Page 14 - Read Online

Cancer Drug Resist 2018;1:266-302 I http://dx.doi.org/10.20517/cdr.2018.18 Page 269

investigated HRR function in primary cultures of cells from ascites taken from patients with ovarian can-
cer. We measured HRR function by the ability to form RAD51 foci following 24 h exposure to rucaparib
(a PARPi). We found that 55% of our samples were HRR dysfunctional (HRD), this was later reinforced by
the estimate of 51% HRD by the TCGA, following an extensive genomic analysis. Subsequent work showed
that those patients identified as HRR defective had better PFS and OS, indicating a better response to Stan-
dard of Care: carboplatin-paclitaxel therapy. We have applied this test to pleural effusions and found HRR
defects were relatively common, including 3 out of 4 non-small-cell lung cancer samples. More recently
we have investigated the HRR status of primary cultures of ascites cells taken from patients with a variety
of different tumour types and found that 8/24 were HRD. Survival of patients treated with platinum was
greater in the HRD group (n = 3) but this was not significant due to the small number of patients (10 in to-
tal). Our data indicate that HRD is relatively common in a variety of tumour types and the limited data on
their response to platinum therapy suggest that adoption of either platinum or PARPi therapy in patients
with any HRD tumour is worthy of investigation.

7. Pharmaco Epigenetics in human cancer

Manel Esteller

IDBELL, Barcelona, Spain

For the last twenty-five years an increasing amount of evidence has shown the relevance of epigenetics
in cell biology and tissue physiology, being DNA methylation aberrations in cancer the flag-ship for the
recognition of its disturbance in human diseases. From the candidate gene approaches, new powerful
technologies such as comprehensive DNA methylation microarrays and whole genome bisulfite sequencing
have recently emerged that reinforce the notion of epigenetic disruption in the crossroad of many sickness.
From the poster-boy cases of MGMT and GSTP1 hypermethylation in the prediction of alkylating drug
response and prostate cancer detection, respectively, to the personalized treatment of leukemia with small
molecules targeted to fusion proteins involving histone modifiers such as DOT1L and MLL, the field has
walked a long path. The current talk will focus on the epigenetic profiling, basically at the level of DNA
methylation and histone modifications, that is starting to provide clinical value in the diagnosis, prognosis
and prediction of response to drug therapies, with an emphasis in neoplasia, but without forgetting the
novel advances in other human disorders. For cancer, we have already a wide view of the undergoing DNA
methylation events that expand beyond classical promoter CpG islands of tumor suppressor genes and we
have a growing list of mutated chromatin remodeler genes that contributes to the tumorigenesis process.
It is time to apply this knowledge in practical clinical situations like the diagnosis of cancers of unknown
primary, the screening of malignancies in high-risk populations or a biomarker selection of the patients
that should receive treatment with epigenetic drugs.

8. A CRISPR-based mutagenesis method for determinants of drug resistance

1
2
1
1
1
Daniel J. O’Neill , Claudia Stellato , Alexis Guernet , Mike Firth , Maryam Clausen ,
Maria Emanuela Cuomo 1
1 Discovery Sciences, IMED Biotech Unit, AstraZeneca, Cambridge, UK
2 Discovery Sciences, IMED Biotech Unit, AstraZeneca, Mölndal, Sweden
Acquired drug resistance represents a major challenge in the development of therapeutic agents that show
long term effectiveness for the treatment of cancer. The problem is exemplified by non-small cell lung