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Page 296 Cancer Drug Resist 2018;1:266-302 I http://dx.doi.org/10.20517/cdr.2018.18

resistance in breast cancer. However, more studies are needed before taking SCO-101 into clinical testing
in patients with anti-estrogen resistant ER positive breast cancer.

54. SCO-101 - an oral drug that interferes with drug resistance mechanisms in cancer

2
1
1
Jan Stenvang , Palle Christophersen , Nils Brünner
1 Scandion Oncology A/S, Ole Maaløvs Vej 3, Copenhagen 2200, Denmark; and University of Copenhagen,
Institute of Drug Design and Pharmacology, Copenhagen, Denmark
2 Saniona A/S, Baltorpvej 154, Ballerup DK-2750, Denmark

SCO-101 is a volume regulated anion channel modulator initially developed to treat patients with sickle
cell anemia (SCA). The drug in the form of an oral capsule has successfully passed 4 clinical phase I studies
in healthy volunteers (n = 92). The studies included different genders, single and multiple dose escalation
studies and potential influence of simultaneous food intake. The drug was safe with very limited toxic-
ity (slight and reversible increase in serum bilirubin). Pharmacokinetic studies showed a T1/2 of 15 h and
Cmax on day 1 of 10 μg/mL = 20 μmol/L and at day 14 of 20 μg/mL = 40 μmol/L. Recommended dose for
phase II was between 100-150 mg/kg. However, due to the increase in serum bilirubin, further develop-
ment for SCA was stopped. SCO-101 significantly increases the effects of certain forms of chemotherapy in
xenotransplanted human cancers. Moreover, SCO-101 reverts resistance to certain types of chemotherapy
and antiestrogens. One recently discovered mechanism of action (MoA) of SCO-101 is inhibition of drug
efflux pumps. Another MoA relates to inhibition of an intracellular signaling pathway being involved in
drug resistance. Scandion Oncology will initiate clinical phase II studies with breast and colorectal cancer
patients, consisting of a run-in part with SCO-101 dose escalations together with standard dose of anti-
cancer therapy followed by a regular phase II study, which will follow Simons two stage design. For the
chemotherapy studies, patients will be treated with one daily oral SCO-101 dose for one week. In week 2,
patients will receive one dose of chemotherapy while continuing daily SCO-101 oral treatment. In week
3, there will be a drug holiday. These three weeks will constitute one treatment cycle. After two and four
cycles, patients will be evaluated for objective response according to RECIST version 1.1. In addition, we
will record progression-free survival and overall survival.

55. The generation of models of acquired resistance using in vitro and in vivo techniques

Steve Wagner, Christopher Hindley, Keisha Hearn, Aurelie Courtin, Tomoko Smyth, Joanne
Munck, Nicola Wallis

Astex Pharmaceuticals, Cambridge, UK

The development of drug resistance against clinically approved targeted agents remains a major challenge
for the treatment of various cancers, with patients frequently relapsing after initial response through multi-
ple mechanisms of resistance. In order to identify and target molecules to overcome resistance to clinically
approved drugs, better models of resistance are required. We have established multiple resistance models
to targeted agents using a number of different techniques. Resistance was generated both in vitro and in
vivo in order to mimic the development of acquired resistance in the patient. In vitro resistance was gener-
ated to targeted agents such as vemurafenib and erlotinib by chronic exposure of cancer cell lines driven
by BRAF (A375, melanoma) and EGFR (HCC827, lung) to these agents over periods of months. Whilst
the generation of resistance to some agents was relatively straight forward, other models required more
optimisation and for some agents we struggled to establish a model of resistance in vitro. In vivo resistance