Abstract A259: Targeted therapies in oncology: Cardiotoxic or protective?
Authors: Scott Shell A. , Wappel Robert L. , Bacus Sarah S. 
Published: June 2012

Background: Targeted cancer therapies can elicit undesired physiological effects including cardiac toxicity which may result from the inhibition of an oncogenic protein that is also required for normal heart health, such as c-Abl by Imatinib or HER2 by Herceptin. Additionally, the promiscuity of a drug to inhibit off-target enzymes can also negatively influence heart health, such as the inhibition of the metabolic regulator AMPK by Sunitinib. However, some oncology compounds such as Erlotinib, have not been associated with cardiac toxicity. Regardless of the mechanism, oncology drugs are at risk for limited application or failure if they negatively influence the high metabolic activity necessary for normal cardiac function. This report aims to build a cellular profile of in vitro protein and genetic biomarkers and metabolomics data that will help predict whether an oncology drug might elicit cardiac toxicity.

Materials and Methods: Primary human cardiac myocytes (HCM) were treated with a variety of oncology compounds including Lapatinib, Erlotinib, Sunitinib, Nilotinib, Imatinib, Sorafenib, or GW-2974 (a derivative of Lapatinib) for protein analysis by Western blot and quantitative lipid staining by Oil Red O. HCMs were also treated with either GW-2974 or Sunitinib for metabolomics analysis of acyl carnitines and amino acids by LC/MS/MS and gene expression analysis by qRT-PCR.

Results: The AMPK metabolic checkpoint pathway was activated by several compounds including GW-2974, Lapatinib, Sorafinib and Nilotinib, None of the compounds that activated the AMPK pathway demonstrated significant intracellular lipid accumulation. However, a variety of compounds that demonstrated inhibition of the AMPK pathway, including Sunitinib, caused an increase in intracellular lipids, indicative of impairment of fatty acid oxidation. Likewise, metabolomic analysis of acyl carnitines and amino acids demonstrated that Sunitinib-treated HCMs caused a reduction in short chain fatty acids and amino acids while concomitantly caused an increase in longer chain fatty acids, indicative of lipid production, whereas GW-2974 demonstrated an opposite effect. Gene expression analysis for enzymes involved in fatty acid oxidation and mitochondrial function, including CPT-1, ERR, and PPAR indicate that fatty acid accumulation in Sunitinib-treated cells may be the result of increased fatty acid production and shuttling into the mitochondria combined with a reduction in fatty acid -oxidation.

Conclusions: By assessing AMPK pathway activation, measuring changes in intracellular lipid content and gene expression, and performing metabolomics screening, we have built a cellular profile that can be leveraged to predict possible cardiac toxicity from targeted oncology therapies. Cytochrome c release assays to demonstrate changes in mitochondrial health and broader gene expression analyses of treated HCMs are being pursued. We believe the results of these studies demonstrate the importance of monitoring the cellular metabolism of in vitro treated HCMs when screening oncology compounds during early stage, preclinical development. This screen could also be very important to retroactively test existing oncology compounds that are in consideration for use in the neoadjuvant setting for negative influences in cardiac metabolism.

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A259.