Deterministic mathematical modelling for cancer chronotherapeutics: cell population dynamics and treatment optimisation

Chronotherapeutics has been designed and used for more than twenty years as an effective treatment against cancer by a few teams around the world, among whom one of the first is Francis Lévi's at Paul-Brousse hospital (Villejuif, France), in application of circadian clock physiology to determine best infusion times within the 24-hour span for anticancer drug delivery. Mathematical models have been called in the last ten years to give a rational basis to such optimised treatments, for use in the laboratory and ultimately in the clinic. While actual clinical applications of the theoretical optimisation principles found have remained elusive so far to improve chronotherapeutic treatments in use, mathematical models provide proofs of concepts and tracks to be explored experimentally, to progress from theory to bedside. Starting from a simple ordinary differential equation model that allowed setting and numerically solving a drug delivery optimisation problem with toxicity constraints, this modelling enterprise has been extended to represent the division cycle in proliferating cell populations with different molecular targets, to allow for the representation of anticancer drug combinations that are used in clinical oncology. The main point to be made precise in such a therapeutic optimisation problem is to establish, here in the frame of circadian chronobiology, physiologically based differences between healthy and cancer cell populations in their responses to drugs. To this aim, clear biological evidence at the molecular level is still lacking, so that, starting from indirect observations at the experimental and clinical levels and from theoretical considerations on the model, speculations have been made, that will be exposed in this review of cancer chronotherapeutics models with the corresponding optimisation problems and their numerical solutions, to represent these differences between the two cell populations, with regard to circadian clock control

Sense of coherence in lung cancer patients: Association with coping, immune function, and fatigue

Sense of coherence (SOC) reflects the degree to which an individual perceives their world as comprehensible, manageable, and meaningful. Among cancer populations, SOC has been linked with greater quality of life and reduced mortality, suggesting that SOC may serve as a marker of resilience in the context of chronic disease. Utilizing a published adaptation of the transactional model of stress and coping, we hypothesized greater SOC would be associated with adaptive coping, more regulated cytokine response, and lower fatigue. Sixty-two lung cancer patients provided self-report data on SOC, coping, and fatigue. PBMC were incubated with stimulators of acquired and innate immunity (PHA, LPS), and cytokines were measured (pro-inflammatory: IL-1beta IL-6, TNF-alpha; Type 1/TH1: IFN-gamma; Type 2/TH2: IL-5). Linear regressions tested hypotheses. Greater SOC was associated with emotionally expressive coping (p=0.005), an attenuated IL-5 response to PHA (p=0.038) and IFN-gamma response to LPS (p=.001); and lower fatigue (p<0.001). The associations between SOC and coping, cytokine response, and fatigue confirmed our hypotheses. As IL-5 is anti- and IFN-gamma is pro-inflammatory, these results suggest that SOC is related to an overall attenuated response to immune challenge. These findings support previous work suggesting SOC may facilitate psychological and physiological adjustment to stressors that accompany lung cancer

Circadian disruption and biomarkers of tumor progression in breast cancer patients awaiting surgery

•Actigraphy, salivary cortisol data provided by patients with active breast tumors.•Circadian disruption linked with evidence of tumor progression and VEGF in serum.•Circadian abnormalities may drive alterations in biomarkers favoring tumor growth.•Circadian/endocrine aberrations may also be manifestations of aggressive tumors.•Data inform understanding prognostic significance of circadian disruption in cancer. Psychological distress, which can begin with cancer diagnosis and continue with treatment, is linked with circadian and endocrine disruption. In turn, circadian/endocrine factors are potent modulators of cancer progression. We hypothesized that circadian rest–activity rhythm disruption, distress, and diurnal cortisol rhythms would be associated with biomarkers of tumor progression in the peripheral blood of women awaiting breast cancer surgery. Breast cancer patients (n=43) provided actigraphic data on rest–activity rhythm, cancer-specific distress (IES, POMS), saliva samples for assessment of diurnal cortisol rhythm, cortisol awakening response (CAR), and diurnal mean. Ten potential markers of tumor progression were quantified in serum samples and grouped by exploratory factor analysis. Analyses yielded three factors, which appear to include biomarkers reflecting different aspects of tumor progression. Elevated factor scores indicate both high levels and strong clustering among serum signals. Factor 1 included VEGF, MMP-9, and TGF-β; suggesting tumor invasion/immunosuppression. Factor 2 included IL-1β, TNF-α, IL-6R, MCP-1; suggesting inflammation/chemotaxis. Factor 3 included IL-6, IL-12, IFN-γ; suggesting inflammation/TH1-type immunity. Hierarchical regressions adjusting age, stage and socioeconomic status examined associations of circadian, distress, and endocrine variables with these three factor scores. Patients with poor circadian coordination as measured by rest–activity rhythms had higher Factor 1 scores (R2=.160, p=.038). Patients with elevated CAR also had higher Factor 1 scores (R2=.293, p=.020). These relationships appeared to be driven largely by VEGF concentrations. Distress was not related to tumor-relevant biomarkers, and no other significant relationships emerged. Women with strong circadian activity rhythms showed less evidence of tumor promotion and/or progression as indicated by peripheral blood biomarkers. The study was not equipped to discern the cause of these associations. Circadian/endocrine aberrations may be a manifestation of systemic effects of aggressive tumors. Alternatively, these results raise the possibility that, among patients with active breast tumors, disruption of circadian activity rhythms and elevated CAR may facilitate tumor promotion and progression

Pro-inflammatory, chemotactic, and anti-inflammatory cytokine responses associate with HPA, but not SNS, function in lung cancer patients

Disrupted cortisol rhythms are associated with earlier mortality across a number of cancer types; however, immune mechanisms by which circadian disruption may accelerate tumor progression have not been adequately defined in humans. Using blood samples from 62 lung cancer patients, PBMC were incubated with stimulators of acquired and innate immunity (PHA, LPS), and cytokines were measured. Serum DHEA, diurnal salivary cortisol, and overnight urinary catecholamines were collected. Hypothesized associations between stimulated analytes (pro-inflammatory: IL-1β, IL-6, TNF-α, IL-17; chemotactic: eotaxin; anti-inflammatory: IL-10; Type 1/TH1: IFN-γ; Type 2/TH2: IL-13, IL-5) and endocrine disruption (HPA axis: DHEA, cortisol; SNS: epinephrine, norepinephrine) were examined using linear regressions. Increased release of eotaxin in unstimulated control (p=0.030) and LPS (p=0.025) was associated with dysregulated diurnal cortisol, while increased release of IL-10 stimulated in LPS (p=0.018) was associated with higher mean cortisol secretion. When adjusting for unstimulated controls, an increased release of IL-6 stimulated in PHA (p=0.021) and IL-10 stimulated in LPS (p=0.019), was associated with higher mean cortisol secretion. Response to an immune challenge was associated with HPA axis disruption, but not markers of SNS function. These findings suggest immune mechanisms may partly explain the prognostic significance of HPA axis dysregulation in patients with lung cancer