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Cancer-type SLCO1B3 as a detection marker and therapeutic target in RDEB-SCC

Completed
Project leadDr. Christina Guttmann-Gruber and Dr. Josefina Piñón Hofbauer
Organisation EB House Austria
Project budgetEUR 43.195,00 (PMU-FFF) and DEBRA Austria core funding to the EB House Austria
Start date / Duration01. Feb 2015 / 24 months
Funder(s) / Co-Funder(s) PMU, DEBRA Austria
Research area Skin cancer & fibrosis

Project details

Short lay summary

Squamous cell carcinomas (SCC) that arise in the general population are easily detectable and highly treatable, with good prognosis for patients. In contrast, those that develop in RDEB are difficult to detect against the background of chronic wounds and skin erosions, and are particularly aggressive and difficult to treat. Especially for these patients, early detection is key to improving survival, and alternative targeted treatment options are urgently needed. This research group previously identified a novel tumour marker in RDEB-SCC whose gene product is currently only distinguishable at the RNA level and whose function is unknown. This study aims to evaluate its potential as a detection marker in liquid biopsies, as well as a therapeutic target by employing an innovative RNA-targeting approach.

Scientific summary

Expression of the solute carrier organic anion transporter family member 1B3 (SLCO1B3) is normally restricted to the liver; however a variant mRNA isoform has been identified in various cancers, including colorectal cancer. We demonstrate that this cancer-type transcript, Ct-SLCO1B3, is specifically expressed in RDEB-SCC but not in non-malignant keratinocytes. This makes it a potential molecular detection marker as well as a tumor-specific therapeutic target. To evaluate its utility as a detection marker, we explored the possibility of utilizing tumor-derived extracellular vesicles (EVs) in liquid biopsies for the detection of Ct-SLCO1B3. We could detect Ct-SLCO1B3 RNA in EVs harvested from conditioned medium of RDEB-SCC cells cultured in vitro and from the serum of tumor-bearing mice. In contrast, the marker was absent from all control samples tested.

For the specific targeting of Ct-SLCO1B3 in RDEB-SCC, we employed spliceosome-mediated RNA trans-splicing (SMaRT) technology to replace the coding sequence of Ct-SLCO1B3 with that of the suicide gene herpes simplex virus 1 thymidine kinase (HSV1tk), thereby enabling tumor cells to convert the non-toxic prodrug ganciclovir (GCV) into an active drug which triggers apoptosis. Based on a previously established screen, we developed an RNA trans-splicing molecule (RTM) capable of targeting Ct-SLCO1B3. We demonstrated generation of the desired chimeric trans-splicing product on both the RNA level and protein level in vitro, which correlated with the induction of apoptosis upon treatment with GCV. Furthermore, we achieved tumor regression in xenograft models wherein mice engrafted with tumor cells stably expressing the therapeutic RNA trans-splicing molecule (RTM) were treated systemically with GCV, thus establishing proof-of-principle and demonstrating the feasibility of this tumor targeting approach. This approach was further used successfully in a colorectal cancer model, expanding the utility of this approach to other major tumor types that express Ct-SLCO1B3.

Strategic relevance

  • DEBRA strategic goal: Skin cancer in EB
  • Project goal: To evaluate the utility of Ct-SLCO1B3 as a detection marker and therapeutic target in RDEB-SCC.
  • Preceding/ follow-on projects, and related projects: Capitalizing on these results we will develop highly specific and sensitive diagnostic assays based on Ct-SLCO1B3 molecular detection.

What did this project achieve?

Ct-SLCO1B3 is a robust and reliable biomarker for RDEB-SCC that can potentially be exploited for screening of this life-threatening cancer. This research demonstrated for the first time the isolation of RDEB-SCC-derived extracellular vesicles both in vitro and from the serum of tumor-bearing mice, highlighting the feasibility of a minimally invasive method for the detection of RDEB-SCC based on the presence of Ct-SLCO1B3.

The data also highlight Ct-SLCO1B3 as an ideal target for the HSVtk SMaRT-suicide system, thereby opening up new translational avenues for Ct-SLCO1B3-targeted cancer therapy. Successful application of this approach in experimental models of colorectal cancer, one of the most common cancers in the world with a global impact on the healthcare industry, make it attractive for further development in this respect.


Keywords

RDEB cancerEarly detectionLiquid biopsyTrans-splicingSuicide gene therapyCancer therapy
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