lde225 and Myelodysplastic-Syndromes

Myeloid neoplasms (myelodysplastic syndrome [MDS], myelofibrosis, and chronic myelomonocytic [CMML]) are aggressive hematological malignancies for which, despite recent approvals, novel therapies are needed to improve clinical outcomes. The hedgehog (HH) pathway is one of the main pathways for cancer stem cells survival and several HH inhibitors (HHi) are approved in clinical practice.. Sixty-two patients (28 [45%] newly diagnosed) were treated in this study, including 10 patients in the dose-finding component and 52 patients in phase 1b. SON 200 mg oral daily on days 1-28 each cycle was deemed the recommended dose for phase 1b. Out of 21 rrAML patients, two achieved response (one complete response/one morphologic leukemia-free state) with no responses seen in seven r/r MDS/CMML patients. In newly diagnosed AML/MDS, response was seen in six (three had complete remission, two had morphological leukemia-free status) of 27 patients. Median overall survival was 26.4 and 4.7 months for newly diagnosed MDS and AML, respectively. Safety was satisfactory with common (>20%) side effects including fatigue, constipation, nausea, cough, insomnia, and diarrhea. Only 7% of patients died in the study, and none of the deaths were deemed related to treatment.. Our study shows that AZA + SON are a safe combination in a patient with MN. Similar to other hedgehog inhibitors, this combination yielded limited response rate in patients with myeloid neoplasms.

Topics: Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Hedgehog Proteins; Humans; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Chronic; Myelodysplastic Syndromes; Myeloproliferative Disorders; Treatment Outcome

Therapy and outcome for elderly acute myeloid leukemia (AML) patients has not improved for many years. Similarly, there remains a clinical need to improve response rates in advanced myelodysplastic syndrome (MDS) patients treated with hypomethylating agents, and few combination regimens have shown clinical benefit. We conducted a 5-azacytidine (5-Aza) RNA-interference (RNAi) sensitizer screen to identify gene targets within the commonly deleted regions (CDRs) of chromosomes 5 and 7, whose silencing enhances the activity of 5-Aza.. An RNAi silencing screen of 270 genes from the CDRs of chromosomes 5 and 7 was performed in combination with 5-Aza treatment in four AML cell lines (TF-1, THP-1, MDS-L, and HEL). Several genes within the hedgehog pathway (HhP), specifically SHH, SMO, and GLI3, were identified as 5-Aza sensitizing hits. The smoothened (SMO) inhibitors LDE225 (erismodegib) and GDC0449 (vismodegib) showed moderate single-agent activity in AML cell lines. Further studies with erismodegib in combination with 5-Aza demonstrated synergistic activity with combination index (CI) values of 0.48 to 0.71 in seven AML lines. Clonogenic growth of primary patient samples was inhibited to a greater extent in the combination than with single-agent erismodegib or 5-Aza in 55 % (6 of 11) primary patient samples examined. There was no association of the 5-Aza/erismodegib sensitization potential to clinical-cytogenetic features or common myeloid mutations. Activation of the HhP, as determined by greater expression of HhP-related genes, showed less responsiveness to single-agent SMO inhibition, while synergy between both agents was similar regardless of HhP gene expression. In vitro experiments suggested that concurrent dosing showed stronger synergy than sequential dosing.. Inhibition of the HhP with SMO inhibitors in combination with the hypomethylating agent 5-Aza demonstrates synergy in vitro and inhibits long-term repopulation capacity ex vivo in AML and MDS. A clinical trial combining 5-Aza with LDE225 (erismodegib) in MDS and AML is ongoing based on these results as well as additional publications suggesting a role for HhP signaling in myeloid disease.

Topics: Acute Disease; Aged; Aged, 80 and over; Anilides; Antimetabolites, Antineoplastic; Azacitidine; Biphenyl Compounds; Cell Line, Tumor; Cell Survival; Chromosomes, Human, Pair 5; Chromosomes, Human, Pair 7; Drug Synergism; Female; Hedgehog Proteins; High-Throughput Nucleotide Sequencing; HL-60 Cells; Humans; Leukemia, Myeloid; Male; Myelodysplastic Syndromes; Pyridines; RNA Interference; Signal Transduction