Office of Technology Transfer – University of Michigan

A non-irritating retinoid for treatment of promyelocytic leukemia

Technology #6397

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Categories
Researchers
James Varani
Managed By
Ed Pagani
Assistant Director, Health Technologies 734-763-3558
Publications
Activity of MDI-301, a novel synthetic retinoid, in xenografts.
Anticancer Drugs. 2004 Nov;15(10):991-6., 2004
MDI 301, a nonirritating retinoid, improves abrasion wound healing in damaged/atrophic skin
Wound Repair and Regeneration. The International Journal of Tissue Repair and Regeneration. Volume 16, Issue 1. January-February 2008. Pages 117-124, 2008
Separation of retinoid-induced epidermal and dermal thickening from skin irritation
Arch Dermatol Res. Nov 2003; 295(6): 255–262. Published online Oct 16, 2003. doi:  10.1007/s00403-003-0416-5, 2003

Leukemia is a blood cancer that, in 2014, will be diagnosed in an estimated 52,380 Americans and cause an estimated 24,090 deaths. Acute myeloid leukemia (AML) is the most common form of leukemia in adults, and the overall survival rate for AML is only about 21%. Promyelocytic leukemia (PML) is a subtype of AML that tends to be responsive to treatment by a derivative of vitamin-A called all-trans retinoic acid (ATRA). Despite its effectiveness in treating PML, ATRA causes an unfortunate side-effect called retinoic acid syndrome in 25 to 30% of patients. Retinoic acid syndrome is characterized by fever, chills, and respiratory distress but can also include edema, weight gain, pleural or pericardial effusions, pulmonary hemorrhage, episodic hypotension, and/or kidney failure. With such dramatic symptoms, fatality occurs in up to 30% of cases. Therefore, a treatment that effectively suppresses PML cell growth but evades the toxic response caused by ATRA would be highly-desirable.

A synthetic retinoid ester has similar efficacy to ATRA without common ATRA-induced side-effects

One molecule related to ATRA is an ester synthesized from 9-cis retinoic acid. In cultured human AML cells, this retinoid inhibited cell growth and increased markers for cell differentiation (indicating they were no longer undifferentiated tumor cells) at levels comparable to ATRA. In mice with a human AML cell xenograft, ATRA treatment did not significantly prevent tumor volume growth, while the retinoid did. One of the mechanisms hypothesized to cause ATRA-induced retinoic acid syndrome is an increased level of pro-inflammatory cytokines, which coincides with increased skin irritation. Mice treated with the retinoid not only avoided the skin irritation, but they also lacked increased levels of a number of pro-inflammatory cytokines that were increased with ATRA treatment. Together these data point to this synthetic retinoid ester as a promising PML treatment that does not have the toxicity commonly seen with ATRA treatment.

Applications

  • Treatment for promyelocytic leukemia
  • Potential development for treatment of other cancers such as some forms of myeloid leukemia, neuroblastoma, and/or squamous cell cancers

Advantages

  • Does not induce toxic side-effects commonly caused by the currently prevalent treatment