A new bioavailable fenretinide formulation with antiproliferative, antimetabolic, and cytotoxic effects on solid tumors

Abstract

Fenretinide is a synthetic retinoid characterized by anticancer activity in preclinical models and favorable toxicological profile, but also by a low bioavailability that hindered its clinical efficacy in former clinical trials. We developed a new formulation of fenretinide complexed with 2-hydroxypropyl-beta-cyclodextrin (nanofenretinide) characterized by an increased bioavailability and therapeutic efficacy. Nanofenretinide was active in cell lines derived from multiple solid tumors, in primary spheroid cultures and in xenografts of lung and colorectal cancer, where it inhibited tumor growth independently from the mutational status of tumor cells. A global profiling of pathways activated by nanofenretinide was performed by reverse-phase proteomic arrays and lipid analysis, revealing widespread repression of the mTOR pathway, activation of apoptotic, autophagic and DNA damage signals and massive production of dihydroceramide, a bioactive lipid with pleiotropic effects on several biological processes. In cells that survived nanofenretinide treatment there was a decrease of factors involved in cell cycle progression and an increase in the levels of p16 and phosphorylated p38 MAPK with consequent block in G0 and early G1. The capacity of nanofenretinide to induce cancer cell death and quiescence, together with its elevated bioavailability and broad antitumor activity indicate its potential use in cancer treatment and chemoprevention.

Stem cell programs in cancer initiation, progression, and therapy resistance

“…A recent study shows that retinoic acid and NR2F1 signaling work together to induce a dormancy-like epigenetic state 269 . Fenretinide treatment in lung and colorectal cancers also induced a quiescent state along with inhibition of the mTOR pathway, cell cycle block, and a mixed death pathway with both autophagic and apoptotic qualities 270 .…”

Stem Cell Plasticity and Dormancy in the Development of Cancer Therapy Resistance

“…However, sleeping strategies must be long-lasting (or even lifetime long) and therefore must deal with unwanted side effects that can limit their long-term usage and reduce patient compliance. In this regard, the use of retinoic acid or fenretinide derivatives to induce cancer cell quiescence appear as a feasible and relatively non-toxic therapeutic approach (12, 158). An additional problem related to sleeping strategies is that not all tumor cells are responsive, as ER-positive breast tumors can give rise to metastases even during hormonal therapy.…”

<p>Nanomicellar Lenalidomide–Fenretinide Combination Suppresses Tumor Growth in an <em>MYCN</em> Amplified Neuroblastoma Tumor</p>

“…Fenretinide is active in NB [7][8][9][10] and many other cancer types [11][12][13][14][15][16] by multiple mechanisms, [17][18][19][20][21][22] and it has shown efficacy against cancer stem cells. [23][24][25][26][27][28] Lenalidomide is another alternative antitumor agent currently used in the post-consolidation maintenance therapy of multiple myeloma and other hematological malignances. We selected lenalidomide to combine with fenretinide for its antiangiogenic properties and its acceptable toxicity profile.…”