Consensus Report of the National Cancer Institute Clinical Trials Planning Meeting on Pancreas Cancer Treatment
ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer mortality, despite significant improvements in diagnostic imaging and operative mortality rates. The 5-year survival rate remains less than 5% because of microscopic or gross metastatic disease at time of diagnosis. The Clinical Trials Planning Meeting in pancreatic cancer was convened by the National Cancer Institute's Gastrointestinal Cancer Steering Committee to discuss the integration of basic and clinical knowledge in the design of clinical trials in PDAC. Major emphasis was placed on the enhancement of research to identify and validate the relevant targets and molecular pathways in PDAC, cancer stem cells, and the microenvironment. Emphasis was also placed on developing rational combinations of targeted agents and the development of predictive biomarkers to assist selection of patient subsets. The development of preclinical tumor models that are better predictive of human PDAC must be supported with wider availability to the research community. Phase III clinical trials should be implemented only if there is a meaningful clinical signal of efficacy and safety in the phase II setting. The emphasis must therefore be on performing well-designed phase II studies with uniform sets of basic entry and evaluation criteria with survival as a primary endpoint. Patients with either metastatic or locally advanced PDAC must be studied separately.
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- "Pancreatic ductal adenocarcinoma (PDA) has a terrible prognosis with a 5-year survival of approximately 6% [1-3]. The approved systemic therapies have a relatively modest impact on survival, and PDA is considered a therapy recalcitrant disease [1, 2, 4]. Interestingly, the treatment of PDA has remained largely dependent on the use of systemic chemotherapy regimens, and there are basically no targeted approaches to treatment that exploit the underlying genetic features of pancreatic cancer. "
ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) has a poor prognosis, in part, due to the therapy-recalcitrant nature of the disease. Loss of the CDK4/6 inhibitor CDKN2A is a signature genetic event in PDA. Therefore, PDA may be amenable to treatment with pharmaceutical CDK4/6 inhibitors. Surprisingly, response to CDK4/6 inhibition was highly variable in PDA models, and associated with differential suppression of gene expression. Mitotic genes were repressed and FOXM1 was uniformly attenuated; however, genes involved in DNA replication were uniquely suppressed in sensitive models. Aberrant induction of Cyclin E1 was associated with resistance, and knockdown demonstrated synergistic suppression of the cell cycle with CDK4/6 inhibition. Combination therapies are likely required for the effective treatment of disease, and drug screening demonstrated additive/antagonistic interactions with CDK4/6 inhibitors. Agents dependent on mitotic progression (taxanes/PLK1 inhibitors) were antagonized by CDK4/6 inhibition, while the response to 5-FU and gemcitabine exhibited drug specific interactions. PI3K/MTOR and MEK inhibitors potently cooperated with CDK4/6 inhibition. These agents were synergistic with CDK4/6 inhibition, blocked the aberrant upregulation of Cyclin E1, and yielded potent inhibition of tumor cell growth. Together, these data identify novel mechanisms of resistance to CDK4/6 inhibitions and provide a roadmap for combination therapies in the treatment of PDA.Oncotarget 08/2014; 5(15):6512-25. DOI:10.18632/oncotarget.2270 · 6.36 Impact Factor
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- "The five-year overall survival rate for pancreatic cancer remains <5% (10). The median survival time of patients with localized, but unresectable disease ranges from eight to 10 months (11). Chemotherapy and external-beam radiotherapy (EBRT) are used as palliative treatments for patients when surgical resection is not feasible. "
ABSTRACT: A novel radiosensitization treatment involving the injection of hydrogen peroxide and sodium hyaluronate, using ultrasonic guidance, into a tumor immediately prior to intraoperative radiotherapy (IORT) was established for patients with stage IVa locally advanced unresectable pancreatic cancer. The aim of the present study was to assess the safety and efficacy of this novel treatment, termed Kochi Oxydol-Radiation Therapy for Unresectable Carcinomas-IORT (KORTUC and IORT). In total, 12 patients were treated with KORTUC-IORT, external-beam radiotherapy and systemic chemotherapy using gemcitabine hydrochloride and S-1. For evaluation of the therapeutic and adverse effects, contrast-enhanced computed tomography was conducted prior to the treatment, and one and six months following KORTUC-IORT. Medical examinations were performed every month at the regularly scheduled follow-up visits. The one- and two-year survival rates were 75 and 25%, respectively, and the median survival time was 16 months. All treatments associated with KORTUC-IORT were well-tolerated by the patients, with a small number of adverse effects and no serious complications. It was identified that the delivery of KORTUC-IORT is safe and effective, in combination with external-beam radiotherapy and systemic chemotherapy, for patients with locally advanced unresectable pancreatic cancer.Oncology letters 07/2014; 8(1):404-408. DOI:10.3892/ol.2014.2101 · 1.55 Impact Factor
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- "In this phase II study, patients with locally advanced pancreatic cancer had a better outcome than those with metastatic pancreatic cancer (median OS, 17.7 vs 5.2 months, respectively). The results in patients with locally advanced, non-metastatic pancreatic cancer compare favorably with previous studies of 5-FU or gemcitabine with radiation, which reported a median OS of 8–10 months.(10–12) Since it has been proven that regional hyperthermia combined with gemcitabine improve the prognosis of patients with locally advanced pancreatic cancer, we hypothesized that epithelial-mesenchymal transition (EMT) inhibition may be the principal mechanism by which hyperthermia deters the progression of pancreatic cancer. "
ABSTRACT: Epithelial-mesenchymal transition (EMT) plays a crucial role in cancer metastasis. In this study, we evaluated the effect of heat treatment on tumor growth factor-β1 (TGF-β1)-induced EMT in pancreatic cancer cells and tried to ascertain the mechanism related to any observed effects. Human pancreatic cancer cell lines (BxPC-3, PANC-1 and MIAPaCa-2) were stimulated by TGF-β1, and evaluated for morphological changes using immunofluorescence and EMT-related factors (i.e., E-cadherin, Vimentin, Snail or ZEB-1) using RT-PCR. To examine the effect of heat on EMT, the cancer cells were heat-treated at 43°C for 1 h then stimulated with TGF-β1. We then evaluated whether or not heat treatment changed the expression of EMT-related factors and cell migration and also whether Smad activation was inhibited in TGF-β signaling. After being treated with TGF-β1, pancreatic cancer cells resulted in EMT and cell migration was enhanced. Heat treatment inhibited TGF-β1-induced changes in morphology, inhibited the expression of EMT-related factors, and attenuated TGF-β1-induced migration in pancreatic cancer cells. Additionally, we observed that heat treatment blocked TGF-β1-induced phosphorylation of Smad2 in PANC-1 cells. Our results suggest that heat treatment can suppress TGF-β1-induced EMT and opens the possibility of a new therapeutic use of hyperthermia as a potential treatment for cancer metastasis.Journal of Clinical Biochemistry and Nutrition 07/2014; 55(1):56-61. DOI:10.3164/jcbn.14-8 · 2.19 Impact Factor