Researchers at UMB discovered novel retinamide RAMBAs and validated their therapeutic utility in animal models of breast and prostate cancer. RAMBAs inhibit the cellular enzyme that metabolizes all-trans retinoic acid (ATRA), which actively directs cells to mature in a controlled manner to ensure normal growth. In addition to enhancing the beneficial effects of ATRA, the mechanism of action for these RAMBAs has been shown to involve degradation of Mnk 1/2 and suppression of the oncogenic eIF4E pathway. For potential use in treating dermatological conditions, UMB researchers obtained promising early results demonstrating that lead retinamide RAMBAs have equal or superior effects over approved retinoids (ATRA and 13-CRA) to inhibit proliferation of normal human adult keratinocytes and sebocytes, and antikeratinizing effects in reconstructed human epidermis. Initial toxicity profiles for a panel of RAMBAs [Njar et al., 2006] also showed good indications for safe therapeutic use.
These novel RAMBAs block the normal metabolism of endogenous ATRA in cells, increasing the beneficial effects of ATRA. They provide a unique approach to achieve the therapeutic benefit of retinoid therapy while potentially circumventing the adverse events associated with it, a very important property for application to dermatology therapy. ATRA deficiencies are associated with dermatological diseases (acne and psoriasis), and retinoid derivatives have been one of the mainstay therapies for acne. Liarozole is in clinical use for the treatment of psoriasis and ichthyosis. Dermatological retinoid deficiencies are characterized by hyperkeratinization and desquamation and include diseases such as acne, eczema, psoriasis, cold sores, wounds, burns, sunburn, ichthyosis, skin cancer, and Kaposi’s Sarcoma, all of which are plausible targets for retinamide RAMBA therapy.
Current Preclinical Study:
In December 2019 Hoth entered a research collaboration agreement with Weill Cornell Medicine to examine the ability of retinoic acid metabolism blocking agents (RAMBA) to block acne pathogenic gene expression in human keratinocytes, mouse skin, and carcinogenesis in mice. Acne is the result, in part, of Propionibacterium acnes or ‘P. acnes’ growth in hair follicles, which leads to a defined set of pathogenic gene expression changes. The research collaboration will be conducted in three phases for a period of one year. Dr. Jonathan Zippin, M.D., Ph.D., FAAD, Associate Professor of Dermatology at Weill Cornell Medicine and HOTH Senior Scientific Advisor, will be the Principal Investigator for the research collaboration.
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