Association between neutropenia and survival to nab-paclitaxel and gemcitabine in patients with metastatic pancreatic cancer

Roviello, Giandomenico; Ramello, Monica; Catalano, Martina; D’Angelo, Alberto; Conca, Raffaele; Gasperoni, Silvia; Dreoni, Lorenzo; Petrioli, Roberto; Ianza, Anna; Nobili, Stefania; Aieta, Michele; Mini, Enrico

doi:10.1038/s41598-020-76465-9

Cited by 13 publications

(13 citation statements)

References 26 publications

(36 reference statements)

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“…Finally, we wanted to assess the relevance of our findings in humans. We observed higher rates of neutropenia in patients who responded to chemotherapy, consistent with our mouse data and the known association between neutropenia and PDAC prognosis 22 (Extended Data Fig. 9d ).…”

Section: -Iaa Has Therapeutic Potentialsupporting

confidence: 90%

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Microbiota-derived 3-IAA influences chemotherapy efficacy in pancreatic cancer

Tintelnot

Lesker

et al. 2023

Nature

188

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Pancreatic ductal adenocarcinoma (PDAC) is expected to be the second most deadly cancer by 2040, owing to the high incidence of metastatic disease and limited responses to treatment1,2. Less than half of all patients respond to the primary treatment for PDAC, chemotherapy3,4, and genetic alterations alone cannot explain this5. Diet is an environmental factor that can influence the response to therapies, but its role in PDAC is unclear. Here, using shotgun metagenomic sequencing and metabolomic screening, we show that the microbiota-derived tryptophan metabolite indole-3-acetic acid (3-IAA) is enriched in patients who respond to treatment. Faecal microbiota transplantation, short-term dietary manipulation of tryptophan and oral 3-IAA administration increase the efficacy of chemotherapy in humanized gnotobiotic mouse models of PDAC. Using a combination of loss- and gain-of-function experiments, we show that the efficacy of 3-IAA and chemotherapy is licensed by neutrophil-derived myeloperoxidase. Myeloperoxidase oxidizes 3-IAA, which in combination with chemotherapy induces a downregulation of the reactive oxygen species (ROS)-degrading enzymes glutathione peroxidase 3 and glutathione peroxidase 7. All of this results in the accumulation of ROS and the downregulation of autophagy in cancer cells, which compromises their metabolic fitness and, ultimately, their proliferation. In humans, we observed a significant correlation between the levels of 3-IAA and the efficacy of therapy in two independent PDAC cohorts. In summary, we identify a microbiota-derived metabolite that has clinical implications in the treatment of PDAC, and provide a motivation for considering nutritional interventions during the treatment of patients with cancer.

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Section: -Iaa Has Therapeutic Potentialsupporting

confidence: 90%

“…Neutrophils are highly abundant in PDAC, and a low neutrophil count (neutropenia) is associated with a good prognosis in mPDAC 22 . 3-IAA is specifically toxic to cells with a high concentration of myeloperoxidase (MPO), which is a hallmark of neutrophils 23 .…”

Section: The Effect Of 3-iaa Is Licensed By Myeloperoxidasementioning

confidence: 99%

Microbiota-derived 3-IAA influences chemotherapy efficacy in pancreatic cancer

Tintelnot

Lesker

et al. 2023

Nature

188

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“…Neutrophils have been shown to produce soluble factors like cytokines and chemokines that potentiate cancer cell-survival mechanisms and consequently inhibit response to therapy [ 6 , 7 , 36 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ]. This observation is underscored by clinical findings that show improved therapeutic response and prognosis in patients with mild chemotherapy-induced neutropenia [ 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 ]. The similar trend elucidated across these studies is notable since it suggests that inhibiting TANs may improve response to chemotherapy independent of other confounders.…”

Section: Neutrophils In Cancer Therapy Resistancementioning

confidence: 99%

Neutrophil Extracellular Traps in Cancer Therapy Resistance

Shahzad

Feng

et al. 2022

Cancers

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Neutrophils and their products are increasingly recognized to have a key influence on cancer progression and response to therapy. Their involvement has been shown in nearly every aspect of cancer pathophysiology with growing evidence now supporting their role in resistance to a variety of cancer therapies. Recently, the role of neutrophils in cancer progression and therapy resistance has been further complicated with the discovery of neutrophil extracellular traps (NETs). NETs are web-like structures of chromatin decorated with a variety of microbicidal proteins. They are released by neutrophils in a process called NETosis. NET-dependent mechanisms of cancer pathology are beginning to be appreciated, particularly with respect to tumor response to chemo-, immuno-, and radiation therapy. Several studies support the functional role of NETs in cancer therapy resistance, involving T-cell exhaustion, drug detoxification, angiogenesis, the epithelial-to-mesenchymal transition, and extracellular matrix remodeling mechanisms, among others. Given this, new and promising data suggests NETs provide a microenvironment conducive to limited therapeutic response across a variety of neoplasms. As such, this paper aims to give a comprehensive overview of evidence on NETs in cancer therapy resistance with a focus on clinical applicability.

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“…Thus, the positive response of this combination, although rather modest, was accompanied by an increase in adverse effects [51,65,67]. Interestingly, recent data suggest that the nabpaclitaxel-gemcitabine treatment-induced neutropenia is associated with longer survival in metastatic pancreatic cancer patients [68].…”

Section: Current Therapy Against Pancreatic Cancer Is Ineffectivementioning

confidence: 99%

Direct Endoplasmic Reticulum Targeting by the Selective Alkylphospholipid Analog and Antitumor Ether Lipid Edelfosine as a Therapeutic Approach in Pancreatic Cancer

Mollinedo

Gajate

2021

Cancers

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Pancreatic ductal adenocarcinoma (PDAC), the most common malignancy of the pancreas, shows a dismal and grim overall prognosis and survival rate, which have remained virtually unchanged for over half a century. PDAC is the most lethal of all cancers, with the highest mortality-to-incidence ratio. PDAC responds poorly to current therapies and remains an incurable malignancy. Therefore, novel therapeutic targets and drugs are urgently needed for pancreatic cancer treatment. Selective induction of apoptosis in cancer cells is an appealing approach in cancer therapy. Apoptotic cell death is highly regulated by different signaling routes that involve a variety of subcellular organelles. Endoplasmic reticulum (ER) stress acts as a double-edged sword at the interface of cell survival and death. Pancreatic cells exhibit high hormone and enzyme secretory functions, and thereby show a highly developed ER. Thus, pancreatic cancer cells display a prominent ER. Solid tumors have to cope with adverse situations in which hypoxia, lack of certain nutrients, and the action of certain antitumor agents lead to a complex interplay and crosstalk between ER stress and autophagy—the latter acting as an adaptive survival response. ER stress also mediates cell death induced by a number of anticancer drugs and experimental conditions, highlighting the pivotal role of ER stress in modulating cell fate. The alkylphospholipid analog prototype edelfosine is selectively taken up by tumor cells, accumulates in the ER of a number of human solid tumor cells—including pancreatic cancer cells—and promotes apoptosis through a persistent ER-stress-mediated mechanism both in vitro and in vivo. Here, we discuss and propose that direct ER targeting may be a promising approach in the therapy of pancreatic cancer, opening up a new avenue for the treatment of this currently incurable and deadly cancer. Furthermore, because autophagy acts as a cytoprotective response to ER stress, potentiation of the triggering of a persistent ER response by combination therapy, together with the use of autophagy blockers, could improve the current gloomy expectations for finding a cure for this type of cancer.

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Association between neutropenia and survival to nab-paclitaxel and gemcitabine in patients with metastatic pancreatic cancer

Cited by 13 publications

References 26 publications

Microbiota-derived 3-IAA influences chemotherapy efficacy in pancreatic cancer

Microbiota-derived 3-IAA influences chemotherapy efficacy in pancreatic cancer

Neutrophil Extracellular Traps in Cancer Therapy Resistance

Direct Endoplasmic Reticulum Targeting by the Selective Alkylphospholipid Analog and Antitumor Ether Lipid Edelfosine as a Therapeutic Approach in Pancreatic Cancer

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