Gemcitabine-cisplatin Combination Research Articles

Retrospective evaluation of our patients diagnosed with advanced pancreatic cancer

Aims: Pancreatic cancer attracts attention with its increasing frequency among gastrointestinal cancers. It has the worst prognosis of all cancer types. In this study, we aimed to retrospectively evaluate the clinical features and treatment results of our patients with advanced pancreatic cancer. Methods: In this study, 131 patients diagnosed with advanced pancreatic cancer and admitted to the Ankara Numune Training and Research Hospital Medical Oncology Polyclinic between November 2002 and January 2014 were retrospectively analyzed. Demographic characteristics of the patients, smoking, family history, basal CEA and basal CA 19-9 levels, treatment modalities, metastasis sites, progression-free survival, and overall survival times were evaluated. Results: The study population consisted of 131 patients, including 94 males and 37 females. Twenty of the patients were in the locally advanced stage, and 111 were in the metastatic stage. The median age of the patients was 60 years. 53.4% of the patients were smokers, and the median amount of smoking was 30 packs/year. Adenocancer was the most common histopathological subtype. The median basal CEA and Ca 19-9 levels were high at the time of diagnosis. Neoadjuvant chemotherapy was given to all locally advanced patients. The most commonly used chemotherapy regimens were single-agent gemcitabine and gemcitabine-cisplatin combination therapies. While 10 of the locally advanced patients received local treatment (chemotherapy or surgery) after neoadjuvant chemotherapy, the remaining 10 patients could not receive local treatment. The median overall and progression-free survival times were found to be significantly longer in patients with locally advanced disease who received local treatment after neoadjuvant chemotherapy [(18 months vs. 6.5 months; p=0.008), (11.3 months vs. 6.4 months; p=0.05)]. The most common site of metastasis in our patients with metastatic pancreatic cancer was the liver (80%). Cisplatin-gemcitabine was preferred as a KT regimen in 63.4% of metastatic cases. The median overall survival time of the patients in the metastatic stage was 8.1 months, and the median progression-free survival time was 5.7 months. The median progression-free survival of all patients included in the study was 6.2 months, while the median overall survival was 8.8 months. Conclusion: The median overall survival of patients with locally advanced pancreatic cancer was significantly longer compared to metastatic patients (18 months vs. 8.1 months; p=0.028). Progression-free survival and overall survival of patients with locally advanced disease who received or did not receive local treatment after neoadjuvant chemotherapy were found to be significantly longer in patients who received local treatment. (11.3 months vs. 6.4 months; p=0.05) (18 months vs. 6.5 months; p=0.008). Response rates of patients with metastatic pancreatic cancer; It was 49% in the gemcitabine-cisplatin combination arm and 30% in the single-agent gemcitabine arm.

Disitamab vedotin in combination with immune checkpoint inhibitors for locally and locally advanced bladder urothelial carcinoma: a two-center's real-world study.

Objective: Our study aims to assess the effectiveness and safety profile of Disitamab Vedotin (DV, RC48-ADC), an innovative humanized anti-HER2 antibody conjugated with tubulin-disrupting antimitotic drug monomethyl auristatin E (MMAE) via a cleavable peptide linker. This treatment combined immune checkpoint inhibitors as part of the bladder sparing approach for selected patients suffering from locally and locally advanced bladder urothelial carcinoma. Patients and methods: We conducted a two-center, real-world study involving locally advanced urothelial carcinoma (UC) patients. Patients were classified based on HER2 expression (IHC 3+/2+/1+) or lack of HER2 expression (IHC 0). The primary endpoint was the objective response rate (ORR), assessed by the investigator following the criteria of RECIST V1.1. Secondary endpoints encompassed the pathological complete response rate (pCR), pathological partial response rate (pPR), and pathological stable disease (pSD), along with recurrence-free survival (RFS), the pathological downstaging rate, and the safety profile of the treatment. Results: In this study, nine patients were enrolled, with a median follow-up duration of 12.0months. The overall confirmed ORR was 88.9%, Five patients achieved a complete response (CR), and three patients achieved a partial response (PR). The radiological complete response (rCR) aligned perfectly with pCR. The median radiological progression-free survival (rPFS) spanned 12.0months (range from 8.0 to 17.0months). One patient diagnosed with disease progression (PD) underwent a radical cystectomy. The pathological stage evolved from T2N0M0 to T3aN2M0, followed by adjuvant chemotherapy with a gemcitabine-cisplatin (GC) combination radiotherapy. At the 9-month follow-up, neither recurrence nor metastasis was observed. The rate and intensity of complications were manageable among these patients, with no evidence of grade 4 and 5 adverse events. Conclusion: The combination of DV and PD-1 demonstrated considerable activity in the objective response rate (ORR) in patients with HER2 IHC 0/1+/2+/3+ muscle-invasive bladder cancer (MIBC), along with the longest reported median radiological progression-free survival (rPFS) to date. With an extended duration of treatment, the safety profile of DV plus PD-1 was also confirmed to be manageable.

A randomized study of consolidation chemo-radiotherapy versus observation after first-line chemotherapy in advanced gall bladder cancers (RACE-GB Study): trial protocol

Background: Chemotherapy (CT) is the standard of care for advanced gall bladder cancer (GBC). However, after completion of 6 cycles of CT, a proportion of patients with good performance status progress within a few months. Retrospective data in locally advanced cases revealed that consolidation chemo-radiotherapy (CTRT) in responders to CT and with good performance status improves overall survival. Methods: FNA proven advanced GBC with predefined clinical-radiological features will be administered 4 cycles CT (cisplatin-gemcitabine combination). After completion of CT, those in good Karnofsky performance status (KPS) will be randomised to consolidation CTRT versus observation (standard of care). The primary end point of the study is to compare OS between the two arms. The secondary end point is to compare progression free survival (PFS), toxicity, and quality of life between the two study arms. The trial is designed to detect an improvement in 2-year overall survival (OS) from 8% in the control arm to 25% in study arm with 80.0% power at a 0.05 significance level. The resultant sample size to achieve this aim is 140 (70 in each arm) over a duration of 4-5 years with a 10% attrition rate. Accrual has been from January 2019 to October 2022. Conclusions: This trial aims to assess the incremental gain in outcomes with consolidation CTRT versus observation in responders to first-line CT in advanced GBCs. This is the first randomised study to evaluate role of consolidation chemoradiation. Trial Registration: The trial is registered with clinical trials registry India (CTRI/2019/04/025204) and clinical trials.gov (NCT05493956).

The path to personalized treatment in advanced and metastatic biliary tract cancers: a review of new targeted therapies and immunotherapy.

To summarize targeted therapies and immunotherapy as treatment for advanced/metastatic biliary tract cancers and discuss ongoing clinical trials. For the first time since gemcitabine-cisplatin was set as the standard of care in first-line advanced/metastatic biliary tract cancers in the ABC-02 trial, the combination of durvalumab and gemcitabine-cisplatin has demonstrated a statistically significant improvement of median overall survival in the TOPAZ-1 phase 3 trial. The ABC-06 trial showed a significant increase of median overall survival for FOLFOX and active symptom control compared with active symptom control alone in second-line regardless of molecular and genetic alterations. However, faced with a heterogeneous cancer, patient prognosis remains poor, leaving room for new, personalized, treatment options such as targeted therapies. Efficacy of fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitors has been demonstrated in different phase 2 trials for previously treated intrahepatic cholangiocarcinomas harboring FGFR2 fusions. Ivosidenib increases significantly median progression-free survival in previously treated cholangiocarcinomas with isocitrate dehydrogenase-1 (IDH-1) mutation. Other targeted therapies are tested for tumors with HER2 amplifications/mutations, BRAFV600E mutations or KRASG12C mutations. In this review, we aim to follow the changes in the treatment of these tumors, moving from very few chemotherapy options to immunotherapy and targeted therapies in the context of molecular selection of biliary tract cancers subtypes.

Advanced Nanoengineering Approach for Target-Specific, Spatiotemporal, and Ratiometric Delivery of Gemcitabine-Cisplatin Combination for Improved Therapeutic Outcome in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is an intractable malignancy with a dismal survival rate. Recent combination therapies have had a major impact on the improvement of PDAC prognosis. Nevertheless, clinically used combination regimens such as FOLFIRINOX and gemcitabine (Gem)/nab-paclitaxel still face major challenges due to lack of the safe and ratiometric delivery of multiple drugs. Here, a rationally designed mesoporous silica nanoparticle (MSN)-based platform is reported for the target-specific, spatiotemporal, ratiometric, and safe co-delivery of Gem and cisplatin (cisPt). It is shown that systemic administration of the nanoparticles results in synergistic therapeutic outcome in a syngeneic and clinically relevant genetically engineered PDAC mouse model that has rarely been used for the therapeutic evaluation of nanomedicine. This synergism is associated with a strategic engineering approach, in which nanoparticles provide redox-responsive controlled delivery and in situ differential release of Gem/cisPt drugs with the goal of overcoming resistance to Pt-based drugs. The platform is also rendered with additional tumor-specificity via a novel tumor-associated mucin1 (tMUC1)-specific antibody, TAB004. Overall, the platform suppresses tumor growth and eliminates the off-target toxicities of a highly toxic chemotherapy combination.

Folfirinox versus gemcitabine-cisplatin combination as first-line therapy in treatment of pancreaticobiliary cancer

Background/aim The purpose of this study was to compare efficacy and safety of a combination chemotherapy regimen consisting of oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) and gemcitabine-cisplatin as first-line therapy in patients with pancreatic cancer.Materials and methods Pancreaticobiliary cancer patients who had Eastern Cooperative Oncology Group performance status score of 0 or 1 (on a scale of 0 to 5, with higher scores indicating greater severity of illness) were evaluated to receive folfirinox or gemcitabine plus cisplatin. The primary endpoints were progression-free and overall survival time. Safety analysis was also evaluated as secondary measures.Results There were 32 patients in the folfirinox group and 36 patients in the gemcitabine-cisplatin group. The median overall survival was 18.1 months (7.5–28.7) in the folfirinox group as compared with 9.7 months (6.5–13) in the gemcitabine-cisplatin group (p = 0.009). Median progression-free survival was 16.2 months (9–23.4) in the folfirinox group and 6.9 months (6.1–7.6) in the gemcitabine-cisplatin group (p = 0.001). Conclusion Folfirinox is an option for the first-line treatment of patients with pancreatic cancer and good performance status.

Second-line Treatment in Advanced Biliary Tract Cancer: Today and Tomorrow.

Biliary tract cancer (BTC) patients usually have poor prognosis. Whereas combination chemotherapy has been shown to improve survival in the frontline setting, second-line treatment is subject to a lot of debate in the scientific community. Recent data of the ABC-06 trial has provided slight evidence for the use of second-line chemotherapy after progression on cisplatin plus gemcitabine combination. In this study, mFOLFOX plus active symptom control (ASC) improved overall survival (OS) after progression on cisplatin-gemcitabine combination compared with ASC alone, with an increase in 6- and 12-month OS rate. Although genomic studies have paved the way for a new age in cancer management, the "Precision Medicine Era" in BTC is still limited to intrahepatic cholangiocarcinoma and primarily focused on isocitrate dehydrogenase (IDH) and fibroblast growth factor receptor (FGFR) targeted therapies. We herein review recent published data regarding the use of second-line treatment after failure of standard first-line therapies in BTC patients, with a particular focus on ongoing active and recruiting clinical trials.

Cisplatin plus irinotecan versus cisplatin plus gemcitabine in the treatment of advanced or metastatic gallbladder or biliary tract cancer: Results of a randomized phase II trial (NCT01859728)– the Gambit trial.

529 Background: The combination of gemcitabine-cisplatin (GC) is the current standard of care chemotherapy for metastatic/unresectable biliary tract cancer (BTC). However, the prognosis remains poor. This randomized trial aimed to evaluate the efficacy and safety of irinotecan plus cisplatin (IP) versus GC in advanced or metastatic BTC. Methods: Patients with biopsy-proven, chemo-naïve, unresectable or metastatic BTC, ECOG 0-2, measurable disease per RECIST 1.1, adequate organ function and written informed consent were stratified by ECOG (0 or 1 vs 2) and distant metastases and randomized to receive irinotecan 65 mg/m² IV D1 and D8 plus cisplatin 60 mg/m² D1 repeated every 3 weeks (IP) or gemcitabine 1000 mg/m² IV D1 and D8 plus cisplatin 25 mg/m² IV D1 and D8 repeated every 3 weeks, until disease progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR). Results: Between January 2013 and April 2018, 47 pts were randomized (1:1) to receive IP (N = 24) or GC (N = 23). Overall, groups were well balanced according to prognostic factors. The ORR was 35% (complete response 5%, partial response 30%) and 31.8% in IP and GC arms, respectively. Median progression-free survival were 5.3 vs 7.8 months (HR = 1.165, 95%CI 0.628-2.161, p = 0.628) and median overall survival were 11.9 and 9.8 months (HR = 0.859, 95%CI 0.431 – 1.710, p = 0.665) for IP and GC, respectively. Adverse events were not statistically different between arms, and results were consistent with previous experiences with these regimens. No therapy-related death were reported. Conclusions: Irinotecan-cisplatin combination is active in BTC, with similar ORR, PFS and OS when compared to gemcitabine-cisplatin. Irinotecan-cisplatin were well tolerated, and adverse events were manageable. Irinotecan-cisplatin could be considered as an alternative to gemcitabine-cisplatin. Clinical trial information: NCT01859728.

LBA15_PR - A phase III trial of empiric chemotherapy with cisplatin and gemcitabine or systemic treatment tailored by molecular gene expression analysis in patients with carcinomas of an unknown primary (CUP) site (GEFCAPI 04)

BackgroundCUP are heterogeneous tumors that share the unique characteristic of metastases with no identifiable origin. The outcome of patients (pts) with CUP is poor despite empiric chemotherapy that has activity against a wide variety of neoplasms such as the cisplatin-gemcitabine combination (Culine S, JCO 2002). Molecular tests may identify primary sites in up to 80% of pts, and results suggest that at least 1/3 of identified primaries may not be sensitive to empiric chemotherapy used in CUPs (Gross-Goupil G 2012). In the GEFCAPI 04 phase III trial, we hypothesized that tailored treatment will improve outcomes. MethodsEligible pts had pathologically-confirmed metastatic CUPs and were treatment naïve. Pts belonging to pre-defined favorable subsets were excluded. After relevant workup had identified no primary site, pts were randomized 1:1 to either Arm A (Cisplatin 100mg/m² d1+ Gemcitabine 1250mg/m², day 1 and 8, q3w) or Arm B (gene expression test followed by à la carte treatment according to the suspected primary). The test consisted of the Tissue Of Origin (Pathwork, n=21) or CancerTYPE ID (Biotheranostics, n=222). The primary endpoint was PFS (HR=0.625, power=80%, 5% bilateral test). Stratification was on site, PS and LDH level. Secondary endpoints were PFS in pts with pre-defined cancers likely insensitive to cisplatin-gemcitabine and OS. ResultsFrom 03/12 to 02/18, 243 pts from 4 EU countries were randomized (Arm A: 120, Arm B: 123). Primary cancers most often reported by tests were pancreatico-biliary cancer (19%), squamous cell carcinoma (11%, kidney cancer (8%), and lung cancer (8%). Treatment was tailored by molecular test results in 91/123 arm B pts (74%). PFS by central review was similar: HR=0.95 (0.72-1.25); p=0.7; medians: 5.3 m arm A vs 4.6 m arm B. PFS by local review also showed no significant difference: HR=0.80 (0.60-1.06); p=0.12; medians 5.8 vs 6.4 m. OS was also similar in the overall population (HR: 0.92 (0.69-1.23), medians: 10 vs 10.7 m) and in 60 pts with suspected cancers likely insensitive to GC. ConclusionsIn GEFCAPI 04, using a molecular test followed by tailored systemic treatment did not improve outcomes of pts with CUP. Clinical trial identification2011-A01202-39. Legal entity responsible for the studyInstitut Gustave Roussy. FundingProgramme Hospitalier de Recherche Clinique (PHRC) from the French Ministry of Health. DisclosureK. Fizazi: Advisory / Consultancy: Astellas; Advisory / Consultancy: AAA; Advisory / Consultancy: Bayer; Advisory / Consultancy: Clovis; Advisory / Consultancy: Curevac; Advisory / Consultancy: Incyte; Advisory / Consultancy: Janssen; Advisory / Consultancy: MSD; Advisory / Consultancy: Orion; Advisory / Consultancy: Sanofi. R. Morales Barrera: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Sanofi; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Astrazeneca; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Asofarma; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Johnson and Jonhson; Honoraria (self), Advisory / Consultancy: Roche. C.A. Schnabel: Full / Part-time employment: bioTheranostics. All other authors have declared no conflicts of interest.

DNA damage repair (DDR) gene alterations as a predictive biomarker for response to platinum-containing chemotherapy in advanced biliary tract cancer (BTC).

4078 Background: Although many studies using whole-exome sequencing or targeted sequencing have reported the molecular profile of BTC, its clinical implications remains unclear. In this study, we assessed a predictive role of DDR gene mutations in advanced BTC patients treated with platinum-containing regimen. Methods: Eighty-eight patients with pathologically-confirmed BTC who received first-line gemcitabine-cisplatin combination (n = 69) or fluoropyrimidine-oxaliplatin combination (n = 19) were included in this analysis. Targeted exome sequencing was performed using Foundation Medicine T7 assay or in-house OncoPanel AMC. Germline or somatic mutations in ATM, ATR, BAP1, BARD1, BRCA1, BRCA2, BRIP1, CHEK2, FAM175A, GEN1, MLH1, MSH2, MSH6, MRE11A, NBN, PALB2, PMS2, RAD50, RAD51, RAD51C, RAD51D, and XRCC2 were classified as DDR gene mutations. Data regarding baseline characteristics and treatment outcomes were retrospectively obtained from medical records. Results: The median age was 62 years (range, 25-78), with male comprising 64.8% (n = 57). By primary tumor site, 21 patients with GBC (23.9%), 44 with ICC (50.0%) and 23 with ECC (26.1%) were included. Most patients received palliative chemotherapy for their initially metastatic (50.0%) or recurred (44.3%) disease; the rest 5.7% had locally advanced disease. The median PFS and OS of overall patients were 7.1 and 16.1 months, respectively with median follow-up duration of 20.2 months. DDR gene mutations were found in 63.5% of patients. BRCA2 (18.2%) was most frequently mutated, followed by ATM (13.6%), and ATR (8.0%). DDR gene mutations were significantly associated with prolonged PFS (presence vs. absence; median, 6.9 vs. 5.7 months; P = 0.013) and OS (median, 21.0 vs. 13.3 months, P = 0.009). The impact of DDR gene mutations remained significant in multivariate analyses for PFS that included other prognostic factors (hazard ratio, 0.51; P = 0.009), but not for OS. Conclusions: The presence of DDR gene mutations might be a promising predictive biomarker for response to platinum-based chemotherapies in advanced BTC. Future investigation using novel agents targeting DDR gene alteration in BTC are warranted.

Therapeutic Effect of Repurposed Temsirolimus in Lung Adenocarcinoma Model.

Lung cancer is one of the major cause of cancer-related deaths worldwide. The poor prognosis and resistance to both radiation and chemotherapy urged the development of potential targets for lung cancer treatment. In this study, using a network-based cellular signature bioinformatics approach, we repurposed a clinically approved mTOR inhibitor for renal cell carcinomans, temsirolimus, as the potential therapeutic candidate for lung adenocarcinoma. The PI3K-AKT-mTOR pathway is known as one of the most frequently dysregulated pathway in cancers, including non-small-cell lung cancer. By using a well-documented lung adenocarcinoma mouse model of human pathophysiology, we examined the effect of temsirolimus on the growth of lung adenocarcinoma in vitro and in vivo. In addition, temsirolimus combined with reduced doses of cisplatin and gemcitabine significantly inhibited the lung tumor growth in the lung adenocarcinoma mouse model compared with the temsirolimus alone or the conventional cisplatin–gemcitabine combination. Functional imaging techniques and microscopic analyses were used to reveal the response mechanisms. Extensive immunohistochemical analyses were used to demonstrate the apparent effects of combined treatments on tumor architecture, vasculature, apoptosis, and the mTOR-pathway. The present findings urge the further exploration of temsirolimus in combination with chemotherapy for treating lung adenocarcinoma.

P-032 - FOLFIRINOX versus gemcitabine-cisplatin combination as first line therapy in treatment of pancreatic cancer

P-032 - FOLFIRINOX versus gemcitabine-cisplatin combination as first line therapy in treatment of pancreatic cancer

Chemotherapy treatment is associated with altered PD-L1 expression in lung cancer patients.

While the predictive value of programmed cell death ligand-1 (PD-L1) protein expression for immune checkpoint inhibitor therapy of lung cancer has been extensively studied, the impact of standard platinum-based chemotherapy on PD-L1 or programmed cell death-1 (PD-1) expression is unknown. The aim of this study was to determine the changes in PD-L1 expression of tumor cells (TC) and immune cells (IC), in PD-1 expression of IC, and in the amount of stromal mononuclear cell infiltration after platinum-based chemotherapy in patients with lung cancer. We determined the amount of stromal mononuclear cells and PD-L1/PD-1 expressions by immunohistochemistry in bronchoscopic biopsy samples including 20 adenocarcinomas (ADC), 15 squamous cell carcinomas (SCC), 2 other types of non-small cell lung cancer, and 4 small cell lung cancers together with their corresponding surgical resection tissues after platinum-based chemotherapy. PD-L1 expression of TC decreased in ten patients (24.4%) and increased in three patients (7.32%) after neoadjuvant chemotherapy (p = 0.051). The decrease in PD-L1 expression, however, was significant only in patients who received cisplatin-gemcitabine combination (p = 0.020), while in the carboplatin-paclitaxel group, no similar tendency could be observed (p = 0.432). There was no difference between ADC and SCC groups. Neither PD-1 expression nor the amount of stromal IC infiltration showed significant changes after chemotherapy. This is the first study, in which both PD-L1 and PD-1 expression were analyzed together with the amount of stromal IC infiltration in different histological subtypes of lung cancer before and after platinum-based chemotherapy. Our results confirm that chemotherapy decreases PD-L1 expression of TC in a subset of patients, therefore, rebiopsy and re-evaluation of PD-L1 expression may be necessary for the indication of immune checkpoint inhibitor therapy.

Single-institution experience with gemcitabine–cisplatin combination therapy as a second-line treatment for patients with unresectable biliary tract cancer after failure of gemcitabine–S-1 combination therapy: a prospective feasibility study

NCCN and Japanese clinical guidelines for the treatment of biliary tract cancer (BTC) addressed gemcitabine-cisplatin combination (GC) as first-line chemotherapy for patients with advanced BTC ineligible for surgery in 2013. However, gemcitabine-S1 combination therapy (GS) has been widely used as first-line treatment in Japan because Japanese social insurance coverage of S-1 for BTC was approved prior to that of cisplatin. To elucidate the efficacy and tolerability of GC as second-line chemotherapy for patients with unresectable BTC after failure of GS. Between September 2008 and August 2011, patients with unresectable BTC who provided informed consent and received GC comprising gemcitabine at 1000mg/m2 and cisplatin at 20mg/m2 given on days 1 and 8 in a 3-week cycle after failure of GS were included in the present study. Clinical data from these patients were collected prospectively. Primary endpoints were overall survival and time to progression (TTP). Secondary endpoints were response and tolerability. Twenty-seven patients were analyzed. Median survival time (MST) and TTP from the beginning of second-line treatment were 6.5 and 3.3months, respectively, whereas MST from the commencement of first-line therapy was 12.06months. One patient showed partial response, 16 had stable disease and 10 experienced disease progression. As a result, disease control rate was 63.0%. In total, 119 courses (median, 4; range, 1-15) were administered. Discontinuation of GC due to drug toxicities was not observed. Although some issues remain to be clarified, mainly due to the small sample size, this single-institution experience with GC as second-line treatment after failure of GS showed acceptable outcomes and good tolerability.

Abstract 97: RNA sequencing of bladder cancer patient-derived xenograft models identifies genes associated with chemoresistance

Abstract Background: Bladder cancer is among the top ten most common cancers, with about ~380,000 new cases and ~150,000 deaths per year worldwide. Platinum-based combination chemotherapy is commonly used to treat advanced bladder cancer. It has been shown that only ~50% of the patients with advanced bladder cancer respond to platinum-based therapy. Methods: We have utilized a patient-derived bladder cancer xenograft (PDX) platform to characterize the molecular mechanisms that contribute to resistance of gemcitabine-cisplatin combination therapy in advanced bladder cancer. We have also identified key regulatory pathways in our PDX models that can be targeted to treat chemotherapy resistant bladder cancer using RNAseq analysis. Transcriptome profiling of P0 (passage 0) bladder cancer xenograft tumors from 4 PDX lines (2 gemcitabine-cisplatin resistant lines and 2 drug sensitive lines) was performed by RNA-Seq analysis, before and after a 21-day cisplatin/gemcitabine drug treatment regimen. Results: The RNA-seq data has indicated significant differences between the transcriptional profiles of drug-sensitive and drug-resistant tumors. PDXs retained morphology and shared 92-97% of genetic alterations of parental cancer cells. We identified 333 genes >2 fold up or down regulated in the drug resistant tumors compared to the drug sensitive tumors. Significantly up-regulated genes in drug resistant tumors analyzed include metabolic enzymes ALDH2, ALDH3A1, ALDH4A1 and ALDH7A1, transporter proteins ABCA1, SLC1A4, SLC2A5, SLC30A1, SLC39A6, SLC7A5 and SLC9A3, Notch ligand JAG2, Growth hormone receptor GHR and transmembrane protein GPNMB. Consistent with the change of cell surface proteins such as GHR and GPNMB, the MAPK and the PI3K-AKT pathways were upregulated when PDXs became resistant to cisplatin treatment. Additional changes in gene expression based on RNA-seq data before and after drug treatment were also found. Conclusion: Chemoresistance to gemcitabine and cisplatin is associated with altered expression of several cell surface proteins and upregulation of the downstream signaling pathways. Targeting these cell surface proteins can possibly be harnessed to overcome chemoresistance. GPNMB is a type I transmembrane protein that has previously been shown to be up-regulated in many metastatic cancers including breast cancer. Potentially targeting GPNMB with glembatumumab vedotin, an antibody-drug-conjugate has shown promising results in treating several cancers including breast cancer and osteosarcoma. Further studies will elucidate whether targeting GPNMB is an effective strategy for the treatment of chemotherapy resistant bladder cancer. This study received funding by a developmental grant from the UCDCC. This work was conducted under the auspices of the USDOE by LLNL (DE-AC52-07NA27344). IM number: LLNL-688318 Citation Format: Kelly A. Martin, Nicholas R. Hum, Aimy Sebastian, Deepa K. Murugesh, Chong-Xian Pan, Ai-Hong Ma, Ralph de Vere White, Gaby Loots. RNA sequencing of bladder cancer patient-derived xenograft models identifies genes associated with chemoresistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 97. doi:10.1158/1538-7445.AM2017-97

Combining two different chemotherapy agents with platinum analogs as induction and consolidation regimes in nonsmall cell lung carcinoma

Background: There are limited data pertaining to the combined use of induction and consolidation chemotherapy with concurrent chemo-radiotherapy (RT) for treating nonsmall cell lung carcinoma (NSCLC). To find out an optimum/effective regime for treating NSCLC utilizing both induction and consolidation approach with concurrent chemo-RT is the primary aim of this study. Materials and Methods: We retrospectively analyzed 132 patients with NSCLC. Fifty-four patients treated with paclitaxel-carboplatin and 78 with gemcitabine-cisplatin combinations in induction and consolidation phases. Concurrent chemo-RT included 60-66 Gray (Gy) of RT with weekly cisplatin and was similar in both the arms. Results: After completion of the consolidation phase, we observed on overall response rate (ORR) of 42.7% in the paclitaxel-carboplatin arm and 42.3% in gemcitabine-cisplatin arm with 2 and 3 years’ survival rates of 32% and 19% with paclitaxel-carboplatin and 38% and 24% with gemcitabine-cisplatin regimes. We also observed higher ORR for squamous cell histology treated with the gemcitabine-cisplatin combination. Conclusion: Although both paclitaxel-carboplatin and gemcitabine-cisplatin combinations are equally effective in treating NSCLC, gemcitabine-cisplatin provided slightly better response rates but with clinically more frequent and relevant toxicities. © 2017 Journal of Medical Sciences.

Abstract 2106: Transcriptome analysis of patient-derived bladder cancer xenografts identifies genes associated with chemoresistance

Abstract Background: Bladder cancer is among the ten most common cancers, with about ∼380,000 new cases and ∼150,000 deaths per year worldwide. Platinum-based combination chemotherapy is commonly used to treat advanced bladder cancer. It has been shown that only ∼50% of the patients with advanced bladder cancer respond to platinum-based therapy. Methods: We employed a patient-derived bladder cancer xenograft (PDX) platform to characterize the molecular mechanisms contributing to resistance to gemcitabine-cisplatin combination therapy in advanced bladder cancer and to identify novel candidates that can be targeted to treat chemotherapy resistant bladder cancer. Transcriptome profiling of P0 (passage 0) bladder cancer xenograft tumors from 4 PDX lines (2 gemcitabine-cisplatin resistant lines and 2 drug sensitive lines) was performed by RNA-Seq analysis. Results: PDXs retained the morphology fidelity and shared 92-97% of genetic alterations of parental cancer cells. The RNA-seq data suggested the presence of significant differences between the transcription profiles of drug-sensitive and drug-resistant tumors. We identified 333 genes >2 fold up or down regulated in the drug resistant tumors compared to the drug sensitive tumors. Genes down-regulated in drug resistant tumors include tight junction protein CLDN3 and regulators of G-protein signaling RGS2 and RGS3. Significantly up-regulated genes include metabolic enzymes ALDH2, ALDH3A1, ALDH4A1 and ALDH7A1, transporter proteins ABCA1, SLC1A4, SLC2A5, SLC30A1, SLC39A6, SLC7A5 and SLC9A3, Notch ligand JAG2, Growth hormone receptor GHR and transmembrane glycoprotein GPNMB. Consistent with the change of cell surface proteins such as GHR and GPNMB, the MAPK and the PI3K-AKT pathways were upregulated when PDXs became resistant to cisplatin treatment. Conclusion: Chemoresistance to gemcitabine and cisplatin is associated with altered expression of several cell surface proteins and upregulation of the downstream signaling pathways. Targeting these cell surface proteins can possibly be harnessed to overcome chemoresistance. GPNMB, a type I transmembrane protein highly up-regulated in the drug resistant tumors, has previously been shown to be over-expressed in various cancers. Targeting GPNMB with an antibody-drug-conjugate, glembatumumab vedotin, has shown promising results in treating several cancers including breast cancer and osteosarcoma. Further studies will elucidate whether targeting GPNMB is an effective strategy for the treatment of chemotherapy resistant bladder cancer. Citation Format: Aimy Sebastian, Kelly A. Martin, Chong-xian Pan, Ai-hong Ma, Ralph W. deVere White, Gabriela G. Loots. Transcriptome analysis of patient-derived bladder cancer xenografts identifies genes associated with chemoresistance. [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 2106.

Sensitivity of Human Intrahepatic Cholangiocarcinoma Subtypes to Chemotherapeutics and Molecular Targeted Agents: A Study on Primary Cell Cultures.

We investigated the sensitivity of intrahepatic cholangiocarcinoma (IHCCA) subtypes to chemotherapeutics and molecular targeted agents. Primary cultures of mucin- and mixed-IHCCA were prepared from surgical specimens (N. 18 IHCCA patients) and evaluated for cell proliferation (MTS assay) and apoptosis (Caspase 3) after incubation (72 hours) with increasing concentrations of different drugs. In vivo, subcutaneous human tumor xenografts were evaluated. Primary cultures of mucin- and mixed-IHCCA were characterized by a different pattern of expression of cancer stem cell markers, and by a different drug sensitivity. Gemcitabine and the Gemcitabine-Cisplatin combination were more active in inhibiting cell proliferation in mixed-IHCCA while Cisplatin or Abraxane were more effective against mucin-IHCCA, where Abraxane also enhances apoptosis. 5-Fluoracil showed a slight inhibitory effect on cell proliferation that was more significant in mixed- than mucin-IHCCA primary cultures and, induced apoptosis only in mucin-IHCCA. Among Hg inhibitors, LY2940680 and Vismodegib showed slight effects on proliferation of both IHCCA subtypes. The tyrosine kinase inhibitors, Imatinib Mesylate and Sorafenib showed significant inhibitory effects on proliferation of both mucin- and mixed-IHCCA. The MEK 1/2 inhibitor, Selumetinib, inhibited proliferation of only mucin-IHCCA while the aminopeptidase-N inhibitor, Bestatin was more active against mixed-IHCCA. The c-erbB2 blocking antibody was more active against mixed-IHCCA while, the Wnt inhibitor, LGK974, similarly inhibited proliferation of mucin- and mixed-IHCCA. Either mucin- or mixed-IHCCA showed high sensitivity to nanomolar concentrations of the dual PI3-kinase/mTOR inhibitor, NVP-BEZ235. In vivo, in subcutaneous xenografts, either NVP-BEZ235 or Abraxane, blocked tumor growth. In conclusion, mucin- and mixed-IHCCA are characterized by a different drug sensitivity. Cisplatin, Abraxane and the MEK 1/2 inhibitor, Selumetinib were more active against mucin-IHCCA while, Gemcitabine, Gemcitabine-Cisplatin combination, the c-erbB2 blocking antibody and bestatin worked better against mixed-IHCCA. Remarkably, we identified a dual PI3-kinase/mTOR inhibitor that both in vitro and in vivo, exerts dramatic antiproliferative effects against both mucin- and mixed-IHCCA.

Association of GSTP1 and RRM1 Polymorphisms with the Response and Toxicity of Gemcitabine-cisplatin Combination Chemotherapy in Chinese Patients with Non-small Cell Lung Cancer

Previous studies showed that genetic polymorphisms of glutathione S-transferase P1 (GSTP1) were involved in glutathione metabolism and genetic polymorphisms of ribonucleotide reductase (RRM1) were correlated with DNA synthesis. Here we explored the effects of these polymorphisms on the chemosensitivity and clinical outcome in Chinese non-small cell lung cancer (NSCLC) patients treated with gemcitabine-cisplatin regimens. DNA sequencing was used to evaluate genetic polymorphisms of GSTP1 Ile105Val and RRM1 C37A-T524C in 47 NSCLC patients treated with gemcitabine-cisplatin regimens. Clinical response was evaluated according to RECIST criteria after 2 cycles of chemotherapy and toxicity was assessed by 1979 WHO criteria (acute and subacute toxicity graduation criteria in chemotherapeutic agents). There was no statistical significance between sensitive and non-sensitive groups regarding the genotype frequency distribution of GSTP1 Ile105Val polymorphism (p>0.05). But for RRM1 C37A-T524C genotype, sensitive group had higher proportion of high effective genotype than non-sensitive group (p=0.009). And according to the joint detection of GSTP1 Ile105Val and RRM1 C37A-T524C polymorphisms, the proportion of type A (A/A+high effective genotype) was significantly higher in sensitive group than in non-sensitive group (p=0.009). Toxicity showed no correlation with the genotypes between two groups (p>0.05). Compared with single detection of genetic polymorphisms of GSTP1 Ile105Val or RRM1 C37A-T524C, joint detection of both may be more helpful for patients with NSCLC to receive gemcitabine-cisplatin regimens as the first-line chemotherapy. Especially, genetic polymorphism of RRM1 is more likely to be used as an important biomarker to predict the response and toxicity of gemcitabine-cisplatin combination chemotherapy in NSCLC.

Defective hCNT1 transport contributes to gemcitabine chemoresistance in ovarian cancer subtypes: Overcoming transport defects using a nanoparticle approach

Nucleoside analogs are used as chemotherapeutic options for the treatment of platinum-resistant ovarian cancers. Human concentrative nucleoside transporter 1 (hCNT1) is implicated in sensitizing solid tumors to nucleoside analogs although its role in determining drug efficacy in ovarian cancers remains unclear. Here we examined the functional expression of hCNT1 and compared its contributions toward gemcitabine efficacy in histological subtypes of ovarian cancer. Radioactivity analysis identified hCNT1-mediated 3H-gemcitabine transport in ovarian cancer cells to be significantly reduced compared with that of normal ovarian surface epithelial cells. Biochemical and immunocytochemical analysis identified that unlike normal ovarian cells which expressed high levels of hCNT1 at the apical cell surface, the transporter was either diminished in expression and/or mislocalized in cell lines of various subtypes of ovarian cancer. Retroviral expression of hCNT1 selectively rescued gemcitabine transport in cell lines representing serous, teratocarcinoma, and endometrioid subtypes, but not clear cell carcinoma (CCC). In addition, exogenous hCNT1 predominantly accumulated in intracytoplasmic vesicles in CCC suggesting defective cellular trafficking of hCNT1 as a contributing factor to transport deficiency. Despite diminution of hCNT1 transport in the majority of ovarian cancers and apparent trafficking defects with CCC, the chemotherapeutic efficacy of gemcitabine was broadly enhanced in all subtypes when delivered via engineered nanoparticles (NPs). Additionally, by bypassing the transport requirement, the delivery of a gemcitabine-cisplatin combination in NP formulation increased their synergistic interactions. These findings uncover hCNT1 as a putative determinant for nucleoside analog chemoresistance in ovarian cancer and may help rationalize drug selection and delivery strategies for various histological subtypes of ovarian cancer.