Nab-paclitaxel Therapy Research Articles

Nab-paclitaxel: An effective third-line chemotherapy in patients with advanced, unresectable gallbladder cancer.

Background & objectives:Gallbladder (GBC) is an aggressive form of cancer and most patients present with advanced unresectable disease due to lack of early signs and symptoms. This retrospective study was conducted to present the treatment outcomes with three lines of chemotherapies in a subset of patients with advanced, unresectable GBC with the primary objective to determine the response rates with nab-paclitaxel as the third-line chemotherapy after failure of the first-line gemcitabine and platinum and the second-line FOLFOX-4 (oxaliplatin, leucovorin and 5-FU) therapy. Another objective was to evaluate the toxicity, progression-free survival (PFS) and overall survival (OS).Methods:Treatment-naive patients with histologically proven inoperable GBC treated with gemcitabine/platinum, FOLFOX-4 and nab-paclitaxel as the first-, second- and third-line chemotherapy were included in this study. The dose of gemcitabine and cisplatin or carboplatin was 1 g/m2 on days 1 and 8 and 75 mg/m2 (or target AUC of 5) on day 1, in a 21-day cycle. FOLFOX-4 was administered every two weeks and nab-paclitaxel was administered as 125 mg/m2 on days 1, 8 and 15 in a 28-day cycle.Results:There were eight men and 13 women with a median age of 57 yr who received nab-paclitaxel therapy. The overall response rate of the first-, second- and third-line chemotherapy was 61.9, 57.1 and 52.4 per cent, respectively. The median PFS for the gemcitabine/platinum, FOLFOX-4 and nab-paclitaxel therapy was 5.5, 5.4 and 2.9 months, respectively. The median OS with three lines of therapies was 14.0 months. Common Terminology Criteria (CTC) grade 3 or 4 haematological toxicities were observed in 28.6, 38.1 and 23.8 per cent of patients on gemcitabine/platinum, FOLFOX-4 and nab-paclitaxel therapy, respectively.Interpretation & conclusions:Our study suggests the clinical benefit of nab-paclitaxel chemotherapy in prolonging OS in a selected subgroup of advanced, unresectable GBC patients after failure of the first-line gemcitabine and platinum and the second-line FOLFOX-4 therapy.

Cost-effectiveness of adding atezolizumab to first-line chemotherapy in patients with advanced triple-negative breast cancer

Background:The effectiveness of atezolizumab plus nab-paclitaxel for advanced triple-negative breast cancer (TNBC) has been demonstrated. We aimed to evaluate its cost-effectiveness on advanced TNBC from the US payer perspective.Methods:A Markov model was adopted to project the disease course of newly diagnosed advanced TNBC. The clinical data were gathered from the IMpassion130 trial. Cost and health preference data were derived from the literature. The incremental cost-effectiveness ratio (ICER) was measured, and one-way sensitivity analysis and probabilistic sensitivity analysis were performed for exploring the model uncertainties.Results:Our results demonstrated that atezolizumab plus nab-paclitaxel augmented versus nab-paclitaxel therapy cost $104,278 and $149,465 and yielded an additional 0.371 and 0.762 of quality-adjusted life year (QALY) in in all patients with unknown PD-L1 status and subpopulation with PD-L1-positive, respectively, which led to an ICER of $281,448 and $196,073 per QALY gained. In all patients with unknown PD-L1 status, atezolizumab plus nab-paclitaxel treatment guiding by PD-L1 expression testing resulted in an ICER of $183,508 per QALY gained. Atezolizumab plus nab-paclitaxel could maintain a trend of positive incremental net health benefits and >50% probabilities of cost-effectiveness at the threshold of $200,000/QALY in more than half of subgroups with PD-L1-positive. One-way and probabilistic sensitivity analyses revealed the results were most sensitive to the hazard ratios (HRs) of overall survival (OS) of atezolizumab plus nab-paclitaxel versus nab-paclitaxel treatment.Conclusion:The atezolizumab plus nab-paclitaxel treatment is likely to be a cost-effective option compared with chemotherapy based on nab-paclitaxel for the patients with PD-L1-positive advanced TNBC.

190P - Details of response with first-line gemcitabine and nab-paclitaxel therapy in patients with advanced pancreatic cancer

BackgroundThe combination of gemcitabine and nab-paclitaxel (GnP) has been established as the first-line chemotherapy in patients (pts) with metastatic pancreatic cancer (M-PC). However, the efficacy of the therapy in pts with borderline resectable PC (BR-PC) and locally advanced PC (LA-PC) is not clear. Although achieving R0 resection is one of the main target for these pts, the details of the response, such as the best time to evaluate the response is not clear. Therefore, we evaluated the details of response with GnP treatment. MethodsWe retrospectively reviewed the medical records of pts with BR-PC, LA-PC, and M-PC who received GnP as the first-line chemotherapy between January 2016 and April 2019 at six hospitals. We investigated time to response (TTR), duration of response (DoR), and depth of response (DpR). The response of the primary tumor and the metastases were evaluated separately in pts with M-PC. The response of the primary tumor was evaluated in all pts. ResultsA total of 47 pts were analyzed; the median age was 70 years, male was 66% and the number of pts with BR-PC/LA-PC/M-PC was 6%/26%/68%. The response rates of primary tumor and metastases were 40% and 31%, respectively. Among the pts with M-PC, seven had a partial response (PR) of the primary tumor without PR of metastases. The median TTR and time to best response of the primary tumor and metastases were 3.17 months (m) and 4.21 m (p = 0.191), and 4.11 m and 5.88 m (p = 0.724), respectively. The median DoR of the primary tumor and metastases were 5.36 m and 4.11 m, respectively (p = 0.277). The median DpR of the primary tumor and metastases were 28.3% and 15.3%, respectively (p = 0.733). The median progression-free survival and overall survival in M-PC pts with and without PR of the primary tumor were 8.48 m and 6.41 m (p = 0.267), and 14.72 m and 7.66 m (p = 0.186), respectively. ConclusionsThe response of the primary tumor tended to be higher and earlier than that of the metastases. A favorable efficacy was observed in pts with BR-PC and LA-PC as well as pts with M-PC. This study indicated that the best time to evaluate the response of the primary site to consider the conversion therapy was around 4 m. Pts with M-PC showing PR of the primary tumor tended to have a favorable prognosis. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Relacorilant (RELA) with nab-paclitaxel (NP): Safety and activity in patients with pancreatic ductal adenocarcinoma (PDAC) and ovarian cancer (OvCA).

4130 Background: Glucocorticoid receptor (GR) pathway activation has been linked with chemotherapy resistance (CTR). RELA (formerly CORT125134, Corcept Therapeutics), a potent selective GR modulator, in combination with paclitaxel reduced CTR and enhanced activity against tumor growth in preclinical models of solid tumors. Methods: Patients (pts) with advanced solid tumors, ≤3 prior lines of cytotoxic therapy, ECOG status 0-1, and adequate marrow function received RELA (100, 150, or 200mg) + NP (60, 80, or 100mg/m2). Once daily RELA was given either continuously (CON) or intermittently (INT) (day before, of, and after NP). NP was dosed weekly for 3 of 4 weeks (wks) of a 28-day cycle. Prior NP therapy was allowed. Results: 72 pts have been enrolled [mean age 60 (range 18-81), mean number of prior therapies 3, prior taxane (TXN) treatment 54/72 (75%)]. 61 pts received ≥1 dose of RELA. Grade ≥3 AE ≥10% for CON: neutropenia (6/43, 14%); INT: neutropenia (6/18, 33%), anemia (2/18, 11%), and mucosal inflammation (2/18, 11%). Prophylactic G-CSF became mandatory in later cohorts. Recommended Phase 2 Dose: RELA 100mg-CON/150mg-INT + NP 80mg/m2 (exposures similar to NP 100mg/m2 due to CYP3A4 inhibition by RELA). Disease control (DC) > 24 wks was noted in 5/27 (19%) PDAC pts: 3 PR, 2 SD (27-50 wks). 3 pts achieved benefit despite progression on prior TXN with time to progression (TTP) 1.9-3.6x longer than prior TXN. 4/13 (31%) OvCA pts had DC > 24 wks: 1 CR, 1 PR, 2 SD (33-54+ wks). 1 pt had TTP 4.4x longer than prior TXN. 3 additional PRs were observed: acinar pancreatic cancer, TTP 31 wks (4.4x prior TXN); vulvar SCC HPV+, TTP 55 wks (3.9x prior TXN); cholangiocarcinoma, DC 29+ wks. Expression of GR-regulated genes involved in inflammation, apoptosis, and CTR distinguished pts with DC from pts without DC, providing proof of mechanism. Conclusions: RELA+NP resulted in durable disease control in pts with metastatic PDAC, OvCA, and other solid tumors, including those that have progressed on prior TXN. TTP was often several-fold longer than previously achieved on TXN therapy. Toxicities are manageable with prophylaxis for neutropenia. Further evaluation in OvCA NCT03776812, PDAC, and others are planned. Clinical trial information: NCT02762981.

Impact of glycemic control on treatment efficacy and safety during nabpaclitaxel plus gemcitabine therapy in unresectable pancreatic cancer.

337 Background: Diabetes mellitus (DM) and hyperglycemia have been widely considered to be associated with the risk of pancreatic cancer. However, the aim of this study was to evaluate the relationship between glycemic control and the efficacy or safety in pancreatic cancer pts receiving treatment with nab-Paclitaxel (nab-PTX) plus Gemcitabine (GEM). Methods: We retrospectively reviewed 285 pts with unresectable pancreatic cancer with nab-PTX plus GEM as the first-line chemotherapy from December 2014 to March 2017 at the National Cancer Center Hospital East, Kashiwa, Japan. The pts were divided into two groups, average blood glucose level during the period of chemotherapy was less than 160 mg/dL (Group GC: Good glycemic control group) and more than 160 mg/dL (Group PC: Poor glycemic control group). Results: A total of 285 pts were enrolled. Median age was 66 years (range: 26-84) and males/females: 180/105, PS (0-1/2-3): 272/13, stage (III/IV): 77/208. There were 226 pts in GC group and 59 pts in PC group. No significant differences were seen in the overall survival between Group GC and PC (median: 16.1 months vs. 13.8 months, p = 0.344) and in the progression free survival between the two groups (median: 7.5 months vs. 8.2 months, p = 0.862). The incidence rate of grade 2-3 chemotherapy-induced peripheral neuropathy (CIPN) was significantly higher in Group PC compared with Group GC (Group GC 28.3%, Group PC 45.8%, p = 0.010). Univariate and multivariate analyses identified glycemic control as significant independent factors associated with the incidence of grade 2-3 of CIPN (Odds ratio 2.182, 95% CI 1.20-3.96, p = 0.010). There was no significant difference in the relative dose intensity of nab-PTX between two groups (median, 56.6% in group GC, 56.5% in group PC, p = 0.952). Conclusions: Glycemic control during the chemotherapy with nab-PTX plus GEM in unresectable pancreatic cancer was not associated with OS. The incidence of severe CIPN was higher in pts with poor glycemic control compared with good glycemic control.

The impact of neutrophil to lymphocyte ratio as a prognostic factor in Japanese patients with unresectable pancreatic cancer treated with gemcitabine-based chemotherapy

Introduction: Gemcitabine-based chemotherapy is one of the standard treatment for unresectable pancreatic cancer. In a previous study, a high neutrophil-to-lymphocyte ratio (NLR) were found to have worse outcomes in patients with advanced pancreatic cancer. However, data on the significance of NLR for unresectable pancreatic cancer treated with gemcitabine-based chemotherapy are not available. Method: This is a retrospective review of Japanese patients who received chemotherapy with gemcitabine or gemcitabine plus nab-paclitaxel as first-line treatment for unresectable pancreatic cancer at our institution between April 2011 and January 2018. Pre-treatment absolute neutrophils-lymphocytes counts were collected and the NLR was calculated. Patients were divided into groups based the NLR. Patient characteristics, progression-free survival (PFS) and overall survival (OS) were compared between the groups. Result: Among the 60 patients, 37 received gemcitabine monotherapy and 23 gemcitabine plus nab-paclitaxel therapy. The median NLR was 2.7, and 3.0 was set as the cut-off value for grouping patients into high NLR (≥3.0) and low NLR (<3.0) groups. There were no significant differences in patient characteristics between the groups. The median PFS was significantly shorter in the high NLR group than in low NLR group (3.5 vs. 6.9 months; hazard ratio (HR) = 1.94; p = 0.03). Also there was a similar trend in the median OS (5.6 vs. 19.2 months; HR = 1.99; p = 0.03). Both univariate and multivariate analysis showed that a high NLR was the only independent prognostic factor (adjusted HR = 2.29; p = 0.02) for OS. A correlation analysis revealed a statistically significant correlation between NLR and OS. Conclusion: Pre-treatment NLR was a prognostic factor in Japanese patients with unresectable pancreatic cancer treated with gemcitabine-based chemotherapy.

A Case of Pancreatic Head Cancer with a Hepatic Metastasis that Showed Complete Response to Administration of Gemcitabine + Nab-Paclitaxel Therapy

症例は73歳，男性．皮膚黄染を指摘され当院を紹介．精査の結果，肝転移巣を伴う膵頭部癌の診断で切除不能と判断．Gemcitabine＋nab-Paclitaxelによる全身化学療法を施行した．４コース終了時点で，原発巣は軽度縮小し，肝転移巣は画像上消失していた．最終的に９コース施行し手術に臨んだ．肝臓の転移巣は完全に消失しており，原発巣も著明な縮小を認め，治療効果判定は組織学的部分奏効と判断した．肝転移巣は術中超音波検査でも指摘できなかったが，組織学的癌遺残の可能性を考慮し，肝外側区域切除，亜全胃温存膵頭十二指腸切除術を施行した．切除検体でも肝転移巣には腫瘍成分は認めなかった．Stage Ⅳ膵癌は予後不良で，その原因の一つに化学療法の奏効率の低さがあげられる．肝転移を伴う切除不能膵頭部癌に対して，化学療法後に根治切除を施行し，肝転移巣に対し組織学的完全奏効が得られた症例を経験したので報告する．

Improvement of Treatment Outcomes for Metastatic Pancreatic Cancer: A Real-world Data Analysis.

FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, oxaliplatin) and gemcitabine plus nab-paclitaxel therapy have recently been introduced for the treatment of metastatic pancreatic cancer. Herein, overall treatment outcomes of metastatic pancreatic cancer after introduction of FOLFIRINOX and gemcitabine plus nab-paclitaxel therapy were evaluated, in daily practice. Metastatic pancreatic cancer patients (n=321) who started systemic chemotherapy between January 2011 and December 2016 were included and were divided into two groups: group A (2011-2013) and group B (2014-2016). Treatment outcomes were evaluated retrospectively. Patient characteristics were similar between the two groups except for the rates of distant lymph node metastasis and peritoneal metastasis. The preferred regimens in groups A and B were gemcitabine monotherapy and gemcitabine plus nab-paclitaxel therapy, respectively. The response rates, median progression-free survival, and median overall survival of groups A and B were 7.8% and 28.4% (p<0.01), 3.1 months and 5.4 months (p<0.01), and 6.7 months and 10.2 months (p<0.01), respectively. Overall treatment outcomes for metastatic pancreatic cancer were significantly improved after introduction of FOLFIRINOX and gemcitabine plus nab-paclitaxel combination therapy in daily practice.

Abstract 4813: Enhancement of nab-paclitaxel response by inhibition of insulin-like growth factor (IGF) signaling in experimental esophageal adenocarcinoma

Abstract Introduction: Esophageal adenocarcinoma (EAC) is the fastest growing cancer in the western world and the overall 5 year survival rate of EAC is below 20 percent. Most patients with EAC present with locally advanced or widespread metastatic disease, where current treatment is largely ineffective. Therefore, new therapeutic approaches are urgently needed. Epidemiological studies have linked obesity with EAC. IGF signaling is an important mediator in obesity-associated EAC. Paclitaxel (PT) has been used in combination with carboplatin as a standard combination therapy for advanced EAC. PT required emulsification with solvents which has resulted in serious adverse effects in patients. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is an albumin-stabilized, cremophor-free and water soluble nanoparticle formulation of PT. Nab-paclitaxel has recently shown greater efficacy over PT in EAC. Here we evaluated the improvement in nab-paclitaxel response by addition of BMS-754807, a small molecule inhibitor of IGF-1R/IR signaling, in experimental EAC. Methods: We first evaluated the phosphorylation status of IGF-1R/IR protein by western blot in a panel of EAC cell lines. BMS-754807 and nab-paclitaxel, alone or in combination were tested for effects on cell growth detected by WST-1 assay and on cell apoptosis detected by western blot of cleavage of caspase 3 and PARP. We then explored the antitumor efficacy with survival advantage following BMS-754807 and nab-paclitaxel mono and combination therapies in murine subcutaneous xenograft and peritoneal metastatic survival models of human EAC. Results: BMS-754807 dose dependently inhibited in-vitro cell proliferation of OE19 and FLO-1 EAC cell lines having strong tyrosine phosphorylation of IGF-1R/IR protein and interestingly the addition of IC25 dose of BMS-754807 significantly decreased the nab-paclitaxel IC50 in these EAC cells. In addition, co-administration of BMS-754807 and nab-paclitaxel effectively enhanced cleavage of caspase-3 and PARP in these EAC cells. In subcutaneous xenografts using OE19 cells, average net tumor growth after two weeks in different therapy groups was 558.67 mm3 in control, 208.47 mm3 after BMS-754807 (p=0.043), 104.60 mm3 after nab-paclitaxel (p=0.013), and 14.30 mm3 after BMS-754807 plus nab-paclitaxel (p=0.0005). In OE19 EAC survival model there was a significant increase in median animal survival after two weeks BMS-754807 plus nab-paclitaxel treatment (85 days) compared to control (47 days, p=0.0034), to BMS-754807 therapy (57 days, p=0.0021) or to nab-paclitaxel (68 days, p=0.0339) therapy. Conclusion: Thus BMS-754807 with nab-paclitaxel treatment resulted in significantly higher antitumor efficacy and survival benefit. These results support the potential of BMS-754807 in combination with nab-paclitaxel as an effective option for EAC therapy. Citation Format: Md Sazzad Hassan, Fiona Williams, Niranjan Awasthi, Margaret A. Schwarz, Roderich E. Schwarz, Urs von Holzen. Enhancement of nab-paclitaxel response by inhibition of insulin-like growth factor (IGF) signaling in experimental esophageal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4813.

A randomised controlled trial of gemcitabine hydrochloride plus S-1 combination therapy versus gemcitabine hydrochloride therapy alone in pancreatic cancer patients aged ≥75 years: a study protocol for an open-label randomised feasibility study

IntroductionIn Japan, the age of patients with pancreatic cancer has increased. Combination chemotherapies such as 5-fluorouracil/leucovorin, oxaliplatin and irinotecan therapy and gemcitabine hydrochloride (GEM) +nab paclitaxel therapy have been developed...

PUB018 Analysis of the Safety and Usefulness of Nab-Paclitaxel Therapy in Patients with Non-Small Cell Carcinoma

PUB018 Analysis of the Safety and Usefulness of Nab-Paclitaxel Therapy in Patients with Non-Small Cell Carcinoma

Caveolae-Mediated Endocytosis Is Critical for Albumin Cellular Uptake and Response to Albumin-Bound Chemotherapy.

Nab-paclitaxel, a nanoparticle conjugate of paclitaxel to human albumin, exhibits efficacy in pancreatic cancer, non-small cell lung cancer and breast cancer. However, there is a lack of predictive biomarkers to identify patients who might benefit most from its administration. This study addresses this gap in knowledge by identifying that caveolin-1 (Cav-1) is a candidate mechanism-based biomarker. Caveolae are small membrane invaginations important for transendothelial albumin uptake. Cav-1, the principal structural component of caveolae, is overexpressed in the cancers noted above that respond to nab-paclitaxel. Thus, we hypothesized that Cav-1 may be critical for albumin uptake in tumors and perhaps determine their response to this drug. Cav-1 protein levels correlated positively with nab-paclitaxel sensitivity. RNAi-mediated attenuation of Cav-1 expression reduced uptake of albumin and nab-paclitaxel in cancer cells and rendered them resistant to nab-paclitaxel-induced apoptosis. Conversely, Cav-1 overexpression enhanced sensitivity to nab-paclitaxel. Selection for cellular resistance to nab-paclitaxel in cell culture correlated with a loss of Cav-1 expression. In mouse xenograft models, cancer cells, where Cav-1 was attenuated, exhibited resistance to the antitumor effects of nab-paclitaxel therapy. Overall, our findings suggest Cav-1 as a predictive biomarker for the response to nab-paclitaxel and other albumin-based cancer therapeutic drugs. Cancer Res; 77(21); 5925-37. ©2017 AACR.

P3-084 - Safety and efficacy of gemcitabine plus nab-paclitaxel therapy in elderly patients with advanced pancreatic cancer

P3-084 - Safety and efficacy of gemcitabine plus nab-paclitaxel therapy in elderly patients with advanced pancreatic cancer

Locally advanced pancreatic cancer successfully treated by distal pancreatectomy with celiac axis resection (DP-CAR) after S-1 with radiation therapy followed by gemcitabine/nab-paclitaxel therapy: a case report

BackgroundThe prognosis for pancreatic cancer remains dismal because many patients are diagnosed with unresectable cancer at the initial diagnosis. Recently, conversion surgery was reported as an effective treatment for initially unresectable pancreatic cancer with a favorable response to non-surgical treatment lasting over 240 days. Here, we describe a case of locally advanced pancreatic cancer (LAPC) successfully resected after treatment with S-1 and radiation followed by gemcitabine/nab-paclitaxel therapy.Case presentationA 73-year-old man with LAPC was referred to our hospital. Computed tomography findings revealed a 2.5-cm mass in the pancreatic body that had invaded the celiac artery, common hepatic artery, and splenic artery. Superior mesenteric artery (SMA) encasement was not observed, but tumor abutment over 180° with the main tumor was detected. Staging laparoscopy showed no findings of distant metastasis, and washing cytology revealed no malignancy. He was diagnosed with unresectable pancreatic cancer. Treatment with S-1 with radiation therapy followed by gemcitabine with nab-paclitaxel was performed. Six months after the initial treatment, the tumor size had decreased to 1.2 cm, and encasement of the main artery was diminished. Though abutment to the main artery, including the SMA, was still detected, distal pancreatectomy with celiac artery resection was performed. The histopathological findings around the celiac artery revealed fibrous changes with an Evans classification of grade IIb. There was no residual cancer at the periphery; thus, R0 resection was achieved. The patient has been healthy and without recurrence for more than 12 months since the initial treatment.ConclusionsGemcitabine/nab-paclitaxel therapy revealed high response rate for metastasic pancreatic cancer (PC), but the effect for LAPC proposing conversion surgery was not well discussed. In this case, we achieve R0 resection combined with chemoradiation therapy and gemcitabine/nab-paclitaxel therapy. This regimen was also effective for LAPC and may be used to increase the population of conversion surgery by its high response rate.

Gemcitabine+nab-paclitaxelにて腫瘍縮小傾向を認めた多形細胞型退形成膵管癌の一例

症例は49歳，女性．背部痛を主訴に受診．造影CTで膵頭部に乏血性の腫瘤を認め，肝臓にも両葉多発の腫瘤を認めた．超音波内視鏡下穿刺吸引法による組織診の結果，退形成膵管癌と診断．化学療法目的に当院へ紹介となり80％doseのgemcitabine＋nab-paclitaxelにて治療開始．治療後3か月で画像上，原発巣のわずかな縮小と肝転移巣の著明な縮小を認めたが, 食思不振とperformance status低下にて治療の継続は困難となった．S-1内服に変更するも急激なCA19-9の上昇と全身衰弱にて初診より約4か月で永眠された．病理解剖の結果，多形細胞型退形成膵管癌との診断となった．化学療法を施行した多型細胞型退形成膵管癌の報告は少なく，画像上奏功した症例はほとんどない．本症例は，切除不能多形細胞型退形成膵管癌の治療を検討する上で貴重な症例と考えた．

Clinical outcome of gemcitabine and Nab-paclitaxel therapy in unresectable pancreatic cancer at high-volume cancer center institution

Clinical outcome of gemcitabine and Nab-paclitaxel therapy in unresectable pancreatic cancer at high-volume cancer center institution

Experience of gemcitabine plus nab-paclitaxel combination therapy in second line and beyond for unresectable progressive and metastatic pancreatic cancer

Experience of gemcitabine plus nab-paclitaxel combination therapy in second line and beyond for unresectable progressive and metastatic pancreatic cancer

Our first experience of gemcitabine and nab-paclitaxel combination therapy for borderline resectable pancreatic cancer

Our first experience of gemcitabine and nab-paclitaxel combination therapy for borderline resectable pancreatic cancer

Abstract 405: Caveolin-1 expression mediates response to albumin-bound paclitaxel

Abstract BACKGROUND: Albumin-bound chemotherapies such as nab-paclitaxel are approved to treat pancreatic cancer, non-small cell lung cancer (NSCLC), and breast cancer. Predictive biomarkers to select patients who may benefit most from nab-paclitaxel are lacking. Nab-paclitaxel is thought to enter cells through a caveolae-gp60 endocytic mechanism. Caveolin-1 (Cav-1) is a principal structural component of caveolae, and Cav-1 has been shown to be important for albumin uptake in endothelial cells. Cav-1 is known to be up-regulated in multiple tumor types, including pancreatic cancer, and certain subtypes of non-small cell lung cancer, and breast cancer. We hypothesize that Cav-1 expression may predict response to nab-paclitaxel therapy. METHODS: We correlated Cav-1 expression with nab-paclitaxel sensitivity in a panel of NSCLC and pancreatic cancer cell lines. We also assessed albumin uptake in tumor and non-tumor cell lines. We genetically depleted Cav-1 by shRNA in cells and performed cytotoxicity assays. In addition, we measured how Cav-1 levels affected albumin and nab-paclitaxel uptake into tumor cells by immunofluorescence, immunoblotting, and mass spectrometry. Annexin V flow cytometry analysis and immunoblotting for apoptosis pathway intermediates were also performed. Nab-paclitaxel resistant cell lines were created by culturing cells with increasing doses of nab-paclitaxel for extended periods of time. The role of Cav-1 expression in mediating response to nab-paclitaxel in vivo was assessed using xenograft models. RESULTS: H23 and MIA-PaCa2 tumor cells uptake more albumin compared to FHs74Int and HBEC3KT non-tumor cell lines. Higher Cav-1 expression in a panel of pancreatic cancer and NSCLC cell lines was correlated with lower IC50 for nab-paclitaxel. Cav-1 depletion resulted in reduced albumin and nab-paclitaxel uptake by tumor cells as measured by immunofluorescence, immunoblotting, and mass spectrometry. Loss of Cav-1 resulted in resistance to nab-paclitaxel but no change in sensitivity to free paclitaxel in vitro. Cav-1 down-regulation resulted in protection from nab-paclitaxel-induced apoptosis. Conversely, re-expression of Cav-1 in low-Cav-1 endogenously expressing cell lines AsPC-1 and HPAFII resulted in increased nab-paclitaxel uptake and sensitization through apoptosis. Furthermore, nab-paclitaxel resistant cells generated by prolonged exposure demonstrated downregulation of Cav-1 levels and reduced albumin uptake. Finally, genetic depletion of Cav-1 rendered tumor cells resistant to nab-paclitaxel in xenograft models, with concomitant reduced albumin uptake and activation of apoptosis. CONCLUSIONS: Our data suggest that Cav-1 expression and caveolae are critical determinants of response to nab-paclitaxel. This data supports further testing of Cav-1 as a potential predictive biomarker of response to nab-paclitaxel and potentially other albumin-bound chemotherapies. Citation Format: Terence M. Williams, Moumita Chatterjee, Ryan Robb, Marally Vedaie, Star Seum, Thirumoorthy Krishnan, Palanichamy Kamalakanan, Edgar Ben-Josef, Arnab Chakravarti. Caveolin-1 expression mediates response to albumin-bound paclitaxel. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 405.

Efficacy of gemcitabine plus nab-paclitaxel combination therapy for locally advanced unresectable pancreatic cancer

Efficacy of gemcitabine plus nab-paclitaxel combination therapy for locally advanced unresectable pancreatic cancer