MicroRNA dysregulation to identify therapeutic target combinations for chronic lymphocytic leukemia

Abstract

Loss of is the most common genetic lesion in chronic lymphocytic leukemia (CLL), promoting overexpression of, which factors in leukemia pathogenesis. Indeed, an inhibitor of Bcl2, venetoclcax, is highly active in the treatment of patients with CLL. However, single-agent venetoclcax fails to eradicate minimal residual disease in most patients. Accordingly, we were interested in other genes that may be regulated by , which may target other drivers in CLL. We found that targets , which encodes an onco-embryonic surface protein expressed on the CLL cells of over 90% of patients, but not on virtually all normal postpartum tissues. CLL with high-level expression of ROR1 also have high-level expression of Bcl2, but low-to-negligible Moreover, CLL cases with high-level ROR1 have deletion(s) at the chromosomal location of the genes encoding (13q14) more frequently than cases with low-to-negligible ROR1, implying that deletion of may promote overexpression of , in addition to ROR1 is a receptor for Wnt5a, which can promote leukemia-cell proliferation and survival, and can be targeted by cirmtuzumab, a humanized anti-ROR1 mAb. We find that this mAb can enhance the in vitro cytotoxic activity of venetoclcax for CLL cells with high-level expression of ROR1, indicating that combining these agents, which target ROR1 and Bcl2, may have additive, if not synergistic, activity in patients with this disease.

Targeting Wnt signaling pseudokinases in hematological cancers

“…shRNA‐mediated ROR1 targeting combined with DSRT in both BCR‐sensitive and BCR‐insensitive MCL cells enhanced cytotoxicity for several apoptotic modulators such as Bcl‐2 family inhibitors. This was especially true for BH3 mimetics navitoclax and venetoclax, currently used in the clinic, and this effect was also observed in CLL . These findings bring to our attention another combinatorial treatment with excellent clinical potential, which can target ROR1 and Bcl‐2 and may have additive, if not synergistic, responses in CLL and MCL patients.…”

“…This was especially true for BH3 mimetics navitoclax and venetoclax, 35 currently used in the clinic, and this effect was also observed in CLL. 58 These findings bring to our attention another combinatorial treatment with excellent clinical potential, which can target ROR1…”

Role of Non-Coding RNAs in the Development of Targeted Therapy and Immunotherapy Approaches for Chronic Lymphocytic Leukemia

“…In that study, Cimmino et al demonstrated that miR-15a/miR-16-1 targets BCL2, a key gene involved in the regulation of apoptosis [15,31]. Several years later, it was revealed that miR-15a/miR-16-1 also targets ROR1, the receptor for Wnt5a that initiates the Wnt non-canonical growth signaling pathway [32]. Mutations and microdeletion leading to loss of function of miR-15a/miR-16-1 were also found not only in CLL (~90%) but in other cancers as well [33,34].…”

“…This discovery opened two new fields of study: the identification of specific sncRNAs signatures in cancer to use as diagnostic tools, and that identification of their targets to evaluate as targets for the development of new therapeutic strategies. Indeed, the discovery that altered expression of sncRNAs is associated with the dysregulation of genes and pathways with a key role in CLL onset, progression, and drug resistance, led to the development of several novel compounds to treat CLL and possibly other malignancies, by targeting cancer-specific molecules involved in apoptosis and cell growth [32]. Some of these compounds are small molecules that target proteins essential for cancer cell survival.…”

“…Thus, a clinical trial to evaluate the safety of cirmtuzumab in combination with ibrutinib was started and proved to be well-tolerated and effective, with few cases of complete response (NCT03088878). Since in vitro experiments showed that cirmtuzumab enhances the venetoclax ADCC activity, a clinical trial to evaluate a combination of cirmtuzumab with venetoclax to treat CLL patients is warranted [32]. Both venetoclax and cirmtuzumab were designed to target the genes that are overexpressed in CLL as a consequence of miR-15a/miR-16-1 loss, thus, the efficiency of this combination therapy provides an additional remarkable indication that microRNAs studies are essential for the development of more effective therapeutic approaches.…”