clinical topic updates
New Pathways to Target in Chronic Lymphocytic Leukemia
Advances in the understanding of the pathobiology of chronic lymphocytic leukemia (CLL) have led to the success of targeted therapies such as Bruton tyrosine kinase (BTK) inhibitors and BCL-2 inhibitors. Additional mechanisms and pathways are under investigation, and this work may lead to future treatment options.
Jennifer R. Brown, MD, PhD
Director, Center for Chronic Lymphocytic Leukemia
“I am enthusiastic about ROR1 as a promising therapeutic target in CLL. Additionally, the MAPK/ERK pathway has emerged as a potentially common bypass pathway associated with resistance to all of the targeted inhibitors in CLL, so MEK inhibition is an interesting possibility.”
When we first identified some of the somatic mutations that recurrently appear in CLL (eg, NOTCH1 and SF3B1), I think that we had hope that targeting these mutations specifically would help treat the relevant subsets of patients. This strategy is used in many other cancers; however, in CLL, we have studied treatment sensitivity in vitro, and, in most cases, there does not seem to be any differential sensitivity to the respective targeted agents between patients with and without the mutations. In such tests, targeted agents may have had some generalized activity in CLL, but we did not see specificity to the relevant molecular alteration. And this is, perhaps, because there are other mechanisms of activating these pathways, beyond the targeted alteration. That does not mean, however, that there is no room for these targets in CLL therapy, but rather that therapies directed against the targets may be broadly applicable.
I am enthusiastic about ROR1 as a promising therapeutic target in CLL. Additionally, the MAPK/ERK pathway has emerged as a potentially common bypass pathway associated with resistance to all of the targeted inhibitors in CLL, so MEK inhibition is an interesting possibility.
Kipps and colleagues have done a considerable amount of work on ROR1 over the years. It is absent from most normal adult tissues but is overexpressed in CLL and in several other malignancies. Additionally, ROR1 is relatively specific for CLL. In fact, studies with ROR1-specific monoclonal antibodies have confirmed that surface ROR1 is expressed by CLL cells but not by normal B lymphocytes. ROR1 is also highly expressed in patients with high-risk disease. An association between a high-level expression of ROR1 and adverse outcomes was established in a large study by the CLL Research Consortium, where high-level ROR1 was significantly associated with adverse prognostic markers such as the expression of unmutated IGHV. Cirmtuzumab, an antibody directed against ROR1, has shown some activity in the clinic, and there is interest in developing an anti-ROR1 strategy as a component of antibody-drug conjugate therapy and, potentially, in chimeric antigen receptor T-cell therapy.
Additionally, the MAPK/ERK pathway has emerged, in our work and in work done by others, as a bypass pathway that may be relevant to resistance to BTK inhibitors, phosphoinositide 3-kinase inhibitors, and venetoclax. I am excited to be initiating a trial of the MEK inhibitor cobimetinib in patients with CLL. We are not expecting to see high response rates to cobimetinib alone, but we are undertaking correlative work to characterize the pharmacodynamic effects of ERK inhibition. Following that, the goal would be to combine the ERK inhibition of cobimetinib with a next-generation BTK inhibitor or with venetoclax to try to reduce the development of resistance.
Over the past 2 decades, MCL1 has been studied as a potential target in a variety of malignancies. Numerous agents that target MCL1 have been developed, but they are associated with significant cardiotoxicity. I think that MCL1 will eventually be an interesting target in CLL, but the toxicity of MCL1 inhibitors is currently prohibitive. This is similar to NOTCH1 in that drugs have been developed and tested, but the toxicity has been prohibitive.
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