Clinical development of fenretinide as an antineoplastic drug: Pharmacology perspectives

Abstract

Fenretinide (4-HPR) is a synthetic retinoid that has cytotoxic activity against cancer cells. Despite substantial in vitro cytotoxicity, response rates in early clinical trials with 4-HPR have been less than anticipated, likely due to the low bioavailability of the initial oral capsule formulation. Several clinical studies have shown that the oral capsule formulation at maximum tolerated dose (MTD) achieved <10 µmol/L concentrations in patients. To improve bioavailability of 4-HPR, new oral powder (LYM-X-SORB®, LXS) and intravenous lipid emulsion (ILE) formulations are being tested in early-phase clinical trials. ILE 4-HPR administered as five-day continuous infusion achieved over 50 µmol/L at MTD with minimal systemic toxicities; multiple complete and partial responses were observed in peripheral T cell lymphomas. The LXS oral powder 4-HPR formulation increased plasma levels approximately two-fold at MTD in children without dose-limiting toxicities and demonstrated multiple complete responses in recurrent neuroblastoma. The clinical activity observed with new 4-HPR formulations is attributed to increased bioavailability. Phase I and II clinical trials of both LXS 4-HPR and ILE 4-HPR are in progress as a single agent or in combination with other drugs. Impact statement One of the critical components in drug development is understanding pharmacology (especially pharmacokinetics) of the drugs being developed. Often the pharmacokinetic properties, such as poor solubility leading to poor bioavailability, of the drug can limit further development of the drug. The development of numerous drugs has often halted at clinical testing stages, and several of them were due to the pharmacological properties of the agents, resulting in increased drug development cost. The current review provides an example of how improved clinical activity can be achieved by changing the formulations of a drug with poor bioavailability. Thus, it emphasizes the importance of understanding pharmacologic characteristics of the drug in drug development.

The UPR Activator ATF6 Responds to Proteotoxic and Lipotoxic Stress by Distinct Mechanisms

“…It did still effectively activate the luminal Y567N-ATF6 mutant (Figure 6B, lane 16; S6E-H). Thus FEN, already being tested in humans as a potential anti-cancer drug for reasons unrelated to ATF6 (Cooper et al, 2017), could be tested for efficacy in ATF6 mutant-related diseases.…”

<p>A Novel Nanomicellar Combination of Fenretinide and Lenalidomide Shows Marked Antitumor Activity in a Neuroblastoma Xenograft Model</p>

“…However, they still faced problems probably related to the strong drug-lipid association that limited drug release, requiring high drug doses to achieve therapeutic plasma drug concentrations. [26][27][28][29] The recent approach of fenretinide nanoencapsulation in amphiphilic macromolecules, polymers or phospholipids, provided high levels of aqueous drug solubilization, bioavailability and absorption at the tumor site. [30][31][32][33][34][35][36][37][38] Preclinical studies on nanoformulations of fenretinide-cyclodextrin complex 37 and fenretinide-phospholipid salts 38 indicated high antitumour activity in cancer stem cells of various origins in vitro, and in tumour xenografts derived from cancer stem cells of lung cancer, colon cancer and melanoma origin.…”

Fenretinide treatment accelerates atherosclerosis development in apoE‐deficient mice in spite of beneficial metabolic effects

“…Fenretinide is a derivative of retinoic acid, widely investigated as chemo-preventive option in different forms of cancer and as chemotherapeutic agent in both paediatric and adult malignancies (Cooper, Reynolds, Cho, & Kang, 2017). Whereas retinoic acid and other related compounds preferentially accumulate in the liver causing hepatic toxicity with prolonged exposure, fenretinide together with its metabolites is preferentially stored in fatty tissues conferring a safer profile for this molecule (Mody & Mcilroy, 2014).…”