Chronic myelogenous leukemia on target

June 2018

Chronic myelogenous leukemia (CML) is commonly treated with tyrosine kinase inhibitors (TKIs) that inhibit the pro-leukemic activity of the BCR-ABL1 oncoprotein. Despite the therapeutic progress mediated by TKI use, off-target effects, treatment-induced drug resistance, and the limited effect of these drugs on CML stem cells (SCs) are major drawbacks frequently resulting in insufficient or unsustainable treatment. Therefore, intense research efforts have focused on development of improved TKIs and alternative treatment strategies to eradicate CML SCs. Alongside efforts to design superior protein inhibitors, the need to overcome the poor therapeutic effect of TKIs on CML SCs has led to a renaissance of antisense strategies, as they are reported as effective in more primitive cell types. Despite the greater drug design flexibility offered by antisense sequence variability and remarkable chemical improvements, antisense drugs exhibit unacceptable levels of off-target effects, precluding them from large-scale clinical testing. Recent advances in antisense drug design have led to a pioneering mRNA recognition concept that may offer a helping hand in eliminating off-target effects, and has potential to bridge the gap between research and clinical practice.

The management of chronic myelogenous leukemia (CML) has undergone profound evolution over a relatively short period of time. Since its identification, the BCR-ABL1 oncoprotein, a hallmark of CML cells, has become the primary molecular target for the development of selective therapeutics for patients with CML. On 28 May 2001, TIME magazine proudly proclaimed “there is new ammunition in the war against cancer – revolutionary new pills like Gleevec combat cancer by targeting only the disease cells.” Gleevec, the first tyrosine kinase inhibitor (TKI) selectively targeting BCR-ABL1, remarkably altered treatment paradigms and, compared to former nonselective chemotherapy regimens, contributed dramatically to substantially prolonged survival times and improved quality of life for patients with CML.

However, 17 years of clinical experience with TKIs has demonstrated that, despite their apparent therapeutic benefit, these drugs are not entirely selective for CML cells, neither are they sufficiently specific for BCR-ABL1. Lack of selectivity, various off-target effects, hematological and nonhematological toxicity, and treatment-induced drug resistance are recurrent and persistent shortcomings of treatment with TKIs that often result in inferior patient outcomes, require switching to an alternative TKI, may force discontinuation of treatment, or cause adverse events, contributing to decreased quality of life. Moreover, TKIs have limited therapeutic effect towards CML stem cells (SCs); therefore, the majority of patients continue to take these drugs indefinitely, and rarely achieve complete recovery. Nevertheless, there are suggestions that a permanent cure can be induced by TKIs, based on results of TKI stop studies, which reported that, after deliberate TKI cessation in a strictly clinically defined cohort of patients with CML, half remained free from disease relapse after 2 years of follow-up. Importantly, because of the restricted detection limit of current methods for monitoring minimal residual disease, it is extremely difficult to discriminate clearly between latent CML and complete cure from the disease. The pitfalls described above highlight the scope for improvement and suggest room for curative treatment approaches with a primary focus on CML SCs and on causal genetic aberrations that trigger leukemogenesis…

Read original article

error: Content is protected !!