Focus Oncotherapies #8


March 17, 2021

Focus Oncotherapies #8

The researchers of the EBRIS Foundation working on the Campania Oncoterapie project continue to focus their attention on a tumor target that the entire scientific community has identified as a limitation for many chemotherapy treatments. In fact, a study that demonstrates the involvement of some proteins belonging to the ATP-binding cassette protein (ABC-protein) family in important and aggressive forms of cancer has recently been published in Cell Reports Medicine, an important international scientific journal. Central nervous system.

High-grade gliomas, and in particular glioblastoma (GBM), are the most common and lethal primary brain tumors. To date, no systemic chemotherapy drug other than temozolomide has shown significant efficacy in the treatment of malignant gliomas. A likely contributing factor to the low efficacy of chemotherapy is the presence of the blood brain barrier (BBB), which limits the brain penetration of many anticancer drugs. Structurally, brain endothelial cells lack clefts and are closely linked together by tight junctions.

In addition to these passive constraints, the presence of an active efflux system represented by ATP-binding cassettes (ABC) proteins is known: transporters P-glycoprotein (P-gp; ABCB1), breast cancer resistance protein (BCRP; ABCG2) , and multidrug resistance-associated protein 4 (MRP4; ABCC4). Although the literature suggests that eventual BBB alteration provides better access of compounds to brain tumors, the results of this study show that drug entry and, consequently, efficacy may still be limited by transport systems. ATP employees. However, it has recently been shown that the distribution and hence the efficacy of temozolomide is also hampered by pharmacological efflux transporters. Furthermore, many of the novel specific chemotherapeutic agents that have shown appreciable responses in patients with extracranial tumor forms are unfortunately excellent substrates for P-gp and / or BCRP and are consequently effectively extruded from the brain. Consequently, it will clearly be advantageous for the treatment of intracranial tumors to focus on those drug candidates capable of easily crossing the BBB. But the concomitant use of powerful inhibitors specific for ABC efflux systems, such as elacridar, a specific inhibitor for P-gp, can be a valid alternative to the use of drugs that do not cross the BBB.

These evidences are the basis of the work of the Ebris Foundation research team.

Read the article: "ATP-binding cassette transporters restrict drug delivery and efficacy against brain tumors even when blood-brain barrier integrity is lost"