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Pancreatic Neoplasms: HELP
Articles by Nelson S. Yee
Based on 16 articles published since 2009
(Why 16 articles?)
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Between 2009 and 2019, N. S. Yee wrote the following 16 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Guideline Locally Advanced Unresectable Pancreatic Cancer: American Society of Clinical Oncology Clinical Practice Guideline Summary. 2017

Balaban, Edward P / Mangu, Pamela B / Yee, Nelson S. ·Cancer Care Partnership, State College; Penn State Hershey Cancer Institute, Hershey, PA; and American Society of Clinical Oncology, Alexandria, VA. ·J Oncol Pract · Pubmed #28399382.

ABSTRACT: -- No abstract --

2 Review TRPM8 Ion Channels as Potential Cancer Biomarker and Target in Pancreatic Cancer. 2016

Yee, Nelson S. ·Program of Experimental Therapeutics, Penn State Hershey Cancer Institute, Penn State Milton S. Hershey Medical Center, Hershey, PA, United States; Pennsylvania State University College of Medicine, Hershey, PA, United States. Electronic address: nyee@hmc.psu.edu. ·Adv Protein Chem Struct Biol · Pubmed #27038374.

ABSTRACT: This article provides a review and discussion of the transient receptor potential melastatin-subfamily member 8 (TRPM8) ion channel as a potential biomarker and target in cancer. TRPM8 is a Ca(2+)-permeable channel that plays a major physiological role in cellular sensation and transduction of cold temperature. TRPM8 is aberrantly expressed in a variety of solid tumors including pancreatic cancer. In pancreatic adenocarcinoma cell lines and tissues, TRPM8 is overexpressed as compared to normal pancreatic ductal epithelia. Analysis of anti-TRPM8 immunoreactivity in pancreatic adenocarcinoma indicates positive correlation of TRPM8 expression with tumor size and stages. The biological roles of TRPM8 in pancreatic cancer cells have been revealed from studies using RNA interference-mediated silencing of TRPM8. The experimental data show that TRPM8 channels are required for sustaining proliferation and cell cycle progression, preventing replicative senescence, and promoting cell invasion. Evidence to date implicates a contributory role of TRPM8 channels in the pathogenesis of pancreatic neoplasms and other tumors. Research focus on the mechanisms that underlie TRPM8-mediated roles in tumor growth and metastasis may help establish a novel link of physicochemical changes with pancreatic carcinogenesis. Translational and clinical investigation to exploit TRPM8 as a molecular biomarker and therapeutic target is expected to make a positive impact on precision medicine in pancreatic cancer and other malignant diseases.

3 Review Immunotherapeutic Approaches in Pancreatic Adenocarcinoma: Current Status and Future Perspectives. 2016

Yee, Nelson S. ·Penn State Hershey Cancer Institute, 500 University Drive, Hershey, PA 17033-0850, USA. nyee@hmc.psu.edu. ·Curr Mol Pharmacol · Pubmed #26177643.

ABSTRACT: Pancreatic adenocarcinoma is highly lethal, and until prevention of this disease is possible, various treatments including the recently developed immunotherapy to improve patients' survival and quality of life are desperately needed. The objectives of this article are to examine the role of tumor-associated immunosuppression in pancreatic cancer development, dissect the cellular and molecular basis of the immunotherapeutic approaches, and discuss the current status and emerging strategies of immunotherapy in this malignant disease. Animal models and experimental evidence have shown that pancreatic tumor-associated stroma produces an immunosuppressive microenvironment, which promotes development and progression of pancreatic tumor. This results from dynamic interactions among pancreatic cancer cells and the immune effector cells through the actions of multiple cytokines and binding of immunomodulatory molecules. Various immunotherapeutic approaches have been developed in attempt to stimulate immune response by cytokine- or tumor-associated antigen-based vaccines, adoptive transfer of immunotoxins or antigen-primed immune cells, or antibodies directed against immune regulators. Results of these clinical studies show that these treatments are generally well tolerated without major serious complications, and demonstrate potential efficacy of immune-based therapies in pancreatic cancer. Strategies to improve the efficacy of immunotherapy may be accomplished by combining it with the conventionally used chemotherapy or targeted agents. Combinatorial approach using molecular profiling and bioinformatics may help identify predictive biomarkers of treatment response as well as identifying potential targets for personalized cancer vaccines. Hopefully, this article will stimulate further research interests and collaborative efforts to optimize therapy for patients with this devastating disease.

4 Review Current Systemic Treatment and Emerging Therapeutic Strategies in Pancreatic Adenocarcinoma. 2015

Yee, Nelson S / Kazi, Abid A / Yee, Rosemary K. ·Penn State Hershey Cancer Institute, 500 University Drive, Hershey, Pennsylvania 17033-0850, USA. nyee@hmc.psu.edu. ·Curr Clin Pharmacol · Pubmed #26548903.

ABSTRACT: The purpose of this article is to provide a critical review of the current systemic treatment and the emerging targeted therapeutic strategies in pancreatic adenocarcinoma. Cytotoxic chemotherapeutic drugs have been used for palliative treatment of pancreatic adenocarcinoma, as well as for neoadjuvant therapy to facilitate surgical resection, and as adjuvant therapy to prevent tumor recurrence. The recent findings of early metastasis of cancer cells in pancreatic adenocarcinoma provide support for systemic therapy even in the case of small and localized tumors. However, the clinical benefits of systemic chemotherapy are generally limited and it is typically associated with a multitude of toxicities. Cancer-specific therapies with improved efficacy and safety are urgently needed. Tremendous advances have been made in understanding the biology and genetic regulation of normal and neoplastic development of the pancreas. These have led to identification of molecular targets in pancreatic cancer cells, the tumor microenvironment, and the cancer stem cells. Tumor-specific modalities are emergent by exploitation of the aberrant signaling pathways and molecular alterations in pancreatic cancer with the goals of improving treatment response. Integrative approaches that combine various targeting strategies with molecular bioinformatics will hopefully lead to the development of personalized therapies that may produce a positive impact on the quality of life and survival for patients with this deadly disease.

5 Review Toward the goal of personalized therapy in pancreatic cancer by targeting the molecular phenotype. 2013

Yee, Nelson S. ·Division of Hematology-Oncology, Department of Medicine, Penn State College of Medicine, Penn State Hershey Cancer Institute, Milton S. Hershey Medical Center, Pennsylvania State University, Hershey, PA 17033-0850, USA. nyee@hmc.psu.edu ·Adv Exp Med Biol · Pubmed #23288637.

ABSTRACT: The purpose of this article is to provide a critical review of the molecular alterations in pancreatic cancer that are clinically investigated as therapeutic targets and their potential impact on clinical outcomes. Adenocarcinoma of exocrine pancreas is generally associated with poor prognosis and the conventional therapies are marginally effective. Advances in understanding the genetic regulation of normal and neoplastic development of pancreas have led to development and clinical evaluation of new therapeutic strategies that target the signaling pathways and molecular alterations in pancreatic cancer. Applications have begun to utilize the genetic targets as biomarkers for prediction of therapeutic responses and selection of treatment options. The goal of accomplishing personalized tumor-specific therapy with tolerable side effects for patients with pancreatic cancer is hopefully within reach in the foreseeable future.

6 Clinical Trial Pharmacological ascorbate with gemcitabine for the control of metastatic and node-positive pancreatic cancer (PACMAN): results from a phase I clinical trial. 2013

Welsh, J L / Wagner, B A / van't Erve, T J / Zehr, P S / Berg, D J / Halfdanarson, T R / Yee, N S / Bodeker, K L / Du, J / Roberts, L J / Drisko, J / Levine, M / Buettner, G R / Cullen, J J. ·Department of Surgery, 1528 JCP-UIHC, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA. ·Cancer Chemother Pharmacol · Pubmed #23381814.

ABSTRACT: BACKGROUND: Treatment for pancreatic cancer with pharmacological ascorbate (ascorbic acid, vitamin C) decreases tumor progression in preclinical models. A phase I clinical trial was performed to establish safety and tolerability of pharmacological ascorbate combined with gemcitabine in patients with biopsy-proven stage IV pancreatic adenocarcinoma. DESIGN: Nine subjects received twice-weekly intravenous ascorbate (15-125 g) employing Simon's accelerated titration design to achieve a targeted post-infusion plasma level of ≥350 mg/dL (≥20 mM). Subjects received concurrent gemcitabine. Disease burden, weight, performance status, hematologic and metabolic laboratories, time to progression and overall survival were monitored. RESULTS: Mean plasma ascorbate trough levels were significantly higher than baseline (1.46 ± 0.02 vs. 0.78 ± 0.09 mg/dL, i.e., 83 vs. 44 μM, p < 0.001). Adverse events attributable to the drug combination were rare and included diarrhea (n = 4) and dry mouth (n = 6). Dose-limiting criteria were not met for this study. Mean survival of subjects completing at least two cycles (8 weeks) of therapy was 13 ± 2 months. CONCLUSIONS: Data suggest pharmacologic ascorbate administered concurrently with gemcitabine is well tolerated. Initial data from this small sampling suggest some efficacy. Further studies powered to determine efficacy should be conducted.

7 Article Locally Advanced, Unresectable Pancreatic Cancer: American Society of Clinical Oncology Clinical Practice Guideline. 2016

Balaban, Edward P / Mangu, Pamela B / Khorana, Alok A / Shah, Manish A / Mukherjee, Somnath / Crane, Christopher H / Javle, Milind M / Eads, Jennifer R / Allen, Peter / Ko, Andrew H / Engebretson, Anitra / Herman, Joseph M / Strickler, John H / Benson, Al B / Urba, Susan / Yee, Nelson S. ·Edward P. Balaban, Cancer Care Partnership, State College · Edward P. Balaban and Nelson S. Yee, Penn State Hershey Cancer Institute, Hershey, PA · Pamela B. Mangu, American Society of Clinical Oncology, Alexandria, VA · Alok A. Khorana, Cleveland Clinic · Jennifer R. Eads, University Hospitals Seidman Cancer Center, Case Western Reserve University, Cleveland, OH · Manish A. Shah, The Weill Cornell Medical Center · Peter Allen, Memorial Sloan Kettering Cancer Center, New York, NY · Somnath Mukherjee, University of Oxford, Oxford, United Kingdom · Christopher H. Crane and Milind M. Javle, The University of Texas MD Anderson Cancer Center, Houston, TX · Andrew H. Ko, University of California San Francisco Comprehensive Cancer Center, San Francisco, CA · Anitra Engebretson, Patient Representative, Portland, OR · Joseph M. Herman, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD · John H. Strickler, Duke University Medical Center, Durham, NC · Al B. Benson III, Lurie Comprehensive Cancer Center of Northwestern, Chicago, IL · and Susan Urba, University of Michigan Cancer Center, Ann Arbor, MI. ·J Clin Oncol · Pubmed #27247216.

ABSTRACT: PURPOSE: To provide evidence-based recommendations to oncologists and others for treatment of patients with locally advanced, unresectable pancreatic cancer. METHODS: American Society of Clinical Oncology convened an Expert Panel of medical oncology, radiation oncology, surgical oncology, gastroenterology, palliative care, and advocacy experts and conducted a systematic review of the literature from January 2002 to June 2015. Outcomes included overall survival, disease-free survival, progression-free survival, and adverse events. RESULTS: Twenty-six randomized controlled trials met the systematic review criteria. RECOMMENDATIONS: A multiphase computed tomography scan of the chest, abdomen, and pelvis should be performed. Baseline performance status and comorbidity profile should be evaluated. The goals of care, patient preferences, psychological status, support systems, and symptoms should guide decisions for treatments. A palliative care referral should occur at first visit. Initial systemic chemotherapy (6 months) with a combination regimen is recommended for most patients (for some patients radiation therapy may be offered up front) with Eastern Cooperative Oncology Group performance status 0 or 1 and a favorable comorbidity profile. There is no clear evidence to support one regimen over another. The gemcitabine-based combinations and treatments recommended in the metastatic setting (eg, fluorouracil, leucovorin, irinotecan, and oxaliplatin and gemcitabine plus nanoparticle albumin-bound paclitaxel) have not been evaluated in randomized controlled trials involving locally advanced, unresectable pancreatic cancer. If there is local disease progression after induction chemotherapy, without metastasis, then radiation therapy or stereotactic body radiotherapy may be offered also with an Eastern Cooperative Oncology Group performance status ≤ 2 and an adequate comorbidity profile. If there is stable disease after 6 months of induction chemotherapy but unacceptable toxicities, radiation therapy may be offered as an alternative. Patients with disease progression should be offered treatment per the ASCO Metastatic Pancreatic Cancer Treatment Guideline. Follow-up visits every 3 to 4 months are recommended. Additional information is available at www.asco.org/guidelines/LAPC and www.asco.org/guidelines/MetPC and www.asco.org/guidelineswiki.

8 Article Translating discovery in zebrafish pancreatic development to human pancreatic cancer: biomarkers, targets, pathogenesis, and therapeutics. 2013

Yee, Nelson S / Kazi, Abid A / Yee, Rosemary K. ·Division of Hematology-Oncology, Program of Experimental Therapeutics, Department of Medicine, Penn State Milton S. Hershey Medical Center, Penn State College of Medicine, Penn State Hershey Cancer Institute, Pennsylvania State University , Hershey, PA 17033-0850, USA. nyee@hmc.psu.edu ·Zebrafish · Pubmed #23682805.

ABSTRACT: Abstract Experimental studies in the zebrafish have greatly facilitated understanding of genetic regulation of the early developmental events in the pancreas. Various approaches using forward and reverse genetics, chemical genetics, and transgenesis in zebrafish have demonstrated generally conserved regulatory roles of mammalian genes and discovered novel genetic pathways in exocrine pancreatic development. Accumulating evidence has supported the use of zebrafish as a model of human malignant diseases, including pancreatic cancer. Studies have shown that the genetic regulators of exocrine pancreatic development in zebrafish can be translated into potential clinical biomarkers and therapeutic targets in human pancreatic adenocarcinoma. Transgenic zebrafish expressing oncogenic K-ras and zebrafish tumor xenograft model have emerged as valuable tools for dissecting the pathogenetic mechanisms of pancreatic cancer and for drug discovery and toxicology. Future analysis of the pancreas in zebrafish will continue to advance understanding of the genetic regulation and biological mechanisms during organogenesis. Results of those studies are expected to provide new insights into how aberrant developmental pathways contribute to formation and growth of pancreatic neoplasia, and hopefully generate valid biomarkers and targets as well as effective and safe therapeutics in pancreatic cancer.

9 Article TRPM8 ion channel is aberrantly expressed and required for preventing replicative senescence in pancreatic adenocarcinoma: potential role of TRPM8 as a biomarker and target. 2012

Yee, Nelson S / Brown, Robert D / Lee, Min Sun / Zhou, Weiqiang / Jensen, Chris / Gerke, Henning / Yee, Rosemary K. ·Division of Hematology-Oncology, Department of Medicine, Penn State College of Medicine, Penn State Hershey Cancer Institute, Milton S. Hershey Medical Center, Pennsylvania State University, Hershey, Pennsylvania, USA. ·Cancer Biol Ther · Pubmed #22555807.

ABSTRACT: Pancreatic adenocarcinoma is mostly fatal and generally resistant to conventional treatments, such that effective therapies with tolerable side effects are desperately needed. Ion channels including the transient receptor potential (TRP) channels have been implicated in human malignancies, but their roles in pancreatic cancer were mostly unknown. Recent identification of the melastatin-subfamily members of the TRP family of ion channels, and their functions in pancreatic epithelia and adenocarcinoma, is expected to provide a new perspective to understanding the mechanism underlying pancreatic tumorigenesis. In this report, we present the clinical and pathological features of a mini-series of patients with pancreatic adenocarcinoma, which aberrantly exhibits immunoreactivity against the TRPM8 channel. We have recently demonstrated the proliferative role of TRPM8 channel in pancreatic cancer cells. Here, we present evidence that RNA interference-mediated silencing of TRPM8 induces replicative senescence in pancreatic adenocarcinoma cells. This suggests that the aberrantly expressed TRPM8 channel may contribute to pancreatic tumorigenesis by preventing oncogene-induced senescence, and targeted inhibition of TRPM8 may enhance tumor sensitivity to therapeutics. Based on these observations, we hypothesize that the TRPM8 ion channel plays a crucial role in the growth and progression of pancreatic neoplasia during tumorigenesis. We propose that TRPM8 can be exploited as a clinical biomarker and as a therapeutic target for developing personalized therapy in pancreatic adenocarcinoma.

10 Article Targeted silencing of TRPM7 ion channel induces replicative senescence and produces enhanced cytotoxicity with gemcitabine in pancreatic adenocarcinoma. 2012

Yee, Nelson S / Zhou, Weiqiang / Lee, Minsun / Yee, Rosemary K. ·Division of Hematology-Oncology, Department of Medicine, Penn State College of Medicine, Pennsylvania State University, 500 University Drive, Hershey, PA 17033, USA. nyee@hmc.psu.edu ·Cancer Lett · Pubmed #22166235.

ABSTRACT: The transient receptor potential TRPM7 ion channel is required for cellular proliferation in pancreatic epithelia and adenocarcinoma. To elucidate the mechanism that mediates the function of TRPM7, we examined its role in survival of pancreatic cancer cells. RNA interference-mediated silencing of TRPM7 did not induce apoptotic cell death. TRPM7-deficient cells underwent replicative senescence with up-regulation of p16(CDKN2A) and WRN mRNA. The combination of anti-TRPM7 siRNA and gemcitabine produced enhanced cytotoxicity as compared to gemcitabine alone. Thus, TRPM7 is required for preventing senescence, and modulation of TRPM7 expression may help improve treatment response of pancreatic cancer by combining with apoptosis-inducing agents.

11 Article Brca2 deficiency and Trp53 deregulation in pancreatic cancer: implications for therapeutic targeting. 2011

Yee, Nelson S. ·Division of Hematology, Oncology, and Blood and Marrow Transplantation, Department of Internal Medicine, Carver College of Medicine; Program of Cancer, Signaling and Experimental Therapeutics, Holden Comprehensive Cancer Center University of Iowa, Iowa City, IA, USA. ·Cancer Biol Ther · Pubmed #21610317.

ABSTRACT: -- No abstract --

12 Article Histone deacetylase 1 is required for exocrine pancreatic epithelial proliferation in development and cancer. 2011

Zhou, Weiqiang / Liang, I-Chau / Yee, Nelson S. ·Division of Hematology, Oncology and Blood & Marrow Transplantation, Department of Internal Medicine, Carver College of Medicine, Program of Cancer Signaling and Experimental Therapeutics, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, USA. ·Cancer Biol Ther · Pubmed #21301206.

ABSTRACT: Histone deacetylases (HDACs) play important roles in the epigenetic control of development, and aberrant expression of HDACs has been implicated in human diseases including cancer. Among the mammalian HDACs, HDAC1 has been extensively studied, but its role in exocrine pancreatic morphogenesis and cancer is still poorly understood. The goal of this study is to determine the functional role of HDAC1 in normal development of exocrine pancreas using zebrafish as the model organism as well as in human pancreatic adenocarcinoma. The zebrafish germline loss-of-function mutation hdac1(hi1618) caused impaired cell cycle progression in pancreatic epithelia, resulting in growth arrest and dysmorphogenesis of exocrine pancreas. In human pancreatic adenocarcinoma tissues and cell lines, HDAC1 was expressed at variably elevated levels. RNA interference-induced silencing of HDAC1 diminished proliferation of the cancer cells and cell cycle progression. The proliferative arrest in the developing exocrine pancreas and pancreatic cancer cells was associated with up-regulated expression of the cyclin-dependent kinase inhibitors and the sonic hedgehog signaling components. This study indicates that HDAC1 is required for pancreatic epithelial proliferation in development and cancer. We hypothesize that aberrant expression of HDAC1 modulates the developmental and signaling pathways in exocrine pancreatic epithelia and consequently the genes required for cellular proliferation during development and progression of pancreatic neoplasia.

13 Article Transient receptor potential ion channel Trpm7 regulates exocrine pancreatic epithelial proliferation by Mg2+-sensitive Socs3a signaling in development and cancer. 2011

Yee, Nelson S / Zhou, Weiqiang / Liang, I-Chau. ·Division of Hematology, Oncology, and Blood & Marrow Transplantation, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA. nelson-yee@uiowa.edu ·Dis Model Mech · Pubmed #21183474.

ABSTRACT: Genetic analysis of pancreatic development has provided new insights into the mechanisms underlying the formation of exocrine pancreatic neoplasia. Zebrafish sweetbread (swd) mutants develop hypoplastic acini and dysmorphic ducts in the exocrine pancreas, with impeded progression of cell division cycle and of epithelial growth. Positional cloning and allelic complementation have revealed that the swd mutations affect the transient receptor potential melastatin-subfamily member 7 (trpm7) gene, which encodes a divalent cation-permeable channel with kinase activity. Supplementary Mg(2+) partially rescued the exocrine pancreatic defects of the trpm7 mutants by improving cell-cycle progression and growth and repressing the suppressor of cytokine signaling 3a (socs3a) gene. The role of Socs3a in Trpm7-mediated signaling is supported by the findings that socs3a mRNA level is elevated in the trpm7 mutants, and antisense inhibition of socs3a expression improved their exocrine pancreatic growth. TRPM7 is generally overexpressed in human pancreatic adenocarcinoma. TRPM7-deficient cells are impaired in proliferation and arrested in the G0-G1 phases of the cell division cycle. Supplementary Mg(2+) rescued the proliferative defect of the TRPM7-deficient cells. Results of this study indicate that Trpm7 regulates exocrine pancreatic development via the Mg(2+)-sensitive Socs3a pathway, and suggest that aberrant TRPM7-mediated signaling contributes to pancreatic carcinogenesis.

14 Article Werner syndrome as a hereditary risk factor for exocrine pancreatic cancer: potential role of WRN in pancreatic tumorigenesis and patient-tailored therapy. 2010

Chun, Stephen G / Yee, Nelson S. ·Department of Surgery, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, Hawaii, USA. ·Cancer Biol Ther · Pubmed #20657174.

ABSTRACT: Advanced age is considered a risk factor for pancreatic cancer, but this relationship at the molecular and genetic level remains unclear. We present a clinical case series focusing on an association between pancreatic adenocarcinoma and Werner syndrome (WS) that is an autosomal recessive genetic disorder characterized by accelerated aging and cancer predisposition, and is caused by loss-of-function mutations in the WS RecQ helicase gene (WRN). Although pancreatic adenocarcinoma mostly occurs in a sporadic fashion, a minority of cases occurs in the context of susceptible individuals with hereditary syndromes. While WS has not been previously recognized as a risk factor for developing malignant tumors of the exocrine pancreas, the clinicopathologic features of three reported patients suggest a contributory role of WRN deficiency in pancreatic carcinogenesis. Molecular genetic analyses support the role of WRN as a tumor suppressor gene, although recent evidence reveals that WRN can alternatively promote oncogenicity depending on the molecular context. Based upon the clinico-pathologic features of these patients and the role of WRN in experimental models, we propose that its loss-of-function predisposes the development of pancreatic adenocarcinoma through epigenetic silencing or loss-of-heterozygosity of WRN. To test this hypothesis, we are investigating the mechanistic role of WRN in pancreatic cancer models including a pancreatic adenocarcinoma cell line generated from a human with WS. These studies are expected to provide new insight into the relationship between aging and pancreatic tumorigenesis, and facilitate development of novel strategies for patient-tailored interventions in this deadly malignancy.

15 Article Transient receptor potential channel TRPM8 is over-expressed and required for cellular proliferation in pancreatic adenocarcinoma. 2010

Yee, Nelson S / Zhou, Weiqiang / Lee, Minsun. ·Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA. nelson-yee@uiowa.edu ·Cancer Lett · Pubmed #20605675.

ABSTRACT: The roles of transient receptor potential (TRP) cation channels in pancreatic tumorigenesis are essentially unknown. Here, we focus on the TRP melastatin-subfamily (TRPM) members. Expression of the thermally regulated transmembrane Ca(2+)-permeable channel TRPM8 is consistently up-regulated in human pancreatic adenocarcinoma cell lines and tissues. TRPM8-deficient pancreatic cancer cells have reduced ability of proliferation and cell cycle progression with elevated levels of cyclin-dependent kinase inhibitors. These results indicate that TRPM8 is aberrantly over-expressed in pancreatic adenocarcinoma and required for cellular proliferation, and they support further investigation of the potential of TRPM8 as a clinical biomarker and therapeutic target in pancreatic adenocarcinoma.

16 Article Combined targeting of histone deacetylases and hedgehog signaling enhances cytoxicity in pancreatic cancer. 2009

Chun, Stephen G / Zhou, Weiqiang / Yee, Nelson S. ·Division of Hematology, Oncology and Blood & Marrow Transplantation, Department of Internal Medicine, University of Iowa, Iowa City, IA, USA. ·Cancer Biol Ther · Pubmed #19421011.

ABSTRACT: Combined targeting of distinct cellular signaling mechanisms may improve the efficacy and reduce the toxicity of therapy in pancreatic cancer. Histone deacetylases (HDACs) control cellular functions through epigenetic modulation, and HDACs inhibitors suppress cell growth in pancreatic adenocarcinoma. The Hedgehog (Hh) pathway regulates the development of the pancreas, and aberrant Hh signaling promotes the initiation and progression of pancreatic neoplasia. We hypothesize that HDACs and the Hh pathway cooperatively interact to regulate cellular proliferation of the exocrine pancreas. A combination of the HDAC inhibitor SAHA and the Smoothened antagonist SANT-1 was evaluated for their ability to suppress growth of the Gemcitabine-resistant pancreatic adenocarcinoma cell lines Panc-1 and BxPC-3. The combination of SAHA and SANT-1 supra-additively suppressed cellular proliferation and colony formation. Flow cytometric and immunohistochemical analyses indicated that enhanced induction of apoptotic cell death, cell cycle arrest in G(0)/G(1) phase, and ductal epithelial differentiation are involved. Cell death was associated with nuclear localization of survivin, increased bax expression, and activation of caspases 3 and 7. Consistent with the cell cycle arrest and cytodifferentiation, the cyclin-dependent kinase inhibitors p21(waf) and p27(kip1) were upregulated, and cyclin D1 downregulated. The potentiated anti-proliferative effect by the combination of SAHA and SANT-1 may involve cooperative suppression of the Hh pathway activity, as shown by the upregulation of HHIP by SAHA, and enhanced repression of of Ptc-1 mRNA expression. In summary, we have developed a molecular target-based therapeutic approach that overcomes chemoresistance in pancreatic cancer cells by chemically inhibiting HDACs and Hh signaling in combination.