Fasting promotes changes in metabolic pathways and cellular processes as in the levels of plasma macro- and micro-nutrients, and consequently in glucose and growth factors with a reduction of glucose and IGF-1 levels. In cancer patients, fasting seems to have the potential of maximizing cancer cell sensitivity to antiblastic treatment with a phenomenon described as differential stress resistance: it seems to protect healthy cells against the adverse effects of chemotherapy while making tumor cells more vulnerable to it. Previous pilot studies have demonstrated that short fasting during neoadjuvant chemotherapy for different tumours is well tolerated and appears to improve quality of life. Scarce data have been reported about fasting and involved molecular pathways in ovarian cancer patients. Higher levels of IGF-1 are found to be associated with increased disease risk, tumour metastasis and poor prognosis in ovarian cancer but data still need to be confirmed.
Also the underlying biologic mechanisms of calorie restriction and fasting and tumorogenic/ anti-tumorogenic effects are not fully understood, but it has been shown to be associated with modulation of metabolic enzymes like adenosine monophosphate activated kinase (AMPK) and sirtuins family, which which have been found to be involved in the cell¿s stress adaption systems, cell metabolism and survival.
The aim of this study is to evaluate the role of short fasting during neoadjuvant chemotherapy in patients affected by advanced ovarian cancer, in particular we want to investigate its impact on metabolic and endocrine parameters including IGF-1 level; we¿ll also try to better correlate the effect of fasting with the SIRTUINs pathways,
It has been previously demonstrated that fasting could slow tumour growth and augment the efficacy of certain systemic agents/chemotherapy drugs in various cancers. Nevertheless, this outcome has not been found in OC yet and the mechanisms behind this proposed idea are still uncertain. It has been proposed that, at least in some part, it may be due to the metabolic regulation by Sirtuin family proteins whose functions are involved in specific aspects of longevity, stress response and metabolism.
To the best of our knowledge, this is the first report investigating the possible role and mechanism of SF in primary advanced ovarian cancer patients receiving neoadjuvant chemotherapy. Previous studies on this topic mainly focused on the metabolic and endocrine outcomes of SF; importantly, our research project is also aimed in better clarifying the possible mechanisms that might explain the effect of SF on tumorigenesis. Therefore, we want to focus not only on the clinical concerns and outcomes of SF but also on the translational implications, which might help in finding new therapeutic opportunities. We believe that our research project might produce interesting evidences from both the clinical, biological and, possibly, therapeutic point of view in the setting of ovarian cancer.
First of all, if SF will be confirmed to be safe and well tolerated and if positive clinical effects will be found, the use of SF use might be proposed largely in ovarian cancer patient spopulation.
We will investigate if SF might have a negative impact on IGF-1 values. We will also correlate the levels of IGF-1 with the clinical response and the surgical cytoreduction rate after NACT in treated patients. If a direct correlation will be found between decrease of IGF-1 levels and response rate after NACT our reaserch might by amplify with a larger population and if data will be confirmed we might use IGF-1 as a biomarker of response; furthermore and more interestingly, we might consider SF as a potential ¿therapeutic¿ approach in order to amplify the response to NACT treatment.
With regard of the translational point of view, as previously explained, we will try to better define the correlation between Sirtuins and fasting, and its possible implication in tumor growth/reduction. In fact, as previously mentioned, the mechanism of fasting-induced cancer cell preferential killing may be attributed to the failure in inducing a stress maintenance response by shifting the cellular metabolism toward energy conservation and damage repair as opposed to normal cells. It would be therefore interesting to check whether Sirtuins are implicated in the response of cancer cells to chemotherapy.
More importantly, a better clarification of the crosstalk between Sirtuins and fasting, which is still incomplete, may provide us a new rationale that may further open up new opportunities for therapeutic interventions.
The understanding of the mechanisms of nutrient sensing and the molecular pathways regulated by fasting might led to the development of pharmaceutical interventions aimed at reproducing the beneficial effects of fasting without food deprivation.
Such intervention would allow longer treatment periods without compromising safety. Although fasting mimicking drugs would be preferred by patients and would lead to a higher compliance compared to dietary interventions, their development will require lengthy clinical trials with connected translational end-points in identifying pharmacological interventions that are both as effective and safe as fasting, even after long-term chronic use.