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Cancer Drug Resist 2018;1:266-302 I http://dx.doi.org/10.20517/cdr.2018.18 Page 295

Irinotecan is a topoisomerase I inhibitor used to treat patients with metastatic colorectal cancer (CRC).
However, although approximately 50% of these patients will initially benefit from first-line irinotecan-
containing treatment, they will all experience progressive disease. We developed pairs of SN38-sensitive
and SN38-resistant human CRC cell lines (Jensen et al., Mol. Oncol, 2015). Two of three cell lines had sig-
nificant upregulation of ABCG2 and inhibition of this drug efflux pump with a synthetic inhibitor (Ko143)
abolished SN38 resistance in ABCG2-upregulated cell lines. An alternative to using pump inhibitors to
block topoisomerase I inhibitor resistance is to use topoisomerase I inhibitors that are not substrates for
ABCG2. LMP400, which belongs to the indenoisoquinoline family, was identified from the NCI60 data
files as a potent topoisomerase I inhibitor. We exposed ABCG2-upregulated SN38-resistant cell lines to
LMP400 and observed a highly significant anti-tumor effect indicating that LMP400 is not a substrate for
the ABCG2 efflux pump. Another notable feature of LMP400 is that it - in contrast to SN38 - is not metab-
olized by UGT-1A1 and it is therefore not expected to result in severe side effects in patients with mutated
UGT-1A1. Finally, LMP400 was also active in colorectal cancer cell lines with acquired oxaliplatin resis-
tance. LMP400 has passed clinical phase I studies in various cancer types with incurable disease (Kummar
et al., Cancer Chemotherapy Pharmacol, 2016). The recommended dose for phase II studies is weekly 90
2
mg/m with myelosuppression as the primary toxicity and with only limited GI side effects. We will initiate
a study in patients with metastatic CRC progressing on irinotecan-containing chemotherapy. We will fol-
low Simons two stage design with ≥ 2 responders among 15 patients (RECIST version 1.1) being sufficient
to include an additional 10 patients.

53. SCO-101 is a first-in-class drug that reverses anti-estrogen resistance in breast cancer cells

2
1
1
Katrine Hartfelt , Ida Christina Barner Madsen , Signe Lykke Nielsen , Palle Christophersen ,
1
Nils Brünner , Jan Stenvang 1,3
1,3
1 Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Co-
penhagen, Jagtvej 160, Copenhagen DK-2100, Denmark
2 Saniona, Baltorpvej 154, Ballerup DK-2750, Denmark
3 Scandion Oncology, COBIS, Ole Maaløesvej 3, Copenhagen DK-2200, Denmark

Eighty percent of all cases of breast cancer patients present with estrogen receptor (ER)-positive disease
and treatment with anti-estrogens is an effective treatment for these patients. However, anti-estrogen re-
sistance uniformly arises in patients with advanced breast cancer. SCO-101, which is an inhibitor of the
volume regulated anion channel (VRAC), is an oral drug, which exhibits a safe toxicology profile as dem-
onstrated in four phase I clinical trials in healthy individuals. We investigated the potential of SCO-101
to act in combination with the anti-estrogens tamoxifen and fulvestrant in anti-estrogen resistant human
breast cancer cell lines (MCF-7/LCC-2, MCF-7/LCC-9, T47D/TR1) and the ER negative MDA-MB-231.
Treatment effects were investigated by MTT cell viability assays, siRNA knock-down experiments and
western blots. SCO-101 only had minor inhibitory effects on cell viability of the cell lines when adminis-
tered alone. However, when combining SCO-101 with tamoxifen or fulvestrant in MCF-7 or T47D anti-
estrogen resistant breast cancer cells, an additive to synergistic effect on cell viability was observed. Thus,
SCO-101 re-sensitized the anti-estrogen resistant LCC-2, LCC-9 and T47D/TR1 cell lines to tamoxifen and
fulvestrant. In contrast, SCO-101 in combination with anti-estrogens had no effects on the triple negative
MDA-MB-231 cell line. As SCO-101 mainly targets VRAC, in which LRRC8A is the essential subunit, we
investigated whether knockdown of LRRC8A would impact the treatment outcome. No apparent changes
in response to SCO-101 and anti-estrogens were observed upon knockdown of LRRC8A. Additionally, the
protein level of LRRC8A was examined upon treatment with anti-estrogens +/- SCO-101 and the treatment
did not alter LRRC8A protein expression. Our findings suggest that SCO-101 interferes with anti-estrogen