Barry J. Maurer

Benign prostatic hyperplasia (BPH) is the most common urologic condition in elderly men, characterized by the reactivation of developmental programs such as prostatic budding and branching. However, the molecular mechanisms underlying this reactivation in BPH remain unclear. In this study, we identified T-lymphoma invasion and metastasis-inducing protein-1 (TIAM1) as a critical regulator of prostatic budding and branching. By generating an unbiased BPH transcriptomic signature from patient datasets, we discovered an upregulation of TIAM1 , which was subsequently validated at the protein level. Functional assays using organoid cultures derived from human prostatic cell lines revealed that TIAM1 is essential for prostatic budding and branching. Additionally, the BPH transcriptomic signature identified NSC23766, a small molecule inhibitor of TIAM1/RAC1 signaling, as a therapeutic proof-of-concept agent for BPH. Genetic knockdown of TIAM1 in human prostatic cell lines markedly reduced organoid branching, an effect mirrored by administration of NSC23766. The translational relevance of these findings is underscored by the growth inhibition observed in patient-derived BPH organoids treated with NSC23766. In conclusion, our findings identify TIAM1 as a key driver of prostatic branching and growth, and they suggest that targeting TIAM1/RAC1 signaling could be a promising therapeutic strategy for BPH.

Purpose: A phase I study was conducted to determine the MTD, dose-limiting toxicities (DLT), and pharmacokinetics of fenretinide delivered as an intravenous emulsion in relapsed/refractory hematologic malignancies. Experimental Design: Fenretinide (80–1,810 mg/m2/day) was administered by continuous infusion on days 1 to 5, in 21-day cycles, using an accelerated titration design. Results: Twenty-nine patients, treated with a median of three prior regimens (range, 1–7), were enrolled and received the test drug. Ninety-seven courses were completed. An MTD was reached at 1,280 mg/m2/day for 5 days. Course 1 DLTs included 6 patients with hypertriglyceridemia, 4 of whom were asymptomatic; 2 patients experienced DLT thrombocytopenia (asymptomatic). Of 11 patients with response-evaluable peripheral T-cell lymphomas, two had complete responses [CR, progression-free survival (PFS) 68+ months; unconfirmed CR, PFS 14+ months], two had unconfirmed partial responses (unconfirmed PR, PFS 5 months; unconfirmed PR, PFS 6 months), and five had stable disease (2–12 cycles). One patient with mature B-cell lymphoma had an unconfirmed PR sustained for two cycles. Steady-state plasma levels were approximately 10 mcg/mL (mid-20s μmol/L) at 640 mg/m2/day, approximately 14 mcg/mL (mid-30s μmol/L) at 905 mg/m2/day, and approximately 22 mcg/mL (mid-50s μmol/L) at 1,280 mg/m2/day. Conclusions: Intravenous fenretinide obtained significantly higher plasma levels than a previous capsule formulation, had acceptable toxicities, and evidenced antitumor activity in peripheral T-cell lymphomas. A recommended phase II dosing is 600 mg/m2 on day 1, followed by 1,200 mg/m2 on days 2 to 5, every 21 days. A registration-enabling phase II study in relapsed/refractory PTCL (ClinicalTrials.gov identifier: NCT02495415) is ongoing. Clin Cancer Res; 23(16); 4550–5. ©2017 AACR.

Patients with relapsed/refractory stage 4 high-risk neuroblastoma were enrolled on a phase I study (NANT2004-03) of intravenous fenretinide emulsion. Pharmacokinetic samples were collected during and after the infusion, and the levels were measured using an HPLC system. A likely case of a fatal drug interaction between fenretinide, ceftriaxone, and acetaminophen is described, including the pharmacokinetics of fenretinide, laboratory data, and post-mortem autopsy in a pediatric neuroblastoma patient treated on this study. On Day 4 of a scheduled 5-day-infusion of intravenous fenretinide, the patient developed a fever, acetaminophen was started, ceftriaxone initiated for possible bacteremia, and fenretinide level doubled from 56 to 110 μM. Over the next three days, although blood cultures remained negative, the patient’s condition deteriorated rapidly. Acute liver failure was diagnosed on Day 7, and the patient expired on Day 20 of fulminant hepatic failure with associated renal, cardiac, and hemorrhagic/coagulation toxicities. Autopsy showed extensive hemorrhagic necrosis of the liver, marked bile duct proliferation, and abundant hemosiderin, consistent with cholestasis and drug toxicity. After extensive review of patient data, the clinical course, and the literature, we conclude that observed hepatic toxicity was likely due to a drug interaction between fenretinide and concomitant ceftriaxone and acetaminophen. None of the other 16 patients treated on this study experienced significant hepatic toxicity. Although the prevalence of cholestasis with ceftriaxone usage is relatively high, the potential drug interaction with these concomitant medications has not been previously reported. Concomitant use of fenretinide, ceftriaxone, and acetaminophen should be avoided.

We previously reported that fenretinide (4-HPR) was cytotoxic to acute lymphoblastic leukemia (ALL) cell lines in vitro in association with increased levels of de novo synthesized dihydroceramides, the immediate precursors of ceramides. However, the cytotoxic potentials of native dihydroceramides have not been defined. Therefore, we determined the cytotoxic effects of increasing dihydroceramide levels via de novo synthesis in T-cell ALL cell lines and whether such cytotoxicity was dependent on an absolute increase in total dihydroceramide mass versus an increase of certain specific dihydroceramides. A novel method employing supplementation of individual fatty acids, sphinganine, and the dihydroceramide desaturase-1 (DES) inhibitor, GT-11, was used to increase de novo dihydroceramide synthesis and absolute levels of specific dihydroceramides and ceramides. Sphingolipidomic analyses of four T-cell ALL cell lines revealed strong positive correlations between cytotoxicity and levels of C22:0-dihydroceramide (ρ = 0.74–0.81, P ≤ 0.04) and C24:0-dihydroceramide (ρ = 0.84–0.90, P ≤ 0.004), but not between total or other individual dihydroceramides, ceramides, or sphingoid bases or phosphorylated derivatives. Selective increase of C22:0- and C24:0-dihydroceramide increased level and flux of autophagy marker, LC3B-II, and increased DNA fragmentation (TUNEL assay) in the absence of an increase of reactive oxygen species; pan-caspase inhibition blocked DNA fragmentation but not cell death. C22:0-fatty acid supplemented to 4-HPR treated cells further increased C22:0-dihydroceramide levels (P ≤ 0.001) and cytotoxicity (P ≤ 0.001). These data demonstrate that increases of specific dihydroceramides are cytotoxic to T-cell ALL cells by a caspase-independent, mixed cell death mechanism associated with increased autophagy and suggest that dihydroceramides may contribute to 4-HPR-induced cytotoxicity. The targeted increase of specific acyl chain dihydroceramides may constitute a novel anticancer approach.

Background A phase I study was conducted to determine the maximum‐tolerated dose, dose‐limiting toxicities (DLTs), and pharmacokinetics of fenretinide (4‐HPR) delivered in an oral powderized lipid complex (LXS) in patients with relapsed/refractory neuroblastoma. Procedure 4‐HPR/LXS powder (352–2,210 mg/m²/day) was administered on Days 0–6, in 21‐day courses, by standard 3 + 3 design. Results Thirty‐two patients (median age = 8 years, range 3–27 years) enrolled with 30 evaluable for dose escalation. Prior therapies included stem cell transplantation/support (n = 26), 13‐cis‐retinoic acid (n = 22), ^125/131I‐MIBG (n = 13), and anti‐GD2 antibody (n = 6). 170+ courses were delivered. Course 1 DLTs were a Grade 3 (n = 1) alkaline phosphatase at 352 mg/m²/day. Other major toxicities were Grade 4 (n = 1) alkaline phosphatases on Courses 5 and 6 at 774 mg/m²/day, and Grade 3 (n = 1) ALT/AST elevation on Course 2 at 1,700 mg/m²/day. Of 29 response‐evaluable patients, six had stable disease (SD) (4–26 courses); four with marrow‐ or bone disease‐only had complete responses (CR) (10–46 courses). 4‐HPR plasma levels were several folds higher (P < 0.05) than previously reported using capsular fenretinide. The Day 6 mean peak 4‐HPR plasma level at 1,700 mg/m²/day was 21 µM. An MTD was not reached. Conclusions 4‐HPR/LXS oral powder obtained higher plasma levels, with minimal toxicity and evidence of anti‐tumor activity, than a previous capsule formulation. A recommended phase II schedule of 4‐HPR/LXS powder is 1,500 mg/m²/day, TID, on Days 0–6, of a 21‐day course. Pediatr Blood Cancer 2013;60:1801–1808.