Biliary and Related Cancer Center

Philadelphia, PA, United States

Biliary and Related Cancer Center

Philadelphia, PA, United States
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News Article | December 7, 2016

A new study published in the just-published "Oncotarget" peer-reviewed medical journal has concluded that “in the setting of previously treated, advanced pancreatic cancer, liquid biopsies are not yet an adequate substitute for tissue biopsies. Further refinement in defining the optimal patient population and timing of blood sampling may improve the value of a blood-based test.” The study was conducted by a team of researchers and clinicians from Perthera, Inc., a precision medicine company based in McLean, VA, the Pancreatic Cancer Action Network (PanCAN), Lombardi Comprehensive Cancer Center of Georgetown University, Cedars-Sinai Medical Center, Ohio State University, City of Hope Cancer Center, Virginia Mason Medical Center, and the Sidney Kimmel Cancer Center at Thomas Jefferson University. The study is entitled "a pilot study evaluating concordance between blood-based and patient-matched tumor molecular testing within pancreatic patients participating in the Know Your Tumor (KYT) Initiative." Know Your Tumor is a benchmark precision cancer therapy program of the Pancreatic Cancer Action Network that is executed by Perthera. The study asserted that “molecular profiling of the tumor itself should remain the gold standard,” or as approved by the FDA. Liquid biopsies can "go wrong" in a variety of ways: mainly because the tumor isn't dumping DNA into the blood, or because the detection assays aren't sensitive enough to detect the DNA when it is too low in abundance to see. The investigators assessed the ability of the circulating genomic information obtained from a blood sample of 34 consecutively screened pancreatic cancer patients with metastatic disease to accurately recapitulate the genomic information obtained by direct analysis of a tumor biopsy obtained from the same patient taken at the same time. They used the high frequency of KRAS mutation (~90%) in pancreatic cancer as a benchmark for comparison, and they found that KRAS mutations “were only detected in 10/34 (29%) blood samples, compared to 20/23 (87%) tumor tissue biopsies." Dr. Jonathan Brody, the last author on the study and Director of Surgical Research and Co-director of the Jefferson Pancreas, Biliary and Related Cancer Center and on the scientific advisory board at Perthera, cautioned that "the results of this study should give people some pause; we need to be very careful about the state of the liquid biopsy field right now." He said, "we need to be very circumspect- in this study, we detected DNA with KRAS mutations in only a third of the patients that you should see the genomic alteration, so what does it say about being able to reliably detect actionable alterations that doctors would use to make critical treatment decisions?” Dr. Michael Pishvaian, the first author of the study and Perthera’s CMO as well as the Director of the Phase I Clinical Program and Co-Director of the Ruesch Center Pancreatic Cancer Program at Georgetown University added that “there will be times when a tumor biopsy is unable to be performed due to medical issues, and then could a liquid biopsy be considered. Pishvaian says: “There are papers that show good but not perfect concordance between the genomic information in tumor samples and blood samples, and our study in pancreatic cancer reveals something different. Some of the disparate results from these studies come from differences in the clinical aspects of the patients studied, but ultimately if liquid biopsies are to be used routinely for precision medicine applications then the field needs more improvements.” In the meantime, Emanuel “Chip” Petricoin, PhD, Perthera’s Chief Science Officer said, “Central to Perthera’s medical philosophy is that the patient should have as extensive molecular profiling as relevant, and blood-based testing will be great to add to our arsenal of testing options as it becomes more reliable and sensitive. So, we are committed to implementing molecular profiling technologies that have the best evidence of impact to patients' precision cancer therapy outcome and we will be constantly monitoring the state of the field on this topic. As the liquid biopsy technologies and approaches improve and become more sensitive, then we can validate them and implement them." ABOUT PERTHERA, INC.: Perthera is a founder- and venture-backed precision medicine company based in McLean, VA, that has achieved more than 1,000 case histories since it was founded about five years ago, often working in an alliance with cancer advocacy agencies as well as hospitals, community oncology practices, and academia. In every patient instance, the Company seeks to become the precision medicine partner on their cancer care team, providing the widest, deepest, and most independent range of service possible.

Relles D.M.,Thomas Jefferson University | Relles D.M.,Biliary and Related Cancer Center | Richards N.G.,Thomas Jefferson University | Richards N.G.,Biliary and Related Cancer Center | And 14 more authors.
Journal of Gastrointestinal Surgery | Year: 2013

Introduction: Pancreaticoduodenectomy (PD) has a high morbidity rate. Previous work has shown that hypoalbuminemia on postoperative day 1 (POD) to be contributory to post-esophagectomy complications. We set out to determine the impact of blood urea nitrogen (BUN) and albumin on POD 1 for patients undergoing PD. Methods: We examined 446 consecutive patients who underwent PD at the Thomas Jefferson University Hospital between January 1, 2000 and December 31, 2008. Complications were graded using the Clavien scale. We examined the incidence of complications based on POD 1 albumin <2.5 versus ≥2.5 mg/dl, as well as POD 1 BUN <10 vs. ≥10 g/dL. Results: Patients with a BUN <10 had a significantly decreased risk of any complication (p < 0.001), serious complication (p < 0.001), and pancreatic fistula (p = 0.011). On multivariate analysis, BUN ≥ 10 was the most significant predictor of grade III or above complication (p = 0.0019, hazard ration (HR) = 2.7) and pancreatic fistula (p = 0.016, HR = 2.6). POD 1 albumin <2.5 mg/dl was also an independent predictor of serious complication (p = 0.01, HR = 2.3). Patients with both risk factors had a 31 % chance of developing serious complications and 18.5 % risk of developing pancreatic fistula, while those patients with neither risk factor had a 6.5 and 3.6 % risk, respectively. Conclusion: Serum albumin and BUN on POD 1 are important predictors of perioperative morbidity following PD. These low-cost and easily accessible tests can be used as a prognostic tool to predict adverse surgical outcomes. © 2012 The Society for Surgery of the Alimentary Tract.

Burkhart R.A.,Biliary and Related Cancer Center | Pineda D.M.,Biliary and Related Cancer Center | Chand S.N.,Biliary and Related Cancer Center | Romeo C.,Biliary and Related Cancer Center | And 7 more authors.
RNA Biology | Year: 2013

Cancer cell metabolism differs from normal cells, yet the regulatory mechanisms responsible for these differences are incompletely understood, particularly in response to acute changes in the tumor microenvironment. HuR, an RNAbinding protein, acts under acute stress to regulate core signaling pathways in cancer through post-transcriptional regulation of mRNA targets. We demonstrate that HuR regulates the metabolic phenotype in pancreatic cancer cells and is critical for survival under acute glucose deprivation. Using three pancreatic cancer cell line models, HuR-proficient cells demonstrated superior survival under glucose deprivation when compared with isogenic cells with siRNA-silencing of HuR expression (HuR-deficient cells). We found that HuR-proficient cells utilized less glucose, but produced greater lactate, as compared with HuR-deficient cells. Acute glucose deprivation was found to act as a potent stimulus for HuR translocation from the nucleus to the cytoplasm, where HuR stabilizes its mRNA targets. We performed a gene expression array on ribonucleoprotein immunoprecipitated mRNAs bound to HuR and identified 11 novel HuR target transcripts that encode enzymes central to glucose metabolism. Three (GPI, PRPS2 and IDH1) were selected for validation studies, and confirmed as bona fide HuR targets. These findings establish HuR as a critical regulator of pancreatic cancer cell metabolism and survival under acute glucose deprivation. Further explorations into HuR's role in cancer cell metabolism should uncover novel therapeutic targets that are critical for cancer cell survival in a metabolically compromised tumor microenvironment. © 2013 Landes Bioscience.

Lazar M.,Biliary and Related Cancer Center | Sullivan J.,Biliary and Related Cancer Center | Chipitsyna G.,Biliary and Related Cancer Center | Aziz T.,Biliary and Related Cancer Center | And 7 more authors.
Surgery | Year: 2010

Background: Cigarette smoke and nicotine are among the leading environmental risk factors for developing pancreatic ductal adenocarcinoma (PDA). We showed recently that nicotine induces osteopontin (OPN), a protein that plays critical roles in inflammation and tumor metastasis. We identified an OPN isoform, OPNc, that is selectively inducible by nicotine and highly expressed in PDA tissue from smokers. In this study, we explored the potential proinflammatory role of nicotine in PDA through studying its effect on the expression of monocyte chemoattractant protein (MCP)-1 and evaluated the role of OPN in mediating these effects. Methods: MCP-1 mRNA and protein in PDA cells treated with or without nicotine (3-300 nmol/L) or OPN (0.15-15 nmol/L) were analyzed by real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Luciferase-labeled promoter studies evaluated the effects of nicotine and OPN on MCP-1 transcription. Intracellular and tissue colocalization of OPN and MCP-1 were examined by immunofluorescence and immunohistochemistry. Results: Nicotine treatment significantly increased MCP-1 expression in PDA cells. Interestingly, blocking OPN with siRNA or OPN antibody abolished these effects. Transient transfection of the OPNc gene in PDA cells or their treatment with recombinant OPN protein significantly (P < .05) increased MCP-1 mRNA and protein and induced its promoter activity. MCP-1 was found in 60% of invasive PDA lesions, of whom 66% were smokers. MCP-1 colocalized with OPN in PDA cells and in the malignant ducts, and correlated well with higher expression levels of OPN in the tissue from patients with invasive PDA. Conclusion: Our data suggest that cigarette smoking and nicotine may contribute to PDA inflammation by inducing MCP-1 and provide a novel insight into a unique role for OPN in mediating these effects. © 2010 Mosby, Inc.

Valsecchi M.E.,Thomas Jefferson University | McDonald M.,Thomas Jefferson University | Brody J.R.,Thomas Jefferson University | Hyslop T.,Thomas Jefferson University | And 6 more authors.
Cancer | Year: 2012

BACKGROUND: The aim of this study was to evaluate the expression of epidermal growth factor receptor (EGFR) and insulinlike growth factor 1 receptor (IGF-1R) proteins and IGF-1R gene copy numbers in pancreatic ductal adenocarcinoma in relation to patients' characteristics and prognosis. METHODS: Immunohistochemical staining was performed on formalin-fixed paraffin-embedded tissue derived from tumor specimens recovered during surgery. Slides were evaluated for membranous EGFR and IGF-1R staining using both the HercepTest and the semiquantitative H-score systems. Chromogenic in situ hybridization was performed to quantify IGF-1R gene copy number. The primary outcome was the association between EGFR expression, IGF-1R expression-in both neoplastic epithelial and stromal cells-or IGF-1R gene copy number and overall survival. Secondary outcomes included associations between EFGR and IGF-1R expression and pathologic variables. RESULTS: A total of 105 patients were included. EGFR expression was present in 30.4% of cases and was associated with lymph node metastasis (P =.038). IGF-1R was overexpressed in 53% of tumors and correlated with higher tumor grade (P =.033). High membranous expression of EGFR (P <.001) and/or IGF-1R (P =.004), the cytoplasmic detection of EGFR (P =.027), and high expression levels of IGF-1R in the tumoral stroma (P <.001) were all associated with shorter overall survival, being significantly better in patients who simultaneously do not express membranous EGFR or stromal IGF-1R. CONCLUSIONS: EGFR and IGF-1R expression, in neoplastic and stromal cells, seems to be an important prognostic factor. © 2011 American Cancer Society.

Rittenhouse D.W.,Thomas Jefferson University | Talbott V.A.,Thomas Jefferson University | Anklesaria Z.,Thomas Jefferson University | Brody J.R.,Thomas Jefferson University | And 5 more authors.
Journal of Gastrointestinal Surgery | Year: 2011

Background: Cystic fibrosis (CF) is the most commonly inherited lethal autosomal recessive genetic disease amongst Caucasians. CF results from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Patients with homozygous or compound heterozygous CFTR mutations have a risk of pancreatitis, but typically do not live long enough to develop pancreatic ductal adenocarcinoma (PDA), a disease that has an average age at diagnosis of 65 years. Little is known about the risk of the development of PDA in people who are heterozygous for mutations in the CFTR gene. Patients and Methods: We report a case of a patient with PDA who underwent resection, who is a carrier for the W1282X nonsense mutation in the CFTR gene. The patient is of Ashkenazi Jewish ethnicity and has a family history of CF, but no family history of PDA. We reviewed the English language literature for the prevalence of PDA in CF patients (and CFTR mutations in the setting of PDA) and their significance in terms of screening, and the use of this mutation as a biomarker for an increased risk of the development of PDA. Conclusion: We conclude that patients with CFTR mutations, who also have other risks for the development of PDA such as a family history of the disease, should undergo screening and be educated about their risks. © 2011 The Society for Surgery of the Alimentary Tract.

Burkhart R.A.,Biliary and Related Cancer Center | Peng Y.,University of Delaware | Norris Z.A.,Biliary and Related Cancer Center | Tholey R.M.,Biliary and Related Cancer Center | And 19 more authors.
Molecular Cancer Research | Year: 2013

Pancreatic ductal adenocarcinoma (PDA) is the fourth leading cause of cancer-related death in the United States, with a 95% five-year mortality rate. For over a decade, gemcitabine (GEM) has been the established first-line treatment for this disease despite suboptimal response rates. The development of PARP inhibitors that target the DNA damage repair (DDR) system in PDA cells has generated encouraging results. Ubiquitinspecific peptidase 11 (USP11), an enzyme that interacts with the DDR protein BRCA2, was recently discovered to play a key role in DNA double-strand break repair and may be a novel therapeutic target. A systematic high-throughput approach was used to biochemically screen 2,000 U.S. Food and Drug Administration (FDA)-approved compounds for inhibition of USP11 enzymatic activity. Six pharmacologically active small molecules that inhibit USP11 enzymatic activity were identified. An in vitro drug sensitivity assay demonstrated that one of these USP11 inhibitors, mitoxantrone, impacted PDA cell survival with an IC50 of less than 10 nM. Importantly, across six different PDA cell lines, two with defects in the Fanconi anemia/ BRCA2 pathway (Hs766T and Capan-1), mitoxantrone is 40- to 20,000-fold more potent than GEM, with increased endogenous USP11 mRNA levels associated with increased sensitivity to mitoxantrone. Interestingly, USP11 silencing in PDA cells also enhanced sensitivity to GEM. These findings establish a preclinical model for the rapid discovery of FDA-approved compounds and identify USP11 as a target of mitoxantrone in PDA. Implications: This high-throughput approach provides a strong rationale to study mitoxantrone in an early-phase clinical setting for the treatment of PDA. © 2013 AACR.

PubMed | Thomas Jefferson University and Biliary and Related Cancer Center
Type: Journal Article | Journal: International journal of biological sciences | Year: 2016

Pancreatic cancer (pancreatic ductal adenocarcinoma, PDA) is infamously moving to the top of the list as one of the most lethal cancers with an overall 5 year survival rate of 7%. Multiple genomic-based and molecular characterization studies of PDA specimens and established animal models have provided the field with multiple targets and a progression model of this disease. Still, to date, the best therapeutic options are surgery and combination cytotoxic therapies. In general, even in the best case scenario (i.e., an early stage diagnosis and a response to a specific therapy), most of these fortunate patients PDA cells acquire or exert resistance mechanisms and eventually kill the patient. Herein, we touch on a growing field of investigation that focuses on PDA cell therapeutic resistance mechanisms. We examine extrinsic elements (i.e., the tumor microenvironment, hypoxia) to the intrinsic processes within the cell (i.e., post-transcriptional gene regulation and somatic mutations) that are important for therapeutic efficacy and resistance. Even as better targeted and personalized approaches move through the clinical trial pipeline the discussed resistance mechanisms will most likely play a role in the management of this deadly disease.

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