Assignment: Drug Resistance
Drug resistance has since become the major challenge in treating patients with a single FLT3 inhibitor. The point mutations identified which lead to resistance include N676, F691, and D835 within the kinase domain of FLT3-ITD . The novel FLT3 inhibitors, G-749 and ASP2215 (active against both FLT3 ITD and D835 mutations), have recently been shown to provide sustained inhibition of FLT3 phosphorylation and increased ability to overcome drug resistance in pre-clinical trials but further studies are needed to determine if it will have clinical efficacy [96,97].
Isocitrate Dehydrogenase (IDH) Inhibitors
The IDH1 inhibitor AG-120 and the IDH2 inhibitor AG-221 have demonstrated promising response rates in patients with AML in two separate phase I clinical trials [98,99]. Preliminary results were recently presented for both trials. The objective response rate (ORR) with AG-221 was 40% and 31% with AG-120 in relapsed/refractory AML patients. More interestingly the duration of the responses for AG-221 and AG-120 were more than 15 and 11 months at the analysis, and remained ongoing. Overall, 76% of responses lasted longer than six months. Based on these data, the Food and Drug Administration (FDA) have granted the medication an orphan drug designation for patients with AML.
8.3. Nuclear Exporter Inhibitors
The anti-leukemic efficacy of reversible inhibitors of the major nuclear export receptor, chromosome region maintenance 1 (CRM1, also termed XPO1) has brought much excitement. CRM1 is a major nuclear exporter protein which mediates the export and inactivation of several tumor suppressors such as p53, p73, FOXO1, RB1 and p21 (CDKN1A) among others . CRM1 has been shown to be upregulated in a range of solid tumors and hematological malignancies, including AML [101,102]. Preclinical studies indicate that treatment of AML cell lines, patient samples and AML xenografts with novel CRM1 inhibitors (Selinexor) induces strong anti-leukemic effects [103,104]. Based on these studies, Phase I/II clinical trials are currently ongoing to assess the safety, tolerability and activity of selinexor in AML patients.
8.4. Immune Therapies
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