We are happy to announce that AACR has published a Scandion Oncology abstract for the AACR virtual annual meeting. The abstract title is “Re-sensitization of irinotecan/SN38 resistant colorectal cancer cells by SCO-101” and CSO Jan Stenvang will present a poster related to the abstract online on June 22.
The abstract can be viewed below or on this link: https://www.abstractsonline.com/pp8/#!/9045/presentation/5992
Session PO.ET03.08 – Mechanisms of Sensitivity and Resistance to Targeted Therapy 3
6340 / 23 – Re-sensitization of irinotecan/SN38 resistant colorectal cancer cells by SCO-101
Presenter/Authors Jan Stenvang1,2, Sophie Ambjørner2, Khwajanezrabodin Sedighi2, Peter Michael Vestlev1, Lasse Saaby2, Birger Brodin2, Nils Brunner1,2.
1Scandion Oncology, Copenhagen, Denmark, 2University of Copenhagen, Copenhagen, Denmark.
Disclosures J. Stenvang: ; Scandion Oncology. S. Ambjørner: None. K. Sedighi: None. P. Vestlev: ; Scandion Oncology. L. Saaby: None. B. Brodin: None. N. Brunner: ; Scandion Oncology.
Abstract
Introduction: Annually, more than 1 million people are diagnosed with Colorectal Cancer (CRC) and more than 500.000 die from CRC. Only three types of chemotherapy are currently being used worldwide to treat CRC patients: 5FU, oxaliplatin and irinotecan. However, chemotherapy resistance is present or develops in the majority of metastatic CRC patients. Resistance to anti-cancer drugs represents the main cause of cancer-related deaths. Thus, re-sensitization of chemotherapy resistant cancer cells constitutes a highly unmet medical need.
Materials and Methods: The drug, SCO-101, is an oral drug and has previously passed 4 Phase I clinical trials where it demonstrated excellent PK (T1/2=15 hours) and favourable safety profile. We used two pairs of parental (sensitive) and SN38-resistant (SN38 is the active metabilote of irinotecan) human colon cancer cell lines (HT29 and LoVo). Cell viability in vitro during 72h exposure to SCO-101 and/or SN38 was adressed by MTT assays. The level of the SN38 efflux transpoter, ABCG2/BCRP, was investigated in the presence or absence of SCO-101. Additionally, various flux assays were applied to investigate the effect of SCO-101 on ABCG2/BCRP activity. A kinase screen revealed that the kinase SRPK1 was inhibited by SCO-101 and the importance of SRPK1 activity in re-sensitization of SN38 resistant colon cancer cells was investigated by two different synthetic SRPK1 inhbitors.
Results: In parental HT29 and LoVo cells, SCO-101 and SN38 each had a dose-dependent effect on cell viability and no combinational effects were observed between the drugs. When exposing SN38-resistant cells to the combination of SCO-101 and SN38, a significant inhibitory effect on cell viability compared to either drug alone was observed, suggesting an additive or synergistic effect between these two drugs with SCO-101 re-sensitizing the resistant cells to SN38. Flux assays with ABCG2 /BCRP substrates clearly demonstrated that SCO-101 inhibited the activity of ABCG2 and protein analysis further demonstrated that SCO-101 causes degradation of ABCG2/BCRP. Cell viability assays with two different SRPK1 inhibitors demonstrated that this kinase is involved in re-sensitization to SN38.
Conclusion and future perspectives: These preclinical studies demonstrate that SCO-101 sensitizes SN38-resistant colon cancer cells to SN38 through two different mechanisms of actions e.g. inhibition of the SRPK1 kinase and degradation of the ABCG2/BCRP drug efflux pump. We are now preparing a clinical phase II study enrolling metastatic CRC patients, who have developed acquired resistance to irinotecan containing treatment. These patients will be re-exposed to the combination of irinotecan containing treatment and SCO-101. Primary end-points will be safety and objective response rate according to RECIST 1.1. Secondary end-points will be clinical benefit rate. The study has been approved by the Danish Medicines Agency. In conclusion, SCO-101 represents a unique drug with an innovative dual mechanism of action.