Translational Cancer Genomics

DNA repair pathway aberrations are an integral part of cancer development but they are absent in normal cells, and thus they constitute as an important therapeutically targetable feature of human cancer. Small molecules that specifically kill DNA repair deficient cells offer significant clinical benefit for, for example, ovarian cancer patients that are treated with PARP inhibitors (niraparib, olaparib). The success of such therapy, however, depends on the presence of specific DNA repair pathway aberrations in a given cancer case.  Our group has developed several next-generation sequencing based methods to achieve this, with some of those reaching the clinical application stage (myChoice HRD assay).

We are also actively searching for agents that can provide PARP inhibitor-like therapeutic benefit in cancer cases with a different DNA repair pathway aberration. We recently developed a diagnostic method to identify nucleotide excision repair deficient cancer cases that will likely benefit from the experimental cancer therapy agent, irofulven. We plan to initiate clinical trials based on this agent in collaboration with the Rigshospitalet.

Cancer immunology has provided major breakthroughs in the treatment of advanced, metastatic cancer. However, we have only limited understanding of the mechanism of action of immunology based therapy and we do not understand why only certain patients respond. ln collaboration with Herlev Hospital (Center for Cancer lmmune Therapy) we are combining next generation sequencing based approaches with translational oncology research to improve the efficacy oi cancer immunotherapy.

Selected publications:

Börcsök J, Diossy M, Sztupinszki Z, Prosz A, Tisza V, Spisak S, Rusz O, Stormoen DR, Pappot H, Csabai I, Brunak S, Mouw KW, Szallasi Z: Detection of Molecular Signatures of Homologous Recombination Deficiency in Bladder Cancer. Clin Cancer Res 2021; online ahead of print

Diossy M, Sztupinszki Z, Krzystanek M, Borcsok J, Eklund AC, Csabai I, Pedersen AG, Szallasi Z: Strand Orientation Bias Detector to determine the probability of FFPE sequencing artifacts. Brief Bioinform 2021; online ahead of print

Börcsök J, Sztupinszki Z, Bekele R, Gao SP, Diossy M, Samant AS, Dillon KM, Tisza V, Spisák S, Rusz O, Csabai I, Pappot H, Frazier ZJ, Konieczkowski DJ, Liu D, Vasani N, Rodrigues JA, Solit DB, H Hoffman-Censits JH, Plimack ER, Rosenberg JE, Lazaro J-B, Taplin M-E, Iyer G, Brunak S, Lozsa R, Van Allen EM, Szüts D, Mouw KW, Szallasi Z: Identification of a Synthetic Lethal Relationship between Nucleotide Excision Repair Deficiency and Irofulven Sensitivity in Urothelial Cancer. Clin Cancer Res 2021; 27(7):2011-2022

Sztupinszki Z, Diossy M, Krzystanek M, Borcsok J, Pomerantz MM, Tisza V, Spisak S, Rusz O, Csabai I, Freedman ML, Szallasi V: Detection of Molecular Signatures of Homologous Recombination Deficiency in Prostate Cancer with or without BRCA1/2 Mutations. Clin Cancer Res 2020; 26(11):2673-2680

Poti A, Berta K, Xiao Y, Pipek O, Klus GT, Ried T, Csabai I, Wilcoxen K, Mikule K, Szallasi Z, Szuts D: Long-term treatment with the PARP inhibitor niraparib does not increase the mutation load in cell line models and tumour xenografts. Br J Cancer 2018;119(11):1392-1400