scholarly journals GATA1 Promotes Gemcitabine Resistance in Pancreatic Cancer through Antiapoptotic Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-16 ◽  
Author(s):  
Zhenyu Chang ◽  
Yanan Zhang ◽  
Jie Liu ◽  
Chengjian Guan ◽  
Xinjin Gu ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Independent Predictor ◽  
Drug Efficacy ◽  
Ductal Adenocarcinoma ◽  
Cancer Targeting ◽  
First Line ◽  
Effective Strategies ◽  
Gemcitabine Resistance ◽  
Promising Strategy ◽  
First Line Treatment

Gemcitabine-based chemotherapy is the first-line treatment for pancreatic cancer. However, chemoresistance is a major obstacle to drug efficacy, leading to poor prognosis. Little progress has been achieved although multiple mechanisms are investigated. Therefore, effective strategies are urgently needed to overcome drug resistance. Here, we demonstrate that the transcription factor GATA binding protein 1 (GATA1) promotes gemcitabine resistance in pancreatic cancer through antiapoptotic pathway. GATA1 is highly expressed in pancreatic ductal adenocarcinoma (PDAC) tissues, and GATA1 status is an independent predictor of prognosis and response to gemcitabine therapy. Further investigation demonstrates GATA1 is involved in both intrinsic and acquired gemcitabine resistance in PDAC cells. Mechanistically, we find that GATA1 upregulates Bcl-XL expression by binding to its promoter and thus induces gemcitabine resistance through enhancing Bcl-XL mediated antiapoptosis invitroand invivo. Moreover, in PDAC patients, Bcl-XL expression is positively correlated with GATA1 level and predicts clinical outcomes and gemcitabine response. Taken together, our results indicate that GATA1 is a novel marker and potential target for pancreatic cancer. Targeting GATA1 combined with Bcl-XL may be a promising strategy to enhance gemcitabine response.

scholarly journals ESMO 2020 update: Pancreatic cancer

2021 ◽  
Author(s):  
Elisabeth Sophie Bergen
Keyword(s):  
Pancreatic Cancer ◽  
Randomized Clinical Trials ◽  
Medical Oncology ◽  
Chemotherapy Regimen ◽  
Ductal Adenocarcinoma ◽  
First Line ◽  
Standard Chemotherapy ◽  
Trial Quality ◽  
Standard Chemotherapy Regimen

SummaryAt the ESMO (European Society for Medical Oncology) 2020 several interesting albeit not practice-changing studies in the field of pancreatic cancer were presented. The Canadian phase II randomized PA.7 trial investigated the additional benefit of dual checkpoint inhibition with durvalumab and tremelimumab to a standard chemotherapy regimen as first-line treatment in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). Unfortunately, no significant improvement of responses or outcome could be achieved rendering this study a negative trial. Within the German platform-based QoliXane trial, quality of life was shown to be an essential prognosticator of survival with fatigue and nausea being independently associated with outcome of patients. Moreover, promising results could be observed with new targeted therapy approaches, which may lead to its investigation in larger randomized clinical trials.

SBP-101, a polyamine metabolic inhibitor, administered in combination with gemcitabine and nab-paclitaxel, shows signals of efficacy as first-line treatment for subjects with metastatic pancreatic ductal adenocarcinoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4127-4127
Author(s):  
Nimit Singhal ◽  
Darren Sigal ◽  
Niall C. Tebbutt ◽  
Aram F Hezel ◽  
Adnan Nagrial ◽  
...  
Keyword(s):  
Adverse Events ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Retinal Toxicity ◽  
Ductal Adenocarcinoma ◽  
Metabolic Inhibitor ◽  
Line Treatment ◽  
Hepatic Toxicity ◽  
First Line ◽  
Phase 1B ◽  
First Line Treatment

4127 Background: SBP-101, a polyamine metabolic inhibitor, inhibited growth in 6 human pancreatic ductal adenocarcinoma (PDA) cell lines and 3 murine xenograft tumor models of human PDA. SBP-101 monotherapy in heavily pre-treated PDA patients (> 2 prior regimens) showed a median survival of 5.9 months at the optimal dose level. Purpose: To assess the PK, safety and efficacy of SBP-101 in combination with gemcitabine (G) and nab-paclitaxel (A) in patients with previously untreated metastatic PDA. Methods: In a modified 3+3 dose escalation scheme, subcutaneous injections of SBP-101 were dosed at 0.2, 0.4 or 0.6 mg/kg days 1-5 of each 28-day cycle. G (1000 mg/m2) and A (125 mg/m2) were administered intravenously on Days 1, 8, and 15 of each cycle. PK was evaluated on day 1 of cycle 1 in cohorts 1-3. Safety was evaluated by clinical and laboratory assessments. Efficacy was assessed by CA19-9 levels, objective response using RECIST criteria, progression-free survival (PFS) and overall survival (OS). A fourth cohort using a modified dosing schedule of 0.4 mg/kg SBP-101 days 1-5 for cycles 1-2 and days 1, 8, and 15 every cycle thereafter was added to mitigate hepatic toxicity, and that dose and schedule were recommended for phase 1b expansion. Interim Results: Fifty patients were enrolled (N=25, phase 1a and N=25, phase 1b) and have received up to 12 treatment cycles. SBP-101 plasma Cmax and AUC0-t increased in a slightly more than dose proportional manner and were unchanged by the addition of G and A. PK parameters of G and A were unaltered by increasing doses of SBP-101. The most common nonserious adverse events related to SBP-101 (>10%) are fatigue (N=15), LFT/transaminase abnormalities (N=15), vision abnormalities (N=6), injection site pain (N=13), dehydration (N=7), diarrhea (N=7) and nausea (N=6). Serious adverse events related to SBP-101 observed in some subjects include hepatic toxicity (N= 6) and retinal toxicity (N=6) both occurring after prolonged treatment and requiring dose reduction or discontinuation. There is no evidence of SBP-101-related bone marrow suppression or peripheral neuropathy. At the recommended dose and schedule (N=30), CA19-9 levels decreased 60-99% in 19 of 29 evaluable patients, with 12/28 evaluable patients achieving partial responses (43%) and 11/28 achieving stable disease at 8 weeks (39%). Nine subjects are ongoing. PFS was confounded by SBP-101 dosing holds implemented to investigate potential toxicity. Median OS has not been reached. Conclusions: Interim results suggest SBP-101 may enhance first-line treatment with G and A in patients with metastatic PDA. Hepatic toxicity can be mitigated with dose reduction or discontinuation. Retinal toxicity that occurred in some subjects is under investigation. Clinical trial information: NCT03412799.

Masitinib plus gemcitabine as first-line treatment of pancreatic cancer with pain: Results from phase 3 study AB12005.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4018-4018
Author(s):  
Joel Ezenfis ◽  
Olivier Hermine ◽  
Keyword(s):  
Pancreatic Cancer ◽  
Statistical Significance ◽  
Locally Advanced ◽  
Disease Stage ◽  
Study Cohort ◽  
Line Treatment ◽  
First Line ◽  
Phase 3 ◽  
Risk Of Death ◽  
First Line Treatment

4018 Background: Masitinib (MAS) is a small molecule drug targeting mast cell and macrophage activity, innate immune cells that are critical components of the tumor microenvironment. Proof of concept that MAS in combination with gemcitabine (GEM) improved overall survival (OS) in pancreatic cancer (PC) patients (pts) with pain, was previously shown [doi 10.1093/annonc/mdv133]. The presence of pain in PC is thought to identify pts whose disease is driven in part by a pro-tumoral immune response. Methods: AB12005 was a prospective, placebo (PBO) controlled, double blind, randomized (2:1 MAS:PBO, stratified by disease stage, ECOG and geographic region) phase 3 trial, evaluating oral MAS (6.0 mg/kg/d) in combination with GEM (1000 mg/m²) against PBO plus GEM for the treatment of unresectable locally advanced PC (LAPC) and/or metastatic PC (mPC) pts with pain criteria; i.e. baseline visual analog scale of pain intensity (VAS) > 20 and/or pt treated with an opioid analgesics dose ≥1 mg/kg/d at baseline. Eligible pts were chemo-naïve with histologically or cytologically confirmed inoperable LAPC or mPC and an ECOG status ≤2. The estimated sample size was ̃330 pts to detect an OS hazard ratio (HR) of 0.68 (80% power, 2-sided α = 0.025) after 310 deaths. The study was successful if improvement in median OS (primary endpoint) relative to control reached a 2.5% level of statistical significance for either a targeted subgroup of LAPC with pain criteria, or the overall study cohort. Results: A total of 384 pts were enrolled (safety population n = 383; mITT n = 379; target subgroup n = 92). In the predefined subgroup of unresectable LAPC with pain, MAS-GEM (n = 62) showed significant benefit over PBO-GEM (n = 30) with median OS of 13.0 months (97.5% CI [11.0;18.0]) vs 11.2 months (97.5% CI [7.4;13.0]); p = 0.007. The HR was 0.46 (97.5% CI [0.2;0.9], p = 0.0047), corresponding to a significant 54% reduction in risk of death for MAS-GEM pts relative to control. Secondary analyses in the same subgroup were convergent with this primary outcome. Median PFS showed a 1.8 month between group difference in favor of MAS-GEM (p = 0.039), with a HR of 0.47 (97.5% CI [0.3;0.9], p = 0.014). The 12-month and 18-month OS rates showed a 1.3 fold and 3.4 fold improvement, respectively, in favor of MAS-GEM (53.2% and 33.9% for MAS-GEM vs 40.0% and 10% for PBO-GEM, respectively). In the overall population, comprising LAPC and mPC pts with pain, no survival benefit was observed; median OS for MAS-GEM (n = 244) was 6.9 months vs 8.0 months for PBO-GEM (n = 135); p = 0.461. The MAS-GEM combination was well tolerated with no sign of add-on toxicity. The proportion of patients presenting at least one adverse event (AE) or serious AE was respectively, 96.3% and 19.1% for MAS-GEM (n = 246) vs 99.3% and 21.3% for PBO-GEM (n = 136). Conclusions: The combination MAS (6.0 mg/kg/d) plus GEM may provide a new first line treatment option for unresectable LAPC pts with associated pain. Clinical trial information: NCT03766295.

Gemcitabine and oxaliplatin combination as first-line treatment for advanced pancreatic cancer: a multicenter phase II study

2008 ◽  
Vol 64 (2) ◽  
pp. 317-325 ◽  
Author(s):  
Kyung Hee Lee ◽  
Min Kyoung Kim ◽  
Yeol Hong Kim ◽  
Baek Yeol Ryoo ◽  
Ho Yeong Lim ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Advanced Pancreatic Cancer ◽  
Line Treatment ◽  
First Line ◽  
Multicenter Phase ◽  
First Line Treatment

A phase II study of lapatinib and capecitabine in first-line treatment of metastatic pancreatic cancer (ICORG 08- 39).

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 315-315 ◽  
Author(s):  
R. S. McDermott ◽  
P. Calvert ◽  
M. Parker ◽  
G. Webb ◽  
B. Moulton ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Overall Survival ◽  
Cancer Patients ◽  
Advanced Pancreatic Cancer ◽  
Metastatic Pancreatic Cancer ◽  
Survival Duration ◽  
Synergistic Activity ◽  
Line Treatment ◽  
First Line ◽  
First Line Treatment

315 Background: The combination of capecitabine plus erlotinib in gemcitabine-refractory advanced pancreatic cancer patients has proved beneficial in terms of median survival duration, objective radiological response rate and decrease in tumour marker levels from baseline. In the phase I study of capecitabine and lapatinib carried out in advanced solid tumors, the optimal tolerated regimen was determined to be lapatinib 1,250 mg plus capecitabine 2,000 mg/m2/day. At these dose levels, the combination was well tolerated with few grade 3 toxicities and no grade 4 toxicity. Our preclinical work suggested synergistic activity of capecitabine and lapatinib in pancreatic cancer. We initiated a study of this combination in the first-line therapy of metastatic pancreas cancer. Methods: This was a single-arm multicenter study in patients with chemotherapy-naive metastatic pancreatic cancer. The primary endpoint was overall survival. The study was designed as a Simons two-stage optimal design and was divided into two stages. The first stage was to recruit up to 12 patients. If at least seven of these patients survived for at least six months, then a further 20 patients would be enrolled into the study. If six or fewer of the initial 12 patients met the specified study survival criteria, the study would be halted. Treatment was to be administered until disease progression or until withdrawal from the study due to unacceptable toxicity or other reasons. Clinical and laboratory parameters were assessed to evaluate disease response and toxicity of therapy. The study patients received lapatinib 1,250 mg/day, plus capecitabine 2000 mg/m2/day on days 1-14 every 21 days. Results: Nine patients were enrolled. Seven of these patients did not achieve the interim protocol response requirement of survival for at least 6 months, to allow for the study to continue to the second cohort of patients. Median overall survival from first dose was 4 months. Median time on treatment was 2 months. There were no objective responses. There were no unexpected toxicities. Conclusions: The addition of lapatinib to capecitabine does not improve overall survival in the first-line treatment of advanced pancreatic cancer patients. [Table: see text]

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