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Pancreatic carcinoma is a cancer disease with high mortality. Thus, new and efficient treatments for this disease are badly needed. Curcumin has previously shown promising effects in pancreatic cancer patients; however, this natural compound suffers from inadequate efficacy and bioavailability, preventing its clinical approval. The synthetic curcuminoid EF24 was developed with activities superior to curcumin against various cancer types. In this study, a series of analogs of EF24 were investigated for anticancer effects on pancreatic carcinoma models. A distinct activity boost was achieved by straightforward N-acrylation of EF24 analogs, in particular, of compounds bearing 3-fluoro-4-methoxybenzylidene, 3,4-difluorobenzylidene, and 4-trifluoromethylbenzylidene moieties, while no improvement was seen for N-acryloyl-modified EF24. Apoptosis induction and suppression of phospho-STAT3 levels were determined, the latter corroborated by docking of active curcuminoids into STAT3. Hence, promising new clues for the development of efficient and superior curcuminoids as valuable treatment options for one of the most lethal cancer diseases were discovered in this study.

Ciclopirox (CPX) is an FDA-approved topical antifungal agent that has demonstrated preclinical anticancer activity in a number of solid and hematologic malignancies. Its clinical utility as an oral anticancer agent, however, is limited by poor oral bioavailability and gastrointestinal toxicity. Fosciclopirox, the phosphoryloxymethyl ester of CPX (Ciclopirox Prodrug, CPX-POM), selectively delivers the active metabolite, CPX, to the entire urinary tract following parenteral administration. We characterized the activity of CPX-POM and its major metabolites in in vitro and in vivo preclinical models of high-grade urothelial cancer. CPX inhibited cell proliferation, clonogenicity and spheroid formation, and increased cell cycle arrest at S and G0/G1 phases. Mechanistically, CPX suppressed activation of Notch signaling. Molecular modeling and cellular thermal shift assays demonstrated CPX binding to γ-secretase complex proteins Presenilin 1 and Nicastrin, which are essential for Notch activation. To establish in vivo preclinical proof of principle, we tested fosciclopirox in the validated N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) mouse bladder cancer model. Once-daily intraperitoneal administration of CPX-POM for four weeks at doses of 235 mg/kg and 470 mg/kg significantly decreased bladder weight, a surrogate for tumor volume, and resulted in a migration to lower stage tumors in CPX-POM treated animals. This was coupled with a reduction in the proliferation index. Additionally, there was a reduction in Presenilin 1 and Hes-1 expression in the bladder tissues of CPX-POM treated animals. Following the completion of the first-in-human Phase 1 trial (NCT03348514), the pharmacologic activity of fosciclopirox is currently being characterized in a Phase 1 expansion cohort study of muscle-invasive bladder cancer patients scheduled for cystectomy (NCT04608045) as well as a Phase 2 trial of newly diagnosed and recurrent urothelial cancer patients scheduled for transurethral resection of bladder tumors (NCT04525131).

Colorectal cancer (CRC) is a leading cause of cancer-related deaths in the US with 53,200 deaths projected in 2020. Although the disease affects older people, recent statistics show an increase in the younger population. CRC is a major problem in veterans and every year ~4,000 veterans are diagnosed with CRC within VA facilities. Hence, there is a dire need to identify novel signaling pathways as targets for therapy. Based on a bedside discovery in CRC patients, we observed that CRC patients complained about dysgeusia or taste alterations. There are 25 bitter taste receptors (TAS2R1-50, TAS2R60). Taste receptors utilize G-protein coupled receptors (GPCRs) and signal through calcium release. In preliminary studies, mining the Cancer Genome Atlas (TCGA) database, we have determined that TAS2R38 is upregulated in multiple cancers, including CRC. Moreover, the higher expression of TAS2R38 transcript in CRC compared to other cancers. Furthermore, we confirmed overexpression of TAS2R38 in CRC tissues and cell lines by immunohistochemistry and RT-PCR. Moreover, N-(3-oxododecanoyl)-L-homoserine lactone (OdDHL), a TAS2R38 agonist, treatment activated calcium mobilization in HCT116 and DLD1 cells suggesting the functionality of the receptor. OdDHL also enhanced mRNA of interleukin (IL)-6 and IL-8 levels in the CRC cells. To determine whether expression of the receptor is affected in vivo, we conducted the dextran sodium sulfate (DSS)-induced acute colitis and colitis-associated cancer model (azoxymethane (AOM)-DSS) in C57BL/6 mice. TAS2R138, the mouse homolog of human TAS2R38 is overexpressed in crypt epithelial cells in the colitis and tumor tissues. These observations suggest that TAS2R38 is overexpressed in the CRC and may play a critical role in disease progression. Citation Format: Krishan Jain, Sangita Bhattacharyya, Afreen Sayed, David Standing, Kathy Benich, Shahid Umar, Shrikant Anant, Scott Weir, Roy Jansen, Prasad Ravindra Dandawate. Role of bitter taste receptor in colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1529.

TPS7069 Background: Fosciclopirox (F) is a γ-secretase inhibitor being developed for the treatment of acute myeloid leukemia (AML). Following intravenous (IV) administration, F is rapidly and completely metabolized to its active metabolite, ciclopirox (CPX). CPX binds to γ-secretase complex proteins Presenilin 1 and Nicastrin, which are essential for Notch activation. In HL60 cells, CPX inhibits Notch 1 and Notch 2 expression, reduces levels of γ-secretase complex proteins Presenilin 1 and Nicastrin, and decreases expression of the downstream Notch target gene Hes-1. Utilizing Notable Labs predictive precision medicine platform, bone marrow (BM) and peripheral blood (PB) samples obtained from 10 AML patients treated with CPX demonstrated significant blast count reductions. Methods: Study CPX-POM-003 (NCT04956042) is an open-label Phase 1B/2A, trial designed to characterize the efficacy, safety, and PK/PD of F alone and in combination with cytarabine (ara-C) in patients with relapsed/refractory AML (R/R AML). Eligible patients must be 18 years of age or older with relapsed AML after complete remission or with primary refractory AML refractory to at least two cycles of induction therapy. There will be up to three cohorts of patients, approximately 42 R/R AML patients, evaluated. If disease response to F alone (Cohort 1a) is observed in at least 4 of 14 patients, an additional 14 patients will be enrolled in Cohort 1b. If disease response is not observed following F alone, the study may be terminated or a second cohort, Cohort 2a, may be initiated to evaluate the combination of F + ara-C. If disease response to F + ara-C is observed in at least 4 of 14 patients, an additional 14 patients will be enrolled in Cohort 2b. If response to F + ara-C is not observed in at least 4 of 14 patients, the study will be stopped for futility. F is being administered as 900 mg/m2 once daily as a 20-minute IV infusion on Days 1 to 5 of each 21-day treatment cycle. Ara-C is administered as 1 gm/m2 once daily on Days 1 to 5 of each cycle. BM and PB samples are collected prior to and during Cycles 1 (C1) and 2 (C2) for disease response assessment and blast count determination. Additional BM and PB samples are obtained after every two cycles beyond C2 for patients continuing treatment. Disease response is determined based on Döhner et al, Blood 2017;129(4)424-447. Next Generation Sequencing (NGS) profiles will be determined prior to and at the end of C1, and thereafter as clinically indicated. Immunohistochemistry will be performed on BM samples to elucidate drug mechanism. Ex vivo Drug Sensitivity Screening (DSS) will be performed on BM and PB samples obtained prior to treatment as well as on C1 Days 8 and 21. The steady-state plasma pharmacokinetics of F are being characterized during C1. Enrollment began in October 2022 with four patients enrolled to date. Clinical trial information: NCT04956042.