OncoSNIPE® Study Protocol, a study of molecular profiles associated with development of resistance in solid cancer patients.

Background: Nowadays, evaluation of the efficacy and the duration of treatment, in context of monitoring patients with solid tumors, is based on the RECIST methodology. With these criteria, resistance and/or insensitivity are defined as tumor non-response which does not allow a good understanding of the diversity of the underlying mechanisms. The main objective of the OncoSNIPE® collaborative clinical research program is to identify early and late markers of resistance to treatment.

ABMA, a small molecule that inhibits intracellular toxins and pathogens by interfering with late endosomal compartments.

Intracellular pathogenic microorganisms and toxins exploit host cell mechanisms to enter, exert their deleterious effects as well as hijack host nutrition for their development. A potential approach to treat multiple pathogen infections and that should not induce drug resistance is the use of small molecules that target host components. We identified the compound 1-adamantyl (5-bromo-2-methoxybenzyl) amine (ABMA) from a cell-based high throughput screening for its capacity to protect human cells and mice against ricin toxin without toxicity.

A Cinnamon-Derived Procyanidin Compound Displays Anti-HIV-1 Activity by Blocking Heparan Sulfate- and Co-Receptor- Binding Sites on gp120 and Reverses T Cell Exhaustion via Impeding Tim-3 and PD-1 Upregulation.

Amongst the many strategies aiming at inhibiting HIV-1 infection, blocking viral entry has been recently recognized as a very promising approach. Using diverse in vitro models and a broad range of HIV-1 primary patient isolates, we report here that IND02, a type A procyanidin polyphenol extracted from cinnamon, that features trimeric and pentameric forms displays an anti-HIV-1 activity against CXCR4 and CCR5 viruses with 1-7 μM ED50 for the trimer. Competition experiments, using a surface plasmon resonance-based binding assay, revealed that IND02 inhibited envelope binding to CD4 and heparan sulphate (HS) as well as to an antibody (mAb 17b) directed against the gp120 co-receptor binding site with an IC50 in the low μM range.

HIV specific responses induced in nonhuman primates with ANRS HIV-Lipo-5 vaccine combined with rMVA-HIV prime or boost immunizations.

We evaluated the immunogenicity of a prime/boost vaccine strategy combining 5 lipopeptides (HIV-Lipo-5) and a recombinant modified vaccinia virus Ankara (rMVA-HIV) in cynomolgus macaques. Both of these vaccine components deliver HIV LAI Gag, Pol, and Nef antigens. Systemic and local safety was excellent in all groups.

Anti-HIV efficacy and biodistribution of nucleoside reverse transcriptase inhibitors delivered as squalenoylated prodrug nanoassemblies.

Due to their hydrophilic nature, most nucleoside reverse transcriptase inhibitors (NRTIs) display a variable bioavailability after oral administration and a poor control over their biodistribution, thus hampering their access to HIV sanctuaries. The limited cellular uptake and activation in the triphosphate form of NRTIs further restrict their efficacy and favour the emergence of viral resistance. We have shown that the conjugation of squalene (sq) to the nucleoside analogues dideoxycytidine (ddC) and didanosine (ddI) leads to amphiphilic prodrugs (ddC-sq and ddI-sq) that spontaneously self-organize in water as stable nanoassemblies of 100-300 nm.

Squalenoyl nucleoside monophosphate nanoassemblies: new prodrug strategy for the delivery of nucleotide analogues.

4-(N)-1,1',2-trisnor-squalenoyldideoxycytidine monophosphate (SQddC-MP) and 4-(N)-1,1',2-trisnor-squalenoylgemcitabine monophosphate (SQdFdC-MP) were synthesized using phosphoramidite chemistry. These amphiphilic molecules self-assembled to about hundred nanometers size nanoassemblies in aqueous medium. Nanoassemblies of SQddC-MP displayed significant anti-HIV activity whereas SQdFdC-MP nanoassemblies displayed promising anticancer activity on leukemia cells.