Targeting aberrant metabolic pathways in kidney cancer

Primo N. Lara, Jr. Eric Jonasch (Editors). kidney cancer (2 ed). Springer International Publishing (2015) → Русский

It is now increasingly apparent that a variety of metabolic alterations accompanies malignant transformation and is essential for the growth and survival of tumors arising in the kidney. Recognition of the key role of metabolism in RCC has spurred significant interest in pharmacologically targeting metabolic pathways thought to be critical for tumor survival and proliferation. While there have been considerable advances in how we think about these targeted strategies, the field is still in its infancy.

It has been suggested that a number of enzymes mediating either glycolysis or glutaminolysis would be ideal targets. Indeed, a wide array of agents with purported activity against targets such as glucose transporters, hexokinase, PKM2, and glutaminase have been evaluated in preclinical models and early phase clinical trials with varying measures of success [71]. At least one agent targeting glutaminase, CB-839, is currently in phase 1 testing, with planned expansion cohorts once MTD is achieved, to evaluate its efficacy in a variety of solid tumors including RCC (NCT02071862). The identification of AMPK as a key mediator of growth and metabolic signals in response to the nutrient and energy status of the cell has kindled interest in metformin, an activator of this molecule. Several trials of this agent, including phase 1 evaluation in combination with mTOR inhibitors in patients with solid tumors, are currently underway. The mTOR inhibitors temsirolimus and everolimus have activity in clear cell and other forms of RCC and are approved by the US FDA for treatment of patients with advanced kidney cancer. Given the importance of mTOR in regulating the metabolic phenotype in many forms of RCC, it is conceivable that the activity of agents targeting mTOR is at least partly a result of metabolic perturbations. The combination of bevacizumab and erlotinib has shown considerable activity in HLRCCassociated kidney cancer in a phase 2 study and is being explored further in this disease and in patients with sporadic papillary RCC [72]. The regimen was designed to exploit the dependence of these tumors on a high glucose flux to sustain aerobic glycolysis; it was hypothesized that the antiangiogenic properties of bevacizumab would limit glucose delivery to the tumor microenvironment while erlotinib might interfere with active glucose transport into the cells.