acy-1215 and Lymphoma--Follicular

Oral selective HDAC6 inhibitors could allow for decreased toxicity compared to pan-class inhibitors, and increased ease of use. ACY-1215 is well tolerated and led to disease stabilization in 50% of patients treated on a twice-daily dosing schedule. Rational drug combinations with ACY-1215 improve efficacy in patients with lymphoma. Biomarkers such as XBP-1 level or HDAC6-score may improve patient selection.. ACY-1215, ricolinostat, is an oral, first-in-class isoform-selective HDAC6 inhibitor. HDAC6 is a class IIb deacetylase and plays a critical role in protein homeostasis via the unfolded protein response (UPR). Lymphocytes generate a large repertoire of antibodies and depend on an activated UPR to maintain proteostasis. Lymphomas utilize this biology to evade programmed cell death. In preclinical models of lymphoma, ACY-1215 disrupted proteostasis, triggering apoptosis.. We translated these findings into a multi-institution, open-label, dose-escalation phase Ib/II study aimed to determine the safety and efficacy in patients with relapsed and refractory lymphoma.. Twenty-one patients with heavily pretreated lymphoma were accrued. Patients in the phase Ib portion were enrolled on one of two dose cohorts [Arm A: 160 mg daily (n = 3) or Arm B: 160 mg twice daily (n = 10)]. ACY-1215 was well tolerated. There were no dose limiting toxicities. Most adverse events were grade 1-2, including diarrhea (57%), nausea (57%), and fatigue (43%). Grade 3-4 toxicities were rare and included anemia (9.5%) and hypercalcemia (9.5%). An additional 8 patients were enrolled on the phase II portion, at 160 mg twice daily. Sixteen patients were evaluable for response. ACY-1215 did not result in any complete or partial responses in patients treated. Eight patients had stable disease (50%) lasting a median duration of 4.5 months, all of whom were treated twice daily. Disease progressed in eight patients (50%) at cycle 2. Five patients were not evaluable due to disease progression prior to cycle 2. The median PFS was 56 days.. ACY-1215 is an oral selective HDAC6 inhibitor that was safe in patients with relapsed and refractory lymphoid malignancies and led to disease stabilization in half of the evaluable patients.

Topics: Histone Deacetylase 6; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Lymphoma, Follicular; Pyrimidines

Follicular lymphoma (FL) is the most common indolent B-cell non-Hodgkin lymphoma (NHL) with genetic alterations of BCL-2, KMT2B, and KMT6. FL is refractory to conventional chemotherapy and is still incurable in most patients. Thus, new drugs and/or novel combination treatment strategies are needed to further improve FL patient outcome. We investigated the efficacy of the histone deacetylase 6 (HDAC6) inhibitor A452 combined with a Bruton's tyrosine kinase (BTK) inhibitor ibrutinib on NHL and the underlying mechanisms compared with the current clinically tested HDAC6 inhibitor ACY-1215. We first showed that FL is the most sensitive to HDAC6 inhibitor. We showed that combining A452 with ibrutinib led to the synergistic inhibition of cell growth and decreased viability of FL cells, as well as increased levels of apoptosis. Similar synergistic interactions occur in chronic lymphocytic leukemia (CLL) and germinal center diffuse large B-cell lymphoma cells (DLBCL). Enhanced cell death is associated with AKT and ERK1/2 inactivation and increased DNA damage (induction of γH2A.X and reduction of pChk1/2). In addition, A452 downregulates c-Myc, an effect significantly enhanced by ibruninib. Although ACY-1215 is less potent than A452, it displays synergism with ibrutinib. Overall, our results suggest that A452 is more effective as an anticancer agent than ACY-1215 in FL. These findings suggest that a combination of HDAC6-selective inhibitor and ibrutinib is a potent therapeutic strategy for NHL including FL.

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cell Movement; Cell Proliferation; Drug Synergism; Gene Expression Regulation, Neoplastic; Histone Deacetylase 6; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Lymphoma, Follicular; MAP Kinase Signaling System; Piperidines; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-myc; Pyrazoles; Pyrimidines