon contact at the tumor.

A recent publication (1) investigated a alternative method utilizing the HaloTag® dehalogenase enzyme HaloTag® is a dehalogenase enzyme (33 kDa) that contains an engineered cavity designed to accommodate the reactive chloroalkane group of a HaloTag® ligand (HTL). Upon entering the enzyme cavity, the terminal chlorine atom rapidly undergoes nucleophilic displacement, and a covalent adduct is formed, effectively anchoring the HaloTag® ligand in a precise location.

Three new HaloTag® ligands were synthesized and each labelled with the SPECT radionuclide indium-111  111In-HTL-1  and the dual-modality HaloTag® ligands,111In-HTL-2 and111;In-HTL-3 containing TMR which allows complementary imaging data).

For the validation of the pretargeting strategy based on these HaloTag® ligands, the target human epidermal growth factor receptor 2 (HER2)was selected. Trastuzumab (Herceptin®) was selected as the primary targeting agent and was modified with HaloTag® protein via the trans-cyclooctene/tetrazine ligation.

All three 111In-labelled HaloTa®g ligands exhibited significantly higher binding to the HER2 expressing when compared to negative controls.

Literature Cited

Knight, J. C et al.(2015) Development of an enzymatic pretargeting strategy for dual-modality imagingChem. Commun. 51, 4055–8.