Gaël Roué, PhD, Josep Carreras Leukemia Research Institute, Barcelona, Spain, highlights study findings exploring the loss of the small GTPase Ras homolog family member A (RhoA) and how this enhances lymphomagenesis and impairs the activity of lenalidomide in patients with mantle cell lymphoma (MCL). These findings were presented at the 2022 American Associated for Cancer Research (AACR) Annual Meeting.

Transcript
My name is Gaël Roué. I'm the head of the Lymphoma Translational Group at the Josep Carreras Leukemia Research Institute in Barcelona, Spain. My main interest is developing a new disease model for high-risk MCL and the development of new therapeutic drugs for this disease.

Oncology Learning Network: What existing data led you and your co-investigators to conduct this research?

Dr Roué: Some years ago, we had evidence that the loss of expression of some Rho GTPases are related to a worst prognosis in some hematological malignancies. We know that, especially in MCL, which is a really aggressive disease, the lower level of RhoA, which is the main component of the Rho GTPase family, is associated with a worst prognosis of these patients.

OLN: Could you briefly describe the study and its findings?

Dr Roué: To analyze the role of RhoA in MCL, we developed a RhoA knock-out model, using cell lines subjected to CRISPR-Cas9 methodology, to deplete RhoA in the cell. Then, we analyzed the impact of RhoA depletion on the transcriptome of the cells, on their mobility of the cells, on the aggressiveness of the lymphoma cells in vivo, in vitro, and also, in the response to lenalidomide, which is a drug approved for the treatment of relapsed or refractory MCL patients.

OLN: Were any of the outcomes particularly surprising?

Dr Roué: Indeed, we confirmed the role of RhoA in the regulation of cytoskeleton (it was almost expected), but we were surprised to see that this modulation of cytoskeleton by RhoA was necessary for the activity of lenalidomide. Indeed, when we lose RhoA in MCL cell, we decreased, significantly, the activity of the immunomodulatory drug in vitro, and also in vivo.

OLN: What are the possible real-world applications of these findings in clinical practice?

Dr Roué: Right now, we are screening for a new compound, that would be able to increase the expression, or the activity, of RhoA in MCL, since it seems that this could be considered as an anti-tumor agent.

Then, to try whether we could improve the response of MCL cell lines, and MCL xenograph models to lenalidomide.

OLN: Do you and your co-investigators indent to expand upon this research? If so, what will be your next steps?

Dr Roué: Next step is to identify the compound, which could be transferred into the clinic, that may have this property to increase RhoA activity in MCL.

OLN: Is there anything else pertaining to your research and finings that you would like to add?

Dr Roué: One of the particularities of the work we presented here, also developing in the lab, is the use of a new in vivo xenograft model, which is the chick chorioallantois membrane model, the CAM assay, which allows us to work in immunocompetent model without the requirement of animals.

We are not using mice in these studies, but we can analyze the effect of genetic modulation in vivo, as well.

Source:
Santos JC, Ribeiro ML, Roue G. Loss of the small GTPase RHOA enhances lymphomagenesis and impairs the activity of lenalidomide in mantle cell lymphoma. Abstract presented at: AACR Annual Meeting; April 8-13, 2022; New Orleans, LA. Abstract 2981/10.