(584ag) Early Prediction of Chemotherapy-Induced Toxicity: A Pharmacometabonomics-Based Approach for Personalized Treatment

Early Prediction of Chemotherapy-induced Toxicity: A Pharmacometabonomics-based Approach for Personalized Treatment

D Jayachandran¹, Jodi Skiles², Jamie Renbarger², Doraiswami Ramkrishna^1,*

¹ School of Chemical Engineering, Purdue University, 480 Stadium Mall Way, West Lafayette, IN 47907, USA

² Riley Hospital for Children, Indiana University School of Medicine 705 Riley Hospital Drive, Indianapolis, IN 46202, USA

Vincristine (VCR) is one of the frontline chemotherapeutic agents, which is cytotoxic to cancer cells and effective in a variety of pediatric and adult cancers. While side-effects include neurotoxicity, hyponatremia, mild myelosuppression, and constipation, vincristine-induced peripheral neuropathy (VIPN) is the dose-limiting toxicity. VIPN is highly variable, cumulative and dose-dependent. Although some cases of VIPN are reversible within weeks to months following discontinuation of the treatment, many others suffer chronically from VIPN, even long after treatment is finished. The inability to predict who will develop significant toxicity severely hampers the optimal administration of VCR since the aforementioned side-effects are limited to a subgroup of patients but dosing is a one-size-fits-all approach. This leads to a suboptimal dosing in a subgroup of patients who are not predisposed to VIPN.

Recent advancements in ‘omics’ and molecular pharmacology technologies have revealed critical information on VCR disposition. VCR is extensively metabolized by cytochrome P450 (CYPs) family of enzymes, specifically CYP 3A4 and 3A5, which are found primarily in human liver microsomes. Studies have shown that tissue distribution of VCR is influenced by the expression of P-Glycoprotein (P-gp), MRP1 and MRP2. Much of the variation in the VCR pharmacokinetics and potentially treatment response can be attributed to genetic polymorphisms observed in these genes. At the molecular level, however, activation or repression of these candidate genes and enzyme activities does not result in accumulation or depletion of corresponding metabolites, which is likely due to the multiplicity and robustness of the metabolic pathway network. Furthermore, human proteome and metabolome are influenced by multiple variables, including epigenetic factors, non-heritable functionally induced (extra-genetic) factors, stochasticity in biochemical reactions, environment, food and lifestyle, micro flora dynamics, and pre- or co-administered drugs, among others. Hence, a focused panel of genetic and phenotypic biomarkers combined with a systems engineering approach is able to effectively predict VIPN. 

In this work, we utilized a pharmacometabonomics approach to identify new endogenous metabolites responsible for VIPN in patient samples collected before a dose of VCR was administered. Metabonomics studies the systematic variation in the metabolic profiles due to external stimuli such as genetic modification, biological stimulus and xenobiotic intervention. Pharmacometabonomics, at the intersection of pharmacology and metabonomics, aims to study the global metabolic fingerprints in the pre-dose bio-fluids and characteristic change in the metabolic profiles due to drug dosing in the post-dose bio-fluids. The approach relies on the global metabolic profiling of the pre- and post-dose bio-fluids of the patients using LC/GC-MS and chemometric modeling of the metabolites and VIPN. This provides an unbiased and hypothesis-free analysis of metabolic profile and helps to identify biomarker combinations that enable early prediction of VIPN. This will ultimately make it possible to effectively predict treatment response and optimal administration of VCR according to a patient’s metabolic make-up.