Scientists discover a new type of resistance to antiangiogenic drugs and how to fight it in renal cancer patients

The collaboration between the Institute of Biomedical Research of Bellvitge (IDIBELL), the Catalan Institute of Oncology (ICO) and the Vall d'Hebron Institute of Oncology (VHIO) has led to the discovery and validation in human tissue samples for the first time of a new type of resistance to anti-angiogenic treatment, called metabolic symbiosis, in renal cell carcinoma tumors. The study, led by Dr. Oriol Casanovas, head of the Tumour Angiogenesis research group of IDIBELL, also points to the use of inhibitors of the mTOR pathway, a kind of drug that is already being used for these cancers, as a blocking mechanism of this type of resistance. The article has been chosen to be the cover of the journal Cell Reports because of the potential impact that this sequential treatment may have in clinical practice, effectively preventing this type of resistance in patients treated with anti-angiogenic drugs in both renal and other types of cancer.

Anti-angiogenic therapies work by destroying the blood vessels that tumor cells generate in order to get the large amounts of oxygen and nutrients that they need to grow and proliferate. This type of treatment is particularly effective in kidney or neuroendocrine cancers, but in many cases the tumor ends up generating resistance, limiting its therapeutic value. In 2014, Dr. Casanovas’ group published a review article in which the main causes of this resistance were described.

Metabolic symbiosis, the type of resistance this new study focuses on, can be the result of anti-angiogenic drug use. In this case, reducing the amount of blood vessels leads to a characteristic cell pattern with two distinct areas: those cells that are closer to a blood vessel and have enough oxygen, and those that are further away and require adaptation to hypoxic conditions to survive. Hypoxic cells, that consume glucose and produce lactate anaerobically, adapt by establishing a symbiotic relationship with those cells close to the vessels, which are able to collect this lactate to transform it back into glucose aerobically. This combined operation is responsible for the resistance to treatment.

Precisely because of their location and type of signaling, cells in hypoxic conditions are more difficult to use as a therapeutic target; on the other hand, normoxic cells (those near the vessels) present typical metabolic signaling, which makes them vulnerable to mTOR pathway inhibitors, a type of drug commonly used in multiple cancers. The study shows how, if at the time that resistance to anti-angiogenic drugs emerges treatment is switched to inhibitors of the mTOR pathway, destruction of the cells near the vessel blocks metabolic symbiosis, killing hypoxic cells and leading to tumor reduction.

The journal Cell Reports accompanies the article with two more studies developed by other internationally renowned research groups that extend and support the same idea. However, the added value of joint work between IDIBELL-ICO and VHIO lies in the possibility of being able to validate the previous results obtained in mice in a series of human tissue samples. This way, the study shows the potential that this new therapeutic approach – combining drugs that are already approved and frequently used - may have in clinical practice, despite implying the need to develop biomarkers to identify the cause of resistance. This is one of the lines in which researchers are currently working.

Article reference:

Jimenez-Valerio, et al. Resistance to anti-angiogenic by Metabolic Therapies Renal Cell Carcinoma Symbiosis in PDX models and Patients. Cell Reports (2016)

http://www.cell.com/cell-reports/fulltext/S2211-1247(16)30428-4

Project funded by the ERC-Starting Grant 2012 – STROMALIGN of the European Research Council within the FP7 program.

Image: Dr. Oriol Casanovas, Tumor Angiogenesis group leader, and Dr. Gabriela Jiménez-Valerio, first author of the article