Stromal disrupting effects of nab-paclitaxel in pancreatic cancer

Abstract

Background:Nab-paclitaxel and gemcitabine have demonstrated a survival benefit over gemcitabine alone in advanced pancreatic cancer (PDA). This study aimed to investigate the clinical, biological, and imaging effects of the regimen in patients with operable PDA.Methods:Patients with operable PDA received two cycles of nab-paclitaxel and gemcitabine before surgical resection. FDG-PET and CA19.9 tumour marker levels were used to measure clinical activity. Effects on tumour stroma were determined by endoscopic ultrasound (EUS) elastography. The collagen content and architecture as well as density of cancer-associated fibroblasts (CAFs) were determined in the resected surgical specimen and compared with a group of untreated and treated with conventional chemoradiation therapy controls. A co-clinical study in a mouse model of PDA was conducted to differentiate between the effects of nab-paclitaxel and gemcitabine.Results:A total of 16 patients were enrolled. Treatment resulted in significant antitumour effects with 50% of patients achieving a >75% decrease in circulating CA19.9 tumour marker and a response by FDG-PET. There was also a significant decrement in tumour stiffness as measured by EUS elastography. Seven of 12 patients who completed treatment and were operated had major pathological regressions. Analysis of residual tumours showed a marked disorganised collagen with a very low density of CAF, which was not observed in the untreated or conventionally treated control groups. The preclinical co-clinical study showed that these effects were specific of nab-paclitaxel and not gemcitabine.Conclusion:These data suggest that nab-paclitaxel and gemcitabine decreases CAF content inducing a marked alteration in cancer stroma that results in tumour softening. This regimen should be studied in patients with operable PDA.

Periductal stromal collagen topology of pancreatic ductal adenocarcinoma differs from that of normal and chronic pancreatitis

“…Enzymatic and small molecule targeting of the periductal stroma has shown promise in remodeling the architecture, softening the tumor, decreasing interstitial pressure, and improving the efficiency of systemic delivery in pancreatic ductal adenocarcinoma. 59,60 As last, disease markers that forecast which patients are most likely to experience accelerated progression or recurrence based on intrinsic tumor biology are critically needed to inform patient expectations, guide patient surveillance measures, and tailor personalized treatment regimens. There is emerging interest to stratify patients on the basis on stromal characteristics.…”

Efficacy and safety of the hypoxia-activated prodrug TH-302 in combination with gemcitabine and nab-paclitaxel in human tumor xenograft models of pancreatic cancer

“…PDAC tumor stroma serves as a mechanical barrier and promotes tumor forma-tion, progression, invasion, and metastasis development. [32][33][34] Treatment with nab-paclitaxel alone or nab-paclitaxel in combination with gemcitabine has been shown to decrease cancer-associated fibroblast (CAF) content, inducing a marked alteration in cancer stroma that result in tumor softening both preclinically 29 and clinically 28 . In our studies, we also found that the G C nP doublet significantly reduced the number of a-SMA positive fibroblasts as well as reduced extracellular collagen.…”

“…Nab-paclitaxel has been shown to affect the tumor stoma. 28,29 In the present study, we evaluated the efficacy and safety profile of TH-302 in combination with gemcitabine and nab-paclitaxel in PDAC preclinical models.…”

Combination Chemotherapy Regimens in Pancreatic Cancer

“…Это отчасти связано с тем, что nab-паклитаксел в отличие от паклитаксела вызывает истощение обильной десмопластической стромы опухо-ли, характерной для РПЖ и участвующей в прогрессии опухоли и химиорезистентности. В итоге концентрация гемцитабина в опухолевой ткани увеличивалась почти в 3 раза [31][32][33].…”