Rational Treatment Modifications to Extend Responses to 5-Azacytidine and Decitabine

The drugs 5-azacytidine and decitabine, both DNA methyltransferase-depleting drugs, are the only two approved by the FDA to treat all subtypes of the blood cancer, myelodysplastic syndromes (MDS). They also extend survival for patients with acute myeloid leukemia (AML). Neither agent is curative, but Cleveland Clinic researchers have found a way to improve their effectiveness.

In a recent study, researchers attempted to understand how MDS/AML cells resist the effects of treatment so they could devise solutions for increasing the rate and duration of response in MDS/AML patients. Results of this study were presented in abstract at the 57th American Society of Hematology Annual Meeting & Exposition in Orlando, Fla.

Researchers asked: What are the mechanisms of resistance? “MDS is genetically heterogeneous, thus, this question has been approached by attempting to correlate MDS genetics with response, or by examining genetics at relapse. Unfortunately, results have been contradictory and inconclusive,” the study says.

Researchers considered achievement of the intended molecular pharmacodynamic (PD) effect of DNA methyltransferase depletion as the minimum requirement for response. They found that in both murine and clinical studies relapse was from failure to deplete DNA methyltransferase in the first place. This prompted them to reframe the question: Why is molecular PD not achieved, and can mechanisms be identified to extend response?

Understanding and overcoming resistance mechanisms of MDS/AML cells

Both 5-azacytidine and decitabine are pro-drugs, i.e., they must undergo metabolism within MDS/AML cells before they can exercise their treatment effects.

“The study showed that MDS/AML cells, in patients and also in mouse models of disease, avoid treatment effects by shifting metabolism such that the drugs are not converted into their active forms,” says study co-author Yogen Saunthararajah, MD, of Cleveland Clinic’s Department of Hematologic Oncology and Blood Disorders.

Fortunately, these stratagems used by MDS/AML cells (and also other cancer cells) can be addressed by simple, safe modifications to the drugs and how they are used, to increase their incorporation into MDS/AML cells.

“We have shown this very clearly in the mouse models, and plan to begin clinical trials of these solutions in patients with MDS/AML in the next few months,” says Dr. Saunthararajah.

Clinical trials planned to improve application of 5-azacytidine, decitabine

5-azacytidine and decitabine are important drugs in that they have succeeded where dozens of other drugs failed, Dr. Saunthararajah notes. This is because they can be used to produce a unique and non-toxic, epigenetic treatment effect. The new findings show how to improve the application of these drugs, in order that the full potential of the epigenetic treatment can be realized in the clinic.

These improvements are based on the observation that resistance is not from selection for malignant cells that ignore the epigenetic pharmacologic effect of the drugs, but by selection for leukemia cells that avoid this pharmacologic effect via shifts in pyrimidine metabolism (both drugs are pyrimidine analogues). This stratagem for resistance was strikingly overcome by non-toxic modifications to improve the pharmacology of these drugs, for example, combination with tetrahydrouridine to inhibit degradation by the pyrimidine metabolism enzyme cytidine deaminase.

“We have been able to develop an improved form of decitabine in the clinic, and we need to complete clinical trials with this improved version of the drug. However, we also need to develop a similarly improved version of 5-azacytidine in the clinic, since these drugs are complementary, and both are needed to maximize patient benefit,” Dr. Saunthararajah says.

“We are moving toward clinical trials with the first strategy to overcome resistance, with the addition of tetrahydrouridine (THU) to decitabine, in a multicenter clinical trial conducted by the NCI which is expected to open by the second quarter of 2016, and in single-center trials at Cleveland Clinic even before then,” he said.

The first strategy to overcome resistance is adding tetrahydrouridine (THU) to decitabine. This will be studied in a multicenter clinical trial conducted by the NCI, which is expected to open by the second quarter of 2016. It will be studied even sooner in single-center trials at Cleveland Clinic and Case Comprehensive Cancer Center.