peretinoin (K-333) / Kowa - LARVOL DELTA

Genetic Profiling of “Idiopathic” Tracheal Stenosis: Uncovering Underlying Mechanisms & Identifying Potential Therapeutic Options (Quick-Shot) (ACS-CLINCON 2024) - "Genetic pathways driving tracheal hypergranulation suggest that “idiopathic” tracheal stenosis may be a consequence of underlying infection, ciliopathy, or immune dysregulation. Our results indicate that retinoic acid, ivermectin, acetaminophen, and 17 beta-estradiol may represent potential medical therapies that can serve as adjuncts to interventional management in ITS. Table: Top dysregulated genes involved in idiopathic tracheal stenosis CALM5: Calmodulin like 5; DPEP1: Dipeptidase 1; KRT6C: Keratin 6C; KRT14: Keratin 14; KRT16: Keratin 16; NPAT: Nuclear protein, coactivator of histone transcription; PRB3: Proline rich protein BstNI subfamily 3; PRB4: Proline rich protein BstNI subfamily 4 Status Gene Name Function Pharmacological Agent(s) Most Upregulated (Range of Fold Change: up to +396x) CALML5 Keratinocyte differentiation • 17 beta-estradiol • Fenretinide KRT16 Immune regulation • Fenretinide/Isotretinoin • Ivermectin • Acetaminophen • Folic acid • Calcipotriol..."

Immunology • Infectious Disease • KRT14 • KRT16

Role of liver resection in the era of advanced systemic therapy for hepatocellular carcinoma. (PubMed, Glob Health Med) - "Since the turn of the century, at least three negative studies have tested adjuvant therapies after curative resection or ablation, including uracil-tegafur, which is an oral chemotherapeutic drug, sorafenib, and peretinoin, which a synthetic retinoid that may induce the apoptosis and differentiation of liver cancer cells. Using more potent immuno-checkpoint inhibitors (ICIs), at least 4 phase III trials of adjuvant immunotherapy are ongoing: nivolumab, durvalumab/ bevacizumab, pembrolizumab, and atezolizumab+bevacizumab...There are 2 neoadjuvant trials for technically or oncologically unresectable HCCs ongoing in Japan: the LENS-HCC trial using lenvatinib and the RACB study using atezolizumab+bevacizumab...They obtained a Japanese consensus on this issue that has been published on the websites of JLCA and JSHPBS. The definition of resectability or borderline resectability provides a common language regarding advanced HCC for investigators and is a useful tool for future..."

Journal • Metastases • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor

Role of liver resection in the era of advanced systemic therapy for hepatocellular carcinoma (APASL 2024) - "After the turn of the century, there have been at least three negative studies testing adjuvant therapies after curative resection or ablation, including Uracil-Tegafur an oral chemotherapeutic drug, sorafenib, and peretinoin, a synthetic retinoid that may induce apoptosis and differentiation of liver cancer cells. Using more potent immunocheckpoint inhibitors (ICIs), there are at least 4 phase-III trials ongoing for adjuvant immunotherapy: Nivolumab, Durvalumab/Bevacizumab, Pembrolizumab, and Atezolizumab+Bevacizumab...There have been 2 neoadjuvant trials for technically or oncologically unresectable HCCs ongoing in Japan: LENS-HCC trial using Lenvatinib and RACB study using Atezolizumab+Bevacizumab...Recently, Japan Liver Cancer Association (JLCA) and the Japanese Society of HPB Surgery (JSHPBS) created a joint working group on "so-called borderline resectable HCC." They compiled a Japanese consensus on this issue and it has been published on the websites of..."

Metastases • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor

A Modular Approach for the Synthesis of Natural and Artificial Terpenoids. (PubMed, Angew Chem Int Ed Engl) - "This chem-stamp could easily be applied repeatedly and separately, empowering the modular concise syntheses of many natural and pharmaceutically active terpenoids including retinal, β-carotene, vitamin A, tretinoin, fenretinide, acitretin, ALRT1550, nigerapyrone C, peretinoin, and lycopene. Due to the diversified availability of the starting materials, aldehydes and 2,3-allenols, creation of new non-natural terpenoids has been realized from four dimensions: the number of isoprene units, side chain, and two terminal groups."

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Acyclic retinoid peretinoin reduces hemorrhage-associated brain injury in vitro and in vivo. (PubMed, Eur J Pharmacol) - "On the other hand, nuclear factor-κB (NF-κB) inhibitors such as pyrrolidine dithiocarbamate (50 μM) and Bay11-7082 (10 μM) prevented thrombin-induced shrinkage of the striatal region...We also found that daily administration of peretinoin reduced histopathological injury and alleviated motor deficits in a mouse model of intracerebral hemorrhage. These results indicate that NR1B agonists including peretinoin may serve as a therapeutic option for hemorrhagic brain injury."

Journal • Preclinical • Cerebral Hemorrhage • CNS Disorders • Gastrointestinal Cancer • Hematological Disorders • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • Vascular Neurology

C-Labeling of acyclic retinoid peretinoin by rapid C-[C]methylation to disclose novel brain permeability and central nervous system activities hidden in antitumor agent. (PubMed, Bioorg Med Chem Lett) - "These various phenomena between the ester and acid became more pronounced in the monkey brain (SUV of >3.0 at 90 min). With the opportunity to identify high brain uptake of [C]peretinoin, we discovered CNS activities of a drug candidate called peretinoin, such as the induction of a stem-cell to neuronal cell differentiation and the suppression of neuronal damages."

Journal • CNS Disorders • Oncology

Peretinoin, an Acyclic Retinoid, for the Secondary Prevention of Hepatocellular Carcinoma. (PubMed, Molecules) - "The synthetic oral retinoid peretinoin is the only agent for the secondary chemoprevention of HCC after curative therapy that is currently well applied into clinical development. Here we present an updated summary of the molecular pathogenesis of HCC and of preclinical and clinical findings with peretinoin, including its clinical characteristics, safety and tolerability profile and future perspectives for clinical use."

Journal • Review • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Oncology • Solid Tumor

Retinoids Repress Human Cardiovascular Cell Calcification With Evidence for Distinct Selective Retinoid Modulator Effects. (PubMed, Arterioscler Thromb Vasc Biol) - "These results establish retinoid regulation of human cardiovascular calcification, provide new insight into mechanisms involved in these responses, and suggest selective retinoid modulators, like acyclic retinoids may allow for treating cardiovascular calcification without the adverse effects associated with cyclic retinoids."

Journal • Atherosclerosis • Cardiovascular • Dyslipidemia

Dedifferentiation of hepatocellular carcinoma: molecular mechanisms and therapeutic implications. (PubMed, Am J Transl Res) - "Additionally, peretinoin as a potential drug is in progress of several phase III clinical trials. It's promising that differentiation therapy for HCC may be a part of options in future HCC treatment."

Journal • Review • Gastrointestinal Cancer • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor • CTNNB1 • KLF4

Peretinoin, an Acyclic Retinoid, Inhibits Hepatitis B Virus Replication by Suppressing Sphingosine Metabolic Pathway In Vitro. (PubMed, Int J Mol Sci) - "This indicates that peretinoin activates HDAC1 and thereby suppresses HBV replication by inhibiting the sphingosine metabolic pathway. Therefore, peretinoin may be a novel therapeutic agent for HBV replication and chemoprevention against HCC."

Journal • Preclinical • Biosimilar • Fibrosis • Gastrointestinal Cancer • Hepatitis C Virus • Hepatocellular Cancer • Immunology • Oncology • Ophthalmology • Solid Tumor

Peretinoin, an acyclic retinoid, inhibits hepatocarcinogenesis by suppressing sphingosine kinase 1 expression in vitro and in vivo. (PubMed, Sci Rep) - "Additionally, diethylnitrosamine-induced hepatoma was fewer and less frequent in SPHK1 knockout compared to wild-type mice. Our data showed crucial roles of SPHK1 in hepatocarcinogenesis and suggests that peretinoin prevents hepatocarcinogenesis by suppressing mRNA levels of SPHK1."

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