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Cancer cells voraciously consume nutrients to support their growth, exposing a metabolic vulnerability that can be therapeutically exploited. Here we show in hepatocellular carcinoma (HCC) cells, xenografts, and in patient-derived HCC organoids that fasting can synergistically sensitize resistant HCC to sorafenib. Mechanistically, sorafenib acts non-canonically as an inhibitor of mitochondrial respiration, causing resistant cells to depend on glycolysis for survival. Fasting, through reduction in glucose and impeded AKT/mTOR-signaling, prevents this Warburg shift. Regulating glucose transporter and pro-apoptotic protein expression, p53 is necessary and sufficient for the sorafenib-sensitizing effect of fasting. p53 is also crucial for fasting-mediated improvement of sorafenib efficacy in an orthotopic HCC mouse model. Together, our data suggest intermittent fasting and sorafenib as rational combination therapy for HCC with intact p53 signaling. As HCC therapy is currently severely limited by resistance, these results should instigate clinical studies aimed at improving therapy response in advanced-stage, and possibly even early-stage, HCC.HIGHLIGHTSFasting sensitizes resistant HCC xenografts and patient-derived organoids to sorafenibSorafenib-mediated Warburg shift is prevented by glucose limitation upon fastingFasting synergistically improves sorafenib efficacy in non-resistant modelsp53 is required for synergism by regulating glucose uptake and apoptosisGRAPHICAL ABSTRACT

Lifestyle-related disorders, such as the metabolic syndrome, have become a primary risk factor for the development of liver pathologies that can progress from hepatic steatosis, hepatic insulin resistance, steatohepatitis, fibrosis and cirrhosis, to the most severe condition of hepatocellular carcinoma (HCC). While the prevalence of liver pathologies is steadily increasing in modern societies, there are currently no approved drugs other than chemotherapeutic intervention in late stage HCC. Hence, there is a pressing need to identify and investigate causative molecular pathways that can yield new therapeutic avenues. The transcription factor p53 is well established as a tumor suppressor and has recently been described as a central metabolic player both in physiological and pathological settings. Given that liver is a dynamic tissue with direct exposition to ingested nutrients, hepatic p53, by integrating cellular stress response, metabolism and cell cycle regulation, has emerged as an important regulator of liver homeostasis and dysfunction. The underlying evidence is reviewed herein, with a focus on clinical data and animal studies that highlight a direct influence of p53 activity on different stages of liver diseases. Based on current literature showing that activation of p53 signaling can either attenuate or fuel liver disease, we herein discuss the hypothesis that, while hyper-activation or loss of function can cause disease, moderate induction of hepatic p53 within physiological margins could be beneficial in the prevention and treatment of liver pathologies. Hence, stimuli that lead to a moderate and temporary p53 activation could present new therapeutic approaches through several entry points in the cascade from hepatic steatosis to HCC., Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe, 963

Bortezomib is an active agent for treatment of multiple myeloma (MM) and may even be effective in patients (pts) with adverse prognostic factors including unfavorable cytogenetic abnormalities. However, it is unknown whether or not bortezomib may overcome the negative prognostic impact of a CKS1B gene amplification at chromosome 1q21 (amp1q21), which has recently been reported as a negative prognostic factor even in the setting of a total therapy approach. We therefore evaluated chromosome 1q21 among other abnormalities in 46 pts with relapsed/refractory MM who were treated with single-agent bortezomib (1.3 mg/m2 on days 1, 4, 8, and 11 every 3 weeks). Median age of pts was 63 years (range, 40 – 82 ) and median time to bortezomib therapy was 40 months (median number of prior therapies: 3; 96% of pts had high-dose pulsed dexamethasone, 61% thalidomide, 85% alkylating agents, and 41% high-dose melphalan). A response to bortezomib was noted in 45% of pts, with 17% of pts achieving a CR/near CR. Amp1q21 as determined by interphase FISH was observed in 20 of the 46 pts (43.5%). Treatment outcome after bortezomib was negatively affected by presence of amp1q21: The overall response rate was 30% (versus 58% in pts with normal 1q21; P = .06) and the CR/near-CR rate was 10% (versus 23%). Moreover, amp1q21 was associated with shortened time to treatment failure (median, 2.4 versus 6.6 months; P = .043) and overall survival (OS) (median, 4.4 versus 19.8 months; P = .003) compared to pts with normal 1q21. Beta-2-microglobulin and 14q32 translocations were unrelated to treatment outcome with bortezomib. In contrast, median OS was short in the presence of low serum albumin (4.8 versus 17.8 months; P = .036) and deletion of 13q14 (6.7 months versus median not yet reached; P = .06). Using amp1q21, low serum albumin, and deletion of 13q14 as risk factors, patients with significantly different median OS after bortezomib treatment were discriminated: Pts with ≥ 2 risk factors had a median OS of only 4.9 months as opposed to pts with 1 risk factor (median OS 16.5 months) or without any risk factor (median OS not yet reached) (P = .004). In conclusion, FISH-defined amp1q21 is a strong adverse prognostic factor for pts with relapsed/refractory MM treated with single-agent bortezomib. We are currently investigating whether or not bortezomib combinations may be more effective in MM pts with amp1q21.