FEBRUARY 2020 - A targeted therapy against renal carcinoma via WNT and NOTCH?

Abstract

Current treatments for clear cell renal cell cancer (ccRCC) are insufficient because two-thirds of patients with metastases progress within two years. Here we report the identification and characterization of a cancer stem cell (CSC) population in ccRCC. CSCs are quantitatively correlated with tumor aggressiveness and metastasis. Transcriptional profiling and single cell sequencing reveal that these CSCs exhibit an activation of WNT and NOTCH signaling. A significant obstacle to the development of rational treatments has been the discrepancy between model systems and the in vivo situation of patients. To address this, we use CSCs to establish non-adherent sphere cultures, 3D tumor organoids, and xenografts. Treatment with WNT and NOTCH inhibitors blocks the proliferation and self-renewal of CSCs in sphere cultures and organoids, and impairs tumor growth in patient-derived xenografts in mice. These findings suggest that our approach is a promising route towards the development of personalized treatments for individual patients.

Interview

In February, Annika Fendler and Daniel Bauer received the Paper of the Month award. We spoke with Mr. Bauer about the excellent publication:

Mr. Bauer, together with Annika Fendler, you and your team have been working on clear cell renal cell carcinoma. What is this carcinoma?

Bauer: Renal carcinoma is the twelfth most common type of cancer, and the clear cell subtype, which is the one we mainly deal with, accounts for about 70% of cases.

What therapies do doctors* use to treat the cancer?

So far, renal carcinoma is mainly treated with targeted therapies, such as receptor thyrosine kinase inhibitors. Often, however, as with many types of cancer, resistance is built up and the disease progresses. Immunotherapies with so-called checkpoint inhibitors, which control the tumor's immune system weakening mechanisms, are also used in renal carcinoma in the late stage of therapy and show success.  

In your study you found that the treatment of cancer stem cells with so-called WNT and NOTCH inhibitors can interfere with their growth. What is WNT and NOTCH and how did you proceed methodically?

WNT and NOTCH are two signaling pathways whose involvement was already known in other types of cancer. However, their role in the cancer stem cells of renal tumors was not known before. Once we identified the cancer stem cells and isolated them using specific surface markers, we were able to analyze them in detail in several preclinical models to gain insight from several perspectives. Here we were able to determine the activation of both signaling pathways in the cancer stem cells and were then able to design a potential therapy strategy that specifically kills the cancer stem cells.  

Do you see a chance that your results could be used to develop a new therapy for renal cancer?

Of course we very much hope that our therapeutic approach will make the leap into the clinic. Since WNT and NOTCH inhibitors are currently in clinical trials for other types of cancer, we are hoping for promising results and subsequent approvals. These would make it much easier to transfer the technology to other cancer types and "off-label" therapies. I am convinced that we will see many therapeutic approaches in the future that target, i.e. specifically attack, cancer stem cells. This would make it possible to kill the very cells that create metastases and are responsible for the tumors growing again. As long as these cells are not destroyed, the tumor can come back every time - this makes their treatment so important.

Thank you very much for the interview!

You are very welcome.

Daniel Bauer with the award Paper of the Month February 2020 Photo: BIH/Ole Kamm