Analysis of variant Ciz1 in pre and post-treatment plasma samples from lung cancer patients attending York hospital

Overview

Lung cancer is responsible for more than 1 million deaths each year, more than breast, colon and prostate cancer combined. C2D2 funding was used to evaluate a potential post-treatment niche for employing a biomarker that can report on reduced tumour burden or on recurrence as part of a wider international research project on screening for the cancer.

It was found that the protein B-variant Ciz1 is a highly stable antigen which can be detected in just 1 millilitre of plasma in lung cancer patients and is capable of distinguishing malign from benign modules. This means that the application of B-variant Ciz1 screening to patients with lung nodules identified by CT scan could halve the number subjected to unnecessary procedures.

Some of these results have been published and a commercial development partnership has begun between Fujirebio Diagnostics Incorporated and Cizzle Biotech. This will co-develop an ELISA test for the detection of early stage lung cancers that can be taken forward through regulatory and clinical development worldwide.

In detail

Lung cancer is responsible for more than 1 million deaths each year, more than breast, colon and prostate cancer combined. C2D2 funding was used to evaluate a potential post-treatment niche for employing a biomarker that can report on reduced tumour burden or on recurrence as part of a wider international research project on screening for the cancer.

Ciz1 is a nuclear matrix protein that promotes initiation of mammalian DNA replication and tumourigenesis in mice. Ciz1 exists as multiple transcript variants, some of which have been implicated in disease. All appear to be primarily nuclear, but have different sub-nuclear patterns and in some cases compromised attachment to the nuclear matrix. Variant isoforms in which the nuclear matrix attachment is disrupted are common in cancer cells. B-variant Ciz1 is prevalent in lung cancer cells and evident in tumour biopsies but not in adjacent tissue, giving rise to a stable protein that can be robustly detected in plasma from patients with lung cancer.

Using a variant-selective antibody, b-variant protein levels in two independent sample sets were quantified. The results of these tests demonstrate that B-variant Ciz1 is a highly stable tumour antigen. It is present in plasma but not serum and easily detected in less than a millilitre of plasma from lung cancer patients. It is evident in patients with stage 1 lung cancer and is capable of discriminating between stage 1 lung cancer and benign lung nodules.
In the context of early detection, application of B-variant Ciz1 screening to patients with lung nodules identified by CT scan could halve the number subjected to unnecessary procedures.

Some of these results have been published and a commercial development partnership has begun between Fujirebio Diagnostics Incorporated and Cizzle Biotech. This will co-develop an ELISA test for the detection of early stage lung cancers that can be taken forward through regulatory and clinical development worldwide.

Outputs

Publications

• Higgins, G., Roper, K. M., Watson, I. J., Blackhall, F. H., Rom, W. N., Pass, H. I., Ainscough, J. F. X., & Coverley, D. (2012). Variant Ciz1 is a circulating biomarker for early-stage lung cancer. Proceedings of the national academy of sciences of the united states of america, 109(45), E3128-E3135, doi: 10.1073/pnas.1210107109

Grants

• Dawn Coverley, Cizzle Biotech, Summer studentship, £2,600