The prognosis of acute myeloid leukemia (AML) is poor, highlighting the urgent need for novel therapeutic approaches. CRM1 is a nuclear export receptor involved in the active transport of tumor suppressors (TS) [e.g. p53] out of the nucleus resulting in their inactivation. Over-expression of CRM1 protein has been described in AML. Targeting CRM1 using oral selective inhibitors resulted in significant nuclear accumulation of p53 and in turn high degree of apoptosis, cell-cycle arrest and myeloid differentiation in AML cell lines and patient blasts. Based on these preliminary data we hypothesize that CRM1 inhibitors will be safe and tolerated and will show single agent anti-leukemic activity in AML patients. A Phase 1 study of KPT-330 (last generation oral CRM1 inhibitors) in refractory/relapsed and newly diagnosed unfit elderly (>65 years) AML was started with the goal to assess safety, tolerability and preliminary efficacy of this compound.
In specific aim 1, we propose to perform correlative studies (PK and PD) using specimens from the Phase 1 clinical trial of KPT-330 in AML patients with the intent to: 1) identify pretreatment molecular/cytogenetic biomarkers associated with clinical response and drug activity, 2) evaluate PD endpoints and 3) asses the relationship between PK and PD endpoints. Because AML is a clinically and molecularly complex disease that is unlikely to be cured with a single agent, it is likely that to achieve maximal anti-leukemia activity we need to combine KPT-330 with other active regimens in AML. Our group recently reported a relatively effective and non toxic single agent decitabine treatment schedule for older AML patients. Our preliminary data support that priming AML blasts with decitabine increases KPT-330 anti-leukemic effects. We hypothesize that this effect is caused by the nuclear accumulation of TS previously induced by decitabine.
In specific aim 2, we propose to conduct a Phase 1 clinical trial of decitabine followed by KPT-330 in newly diagnosed unfit elderly (>60) or refractory/relapsed AML patients in order to determine: 1) the safety and tolerability of the regimen;2) the Phase 2 recommended dose;3) preliminary efficacy and 4) PD endpoints including CRM1 dependent targets expression, methylome, transcriptome and miRNA profiling using next generation sequencing. Last, since treatment with CRM1 inhibitors results in up-regulation and nuclear accumulation of p53 and Topoisomerase (Topo) II? (a key enzyme that is required for Topo II inhibitors to induce DNA-cleavage complexes and cell death) in AML blasts, we hypothesize that restoring p53 expression and nuclear localization of Topo II? may increase chemotherapy sensitivity to cytarabine/topo II inhibitors in refractory/relapsed AML blasts. Our data support the hypothesis that KPT-330 synergizes with cytarabine and idarubicin.
In specific aim 3 we propose to overcome chemotherapy resistance in refractory/relapsed AML blasts by enhancing cytarabine and/or Topo II? inhibitors anti-leukemic effects using concomitant or sequential treatment with KPT-330. The main goal of this proposal is to develop oral CRM1 Inhibitors treatment for AML.
Over the past 20 years there has been little improvement in AML treatments, especially for elderly (>60) patients or for patients with refractory disease, with only a few of them surviving for more than 2 years. Lack of significant improvement in the current results calls attention to the need for development of novel therapeutic strategies. The overall goal of this proposal is to test in the clinic a novel approach to target leukemia mechanisms using a new class of drugs called CRM1 inhibitors. These agents are able to restore the expression of cancer protectors (tumor suppressors) and block cancer promoter genes (oncogenes). We are planning to test the CRM1 inhibitors in combination with drugs that have been already approved for use in mankind, but combined in a new manner that may enhance their antileukemic activities and improve the outcome of AML patients.
|Hing, Z A; Fung, H Y J; Ranganathan, P et al. (2016) Next-generation XPO1 inhibitor shows improved efficacy and in vivo tolerability in hematological malignancies. Leukemia 30:2364-2372|
|Ranganathan, Parvathi; Kashyap, Trinayan; Yu, Xueyan et al. (2016) XPO1 Inhibition using Selinexor Synergizes with Chemotherapy in Acute Myeloid Leukemia by Targeting DNA Repair and Restoring Topoisomerase IIÎ± to the Nucleus. Clin Cancer Res 22:6142-6152|
|Ranganathan, Parvathi; Yu, Xueyan; Santhanam, Ramasamy et al. (2015) Decitabine priming enhances the antileukemic effects of exportin 1 (XPO1) selective inhibitor selinexor in acute myeloid leukemia. Blood 125:2689-92|