A clinical-molecular update on azanucleoside-based therapy for the treatment of hematologic cancers

Abstract

The azanucleosides azacitidine and decitabine are currently used for the treatment of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) in patients not only eligible for intensive chemotherapy but are also being explored in other hematologic and solid cancers. Based on their capacity to interfere with the DNA methylation machinery, these drugs are also referred to as hypomethylating agents (HMAs). As DNA methylation contributes to epigenetic regulation, azanucleosides are further considered to be among the first true “epigenetic drugs” that have reached clinical application. However, intriguing new evidence suggests that DNA hypomethylation is not the only mechanism of action for these drugs. This review summarizes the experience from more than 10 years of clinical practice with azanucleosides and discusses their molecular actions, including several not related to DNA methylation. A particular focus is placed on possible causes of primary and acquired resistances to azanucleoside treatment. We highlight current limitations for the success and durability of azanucleoside-based therapy and illustrate that a better understanding of the molecular determinants of drug response holds great potential to overcome resistance.

Epigenetic regulation by DNA methylation and miRNA molecules in cancer

“…Despite significant improvement in treatment of cancers, patients have still overall poor prognosis. It is necessary to better understand how these inhibitors act and to identify and validate biomarkers for prediction of treatment response and to find effective combination of demethylation agents with other drugs to improve treatment success and its durability for patients [9].…”

Therapeutic Resistance in Acute Myeloid Leukemia: The Role of Non-Coding RNAs

“…At a dose of only 20 mg twice daily for 10 days every four weeks, it demonstrated increased survival as compared to best supportive care only [78]. While LDAC served as the mainstay of AML LITR for a long time, the recent introduction of HMA treatments remarked a further significant development in this area [1,8], with the cytidine analogues azacitidine (5-azacytidine) and decitabine (5-aza-2′-deoxycytidine) representing the currently best studied substances within this category. Two main anti-tumorigenic effects of these drugs have been described [8]: (a) Both drugs act as antimetabolites and are incorporated into DNA (decitabine) or DNA and RNA (azacitidine), respectively.…”

“…While LDAC served as the mainstay of AML LITR for a long time, the recent introduction of HMA treatments remarked a further significant development in this area [1,8], with the cytidine analogues azacitidine (5-azacytidine) and decitabine (5-aza-2′-deoxycytidine) representing the currently best studied substances within this category. Two main anti-tumorigenic effects of these drugs have been described [8]: (a) Both drugs act as antimetabolites and are incorporated into DNA (decitabine) or DNA and RNA (azacitidine), respectively. Consequently, DNA damage response is induced; (b) Both drugs cause hypomethylation of DNA by inhibiting DNA methyltransferases, which is thought to restore the expression of silenced tumor suppressor genes.…”

“…Consequently, DNA damage response is induced; (b) Both drugs cause hypomethylation of DNA by inhibiting DNA methyltransferases, which is thought to restore the expression of silenced tumor suppressor genes. Both drugs have been tested in multicenter, randomized phase III trials, where they have shown efficacy when compared to LDAC, BSC and/or intensive chemotherapy [8]. Consequently, these drugs evolved as mainstay of AML treatment in older patients who are ineligible to high-intensity chemotherapy, thereby causing a significant amelioration of survival within this subgroup.…”

“…Unfortunately, outcomes are even worse in very old patients, or in those with additional comorbidities excluding them from high-dose approaches. Although the introduction of low-intensity therapeutic regimens (LITR), in particular the hypomethylating agents (HMA) azacitidine and decitabine, has resulted in both increased response rates and extended survival within this cohort, the vast majority of these patients ultimately succumbs to therapy-resistant, progressive disease [1,8,9]. Prognosis of AML patients is influenced by patient-associated factors on the one hand and by disease-related factors on the other hand.…”