Nuclear Imaging Study of the Pharmacodynamic Effects of Debio 1143, an Antagonist of Multiple Inhibitor of Apoptosis Proteins (IAPs), in a Triple-Negative Breast Cancer Model.

Background: Debio 1143, a potent orally available SMAC mimetic, targets inhibitors of apoptosis proteins (IAPs) members and is currently in clinical trials. In this study, nuclear imaging evaluated the effects of Debio 1143 on tumor cell death and metabolism in a triple-negative breast cancer (TNBC) cell line (MDA-MB-231)-based animal model.

Methods: Apoptosis induced by Debio 1143 was assessed by FACS (caspase-3, annexin 5 (A5)), binding of Tc-HYNIC-Annexin V, and a cell proliferation assay.

Unraveling the Interaction between Carboxylesterase 1c and the Antibody-Drug Conjugate SYD985: Improved Translational PK/PD by Using Ces1c Knockout Mice.

Carboxylesterase 1c (CES1c) is responsible for linker-drug instability and poor pharmacokinetics (PK) of several antibody-drug conjugates (ADC) in mice, but not in monkeys or humans. Preclinical development of these ADCs could be improved if the PK in mice would more closely resemble that of humans and is not affected by an enzyme that is irrelevant for humans. SYD985, a HER2-targeting ADC based on trastuzumab and linker-drug vc--DUBA, is also sensitive to CES1c.

Discovery of a 9-mer Cationic Peptide (LTX-315) as a Potential First in Class Oncolytic Peptide.

Oncolytic immunotherapies represent a new promising strategy in the treatment of cancer. In our efforts to develop oncolytic peptides, we identified a series of chemically modified 9-mer cationic peptides that were highly effective against both drug-resistant and drug-sensitive cancer cells and with lower toxicity toward normal cells. Among these peptides, LTX-315 displayed superior anticancer activity and was selected as a lead candidate.

KRN951, a highly potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, has antitumor activities and affects functional vascular properties.

Vascular endothelial growth factor (VEGF) plays a key role in tumor angiogenesis by stimulating the proangiogenic signaling of endothelial cells via activation of VEGF receptor (VEGFR) tyrosine kinases. Therefore, VEGFRs are an attractive therapeutic target for cancer treatment. In the present study, we show that a quinoline-urea derivative, KRN951, is a novel tyrosine kinase inhibitor for VEGFRs with antitumor angiogenesis and antigrowth activities.

Tumor penetration of gefitinib (Iressa), an epidermal growth factor receptor tyrosine kinase inhibitor.

The relative distribution of gefitinib-related material in nude mice bearing s.c. human tumor xenografts and in an orthotopic rat lung tumor model was investigated following oral administration (50 mg/kg) of [14C]-gefitinib.

Rationale supporting the use of vasoconstrictors for intraperitoneal chemotherapy with platinum derivatives.

By decreasing drug drainage through the peritoneal and tumoral vascular networks, epinephrine increases the penetration of cisplatin and oxaliplatin into the metastatic peritoneal tumor nodules. This improved drug penetration increases their antitumor efficacy, allowing the cure of millimetric-sized peritoneal tumor nodules that could not be obtained with cisplatin or oxaliplatin used alone. However, limited drug diffusion into supramillimetric nodules did not result in curing advanced peritoneal carcinomatosis, unless complete resection of macroscopic localized tumor nodules is performed before intraperitoneal chemotherapy.