Novel cancer chemotherapies targeting loss of heterozygosity

New cancer therapeutics are sorely needed to extend the treatment options for cancer.

Our research aims at development of a new class of individualized cancer therapies that target cells with loss-of-heterozygosity (LOH).

Here we exploit the concept of collateral lethality to target of drug metabolizing enzymes located in regions that frequently undergo LOH in cancer.

The rationale is that heterozygous individuals with one normal activity allele and one low activity allele will be eligible for treatment with agents that selectively kill cancer cells that have undergone LOH of the genomic region and therefore express only a variant with low drug metabolizing activity while sparing the normal cells that retain the normal activity allele.

We have recently provided proof-of-concept for this treatment strategy for NAT2, identifying the novel kinase inhibitor APA as a candidate for CRC treatment which could be applicable for 80 000 patients annually.

In this project we will proceed to screen for better NAT2 selective substances using existing cell models, develop new cell models to study and screen for cytostatic drugs selective for a second LOH therapy target, and analyze genomic and transcriptomic datasets to identify novel target genes for LOH therapy.

The project spans over four years, focusing on establishment of cell models, cell based drug library screens, and follow up by pharmacokinetic and target identification analysis of drug hits.