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Page 268 Cancer Drug Resist 2018;1:266-302 I http://dx.doi.org/10.20517/cdr.2018.18

for BRAF mutated melanomas. But, in general tumours are characterized by the presence of numerous
oncogenes, genetic aberrations and a dynamic growth control. That complex and individual pattern even
nowadays cannot fully be understood and mirrored by medical systems biology. Another attractive option
to maintain the typical features of a patient tumour is by growing it in a foreign host how it is practised
since the invention of the patient-derived xenografts (PDX). This method has been used for more than 30
years but got recently increasing attractivity for the identification of novel biomarkers and as so-called ava-
tars for a patient-related optimization of therapy. Meanwhile, worldwide several thousands of PDX models
covering the broad variety of tumour types exist and are used both for fundamental research and for com-
mercial offer. It has been proved in several investigations that the PDX highly resemble the original tumour
specimen concerning histology, molecular marker and response to therapy. Within the talk our own long-
standing experiences concerning the establishment and characterization of PDX will be reflected. Addi-
tional efforts have been made to further “humanize” the mice. For that purpose, in general two procedures
exist. A transient humanization can be reached by co-transplanting human mononuclear cells or subtypes
of leukocytes like NK cells. A lifelong humanization of the mouse immune system can be reached by
transplanting human stem cells. In these humanized mice immunopharmacological drugs like checkpoint
inhibitors can be functionally tested. Methods and experiences with this sophisticated preclinical model
system will be presented.

5. Drug resistance to synthetic lethal treatments for cancer

Chris Lord

The Institute of Cancer Research, London, UK

The first synthetic lethal treatments for cancer, poly (ADP-ribose) polymerase (PARP) inhibitors, are now
approved for use. Despite PARP inhibitors delivering some sustained and profound clinical responses, drug
resistance is a growing problem. I will discuss how genetic perturbation screens can identify mechanisms
of PARP inhibitor resistance and how genetic reversions in BRCA genes, mutations in PARP1 and loss of
the newly identified Shieldin protein complex can result in PARP inhibitor resistance. I will also discuss
how the mechanism of PARP inhibitor resistance that emerges defines the sensitivity to other therapeutics.

6. Assessment of homologous recombination DNA repair function in human tumours and
potential for selection of patients for platinum or PARP inhibitor therapy

Nicola Curtin

Newcastle University, UK

All cells experience a high level of base lesions and DNA single strand breaks (SSBs) caused by endog-
enously generated reactive oxygen species. Poly (ADP-ribose) polymerase (PARP) is crucial for the repair
of SSBs and any left unrepaired will collapse replication forks, which can only be resolved by HRR. We first
described the selective killing of cells defective in homologous recombination DNA repair (HRR) by PARP
is in 2005, which has led to an explosion in PARP inhibitor (PARPi) research. BRCA1 and BRCA2, the
breast and ovarian cancer genes are key components of HRR and 3 PARPi are approved for use in ovarian
cancer. Since (1) < 20% of ovarian cancers are associated with BRCA mutations; (2) HRR is a multi-compo-
nent pathway such that defects in any one of them may compromise HRR function; and (3) HRR dysfunc-
tion confers sensitivity to platinum agents and 60% of ovarian cancers respond to platinum therapy, we