Metabolic interrogation as a tool to optimize chemotherapeutic regimens

Abstract

Platinum-based (Pt) chemotherapy is broadly utilized in the treatment of cancer. Development of more effective, personalized treatment strategies require identification of novel biomarkers of treatment response. Since Pt compounds are inactivated through cellular metabolic activity, we hypothesized that metabolic interrogation can predict the effectiveness of Pt chemotherapy in a pre-clinical model of head and neck squamous cell carcinoma (HNSCC).We tested the effects of cisplatin (CDDP) and carboplatin (CBP) on DNA damage, activation of cellular death cascades and tumor cell metabolism, specifically lactate production. Pt compounds induced an acute dose-dependent, transient drop in lactate generation in vitro, which correlated with effects on DNA damage and cell death. Neutralization of free radical stress abrogated these effects. The magnitude of this effect on lactate production correlated with the differential sensitivity of HNSCC cells to Pt compounds (CDDP vs CBP) and p53-driven Pt chemotherapy resistance. Using dual flank xenograft tumors, we demonstrated that Pt-driven effects on lactate levels correlate with effects on tumor growth delay in a dose-dependent manner and that lactate levels can define the temporal profile of Pt chemotherapy-induced metabolic stress. Lactate interrogation also predicted doxorubicin effects on cell death in both solid tumor (HNSCC) and acute myelogenous leukemia (AML) cell lines.Real-time metabolic interrogation of acute changes in cell and tumor lactate levels reflects chemotherapy effects on DNA damage, cell death and tumor growth delay. We have identified a real-time biomarker of chemotherapy effectiveness which can be used to develop adaptive, iterative and personalized treatment regimens against a variety of solid and hematopoietic malignancies.

Acquisition of Cisplatin Resistance Shifts Head and Neck Squamous Cell Carcinoma Metabolism toward Neutralization of Oxidative Stress

“…13 C flux experiments demonstrated higher glucose uptake and flux into 3-carbon intermediates and TCA cycle intermediates, with decreased incorporation into pentose phosphate pathway (PPP) intermediates in the cisplatin-resistant cells consistent with increased overall catabolic activity ( Figure 5 ). The Warburg effect (conversion of glucose into lactate) was similar between parental and cisplatin resistant cells, consistent with our previous work [ 8 , 9 , 10 , 11 ]. However, cisplatin resistant cells demonstrated drastically different rates of serine and aspartate catabolism and synthesis ( Figure 5 ).…”

“…Over the last decade, we have shown that generation of oxidative stress either through application of ionizing radiation (IR) or platinum derivatives triggers acute, reversible metabolic changes in a variety of tumor models including HNSCC [7][8][9][10]. This has allowed us to develop a relatively quantitative, albeit indirect relationship between metabolic perturbations linked to carbon flux and generation of intra-cellular oxidative stress and DNA damage [7][8][9][10]. Initially, this relationship was limited to the most common metabolic reaction common to solid tumors, namely the conversion of pyruvate into lactate, the lynchpin of the Warburg effect [7][8][9][10].…”

“…This has allowed us to develop a relatively quantitative, albeit indirect relationship between metabolic perturbations linked to carbon flux and generation of intra-cellular oxidative stress and DNA damage [7][8][9][10]. Initially, this relationship was limited to the most common metabolic reaction common to solid tumors, namely the conversion of pyruvate into lactate, the lynchpin of the Warburg effect [7][8][9][10]. More recently we showed that cisplatin effects on tumor metabolism propagate through central carbon metabolic pathways such as the pentose phosphate pathway, glycolysis and the Krebs cycle [11].…”

Synergistic effect of cisplatin chemotherapy combined with fractionated radiotherapy regimen in HPV-positive and HPV-negative experimental pharyngeal squamous cell carcinoma

“…In clinical practice, cisplatin adds a benefit to radiotherapy, with significant improvement of overall survival at five years in head and neck SCC patients 35,36 . It is known that cisplatin treatment increases the duration of S phase and arrests cells in the G 2 /M phase 8,34,[37][38][39] , which could contribute to radiosensitization. In the present study we share similar observations.…”

High-Risk TP53 Mutations Are Associated with Extranodal Extension in Oral Cavity Squamous Cell Carcinoma

“…The impact of TP53 mutation on HNSCC biology and response to treatment has been thoroughly documented by our group and others using both pre-clinical disease models and retrospective patient cohorts. (8,9,11,13,15,24–26) TP53 mutations can behave in a heterogeneous manner with response to both tumorigenesis and treatment response. (8,9,14) Most recently, we developed an evolutionarily-based scoring system to classify TP53 mutations as: 1) “low-risk” missense mutations, 2) “high-risk” missense mutations, and 3) “other” TP53 mutations (e.g.…”