Retinoid Differentiation Therapy for Common Types of Acute Myeloid Leukemia

Abstract

<jats:p>Many cancers arise in a tissue stem cell, and cell differentiation is impaired resulting in an accumulation of immature cells. The introduction of all-<jats:italic>trans</jats:italic>retinoic acid (ATRA) in 1987 to treat acute promyelocytic leukemia (APL), a rare subtype of acute myeloid leukemia (AML), pioneered a new approach to obtain remission in malignancies by restoring the terminal maturation of leukemia cells resulting in these cells having a limited lifespan. Differentiation therapy also offers the prospect of a less aggressive treatment by virtue of attenuated growth of leukemia cells coupled to limited damage to normal cells. The success of ATRA in differentiation therapy of APL is well known. However, ATRA does not work in non-APL AML. Here we examine some of the molecular pathways towards new retinoid-based differentiation therapy of non-APL AML. Prospects include modulation of the epigenetic status of ATRA-insensitive AML cells, agents that influence intracellular signalling events that are provoked by ATRA, and the use of novel synthetic retinoids.</jats:p>

An ATRActive future for differentiation therapy in AML

“…IMPDH is expressed at high levels in AML blasts 66 . Though the mechanism by which guanine nucleoside levels might affect RAR activity has not been determined, treatment of ATRA-sensitive cell lines with ATRA and an IMPDH inhibitor results in a greater degree of differentiation than with either agent alone 67, 68 .…”

RRD-251 enhances all-trans retinoic acid (RA)-induced differentiation of HL-60 myeloblastic leukemia cells

“…From once being considered one of the most difficult to medically manage, APL is now one of the most treatable, with cure rates of 80-90% using combined RA and arsenic trioxide treatment [1]. The resounding success of RA treatment with APL, the lower toxicity of RA compared to traditional chemotherapeutic agents, and the lack of secondary tumors emerging much later as a sequela has motivated immense interest in its use in other cancers and leukemias, especially in acute myeloid leukemia (AML), where there is uncontrolled proliferation of non-terminally differentiated myeloid precursor cells [2, 3]. Currently, chemotherapy for AML can achieve remission in 60 to 80% of patients less than 60 years of age [4].…”

Elevated PRAME Expression: What Does this Mean for Treatment of Head and Neck Squamous Cell Carcinoma?

“…However, in contrast to effectiveness of ATRA in leukemias [19], retinoids did not reliably improve the outcome in HNSCC. For example, in a Phase III study involving 103 patients with stage I–IV HNSCC, who received either 50–100 mg/m 2 isotretinoin daily or a placebo, no significant differences in the frequency of secondary primary tumors or in the number of local, regional or distant recurrences of the primary cancers were observed [20].…”