Recent Patents on Anti-Cancer Drug Discovery - Volume 13, Issue 3, 2018

Background: Oral submucous fibrosis is an oral potentially malignant disorder with high incidence of malignant transformation and rising global prevalence. However, the genesis of oral submucous fibrosis is still unclear despite superfluity of literature. In the background of ineffective treatment, it is necessary to decode its onset and progression before designing customized treatment regimens. Objective: The objective of this article is to decipher the pathogenesis of oral submucous fibrosis in order to identify novel drug targets. Methods: A thorough literature review based on oral submucous fibrosis being an overhealing wound was conducted; several related patents were identified and herewith reviewed. Necessary pathways were elaborated and deliberated in the manuscript in the form of schemas, keeping our hypothesis in mind. Several novel molecular targets were identified and discussed in detail. Results: Several patents demonstrating inhibition of fibrosis via chemokine ligand mimetics, anticonnexon antibodies, stem cell therapy, fibronectin blocking peptides, HIF inhibitors, recombinant erythropoietin, xanthine oxidase inhibitors, long non-coding RNAs, targeting inflammation, increasing TH-1/TH-2 cytokine ratio, t-box protein 4, chromium containing compositions, Iron-based nanocomposites, Lactate Dehydrogenase-5 inhibitors, Carbonic Anhdrase-9 inhibitors, proton pump inhibitors, liposomal encapsulated glutathione, monocarboxylate-4 inhibitors, autophagy inhibitors, Submucosal anti-IL-6 antibodies, fibrin degradation products for monitoring of malignancy and fibrosis, small molecule antagonists like vorapaxar, tiplaxtinin, and TM-5275, TGF-β signalling inhibitors were identified as future therapeutic avenues. Conclusion: Considering, oral submucous fibrosis as an overhealing wound explains both pathogenesis and malignant transformation. Certainly, abnormalities in coagulation and fibrinolytic system are a common denominator in the profibrotic milieu and associated malignancy.

Background: It is increasingly evident that lncRNAs have various biological functions playing as essential regulators, getting involved in diverse cellular processes. Many of the lncRNAs show aberrant expression in cancer, which is associated with different cancer types. The dysregulation of lncRNAs has been increasingly linked to cancer carcinogenesis and progression. Objective: Due to their tissue-specific expression and key role in cancer, lncRNAs have the potential to be novel biomarkers or effective drug targets for cancer. This review aims to present the application of lncRNAs in cancer diagnosis and targeted cancer therapies, elaborates molecular mechanisms and provides a deeper understanding of cancer-related lncRNA functions. Methods: Relevant recent patents are collected to summarize the application of lncRNAs in cancer. Combined with published articles, functions and mechanisms of lncRNAs are elaborated. Results: Patents revealed that a series of reagents and kits have been applied for early cancer diagnosis by detecting specific lncRNAs, having the advantages of high sensitivity, specificity and stability. In addition, lncRNAs as effective targets have been applied in developing targeted cancer drugs. With regard to their role in cancer, lncRNAs regulate target genes, thus to medicate cancer physiological and pathological processes through diverse mechanisms at epigenetic, transcriptional and posttranscriptional levels. Conclusion: Current knowledge of lncRNAs presents prosperous prospects in cancer. However, functions of lncRNAs are still far from fully being understood. Therefore, further study is needed to advance imminent applications of these findings to the clinic.

Background: Tamoxifen is widely administered for patients with estrogen receptor-positive breast cancer. Despite many patients benefiting from Tamoxifen as an effective anti-hormonal agent in adjuvant therapy, a noticeable number of patients tend to develop resistance. Objective: The aim of this study was to shed light upon the molecular mechanisms associated with Tamoxifen resistance which can help improve current treatment strategies available for stimulating responsiveness and combating resistance. Methods: Relevant articles were obtained from PubMed and google scholar, nearly all dated from 2010 to 2017. Articles were screened to select the ones meeting the objective. The molecular interactions in the resistant network were extracted from the appropriate articles. Results: The mechanisms of developing Tamoxifen resistance were briefly outlined. Overactivation of Receptor Tyrosine Kinases (RTKs) pathways, commonly known as alternative growth cascades, is one of the main players in acquired cancer cell stemness, which can induce unrestricted proliferation in the presence of Tamoxifen. There are seven recent patents including 6291496B1 as an anti-HER2, 8143226B2 as an inhibitor of RTK phosphorylation, 9062308B2 as an anti-HOXB7, Lapatinib functioning as an anti-EGFR/HER2, Everolimus as an inhibitor of mTOR, Exemestane as an aromatase inhibitor and Perifosine as an AKT inhibitor. Conclusion: Altogether, it seems that tumor cells express a stemness phenotype which tends to override anti-hormonal adjuvant therapies. Since RTKs are overactivated and overexpressed in such cells, specialized targeted therapies suppressing RTKs would be a novel and effective way in restoring Tamoxifen sensitivity in resistant breast cancer tumor cells.

Objective: Mature T-cell lymphomas are a heterogeneous group of T-cell malignancies with a poor outcome. The discovery of new molecular biomarkers has led to the emergence of new drugs in recent years that target various signaling pathways. Methods: We examined all pertinent published patents through 2015 that analyzed novel methods for the diagnosis and treatment of T cell lymphoma, as well as related published and unpublished studies. Selection criteria were established before data collection. An exhaustive literature search was performed using MEDLINE and Science Direct databases. The search criteria were T-cell lymphoma, diagnosis, and treatment. Results: Recent papers have identified recurrent epigenetic factor mutations in RHOA and FYN kinase in PTCL allowing new perspectives for epigenetic-based therapy, molecular classification model using CD28, ABCA5 transporter, coiled-coil domain-containing protein 3, and angiogenic factor SMOC2 biomarkers for differentiating forms of lymphomas, as well as expression of receptors forTNFR-1, TNFR-2, and IL12p40/70 in CTCL. New therapeutic targets have been reported such as MicroRNAs - 155 inhibitors and synthetic Toll-Like Receptor 7/8 agonists for treating CTCL, Anti CTLA-4 antibodies, anti- Killer cell immunoglobulin-like receptors 3DL2 and NK-p46 (NCR receptors) antibodies for treating PTCL, Cd1d antagonist-restricted gamma/delta-T cell lymphomas, antiEZH2, novel antihistone deacetylase, and NK cells engineered therapy. In the transplantation setting, the objective was to eradicate overcoming of the residual disease immunity and to induce an immune tolerance by anti-third part cells with a central memory T-lymphocyte phenotype. Conclusion: Therapeutic strategies based on a better molecular characterization of various histological types are certain to be used in the future.

Background: Paclitaxel (PTX) has remarkable anti-tumor activity, but it causes severe toxicities. There is an urgent need to seek an appropriate pharmacokinetic parameter of PTX to improve treatment efficacy and reduce adverse effects. Objective: To evaluate the association of pharmacokinetic parameter TC > 0.05 of paclitaxel (PTX) and its therapeutic efficacy and toxicity in patients with solid tumors. Methods: A total of 295 patients with ovarian cancer, esophageal cancer, breast cancer, and non-small cell lung cancer (NSCLC), who were admitted to the Tumor Hospital of Shantou University Medical College, China, were recruited for this study. Patients received 3 weeks of PTX chemotherapy. The plasma concentrations of PTX were examined using the MyPaclitaxel™ kit. The patients' PTX TC > 0.05 (the time during which PTX plasma concentration exceed 0.05μmol/L) were calculated based on pharmacokinetic analysis. Results: The results showed that: (1) the concentrations of PTX in these 295 patients ranged from 0.0358-0.127 μmol/L; (2) the PTX TC > 0.05 ranged from 14 to 38h with a median time of 27h; (3) among all treatment cycles, there was a statistically significant difference in the PTX TC > 0.05 between CR+PR and SD+PD; (4) with the increasing value of TC > 0.05, level of leukopenia and leukopenic fever increased; (5) high PTX TC > 0.05 led to the occurrence of neutropenia, neutropenic fever, severe anemia, and severe peripheral neurotoxicity. Taken together, our results indicated that the pharmacokinetic parameter PTX TC > 0.05 was an effective measure of treatment efficacy and toxicity in patients with solid tumors. Maintaining PTX TC > 0.05 at 26 to 30h could improve its efficacy and reduce the incidence of leukopenia, neutropenia, anemia, and peripheral neurotoxicity in these patients. Conclusion: PTX TC > 0.05 is a key pharmacokinetic parameter of PTX which should be monitored to optimize individual treatment in patients with solid tumors.

Background: Despite dramatic advances in cancer treatment that lead to long-term survival, there is an increasing number of patients presenting with clinical manifestations of cerebral metastasis in breast cancer, for whom only palliative treatment options exist. Objective: The present review based on researches aims to provide identification of recent patens of breast cancer brain metastasis that may have application in improving cancer treatment. Methods: Recent patents regarding the breast cancer brain metastasis were obtained from USPTO patent databases, Esp@cenet, Patentscope and Patent Inspiration®. Results: A total of 55 patent documents and 35 drug targets were recovered. Of these, a total of 45 patents and 10 patents were biotech drugs and chemical drugs, respectively. Among the target drugs analyzed were neurotrophin-3, protocadherin 7, CXCR4, PTEN, GABA receptor 3, L1CAM, PI3K-Akt / mTOR, VEGFR2, Claudin-5, Occludin, and NKG2A, among others. Conclusion: In this study, we found 35 drug targets for metastasis to the brain in breast cancer, with 60% of them including only one patent, which establishes that this area of research is very recent, and that these targets have recently been linked to metastasis to the brain. On the other hand, 19 drug targets, among them VEGF, VEGFR2, CXCL12, and CXCR4, have been addressed for the first time until 6 years ago, confirming that the development of drugs for brain metastasis in breast cancer is an incipient area, but with interesting potential. Interestingly, the stage of inside the brain, was the stage with the lowest amount of drug targets, which places it as a priority for research and drug development.

Background: CS5931, a novel marine peptide, was extracted and purified from the sea squirt Ciona savignyi. Our previous studies showed that recombinant CS5931 can significantly inhibit tumor growth both in vitro and in vivo. However, its molecular targets have not been elucidated. Methods: The target of the recombinant CS5931 was identified by pull-down/SDS-PAGE/MS approaches and confirmed by Western blot and surface plasmon resonance analysis. Transwell experiments were used to detect whether the recombinant CS5931 inhibited cancer migration and invasion via enolase 1. Dot blotting analysis was used to detect the effect of CS5931 on the interaction of enolase 1 and plasminogen, as well as enolase 1 and uPA/uPAR. Results: Enolase 1 was identified as the molecular target interacting with the recombinant CS5931. Transwell experiment showed that the recombinant CS5931 was able to inhibit migration and invasion of HCT116 cells and enolase 1 overexpression reversed the effects of the recombinant CS5931 on migration and invasion of cancer cells. Dot blotting analysis revealed that the recombinant CS5931 interfered with the interaction among enolase 1 and plasminogen as well as enolase 1 and uPA/uPAR. Conclusion: Our present study showed that the recombinant CS5931 could inhibit tumor invasion and matastasis via interacting with enolase 1, suggesting that the new marine polypeptide CS5931 possesses the potential to be developed as a novel anticancer agent.

Background: Phytoestrogens have been proposed as replaceable medicines for climacteric hormone replacement therapy, on the basis of EP3138562 and US5516528. However, recent studies demonstrated that phytoestrogens might promote the proliferation of breast cancer cells, which is rooted in their estrogenic activity. Acacetin, as one phytoestrogen, has been reported to exhibit estrogenic activity. But the effect of acacetin on breast cancer cells proliferation and its mechanism has not been explored. Objective: This study aims to evaluate the effects of acacetin on breast cancer MCF-7 cells proliferation and to explore its possible mechanism. Methods: Sulforhodamine B (SRB) assay was used to test the proliferation rate of MCF-7 cells. Flow cytometry was utilized to determine cell cycle. RT-qPCR and western blot were employed to evaluate the expressions of proliferation-related factors in mRNA and protein levels. Results: According to SRB assay and flow cytometric analysis, low dose of acacetin from 10-3 to 1μM promoted the MCF-7 cells proliferation in a dose-dependent and time-dependent manner. Moreover, the expressions of cell cycle-related molecules, ERK1/2 and PI3K/AKT were increased after treatment with acacetin, while the increases were effectively reversed by ER antagonist ICI 182,780. Further studies showed that acacetin notably induced increasing mRNA and proteins levels of ERα, which were strongly reversed by ERα antagonist MPP. Conclusion: Low dose of acacetin from 10-3 μM to μM promoted the proliferation of MCF-7 cells through the ERK/PI3K/AKT pathway and its downstream cyclin signaling. And ERα is mainly responsible for acacetin promoting proliferation in MCF-7 cells.

Background: Hydroxyurea (HU) is used to treat cancer. HU has a short half-life due to its small molecular weight and high polarity, therefore a high dosage of the drug should be used which introduces side effects and more rapid development of resistance. Objective: The objective of the current study is to design new lipophilic analogues of hydroxyurea with higher stability and better cell penetration. The designed compounds were synthesized and then evaluated in terms of their cytostatic activities against two human cell lines. Methods: The synthesis of designed ligands was achieved via two-step procedure. Detail of the synthesis and chemical characterization of the analogs are described. The cytotoxic activity of the designed ligands was evaluated in vitro against two different cancer cell lines at 24 and 48h using MTT test. Results: Based on the IC50 values, all the designed and prepared compounds were more potent than hydroxyurea at 24 and 48h on both cell lines that the cytostatic activity at 48h was more than 24h. Drug-receptor interactions study indicated compound 7 as the most potent ligand, tightly bonded to surrounding amino acids in the active site of receptor via two strong hydrogen bonds and some hydrophobic interactions. Conclusion: Compound 7 with the suitable volume, log p and shape is the most active ligand against both cell lines. It is concluded or suggested that the size, shape and hydrophobic character of substituents strongly affect the pharmacodynamics and pharmacokinetics of these type of ligands.