The combination of everolimus and zoledronic acid increase the efficacy of gemcitabine in a mouse model of pancreatic adenocarcinoma

Vitellius, Carole; Fizanne, Lionel; Menager-Tabourel, Elodie; Nader, Joelle; Baize, Nathalie; Laly, Margot; Lermite, Émilie; Bertrais, Sandrine; Caroli-Bosc, François-Xavier

doi:10.18632/oncotarget.25560

Cited by 6 publications

(6 citation statements)

References 32 publications

(41 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…CD73 upregulation and subsequent accumulation of immunosuppressive adenosine has been targeted via anti‐CD73 antibodies, as well as anti‐A2A adenosine receptor inhibition, which is present on T cells [78,120]. Preventing hypoxic upregulation of MMP‐9, used in cancer cell and MDSC migration, via zoledronic acid is also being studied as combination therapy in PDA [223,224]. Cytokine and chemokines that are upregulated in hypoxia have also been targeted.…”

Section: Future Directionsmentioning

confidence: 99%

Hypoxia as a barrier to immunotherapy in pancreatic adenocarcinoma

Daniel

Sullivan

Labadie

et al. 2019

Clinical & Translational Med

165

109

View full text Add to dashboard Cite

Pancreatic ductal adenocarcinoma (PDA) is a lethal disease with limited response to cytotoxic chemoradiotherapy, as well as newer immunotherapies. The PDA tumor microenvironment contains infiltrating immune cells including cytotoxic T cells; however, there is an overall immunosuppressive milieu. Hypoxia is a known element of the solid tumor microenvironment and may promote tumor survival. Through various mechanisms including, but not limited to, those mediated by HIF-1α, hypoxia also leads to increased tumor proliferation and metabolic changes. Furthermore, epithelial to mesenchymal transition is promoted through several pathways, including NOTCH and c-MET, regulated by hypoxia. Hypoxia-promoted changes also contribute to the immunosuppressive phenotype seen in many different cell types within the microenvironment and thereby may inhibit an effective immune system response to PDA. Pancreatic stellate cells (PSCs) and myofibroblasts appear to contribute to the recruitment of myeloid derived suppressor cells (MDSCs) and B cells in PDA via cytokines increased due to hypoxia. PSCs also increase collagen secretion in response to HIF-1α, which promotes a fibrotic stroma that alters T cell homing and migration. In hypoxic environments, B cells contribute to cytotoxic T cell exhaustion and produce chemokines to attract more immunosuppressive regulatory T cells. MDSCs inhibit T cell metabolism by hoarding key amino acids, modulate T cell homing by cleaving L-selectin, and prevent T cell activation by increasing PD-L1 expression. Immunosuppressive M2 phenotype macrophages promote T cell anergy via increased nitric oxide (NO) and decreased arginine in hypoxia. Increased numbers of regulatory T cells are seen in hypoxia which prevent effector T cell activation through cytokine production and increased CTLA-4. Effective immunotherapy for pancreatic adenocarcinoma and other solid tumors will need to help counteract the immunosuppressive nature of hypoxia-induced changes in the tumor microenvironment. Promising studies will look at combination therapies involving checkpoint inhibitors, chemokine inhibitors, and possible targeting of hypoxia. While no model is perfect, assuring that models incorporate the effects of hypoxia on cancer cells, stromal cells, and effector immune cells will be crucial in developing successful therapies.

show abstract

Section: Future Directionsmentioning

confidence: 99%

Hypoxia as a barrier to immunotherapy in pancreatic adenocarcinoma

Daniel

Sullivan

Labadie

et al. 2019

Clinical & Translational Med

165

109

View full text Add to dashboard Cite

show abstract

“…Of the 201 patients randomized to receive gemcitabine (gemcitabine 2 g in 100 mL of saline vs saline) and 205 to receive saline in the intention‐to‐treat analysis, 35% vs 47%, respectively, experienced a recurrence by 4‐year median follow‐up (HR, 0.66; 95% CI, 0.48‐0.90; P < .001). Gemcitabine was administered in combination with other drugs, like everolimus or docetaxel, in patients after BCG failure 20 . Steinberg et al investigated 276 BCG failure patients who received intravesical gemcitabine plus docetaxel 21 .…”

Section: Discussionmentioning

confidence: 99%

Intravesical gemcitabine as bladder‐preserving treatment for BCG unresponsive non‐muscle‐invasive bladder cancer. Results from a single‐arm, open‐label study

et al. 2020

View full text Add to dashboard Cite

Background There is an unmet alternative medical therapy for BCG unresponsive patients. Objective To report efficacy of intravesical gemcitabine in NMIBC patients, who failed a previous course of BCG, or intolerant, and unwilling to undergo radical cystectomy (RC). Material and methods This is an open‐label, single‐arm study, which enrolled patients showing a failure or were intolerant to BCG and unwilling to undergo the RC. Intravesical gemcitabine was administered once a week for six consecutive weeks and once a month for 12 months. The primary outcome was DFS defined as the lack of a tumor on cystoscopy and negative urine cytology. Secondary endpoint was safety defined according a grading of side effects. OS, PFS, and DFS were described with Kaplan–Meier method at 12 and 24 months. Results and limitations Overall 36 patients were enrolled. The median follow‐up was 27 months. The DFS was 68.75% at the end of induction phase and 44.44% and 31.66% at 12 and 24 months of, respectively. The PFS was 43.75%. The OS and CSS were 77.9% (95% CI 58.78%‐88.92%) and 80.68% (95% CI 61.49%‐90.96%), respectively. There was no life threatening event or treatment‐related death (grade 4 or 5). The most common mild and moderate adverse events reported were urinary symptoms (LUTS) and fatigue (G1‐G2). Conclusion Patients who presented an unresponsive‐BCG recurrent NMIBC and unwilling to receive a RC, could benefit from intravesical gemcitabine as salvage organ‐sparing treatment.

show abstract

“…ZA can inhibit cancer cell growth by inducing apoptosis, cell cycle arrest, and by stimulating autophagy (7,(9)(10)(11)(12), which are crucial for tumor growth and survival. Moreover, the antitumor effect of ZA was also demonstrated in various cancer mouse models, such as breast (13) and pancreas (14), indicating that ZA is an effective agent for controlling human cancer. Indeed, clinical trials of ZA as an adjuvant therapy have been conducted for breast cancer (15,16).…”

Section: Introductionmentioning

confidence: 93%

Zoledronic acid impairs oral cancer stem cells by reducing CCL3

Lee¹,

Rigas²,

Martin³

et al. 2020

Oncol Rep

View full text Add to dashboard Cite

Cancer stem-like cells (CSCs; also referred to as tumor-initiating cells) play crucial roles in tumor progression and aggressiveness. Recent studies have demonstrated the antitumor activity of zoledronic acid (ZA), a third-generation bisphosphonate, in various types of human cancer. However, its effect on oral CSCs and the underlying mechanism remain obscure. The present study demonstrated that ZA suppresses the growth and stemness properties of oral/oropharyngeal squamous cell carcinoma (OSCC) cells. ZA inhibited the malignant characteristics of OSCC cells, such as anchorage-independent growth and epithelial thickening in organotypic raft cultures. Moreover, ZA treatment resulted in suppression of self-renewal capacity, a key feature of CSCs. ZA also inhibited important CSC properties, such as migration and chemo-radioresistance. Mechanistically, ZA exposure significantly decreased chemokine (C-C motif) ligand 3 (CCL3) expression in OSCC cells. It was further demonstrated that CCL3 signaling via its receptor is crucial for supporting the CSC phenotype in OSCC cells. Moreover, an antagonist of the CCL3 receptor reversed the effect of CCL3 on CSC properties, and exogenous CCL3 rescued the suppressaed CSC phenotype in ZA-treated OSCC cells. These results demonstrated that ZA suppresses the CSC phenotype in OSCC cells by reducing CCL3 expression, suggesting that ZA may be an effective therapeutic agent for oral cancer by targeting CSCs.

show abstract

The combination of everolimus and zoledronic acid increase the efficacy of gemcitabine in a mouse model of pancreatic adenocarcinoma

Cited by 6 publications

References 32 publications

Hypoxia as a barrier to immunotherapy in pancreatic adenocarcinoma

Hypoxia as a barrier to immunotherapy in pancreatic adenocarcinoma

Intravesical gemcitabine as bladder‐preserving treatment for BCG unresponsive non‐muscle‐invasive bladder cancer. Results from a single‐arm, open‐label study

Zoledronic acid impairs oral cancer stem cells by reducing CCL3

Contact Info

Product

Resources

About