Safety and feasibility of targeted agent combinations in solid tumours

Abstract

The plethora of novel molecular-targeted agents (MTAs) has provided an opportunity to selectively target pathways involved in carcinogenesis and tumour progression. Combination strategies of MTAs are being used to inhibit multiple aberrant pathways in the hope of optimizing antitumour efficacy and to prevent development of resistance. While the selection of specific agents in a given combination has been based on biological considerations (including the role of the putative targets in cancer) and the interactions of the agents used in combination, there has been little exploration of the possible enhanced toxicity of combinations resulting from alterations in multiple signalling pathways in normal cell biology. Owing to the complex networks and crosstalk that govern normal and tumour cell proliferation, inhibiting multiple pathways with MTA combinations can result in unpredictable disturbances in normal physiology. This Review focuses on the main toxicities and the lack of tolerability of some common MTA combinations, particularly where evidence of enhanced toxicity compared to either agent alone is documented or there is development of unexpected toxicity. Toxicities caused by MTA combinations highlight the need to introduce new preclinical testing paradigms early in the drug development process for the assessment of chronic toxicities resulting from such combinations.

Targeting mTOR and p53 Signaling Inhibits Muscle Invasive Bladder Cancer In Vivo

“…Therefore, simultaneous inhibition of multiple tumor cell pathways may result in more effective inhibition (34). Overall, our study clearly demonstrates for the first time that the combination of mTOR and p53 modulators has better inhibitory effects on urothelial tumor growth and invasion than the individual treatments, and supports the use of a combinational approach for better efficacy and management of cancers (34, 49–50). Importantly simultaneous targeting of mTOR and p53 pathways could be novel choice of treatment option for patients with non-muscle-invasive bladder cancer in the post-operative prevention setting with high risk for disease recurrence and progression to MIBC.…”

Targeting bacterial adherence inhibits multidrug-resistant Pseudomonas aeruginosa infection following burn injury

“…An altered dosing schedule with higher concentrations and more frequent applications of GST-MAM7 beads over the first 24–48 hours following infection might reduce bacterial colonization further. Alternatively, this strategy may be combined with other, classical, antimicrobials to improve clinical outcomes, and such combination therapies have now become the standard for treatment of infectious and non-infectious diseases alike2930.…”

Activating mTOR Mutations in a Patient with an Extraordinary Response on a Phase I Trial of Everolimus and Pazopanib

“…At the same time, toxicities from therapeutic combinations often produce unacceptable toxicities(2). Therefore, careful pharmacokinetic investigation is needed during phase I studies to determine which combination therapies should be considered for further evaluation.…”