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AML cells in the bone marrow

SAN DIEGO—A small molecule that has previously proven effective against solid tumors exhibits activity against leukemias and lymphomas, preclinical research suggests.

The molecule, LOR-253, showed antiproliferative activity in a range of leukemia and lymphoma cell lines, induced apoptosis in acute myeloid leukemia (AML) in vitro, and demonstrated synergy with chemotherapeutic agents.

Ronnie Lum, PhD, and colleagues at Lorus Therapeutics, Inc., the Toronto, Canada-based company developing LOR-253, presented these results at the AACR Annual Meeting 2014 (abstract 4544).

LOR-253 acts through induction of the innate tumor suppressor KLF4. Recent research has suggested that upregulation of the transcription factor CDX2 drives the development or progression of leukemic disease. And CDX2 has been shown to silence KLF4, which is reported to be a critical oncogenic event in AML.

Wih this in mind, the researchers decided to test LOR-253’s activity against AML and other hematologic malignancies in vitro.

Experiments revealed that LOR-253 exerts antiproliferative activity against a range of leukemia and lymphoma cell lines, including Ramos, Raji, K-562, Jurkat, MOLT-4, CCRF-CEM, HEL92.1.7, MOLM-13, THP-1, MV411, NB4, HL-60, KG-1, NOMO-1, SKM-1, OCI-AML-2, EOL-1, and Kasumi-1.

IC50 values were substantially lower in these cell lines than in melanoma cell lines, as well as lines of lung, bladder, colon, prostate, and breast cancers.

The researchers also found that LOR-253 induces KLF4 mRNA expression in the AML cell lines HL60 and THP1. This prompts increased expression of p21, a cyclin-dependent kinase inhibitor that is transcriptionally regulated by KLF4.

Consistent with these results, LOR-253 induced cell-cycle arrest and apoptosis in the AML cell lines, which suggests the molecule acted through its intended mechanism of action.

LOR-253 also showed “strong anticancer synergy” in HL60 cells when delivered in combination with daunorubicin, azacitidine, decitabine, or cytarabine.

When LOR-253 was delivered concurrently with chemotherapy, cell viability decreased the most with cytarabine, followed by decitabine, azacitidine, and daunorubicin. With sequential treatment, cell viability decreased the most when LOR-253 was delivered with decitabine, followed by azacitidine, cytarabine, and daunorubicin.

The researchers said these results suggest LOR-253 could provide a new approach to treat AML and, possibly, other hematologic malignancies.

They are now conducting studies to further characterize the pathway that mediates KLF4 induction by LOR-253, to characterize the effects of LOR-253 in combination with approved chemotherapies for AML, and to assess the efficacy of LOR-253 in animal models of AML.

Lorus Therapeutics is also planning a dose-escalating, phase 1b trial of LOR-253 as monotherapy in AML, myelodysplastic syndromes, and other hematologic malignancies. The company expects to begin the trial this summer. ht-logo-end

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