Advances in the management of pancreatic ductal adenocarcinoma

O’Kane, Grainne M.; Ladak, Farah; Gallinger, Steven

doi:10.1503/cmaj.201450

Cited by 13 publications

(11 citation statements)

References 78 publications

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“…PDA is predicted to become the third most common cause of cancer‐related death in the European Union (Ferlay et al , 2016), a ranking already reached in the USA (Siegel et al , 2019). Among PDA patients, 80–85% are not eligible for a potentially curative surgical resection because of an unresectable tumor or presence of metastases, and chemotherapy remains the only therapeutic option with limited impact on overall survival (Mizrahi et al , 2020; O'Kane et al , 2021). This therapeutic void in part reflects an incomplete understanding of disease pathogenesis that limits opportunities to uncover new therapies.…”

Section: Introductionmentioning

confidence: 99%

Ketogenic HMG‐CoA lyase and its product β‐hydroxybutyrate promote pancreatic cancer progression

et al. 2022

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Pancreatic ductal adenocarcinoma (PDA) tumor cells are deprived of oxygen and nutrients and therefore must adapt their metabolism to ensure proliferation. In some physiological states, cells rely on ketone bodies to satisfy their metabolic needs, especially during nutrient stress. Here, we show that PDA cells can activate ketone body metabolism and that b-hydroxybutyrate (bOHB) is an alternative cell-intrinsic or systemic fuel that can promote PDA growth and progression. PDA cells activate enzymes required for ketogenesis, utilizing various nutrients as carbon sources for ketone body formation. By assessing metabolic gene expression from spontaneously arising PDA tumors in mice, we find HMG-CoA lyase (HMGCL), involved in ketogenesis, to be among the most deregulated metabolic enzymes in PDA compared to normal pancreas. In vitro depletion of HMGCL impedes migration, tumor cell invasiveness, and anchorage-independent tumor sphere compaction. Moreover, disrupting HMGCL drastically decreases PDA tumor growth in vivo, while bOHB stimulates metastatic dissemination to the liver. These findings suggest that bOHB increases PDA aggressiveness and identify HMGCL and ketogenesis as metabolic targets for limiting PDA progression.

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Section: Introductionmentioning

confidence: 99%

Ketogenic HMG‐CoA lyase and its product β‐hydroxybutyrate promote pancreatic cancer progression

et al. 2022

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“…Immunotherapy has not been successful in pancreatic cancer, being largely refractory to immune checkpoint inhibitors (ICI) [116]. However, systemic autophagy inhibition with CQ, as well as tumor-specific autophagy inhibition, sensitizes PDAC to immune blockade.…”

Section: Preclinical Trialsmentioning

confidence: 99%

Autophagy Contributes to Metabolic Reprogramming and Therapeutic Resistance in Pancreatic Tumors

Reyes-Castellanos

Hadi

Carrier

2022

Cells

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Metabolic reprogramming is a feature of cancers for which recent research has been particularly active, providing numerous insights into the mechanisms involved. It occurs across the entire cancer process, from development to resistance to therapies. Established tumors exhibit dependencies for metabolic pathways, constituting vulnerabilities that can be targeted in the clinic. This knowledge is of particular importance for cancers that are refractory to any therapeutic approach, such as Pancreatic Ductal Adenocarcinoma (PDAC). One of the metabolic pathways dysregulated in PDAC is autophagy, a survival process that feeds the tumor with recycled intracellular components, through both cell-autonomous (in tumor cells) and nonautonomous (from the local and distant environment) mechanisms. Autophagy is elevated in established PDAC tumors, contributing to aberrant proliferation and growth even in a nutrient-poor context. Critical elements link autophagy to PDAC including genetic alterations, mitochondrial metabolism, the tumor microenvironment (TME), and the immune system. Moreover, high autophagic activity in PDAC is markedly related to resistance to current therapies. In this context, combining autophagy inhibition with standard chemotherapy, and/or drugs targeting other vulnerabilities such as metabolic pathways or the immune response, is an ongoing clinical strategy for which there is still much to do through translational and multidisciplinary research.

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“…Furthermore, 13% (5/36) of the GEM group had synchronous metastasis and local recurrence vs. 50% (5/10) of the OXA group (p = 0.04). 4.5 [1][2][3][4][5][6] pTNM is defined according to the American Joint Committee on Cancer AJCC 8th edition as: T1 (tumor ≤ 2 cm in the greatest dimension), T2 (tumor between 2 and 4 cm in the greatest dimension), T3 (tumor more than 4 cm in the greatest dimension) and T4 (tumor involves celiac axis or superior mesenteric artery). Nodal status was defined as N0 (no lymph node involvement), N1 (lymph node involvement between 1 and 3) and N2 (lymph node involvement more than 4).…”

Section: Adjuvant Therapymentioning

confidence: 99%

“…In 2030, pancreatic adenocarcinoma is estimated to become the second leading cause of cancer-related death [ 2 ]. Approximately one-third of patients with pancreatic adenocarcinomas are resectable upon diagnosis and eligible for surgery, one-third are already metastatic and the other third are locally advanced and potentially resectable after neoadjuvant therapy [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

Impact of Sarcopenia on Patients with Localized Pancreatic Ductal Adenocarcinoma Receiving FOLFIRINOX or Gemcitabine as Adjuvant Chemotherapy

Mortier

Wei

Pellat

et al. 2022

Cancers

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Pancreas cancer will become the second deadliest cancer in 2030. One-third of patients with pancreatic cancer are treated with surgery followed by intravenous chemotherapy. This aggressive treatment has to be delivered to people fit enough to receive it. Many variables are used to define this status, such as performance status, albuminemia or sarcopenia. In our study, we calculated the sarcopenia status by measuring via computer tomography the area of the psoas; if it is low in terms of sex and BMI, the patient is considered sarcopenic. We found out that sarcopenic patients with operated pancreatic cancer have a lower overall survival no matter the type of chemotherapy used.Abstract: Background: Despite its toxicity, modified FOLFIRINOX is the main chemotherapy for localized, operable pancreatic adenocarcinomas. Sarcopenia is known as a factor in lower overall survival (OS). The purpose of this study was to assess the impact of sarcopenia on OS in patients with localized pancreatic ductal adenocarcinoma (PDAC) who received modified FOLFIRINOX or gemcitabine as adjuvant chemotherapy. Methods: Patients with operated PDAC who received gemcitabine-based (GEM group) or oxaliplatin-based (OXA group) adjuvant chemotherapy between 2008 and 2021 were retrospectively included. Sarcopenia was estimated on a baseline computed tomography (CT) examination using the skeletal muscular index (SMI). The primary evaluation criterion was OS. Secondary evaluation criteria were disease-free survival (DFS) and toxicity. Results: Seventy patients treated with gemcitabine-based (n = 49) and oxaliplatin-based (n = 21) chemotherapy were included, with a total of fifteen sarcopenic patients (eight in the GEM group and seven in the OXA group). The median OS was shorter in sarcopenic patients (25 months) compared to non-sarcopenic patients (158 months) (p = 0.01). A longer OS was observed in GEM non-sarcopenic patients (158 months) compared to OXA sarcopenic patients (14.4 months) (p < 0.01). The median OS was 157.7 months in the GEM group vs. 34.1 months in the OXA group (p = 0.13). No differences in median DFS were found between the GEM group and OXA group. More toxicity events were observed in the OXA group (50%) than in the GEM group (10%), including vomiting (p = 0.02), mucositis (p = 0.01) and neuropathy (p = 0.01). Conclusion: Sarcopenia is associated with a worse prognosis in patients with localized operated PDAC whatever the delivered adjuvant chemotherapy.

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Advances in the management of pancreatic ductal adenocarcinoma

Cited by 13 publications

References 78 publications

Ketogenic HMG‐CoA lyase and its product β‐hydroxybutyrate promote pancreatic cancer progression

Ketogenic HMG‐CoA lyase and its product β‐hydroxybutyrate promote pancreatic cancer progression

Autophagy Contributes to Metabolic Reprogramming and Therapeutic Resistance in Pancreatic Tumors

Impact of Sarcopenia on Patients with Localized Pancreatic Ductal Adenocarcinoma Receiving FOLFIRINOX or Gemcitabine as Adjuvant Chemotherapy

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