α4-α5 Helices on Surface of KRAS Can Accommodate Small Compounds That Increase KRAS Signaling While Inducing CRC Cell Death.

KRAS is the most frequently mutated oncogene associated with the genesis and progress of pancreatic, lung and colorectal (CRC) tumors. KRAS has always been considered as a therapeutic target in cancer but until now only two compounds that inhibit one specific KRAS mutation have been approved for clinical use. In this work, by molecular dynamics and a docking process, we describe a new compound (P14B) that stably binds to a druggable pocket near the α4-α5 helices of the allosteric domain of KRAS.

Peptidomimetics designed to bind to RAS effector domain are promising cancer therapeutic compounds.

Oncogenic RAS proteins are important for driving tumour formation, and for maintenance of the transformed phenotype, and thus their relevance as a cancer therapeutic target is undeniable. We focused here on obtaining peptidomimetics, which have good pharmacological properties, to block Ras-effector interaction. Computational analysis was used to identify hot spots of RAS relevant for these interactions and to screen a library of peptidomimetics.

RAD51 is a druggable target that sustains replication fork progression upon DNA replication stress.

Solving the problems that replication forks encounter when synthesizing DNA is essential to prevent genomic instability. Besides their role in DNA repair in the G2 phase, several homologous recombination proteins, specifically RAD51, have prominent roles in the S phase. Using different cellular models, RAD51 has been shown not only to be present at ongoing and arrested replication forks but also to be involved in nascent DNA protection and replication fork restart.

KRAS phosphorylation regulates cell polarization and tumorigenic properties in colorectal cancer.

Oncogenic mutations of KRAS are found in the most aggressive human tumors, including colorectal cancer. It has been suggested that oncogenic KRAS phosphorylation at Ser181 modulates its activity and favors cell transformation. Using nonphosphorylatable (S181A), phosphomimetic (S181D), and phospho-/dephosphorylatable (S181) oncogenic KRAS mutants, we analyzed the role of this phosphorylation to the maintenance of tumorigenic properties of colorectal cancer cells.

Total body irradiation using helical tomotherapy: Set-up experience and in-vivo dosimetric evaluation.

Purpose: Helical Tomotherapy (HT) appears as a valuable technique for total body irradiation (TBI) to create highly homogeneous and conformal dose distributions with more precise repositioning than conventional TBI techniques. The aim of this work is to describe the technique implementation, including treatment preparation, planning and dosimetric monitoring of TBI delivered in our institution from October 2016 to March 2019.

Material And Method: Prior to patient care, irradiation protocol was set up using physical phantoms.