An experimental drug that works by blocking the export of key control molecules from the nucleus of cancer cells shows promise as a treatment for chronic lymphocytic leukemia (CLL) and other incurable B-cell malignancies, according to a new study by researchers at the Ohio State University Comprehensive Cancer Center ? Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC ? James).

The agent, called KPT-SINE, belongs to a new class of drugs called selective inhibitors of nuclear export (SINE). The agent was developed by Karyopharm Therapeutics Inc. It is designed to kill cancer cells by restoring biochemical pathways that normally cause unhealthy cells to self-destruct through a process called programmed cell death, or apoptosis.The agent targets and irreversibly binds to a protein called CRM1 (Exportin 1, XPO1) and blocks it’s function.

Apoptotic pathways
CRM1 has been shown to be up-regulated in hematologic and various solid tumors, making it a highly attractive molecular target impacting multiple pro apoptotic pathways. However, until now, researchers confirm that the role of CRM1 and the consequences of its mutation in the development of CLL have not been adequately explored. What’s known is that during disease progression, cancer cells use CRM1 to shunt certain apoptosis-related proteins, including p53, I-?B, and FOXO3A, out of the nucleus, thereby avoiding cell death.

CRM1 in the pathogenesis of CLL
Recently, whole-genome sequencing in patients with CLL allowed researchers to identify recurrent mutations in a highly conserved region of CRM1 that can potentially affects its gene function, suggesting a direct role for CRM1 in the pathogenesis of CLL [1]

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Crucial pursuit
Because of the distinct subtypes of CLL and multiple signaling pathways dysregulated, a therapeutic agent targeting just a single biological pathway is unlikely to be effective. Thus, pursuit of CRM1 inhibition as a novel strategy aimed to restore multiple death pathways is crucial and has broad implications for many types of patients.

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?We believe that KPT-SINE and other nuclear-export inhibitors may represent a unique, entirely new therapeutic strategy for treating cancer by simultaneously restoring multiple normal cell death pathways,? says OSUCCC ? James research scientist Rosa Lapalombella, Ph.D, who is a co-investigator on the study withJohn Byrd, MD, director of the division of hematology and co-director of the OSUCCC ? JamesCLL Experimental Therapeutics Laboratory at OSUCCC ? James. The researchers hypothesize that KPT-SINE will inhibit CRM1 and keep these regulatory proteins in the nucleus where they can initiate programmed cell death.

The study, which used CLL cells from patients and a mouse model of CLL, provides essential proof-of-concept data to design and initiate phase I clinical testing of KPT-SINE in patients with these incurable diseases, Lapalombella notes.?We are excited by our preliminary findings that KPT-SINE represents a promising targeted therapy for CLL patients,? Byrd says. ?We look forward to transitioning our research toward early clinical development in patients with CLL and related diseases, based upon the data generated by our team.?

CLL is the most common form of adult leukemia, with about 15,000 new cases annually in the United States. Despite recent therapeutic advancements, all CLL patients will eventually relapse after treatments, and most will die of their leukemia. About 4,400 Americans die of the disease each year.

Other hematologic malignancies
Selective Inhibitors of Nuclear Export (SINE) modulators are studied in the treatment of a variety of hematologic malignancies including chronic lymphocytic leukemia (CLL), non-Hodgkin?s lymphoma (NHL), multiple myeloma (MM), acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), and blast-crisis chronic myelogenous leukemia (bc-CML).

Commenting on the development of novel CRM1 inhibitors for the treatment of non-Hodgkin?s lymphoma, on of the other hematologic malignancies in which KPT-SINE is studied, Ramzi Mohammad, PhD, Hematology and Oncology, Karmanos Cancer Institute, Detroit, MI, said: ?This is the first time we have seen such high potency and specificity of an orally available small molecule CRM1 inhibitor that has shown activity in various models including those with a dysfunctional p53 pathway.?

The Leukemia and Lymphoma Society Translational Research Program, D. Warren Brown Foundation and the Harry T. Mangurian Foundation supported this research.Other Ohio State researchers involved in the study are Caroline Berglund, Emilia Mahoney, Katie Williams, Shruti Jha and Asha Ramanunni.

Rosa Lapalombella will discuss the role of CRM1 inhibition in the treatment of CLL on Monday, December 12, at 7:45 a.m. during the 53rd Annual Meeting of the American Society of Hematology.

Program: Oral and Poster Abstracts
Type: Oral
Session:604. Molecular Pharmacology, Drug Resistance: Novel Targets and Response Determinants
Abstract:
232 CRM1/XPO1 Represents a Promising Therapeutic Target for Treatment of Chronic Lymphocytic Leukemia
When:
Monday, December 12, 2011: 7:00 AM-8:30 AM
Where: Room 5AB (San Diego Convention Center)
Moderators:Paolo Neviani, PhD, The Ohio State University and B van der Reijden, Radboud University Nijmegen Medical Centre (RUNMC)

References:
[1] Puente XS, Pinyol M, Quesada V, Conde L, Ord??ez GR, Villamor N,et al. Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature. 2011 Jun 5;475(7354):101-5.

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