Abstract A34: Hypoxia-activated prodrug TH-302 in combination with gemcitabine for the treatment of pancreatic adenocarcinoma: Preclinical and clinical studies.
Charles P. HartJessica D. SunQian LiuDharmendra AhluwaliaClarence EngDavid P. RyanMitesh J. BoradStew Kroll
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Hypoxia is a prevalent feature of solid tumors and is a negative prognostic factor associated with treatment failure and the emergence of a more aggressive, invasive, and metastatic phenotype. Hypoxia in human pancreatic adenocarcinoma (PAC) has been characterized by Eppendorf needle oxygen electrodes, and more recently by the use of the exogenous hypoxia biomarker pimonidazole in patient biopsies. Both methods have demonstrated significant subregional hypoxia. TH-302 (T) is a hypoxia-activated bioreductive prodrug that is selectively activated in regions of severe hypoxia, and upon activation releases the bis-alkylating DNA cross-linker bromoisophosphoramide mustard (Br-IPM). T exhibits hypoxia-selective in vitro cytotoxicity across a wide panel of human cancer cell lines including PAC cell lines and in vivo anti-tumor efficacy in a range of human tumor models including a PAC orthotopic model. T is currently under investigation in multiple oncology clinical trials. A panel of human PAC human tumor xenograft models were established (Hs766t, SU.86.86, BxPc3, MIA PaCa2) and tested with gemcitabine (G) and T both as monotherapies and in combination (G+T) for antitumor efficacy. Select tissue biomarkers, focused on characterizing the magnitude and extent of tumor hypoxia, tumor vascularity, and EMT and G resistance/sensitivity phenotypic markers were assessed by IHC and compared with the corresponding drug efficacy profiles observed in the models. Initial clinical study of G+T combination was a phase 1/2a trial with G administered at its full labeled dose and schedule (1000 mg/m 2 on days 1, 8, and 15 of a 28 day cycle) and T dose escalated starting at 240 mg/m 2 in combination with G with the same schedule (T administered 2 hr before G). An expansion phase 2a portion of the trial explored both 240 and 340 mg/m 2 T in combination with G (n=47 pts). A 21% response rate (RR), median PFS and OS of 5.9 and 8.5 mo, and one-yr survival of >40% was observed. These promising results led to initiation of a randomized controlled Phase 2b trial (G vs. G+T240 vs. G+T340). This trial had 80% power to detect 50% improvement in the primary endpoint of PFS with one-sided alpha of 10%. 214 pts were treated across the three arms (~1:1:1). Primary efficacy endpoint was met with a median PFS of 3.6 mo in G arm vs. 5.6 mo in G+T arms with HR of 0.61 (95%CI: 0.43-0.87; logrank p-value of 0.005). Median PFS in G+T340 was 6.0 mo. RR was 12% in G, 17% in G+T240 and 27% in G+T340. Decreases in circulating PAC biomarker CA19-9 were greater in G+T groups than in the G group and greatest in G+T340. G+T was well-tolerated with skin and mucosal toxicities and myelosuppression the most common TH-302 related AEs with no increase in discontinuations for AE. SAEs were balanced across the three arms. These studies of safety and activity of TH-302 in combination with gemcitabine are consistent with the novel design and hypoxia selective characterization of TH 302. Animal and human studies indicate that TH-302, a tumor hypoxia targeting prodrug, can significantly improve the activity of chemotherapy. Citation Format: Charles P. Hart, Jessica D. Sun, Qian Liu, Dharmendra Ahluwalia, Clarence Eng, David P. Ryan, Mitesh J. Borad, Stew Kroll. Hypoxia-activated prodrug TH-302 in combination with gemcitabine for the treatment of pancreatic adenocarcinoma: Preclinical and clinical studies. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Progress and Challenges; Jun 18-21, 2012; Lake Tahoe, NV. Philadelphia (PA): AACR; Cancer Res 2012;72(12 Suppl):Abstract nr A34.Keywords:
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Pancreatic cancer is one of the highly aggressive malignant diseases worldwide. To achieve better treatment outcome of pancreatic cancer, in the current study we explore the underlying molecular mechanism of drug resistance in pancreatic cancer cells. We found that resistance to gemcitabine is associated with epithelial-mesenchymal transition (EMT) phenotype in a panel of pancreatic cancer cell lines. Notably, gemcitabine-resistant pancreatic cancer cells acquire EMT phenotype. Moreover, gemcitabine-resistant cells have increased migration and invasion activities. Furthermore, we observed the high expression of HIF-1α in gemcitabine-resistant cells. More importantly, inhibition of HIF-1α in gemcitabine-resistant cells caused partial reversal of EMT phenotype, suggesting that HIF-1α was critically involved in gemcitabine-resistant-mediated EMT. Therefore, targeting HIF-1α could be an effective strategy for the treatment of pancreatic cancer.
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Survival rate for pancreatic cancer remains poor and newer treatments are urgently required. Selenium, an essential trace element, offers protection against several cancer types and has not been explored much against pancreatic cancer specifically in combination with known chemotherapeutic agents. The present study was designed to investigate selenium and Gemcitabine at varying doses alone and in combination in established pancreatic cancer cell lines growing in 2D as well as 3D platforms. Comparison of multi-dimensional synergy of combinations' (MuSyc) model and highest single agent (HSA) model provided quantitative insights into how much better the combination performed than either compound tested alone in a 2D versus 3D growth of pancreatic cancer cell lines. The outcomes of the study further showed promise in combining selenium and Gemcitabine when evaluated for apoptosis, proliferation, and ENT1 protein expression, specifically in BxPC-3 pancreatic cancer cells in vitro.
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Pancreatic cancer normally is lethal and difficult to treat.Recently,although chemotherapy drugs such as gemcitabine for the treatment achieved a certain effect, but the survival rate has not improved significantly. Over the past decade, a large number of studies that aimed to implicated in pancreatic tumor gemcitabine metabolism and resistance mechanisms. Recent data show that it is a great value for predicting efficacy in the treatment of pancreatic cancer with gemcitabine by detecting pancreatic cancer -related molecules and genes, especially in the field of individual therapy. This review describes advances in the studies of related molecules and genes affecting the efficacy of gemcitabine for pancreatic cancer.
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Pancreatic neoplasms; Gemcitabine; Genes; Molecular mechanisms of action
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Pancreatic cancer is one of the most lethal malignancies with very limited treatment option. In the effort of enhancing the effect of the conventional chemotherapeutic drug gemcitabine against pancreatic cancer, we investigated in vitro and in vivo the anticancer effect of a β-carboline-enriched extract from the plant Rauwolfia vomitoria (Rau), either alone or in combination with gemcitabine, in preclinical pancreatic cancer models. Rau induced apoptosis in pancreatic cancer cells in a concentration-dependent manner, and completely inhibited colony formation of PANC-1 cells in soft agar. The combination of Rau and gemcitabine had synergistic effect in inhibiting cell growth with dose reduction effect for gemcitabine. In an orthotopic pancreatic cancer mouse model, PANC-1 tumor growth was significantly suppressed by Rau treatment. Metastasis was inhibited by Rau. Adding Rau to gemcitabine treatment reduced tumor burden and metastatic potential in the gemcitabine non-responsive tumor. These data suggest that Rau possesses anti–pancreatic cancer activity and could improve effect of gemcitabine.
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Owing to the high heterogeneity of pancreatic cancer, patient-derived xenografts (PDX) can compensate for the defects of cell line-derived xenografts (CDX) and also better preserve the heterogeneity and tumor microenvironment of primary tumors. Further, gemcitabine, which is used for the treatment of various cancers, is prone to tumor drug resistance, and this limits its sustained efficacy. Therefore, in this study, our objective was to screen appropriate individual therapeutic drugs for pancreatic cancer. To this end, we established pancreatic cancer PDX models from different patients and screened gemcitabine sensitivity regulatory molecules via high-throughput transcriptome sequencing and bioinformatics analysis. Based on the results obtained, gemcitabine was identified as the most suitable chemotherapeutic drug in a variety of PDX models. Additionally, our results indicated that Lipocalin 2 (LCN 2) may play an important role in the sensitivity of pancreatic cancer to gemcitabine treatment. Thus, the study provides a new potential intervention target for the treatment of pancreatic cancer in clinical practice.
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Objective To investigate the differentially expressed circulating microRNAs of pancreatic cancer,and of the pancreatic cancer with gemcitabine resistance,to find potential biomarkers for noninvasive diagnosis of pancreatic cancer and the prediction of prognosis of gemcitabine.Methods To screen the highly deregulated microRNAs in the plasma samples of pancreatic cancer,and in the plasma samples ofpancreatic cancer patients with gemcitabine resistance using reverse transcription and quantitative PCR.Results Twenty-eight microRNAs expressing differentially with fold-exchange ＞ 2 was screened out comparing pancreatic cancer and healthy controls,and 28 microRNAs was screened out comparing gemcitabine resistant patients and gemcitabine positive patients.Conclusions There is a specific circulating mIcroRNA profile in pancreatic cancer as well as in pancreatic cancer with gemcitabine resistance.These profiles may have potential in noninvasive diagnosis of pancreatic cancer and the prediction of prognosis of gemcitabine.
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Pancreatic neoplasms ; Plasma; Circulating microRNA ; Gemcitabine; Drug resistance ; MicroRNAs
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The prognosis of patients with advanced pancreatic cancer remains very poor. This study was designed to elucidate the prognostic factors of patients with pancreatic cancer to evaluate appropriate treatment with gemcitabine.Ninety-nine consecutive patients with stage IV pancreatic cancer were treated in the gemcitabine era at the Kobe University Hospital. Prognostic variables for survival were analyzed (sex, age, performance status, main site of the tumor, tumor size, major vessel invasion, distal metastasis, resection, gemcitabine, radiation, and pathological factors). The Cox proportional hazards model was used to determine the factors influencing the survival of patients with stage IV pancreatic cancer.Multivariate analysis revealed that pancreatic resection, gemcitabine, and distant metastasis significantly influenced the survival of all patients with stage IV pancreatic cancer. Pancreatic resection and gemcitabine were significant factors influencing the survival of patients with stage IVa pancreatic cancer, whereas gemcitabine was the strongest factor influencing stage IVb pancreatic cancer.Gemcitabine has a possible role for stage IV pancreatic cancer.
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Pancreatic cancer is one of the most lethal malignancies accounting for the fourth leading cause of cancer-related deaths in the United States. Among several explored anticancer agents, Gemcitabine, a nucleoside analogue remained a front line chemotherapeutic agent for the treatment of pancreatic cancer. However, gemcitabine exerts a low response rate with limited progression free survival in patients due to cellular resistance of pancreatic tumors to this therapy. Several chemotherapeutic agents have been explored in combination with gemcitabine against pancreatic cancer with overall mixed responses and survival rates. Naturally occurring dietary agents possess promising anticancer properties and have been shown to target various oncogenic signaling pathways in in-vitro and in-vivo pancreatic cancer models.Multiple studies using natural compounds have shown increased therapeutic efficacy of gemcitabine in pancreatic cancer models.This review is focused on recent updates on cellular, preclinical and clinical studies utilizing natural anticancer agents with gemcitabine against pancreatic cancer.
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