piperidines and Burkitt-Lymphoma

Novel insights into the pathophysiology of primary central nervous system lymphoma (PCNSL) have identified the B-cell receptor and Toll-like receptor pathway as well as immune evasion and suppressed tumor immune microenvironment as a key mechanism in the pathogenesis of PCNSL. Small molecules and novel agents targeting these aberrant pathways have been introduced into clinical trials targeting the recurrent or refractory PCNSL patient population. Agents like the Bruton tyrosine kinase (BTK) inhibitor ibrutinib or immunomodulatory drugs (IMiDs) like pomalidomide and lenalidomide have shown promising high response rates in the salvage setting. Here, we give an overview about the recent, exciting developments in PCNSL and summarize the results of clinical trials using novel agents in the recurrent and refractory salvage setting, which include immune checkpoint inhibitors, IMiDs, as well as BTK, phosphatidylinositol-3 kinase, and mammalian target of rapamycin inhibitors.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aminopyridines; Antineoplastic Agents, Immunological; Burkitt Lymphoma; Central Nervous System Neoplasms; Humans; Immunologic Factors; Lenalidomide; Lymphoma, Large B-Cell, Diffuse; Lymphoma, T-Cell; Morpholines; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Rituximab; Salvage Therapy; Thalidomide; Toll-Like Receptors; TOR Serine-Threonine Kinases; Tumor Escape

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Burkitt Lymphoma; Disease Models, Animal; Drug Discovery; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Lymphoma, B-Cell, Marginal Zone; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Mice; Phosphatidylinositol 3-Kinases; Piperidines; Precision Medicine; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Signal Transduction; Xenograft Model Antitumor Assays

Topics: Adenine; Antineoplastic Agents; Bone Marrow; Burkitt Lymphoma; Diagnosis, Differential; Disease Progression; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Oncogene Proteins, Fusion; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines

The tumor microenvironment represents a burden that hampers the proper activation of immune cells, including the dendritic cells (DCs). It is, therefore, desired that the important characteristics of a given anticancer drug candidate be seen as consisting not solely of its antitumor properties, but that it also lacks potential side effects that could additionally constrain the development and function of immune cells associated with tumor immunity. We have previously identified compounds with a N-amidinopiperidine scaffold that selectively induce apoptosis in Burkitt's lymphoma cells through proteasome inhibition. Here, we demonstrate that SPI-15 affected neither the viability of DCs nor their differentiation. In addition, the compound had no significant effect on their cytokine secretion or allostimulatory capacity. Moreover, DC functionality in the context of tumor microenvironment was also unaffected, as demonstrated by experiments performed on DCs differentiated in Ramos-conditioned media in the presence or absence of SPI-15. The cytokine profile and functional assays revealed that SPI-15 rescues DC differentiation from the immunosuppressive environment produced by Ramos cells; this was seen by their reacquired ability to induce IFN-γ-secretion from naïve CD4(+)CD45RA(+) T cells and the consequently induced Th1-effector differentiation. Herein, we present novel characteristics of an N-amidinopiperidine-based protease inhibitor whose anticancer properties are not associated with the immunosuppression of DCs. We propose future studies toward the design of structurally similar compounds with the aim of developing potent anticancer drugs with minimal negative effects on crucial factors involved in tumor immunity.

Topics: Amidines; Antineoplastic Agents; Apoptosis; Blotting, Western; Burkitt Lymphoma; Cell Differentiation; Cell Proliferation; Cells, Cultured; Cytokines; Dendritic Cells; Flow Cytometry; Humans; Lymphocyte Activation; Piperidines; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Th1 Cells; Tumor Microenvironment

A 14-year-old girl with multiple intra-abdominal tumors was diagnosed with stage III Burkitt's lymphoma. She achieved complete remission after multi-drug chemotherapy, but she relapsed after six courses. Autologous peripheral blood stem cells (PBSC) or allogeneic PBSC harvested from an HLA-identical sibling were insufficient, and her family did not agree to bone marrow collection from the sibling. Although the patient relapsed nine times (the relapses involved intra-abdominal organs or bone) during the following 4 years 7 months, treatment with rituximab monotherapy or in combination with ifosphamide, carboplastin, and etoposide, or local irradiation (33.8-40.0 Gy) to treat the bone metastases, proved effective, resulting in complete or partial remission. At the time of writing, the patient was in a 10th cycle of remission lasting 1 year 6 months and had not required transplantation. Thus, a chemotherapy regimen including rituximab might be effective for Burkitt's lymphoma in patients experiencing multiple relapse.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Burkitt Lymphoma; Carboplatin; Etoposide; Female; Humans; Neoplasm Recurrence, Local; Neoplasm Staging; Piperidines; Remission Induction; Rituximab

Serine proteases have proven to be promising pharmacological targets in contemporary drug discovery for cancer treatment. Since azaphenylalanine-based compounds manifest cytotoxic activity, we have selected serine protease inhibitors designed and synthesized in-house with large hydrophobic naphthalene moiety for screening. The cytotoxic potential of screened molecules was correlated to modifications of R(1) residues. The most cytotoxic were compounds with greater basicity; amidinopiperidines, piperidines and benzamidines. Amidinopiperidine-based compounds exert cytotoxicity in low µM range, with IC(50) 18 µM and 22 µM for inhibitors 15 and 16 respectively. These compounds exhibited selective cytotoxicity towards the Burkitt's lymphoma cells Ramos and Daudi, and proved nontoxic to PMBC, Jurkat and U937. They induce caspase-dependent apoptotic cell death, as demonstrated by the use of a pan-caspase inihibitor, zVADfmk, which was able to rescue Ramos cells from compound(s)-induced apoptosis. We confirm a disruption of the pro-survival pathway in Burkitt's lymphoma through NFκB inhibition. The accumulation of phosphorylated precursor (p105) and inhibitory (IκB) molecules with no subsequent release of active NFκB implicated the involvement of proteasome. Indeed, we show that the amidinopiperidine-based compounds inhibit all three proteolytical activities of the human 20S proteasome, with the most prominent effect being on the trypsin-like activity. Consistently, treatment of Ramos cells with these compounds led to an increase in ubiquitinated proteins. The amidinopiperidine-based serine protease inhibitors presented are, as selective inducers of apoptosis in Burkitt's lymphoma cells, promising leads for the development of novel chemotherapeutics.

Topics: Antineoplastic Agents; Apoptosis; Burkitt Lymphoma; Cell Line, Tumor; Humans; NF-kappa B; Piperidines; Proteasome Endopeptidase Complex; Proteasome Inhibitors

The in vitro efficacies of three new drugs--clofarabine (CLOF), nelarabine (NEL) and flavopiridol (FP) - were assessed in a panel of acute lymphoblastic leukaemia (ALL) cell lines. The 50% inhibitory concentration (IC50) for CLOF across all lines was 188-fold lower than that of NEL. B-lineage, but not T-lineage lines, were >7-fold more sensitive to CLOF than cytosine arabinoside (ARAC). NEL IC50 was 25-fold and 113-fold higher than ARAC in T- and B-lineage, respectively. T-ALL cells were eightfold more sensitive to NEL than B-lineage but there was considerable overlap. FP was more potent in vitro than glucocorticoids and thiopurines and at doses that recent phase I experience predicts will translate into clinical efficacy. Potential cross-resistance of CLOF, NEL and FP was observed with many front-line ALL therapeutics but not methotrexate or thiopurines. Methotrexate sensitivity was inversely related to that of NEL and FP. Whilst NEL was particularly effective in T-ALL, a subset of patients with B-lineage ALL might also be sensitive. CLOF appeared to be marginally more effective in B-lineage than T-ALL and has a distinct resistance profile that may prove useful in combination with other compounds. FP should be widely effective in ALL if sufficient plasma levels can be achieved clinically.

Topics: Adenine Nucleotides; Antineoplastic Agents; Arabinonucleosides; Burkitt Lymphoma; Child; Clofarabine; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Flavonoids; Humans; Inhibitory Concentration 50; Leukemia-Lymphoma, Adult T-Cell; Piperidines; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Tumor Cells, Cultured