Purpose: Despite adjuvant endocrine therapy for patients with estrogen receptor alpha (ER)-positive breast cancer, dormant residual disease can persist for years and eventually cause tumor recurrence. We sought to deduce mechanisms underlying the persistence of dormant cancer cells to identify therapeutic strategies. Experimental Design: Mimicking the aromatase inhibitor-induced depletion of estrogen levels used to treat patients, we developed preclinical models of dormancy in ER+ breast cancer induced by estrogen withdrawal in mice. We analyzed tumor xenografts and cultured cancer cells for molecular and cellular responses to estrogen withdrawal and drug treatments. Publicly available clinical breast tumor gene expression datasets were analyzed for responses to neoadjuvant endocrine therapy. Results: Dormant breast cancer cells exhibited upregulated 5' adenosine monophosphate-activated protein kinase (AMPK) levels and activity, and upregulated fatty acid oxidation. While the anti-diabetes AMPKactivating drug metformin slowed the estrogen-driven growth of cells and tumors, metformin promoted the persistence of estrogen-deprived cells and tumors through increased mitochondrial respiration driven by fatty acid oxidation. Pharmacologic or genetic inhibition of AMPK or fatty acid oxidation promoted clearance of dormant residual disease, while dietary fat increased tumor cell survival.Conclusions: AMPK has context-dependent effects in cancer, cautioning against the widespread use of an AMPK activator across disease settings. The development of therapeutics targeting fat metabolism is warranted in ER+ breast cancer.

Objective: The aryl hydrocarbon receptor (AHR) plays a key role in obesity. In vitro studies revealed that the tryptophan metabolite kynurenine (Kyn) activates AHR signaling in cultured hepatocytes. The objective of this study was to determine whether Kyn activated the AHR in mice to induce obesity. Methods: Mice were fed a low-fat diet and the same diet supplemented with Kyn. Body mass, liver status, and the expression of identified relevant genes were determined. Results: Kyn caused mice to gain significant body mass, develop fatty liver and hyperglycemia, and increase expression levels of cytochrome P450 1B1 and stearoyl-CoA desaturase 1. The hyperglycemia was accompanied with decreased insulin levels, which may have been due to the repression of genes involved in insulin secretion. Kyn plasma concentrations and BMI were measured in female patients, and a significant association was observed between Kyn and age in patients with obesity but not in patients who were lean. Conclusions: Results show that (1) Kyn or a metabolite thereof is a ligand responsible for inducing AHR-based obesity, fatty liver, and hyperglycemia in mice; (2) plasma Kyn levels increase with age in women with obesity but not in lean women; and (3) an activated AHR is necessary but not sufficient to attain obesity, a status that also requires fat in the diet.

It is well recognized that many cancers are addicted to a constant supply of fatty acids (FAs) and exhibit brisk de novo FA synthesis. Upregulation of a key lipogenic enzyme, fatty acid synthase (FASN), is a near-universal feature of human cancers and their precursor lesions, and has been associated with chemoresistance, tumor metastasis, and diminished patient survival. FASN inhibition has been shown to be effective in killing cancer cells, but progress in the field has been hindered by off-target effects and poor pharmaceutical properties of candidate compounds. Our initial hit (compound 1) was identified from a high-throughput screening effort by the Sanford-Burnham Center for Chemical Genomics using purified FASN thioesterase (FASN-TE) domain. Despite being a potent inhibitor of purified FASN-TE, compound 1 proved highly unstable in mouse plasma and only weakly cytotoxic to breast cancer (BC) cells in vitro. An iterative process of synthesis, cytotoxicity testing, and plasma stability assessment was used to identify a new lead (compound 41). This lead is more cytotoxic against multiple BC cell lines than tetrahydro-4-methylene-2S-octyl-5-oxo-3R-furancarboxylic acid (the literature standard for inhibiting FASN), is stable in mouse plasma, and shows negligible cytotoxic effects against nontumorigenic mammary epithelial cells. Compound 41 also has drug-like physical properties based on Lipinski's rules and is, therefore, a valuable new lead for targeting fatty acid synthesis to exploit the requirement of tumor cells for fatty acids. SIGNIFICANCE STATEMENT An iterative process of synthesis and biological testing was used to identify a novel thioesterase domain FASN inhibitor that has drug-like properties, is more cytotoxic to breast cancer cells than the widely used tetrahydro-4-methylene-2S-octyl-5-oxo-3R-furancarboxylic acid, and has negligible effects on the growth and proliferation of noncancerous mammary epithelial cells. Our studies have confirmed the value of using potent and selective FASN inhibitors in the treatment of BC cells and have shown that the availability of exogenous lipoproteins may impact both cancer cell FA metabolism and survival. s This article has supplemental material available at jpet.aspetjournals.org.

Aims We evaluated the potential effect of sonidegib at an oral dose of 800 mg once daily (QD) on the pharmacokinetics (PK) of the probe drugs warfarin (CYP2C9) and bupropion (CYP2B6). Methods This was a multicentre, open‐label study to evaluate the effect of sonidegib on the PK of the probe drugs warfarin and bupropion in patients with advanced solid tumours. Cohort 1 patients received a single warfarin 15‐mg dose on Day 1 of the run‐in period and on Cycle 2 Day 22 (C2D22) of sonidegib administration. Cohort 2 patients received a single bupropion 75‐mg dose on Day 1 of run‐in period and on C2D22 of sonidegib administration. Sonidegib 800 mg QD oral dosing began on Cycle 1 Day 1 of a 28‐day cycle after the run‐in period in both cohorts. Results The geometric means ratios [90% confidence interval] for (S)‐warfarin with and without sonidegib were: area under the concentration–time curve from time 0 to infinity (AUCinf) 1.15 [1.07, 1.24] and maximum plasma concentration (Cmax) 0.88 [0.81, 0.97]; and for (R)‐warfarin were: AUCinf 1.10 [0.98, 1.24] and Cmax 0.93 [0.87, 1.0]. The geometric means ratios [90% confidence interval] of bupropion with and without sonidegib were: AUCinf 1.10 [0.99, 1.23] and Cmax 1.16 [0.95, 1.42]. Sonidegib 800 mg had a safety profile that was similar to that of lower dose sonidegib 200 mg and was unaffected by single doses of the probe drugs. Conclusions Sonidegib dosed orally at 800 mg QD (higher than the Food and Drug Administration‐approved dose) did not impact the PK or pharmacodynamics of warfarin (CYP2C9 probe substrate) or the PK of bupropion (CYP2B6 probe substrate).

Chronic lymphocytic leukemia (CLL) was projected to cause 4320 deaths in 2021 in the US [1]. Chemo-immunotherapy regimens are commonly associated with unfavorable adverse events (AEs) [2, 3]. Targeted therapies such as the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib are better tolerated and have become standard of care for CLL. Ibrutinib causes egress of CLL cells from their stromal niche leading to peripheral lymphocytosis [4]. While initially successful in treatment of naïve, relapsed/refractory, and high risk CLL (deletion 17p), most high risk patients experienced disease progression, indicating a need to improve BTK-targeted therapy regimens [5-8]. Microtubule inhibitors kill CLL cells ex vivo with dependence on c-Jun N-terminal kinase (JNK) activation and induction of NOXA [9]. Vincristine activated JNK but not NOXA in circulating CLL cells in vivo [10]. BNC105, a colchicine-site microtubule inhibitor, was more potent at activating the JNK-NOXA apoptotic cascade [11]. BNC105P, the prodrug of BNC105, had a monotherapy maximum tolerated dose (MTD) of 16 mg/m 2 in solid tumor patients with on-target polymerized tubulin reduction activity starting at 12.6 mg/m 2 [12]. The study rationale was to target CLL cell egress from the stromal niche with ibrutinib and eliminate CLL cells in circulation with BNC105P to potentially obtain deep, long-lasting responses [13]. We therefore conducted an open-label, Phase Ib, dose escalation study of BNC105P and ibrutinib in patients with relapsed/refractory CLL (NCT03454165). Patients were enrolled at the Dartmouth Cancer Center using a Dartmouth College and Dartmouth-Hitchcock Health Institutional Review Board approved protocol and written informed consent. Study patients provided written informed consent prior to the performance of any study procedures and given a copy of the signed written informed consent.BNC105P (Bionomics Limited, Thebarton, Australia) was administered via IV infusion on days 1 and 8 (cycle 1) and days 8 and 15 (cycles 2-6) of 21-day cycles. Ibrutinib 420 mg was self-administered orally on days 1-21 (cycles 2-6). In drug combination cycles, ibrutinib was taken ≥30 min prior to BNC105P infusion. A standard 3 + 3 Phase I dose escalation design was used with planned BNC105P dose cohorts of 8 mg/m 2 (cohort 1), 12 mg/m 2 (cohort 2), and 16 mg/m 2 (cohort 3).The primary study objective was to determine the MTD of BNC105P in combination with ibrutinib in CLL patients.All patient inclusion and exclusion criteria for study NCT03454165 are detailed at https://clinicaltrials.gov/ct2/show/NCT03454165.