Pick Topic
Review Topic
List Experts
Examine Expert
Save Expert
  Site Guide ··   
Pancreatic Neoplasms: HELP
Articles by Andrew M. Lowy
Based on 48 articles published since 2009
(Why 48 articles?)
||||

Between 2009 and 2019, A. Lowy wrote the following 48 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Guideline Pancreatic Adenocarcinoma, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology. 2017

Tempero, Margaret A / Malafa, Mokenge P / Al-Hawary, Mahmoud / Asbun, Horacio / Bain, Andrew / Behrman, Stephen W / Benson, Al B / Binder, Ellen / Cardin, Dana B / Cha, Charles / Chiorean, E Gabriela / Chung, Vincent / Czito, Brian / Dillhoff, Mary / Dotan, Efrat / Ferrone, Cristina R / Hardacre, Jeffrey / Hawkins, William G / Herman, Joseph / Ko, Andrew H / Komanduri, Srinadh / Koong, Albert / LoConte, Noelle / Lowy, Andrew M / Moravek, Cassadie / Nakakura, Eric K / O'Reilly, Eileen M / Obando, Jorge / Reddy, Sushanth / Scaife, Courtney / Thayer, Sarah / Weekes, Colin D / Wolff, Robert A / Wolpin, Brian M / Burns, Jennifer / Darlow, Susan. · ·J Natl Compr Canc Netw · Pubmed #28784865.

ABSTRACT: Ductal adenocarcinoma and its variants account for most pancreatic malignancies. High-quality multiphase imaging can help to preoperatively distinguish between patients eligible for resection with curative intent and those with unresectable disease. Systemic therapy is used in the neoadjuvant or adjuvant pancreatic cancer setting, as well as in the management of locally advanced unresectable and metastatic disease. Clinical trials are critical for making progress in treatment of pancreatic cancer. The NCCN Guidelines for Pancreatic Adenocarcinoma focus on diagnosis and treatment with systemic therapy, radiation therapy, and surgical resection.

2 Review Clinical Management: Resectable Disease. 2017

White, Rebekah R / Lowy, Andrew M. · ·Cancer J · Pubmed #29189330.

ABSTRACT: Despite the identification of more active systemic therapy combinations for pancreatic cancer, cures remain elusive and feasible only in patients with localized, operable disease. When examining outcome data from phase III adjuvant trials conducted during the past decade, the survival for patients with localized disease has improved, likely owing to a combination of factors including more active adjuvant therapy and improved surgical and perioperative care. Perhaps the greatest recent change in the care of patients with localized pancreatic cancer has been the extension of surgery to tumors previously thought to be inoperable because of involvement of major blood vessels. These so-called "borderline resectable pancreatic cancers" have now been objectively defined, and their management is being studied in randomized trials. This has been made feasible by the availability of more active systemic therapy combinations that are increasingly being used in the neoadjuvant setting. Given the increasing activity of systemic regimens, the challenges in delivering such therapy in the postoperative setting, and the numerous novel agents in late stages of clinical development, it is reasonable to hypothesize that the neoadjuvant setting may eventually become the standard of care for patients with resectable disease.

3 Review Approach to patients with pancreatic cancer without detectable metastases. 2015

Heestand, Gregory M / Murphy, James D / Lowy, Andrew M. ·All authors: Moores Cancer Center, University of California at San Diego, La Jolla, CA. · All authors: Moores Cancer Center, University of California at San Diego, La Jolla, CA. alowy@ucsd.edu. ·J Clin Oncol · Pubmed #25918279.

ABSTRACT: The poors outcomes associated with pancreatic cancer clearly reflect the advanced stage of disease at diagnosis for most patients. Through this lens, it is easy to lose sight of the fact that roughly 50% of patients with pancreatic cancer have no clinically detectable metastases at presentation. Herein, we discuss how patients with localized pancreatic cancer are currently managed. The primary goal of care for patients with resectable and borderline-resectable tumors is cure, facilitated by achieving margin-negative resection of the primary disease and delivering effective adjuvant and/or neoadjuvant therapy. For patients with locally advanced disease, the focus is on limiting local progression and outgrowth of metastatic disease and maintaining quality of life. Although it was once a centerpiece of therapy for localized pancreatic cancer, the value and place of radiation therapy in the treatment algorithm is now under increased scrutiny. In contrast, given its value as demonstrated in multiple prospective trials, chemotherapy is an established part of the treatment paradigm for all patients. With the demonstration that cytotoxic combinations such as fluorouracil, leucovorin, irinotecan, and oxaliplatin as well as gemcitabine/nab-paclitaxel are active in the metastatic setting, these agents are now being studied in patients with localized disease. The neoadjuvant setting provides a particularly favorable setting for evaluating new systemic strategies. Given the array of new targets, including immunomodulatory approaches, there is reason for optimism that we can markedly improve survival for all patients with pancreatic cancer and enter an era in which surgery with curative intent actually fulfills this goal on a much more regular basis.

4 Review Borderline resectable pancreatic cancer: definitions and management. 2014

Lopez, Nicole E / Prendergast, Cristina / Lowy, Andrew M. ·Nicole E Lopez, Cristina Prendergast, Andrew M Lowy, Division of Surgical Oncology, Department of Surgery, Moores Cancer Center, University of California San Diego, La Jolla, CA 92093-0987, United States. ·World J Gastroenterol · Pubmed #25152577.

ABSTRACT: Pancreatic cancer is the fourth leading cause of cancer death in the United States. While surgical resection remains the only curative option, more than 80% of patients present with unresectable disease. Unfortunately, even among those who undergo resection, the reported median survival is 15-23 mo, with a 5-year survival of approximately 20%. Disappointingly, over the past several decades, despite improvements in diagnostic imaging, surgical technique and chemotherapeutic options, only modest improvements in survival have been realized. Nevertheless, it remains clear that surgical resection is a prerequisite for achieving long-term survival and cure. There is now emerging consensus that a subgroup of patients, previously considered poor candidates for resection because of the relationship of their primary tumor to surrounding vasculature, may benefit from resection, particularly when preceded by neoadjuvant therapy. This stage of disease, termed borderline resectable pancreatic cancer, has become of increasing interest and is now the focus of a multi-institutional clinical trial. Here we outline the history, progress, current treatment recommendations, and future directions for research in borderline resectable pancreatic cancer.

5 Review The RON receptor tyrosine kinase in pancreatic cancer pathogenesis and its potential implications for future targeted therapies. 2014

Kang, Chang Moo / Babicky, Michele L / Lowy, Andrew M. ·From the *Division of Hepatobiliary and Pancreas, Department of Surgery, Yonsei University College of Medicine, Pancreaticobiliary Cancer Clinic, Institute of Gastroenterology, Yonsei University Health System, Seoul, Korea; and †Department of Surgery, Division of Surgical Oncology, Moores Cancer Center, University of California, San Diego, La Jolla, CA. ·Pancreas · Pubmed #24518495.

ABSTRACT: Pancreatic cancer remains a devastating disease with a mortality rate that has not changed substantially in decades. Novel therapies are therefore desperately needed. The RON receptor tyrosine kinase has been identified as an important mediator of KRAS oncogene addiction and is overexpressed in the majority of pancreatic cancers. Preclinical studies show that inhibition of RON function decreases pancreatic cancer cell migration, invasion, and survival and can sensitize pancreatic cancer cells to chemotherapy. This article reviews the current state of knowledge regarding RON biology and pancreatic cancer and discusses its potential as a therapeutic target.

6 Review Therapeutic advances in pancreatic cancer. 2013

Paulson, Andrew Scott / Tran Cao, Hop S / Tempero, Margaret A / Lowy, Andrew M. ·University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, California 94115, USA. ·Gastroenterology · Pubmed #23622141.

ABSTRACT: Despite our improved understanding of pancreatic cancer biology and ability to perform more complex pancreatic cancer surgeries that produce better short-term outcomes, major progress toward increasing survival times has been painstakingly slow. Through the often-repeated, dismal survival statistics, it is easy to lose sight of real progress that has been made in pancreatic cancer therapy. It is particularly interesting to observe the extent to which these advances are interdependent and the effects they have had on practice. For example, during the past 5-10 years, we have seen widespread adoption of pancreatic imaging protocols that allow for objectively defined criteria of resectability. This has led to the definition of "borderline resectable pancreatic cancer"--a new clinical category that has affected the design of clinical trials. A major change in our surgical approach has been the move to minimally invasive pancreatectomy, which continues to gain broader acceptance and use, particularly for left-sided lesions. Although many new agents have been developed aimed at putative molecular targets, recent breakthroughs in therapy for advanced disease have arisen from our ability to safely give patients combination cytotoxic chemotherapy. We are now faced with the challenge of combining multidrug, cytotoxic chemotherapies with newer-generation agents. Ultimately, the hope is that drug combinations will be selected based on biomarkers, and strategies for pancreatic cancer therapy will be personalized, which could prolong patients' lives and reduce toxicity. We review the major advances in pancreatic cancer therapy during the last 5 years, and discuss how these have set the stage for greater progress in the near future.

7 Review Borderline resectable pancreatic cancer: need for standardization and methods for optimal clinical trial design. 2013

Katz, Matthew H G / Marsh, Robert / Herman, Joseph M / Shi, Qian / Collison, Eric / Venook, Alan P / Kindler, Hedy L / Alberts, Steven R / Philip, Philip / Lowy, Andrew M / Pisters, Peter W T / Posner, Mitchell C / Berlin, Jordan D / Ahmad, Syed A. ·Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. mhgkatz@mdanderson.org ·Ann Surg Oncol · Pubmed #23435609.

ABSTRACT: BACKGROUND: Methodological limitations of prior studies have prevented progress in the treatment of patients with borderline resectable pancreatic adenocarcinoma. Shortcomings have included an absence of staging and treatment standards and pre-existing biases with regard to the use of neoadjuvant therapy and the role of vascular resection at pancreatectomy. METHODS: In this manuscript, we review limitations of studies of borderline resectable PDAC reported to date, highlight important controversies related to this disease stage, emphasize the research infrastructure necessary for its future study, and present a recently-approved Intergroup pilot study (Alliance A021101) that will provide a foundation upon which subsequent well-designed clinical trials can be performed. RESULTS: We identified twenty-three studies published since 2001 which report outcomes of patients with tumors labeled as borderline resectable and who were treated with neoadjuvant therapy prior to planned pancreatectomy. These studies were heterogeneous in terms of the populations studied, the metrics used to characterize therapeutic response, and the indications used to select patients for surgery. Mechanisms used to standardize these and other issues that are incorporated into Alliance A021101 are reviewed. CONCLUSIONS: Rigorous standards of clinical trial design incorporated into trials of other disease stages must be adopted in all future studies of borderline resectable pancreatic cancer. The Intergroup trial should serve as a paradigm for such investigations.

8 Review Changing the way we do business: recommendations to accelerate biomarker development in pancreatic cancer. 2013

Tempero, Margaret A / Klimstra, David / Berlin, Jordan / Hollingsworth, Tony / Kim, Paula / Merchant, Nipun / Moore, Malcolm / Pleskow, Doug / Wang-Gillam, Andrea / Lowy, Andrew M. ·Pancreas Center, University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94115, USA. mtempero@medicine.ucsf.edu ·Clin Cancer Res · Pubmed #23344262.

ABSTRACT: Pancreatic ductal adenocarcinoma is the most aggressive of all epithelial malignancies. In contrast to the favorable trends seen in most other common malignancies, the five-year survival of patients with this disease remains only 6%, a statistic that has changed minimally for decades. Only two drugs have been approved by the U.S. Food and Drug Administration (FDA) for use in pancreatic cancer in the last 15 years, and there are no established strategies for early detection.

9 Review Cystic neoplasms of the pancreas. 2010

Tran Cao, Hop S / Kellogg, Benjamin / Lowy, Andrew M / Bouvet, Michael. ·Department of Surgery, Moores Cancer Center, University of California, San Diego School of Medicine, 3855 Health Sciences Drive, La Jolla, CA 92093-0803, USA. htrancao@ucsd.edu ·Surg Oncol Clin N Am · Pubmed #20159515.

ABSTRACT: Cystic neoplasms of the pancreas are a heterogeneous group of pancreatic tumors that vary in pathophysiology, malignant potential, clinical course, and outcomes. Their management is heavily predicated on establishing an accurate diagnosis. This can be particularly challenging, but can often be achieved by a thorough history and physical examination combined with high-quality, thin-slice computed tomography, although additional diagnostic tools may be required. Once the diagnosis is established, treatment can range from simple observation to total pancreatectomy. This decision rests on a clear and complete understanding of each disease process in the context of the patient's age and comorbidities. This article reviews the most common cystic neoplasms of the pancreas, focusing on their diagnosis and management.

10 Review Consensus report of the national cancer institute clinical trials planning meeting on pancreas cancer treatment. 2009

Philip, Philip A / Mooney, Margaret / Jaffe, Deborah / Eckhardt, Gail / Moore, Malcolm / Meropol, Neal / Emens, Leisha / O'Reilly, Eileen / Korc, Murray / Ellis, Lee / Benedetti, Jacqueline / Rothenberg, Mace / Willett, Christopher / Tempero, Margaret / Lowy, Andrew / Abbruzzese, James / Simeone, Diane / Hingorani, Sunil / Berlin, Jordan / Tepper, Joel. ·Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA. philipp@karmanos.org ·J Clin Oncol · Pubmed #19858397.

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.

11 Clinical Trial An Intergroup Randomized Phase II Study of Bevacizumab or Cetuximab in Combination with Gemcitabine and in Combination with Chemoradiation in Patients with Resected Pancreatic Carcinoma: A Trial of the ECOG-ACRIN Cancer Research Group (E2204). 2018

Berlin, Jordan D / Feng, Yang / Catalano, Paul / Abbruzzese, James L / Philip, Philip A / McWilliams, Robert R / Lowy, Andrew M / Benson, Al B / Blackstock, A William. ·Vanderbilt-Ingram Cancer Center, Nashville, TN, USA. ·Oncology · Pubmed #29040974.

ABSTRACT: OBJECTIVES: Evaluate toxicity of two treatment arms, A (cetuximab) and B (bevacizumab), when combined with gemcitabine, and chemoradiation in patients with completely resected pancreatic carcinoma. Secondary objectives included overall survival (OS) and disease-free survival (DFS). METHODS: Patients with R0/R1 resection were randomized 1:1 to cetuximab or bevacizumab administered in combination with gemcitabine for two treatment cycles. Next three cycles included concurrent cetuximab/bevacizumab plus chemoradiation, followed by one cycle of cetuximab/bevacizumab. Cycles 7-12 included cetuximab/bevacizumab with gemcitabine. Cycles were 2 weeks. Frequency of specific toxicities was summarized for each treatment arm at two times during the study, after chemotherapy but prior to chemoradiation and after all therapy. RESULTS: A total of 127 patients were randomized (A, n = 65; B, n = 62). Prior to chemoradiation, the overall rate for toxicities of interest was 10% for arm A and 2% for arm B. After all therapy, the overall rates for toxicities of interest were 30 and 25% for arms A and B, respectively. Overall median OS and DFS were 17 and 11 months, respectively, which is not a significant improvement over expected survival rates for historical controls. CONCLUSIONS: Both treatments were tolerable with manageable toxicities, and were safe enough for a phase III trial had this been indicated.

12 Clinical Trial Effect of Selumetinib and MK-2206 vs Oxaliplatin and Fluorouracil in Patients With Metastatic Pancreatic Cancer After Prior Therapy: SWOG S1115 Study Randomized Clinical Trial. 2017

Chung, Vincent / McDonough, Shannon / Philip, Philip A / Cardin, Dana / Wang-Gillam, Andrea / Hui, Laifong / Tejani, Mohamedtaki A / Seery, Tara E / Dy, Irene A / Al Baghdadi, Tareq / Hendifar, Andrew E / Doyle, L Austin / Lowy, Andrew M / Guthrie, Katherine A / Blanke, Charles D / Hochster, Howard S. ·City of Hope National Medical Center, Duarte, California. · SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, Washington. · Karmanos Cancer Institute, Wayne State University, Detroit, Michigan. · Vanderbilt University Medical Center, Nashville, Tennessee. · Washington University in St Louis, St Louis, Missouri. · Kaiser Permanente NCORP, Sacramento, California. · University of Rochester, Rochester, New York. · University of California, Irvine, Orange. · Crossroads Cancer Center/Heartland NCORP, Effingham, Illinois. · St Joseph Mercy Hospital/Michigan CRC NCORP, Ann Arbor. · Cedars-Sinai Medical Center, Los Angeles, California. · Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland. · University of California, San Diego, La Jolla. · SWOG Group Chair's Office/Knight Cancer Institute, Oregon Health and Science University, Portland. · Yale Cancer Center, New Haven, Connecticut. ·JAMA Oncol · Pubmed #27978579.

ABSTRACT: Importance: KRAS mutations are common in pancreatic cancer, but directly targeting the KRAS protein has thus far been unsuccessful. The aim of this trial was to block the MEK and PI3K/AKT pathways downstream of the KRAS protein as an alternate treatment strategy to slow cancer growth and prolong survival. This was the first cooperative group trial to evaluate this strategy using molecularly targeted oral combination therapy for the treatment of chemotherapy-refractory pancreatic cancer. Objective: To compare selumetinib and MK-2206 vs modified FOLFOX (mFOLFOX) in patients with metastatic pancreatic cancer for whom gemcitabine-based therapy had failed. Design, Setting, and Participants: SWOG S1115 was a randomized phase 2 clinical trial. Between September 2012 and May 2014, 137 patients with metastatic pancreatic adenocarcinoma for whom gemcitabine-based chemotherapy had failed were randomized to selumetinib plus MK-2206 or mFOLFOX. Patients were randomized in a 1:1 fashion and stratified according to duration of prior systemic therapy and presence of liver metastases. Interventions: Patients received selumetinib 100 mg orally per day plus MK-2206 135 mg orally once per week or mFOLFOX (oxaliplatin, 85 mg/m2 intravenous, and fluorouracil, 2400 mg/m2 intravenous infusion over 46-48 hours) on days 1 and 15 of a 28-day cycle. Main Outcomes and Measures: The primary end point of the study was overall survival. Secondary objectives included evaluating toxic effects, objective tumor response, and progression-free survival. Results: There were 58 patients in the selumetinib plus MK-2206 (experimental) arm (60% male; median [range] age, 69 [54-88] years) and 62 patients in the mFOLFOX arm (35% male; median [range] age, 65 [34-82] years). In the experimental arm, median overall survival was shorter (3.9 vs 6.7 months; HR, 1.37; 95% CI, 0.90-2.08; P = .15), as was median progression-free survival (1.9 vs 2.0 months; HR, 1.61; 95% CI, 1.07-2.43; P = .02). One vs 5 patients had a partial response and 12 vs 14 patients had stable disease in the experimental arm vs mFOLFOX arm. Grade 3 or higher toxic effects were observed in 39 patients treated with selumetinib and MK-2206 vs 23 patients treated with mFOLFOX. More patients in the experimental arm discontinued therapy due to adverse events (13 vs 7 patients). Conclusions and Relevance: Dual targeting of the MEK and PI3K/AKT pathways downstream of KRAS by selumetinib plus MK-2206 did not improve overall survival in patients with metastatic pancreatic adenocarcinoma for whom gemcitabine-based chemotherapy had failed. This was the first randomized prospective evaluation of mFOLFOX in the US population that showed comparable results to CONKO-003 and PANCREOX. Trial Registration: clinicaltrials.gov Identifier: NCT01658943.

13 Clinical Trial Preoperative Modified FOLFIRINOX Treatment Followed by Capecitabine-Based Chemoradiation for Borderline Resectable Pancreatic Cancer: Alliance for Clinical Trials in Oncology Trial A021101. 2016

Katz, Matthew H G / Shi, Qian / Ahmad, Syed A / Herman, Joseph M / Marsh, Robert de W / Collisson, Eric / Schwartz, Lawrence / Frankel, Wendy / Martin, Robert / Conway, William / Truty, Mark / Kindler, Hedy / Lowy, Andrew M / Bekaii-Saab, Tanios / Philip, Philip / Talamonti, Mark / Cardin, Dana / LoConte, Noelle / Shen, Perry / Hoffman, John P / Venook, Alan P. ·Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston. · Alliance for Clinical Trials in Oncology Statistics and Data Center, Mayo Clinic, Rochester, Minnesota. · Department of Surgery, University of Cincinnati, Cincinnati, Ohio. · Department of Radiation Oncology, Johns Hopkins University, Baltimore, Maryland. · Department of Medical Oncology, NorthShore University HealthSystem, University of Chicago, Chicago, Illinois. · Department of Medical Oncology, University of California-San Francisco, San Francisco. · Department of Radiology, Columbia University, New York, New York. · Department of Pathology, Ohio State University, Columbus. · Department of Surgery, University of Louisville, Louisville, Kentucky. · Department of Surgery, Ochsner Medical Center, New Orleans, Louisiana. · Department of Surgery, Mayo Clinic, Rochester, Minnesota. · Department of Medical Oncology, University of Chicago, Chicago, Illinois. · Department of Surgery, University of California, San Diego. · Department of Medical Oncology, Ohio State University, Columbus. · Department of Medical Oncology, Karmanos Cancer Center, Detroit, Michigan. · Department of Surgery, NorthShore University HealthSystem, University of Chicago, Chicago, Illinois. · Department of Medical Oncology, Vanderbilt University, Nashville, Tennessee. · Department of Medical Oncology, University of Wisconsin-Madison, Madison, Wisconsin. · Department of Surgery, Wake Forest University, Winston Salem, North Carolina. · Department of Surgery, Fox Chase Cancer Center, Philadelphia, Pennsylvania. ·JAMA Surg · Pubmed #27275632.

ABSTRACT: IMPORTANCE: Although consensus statements support the preoperative treatment of borderline resectable pancreatic cancer, no prospective, quality-controlled, multicenter studies of this strategy have been conducted. Existing studies are retrospective and confounded by heterogeneity in patients studied, therapeutic algorithms used, and outcomes reported. OBJECTIVE: To determine the feasibility of conducting studies of multimodality therapy for borderline resectable pancreatic cancer in the cooperative group setting. DESIGN, SETTING, AND PARTICIPANTS: A prospective, multicenter, single-arm trial of a multimodality treatment regimen administered within a study framework using centralized quality control with the cooperation of 14 member institutions of the National Clinical Trials Network. Twenty-nine patients with biopsy-confirmed pancreatic cancer preregistered, and 23 patients with tumors who met centrally reviewed radiographic criteria registered. Twenty-two patients initiated therapy (median age, 64 years [range, 50-76 years]; 55% female). Patients registered between May 29, 2013, and February 7, 2014. INTERVENTIONS: Patients received modified FOLFIRINOX treatment (85 mg/m2 of oxaliplatin, 180 mg/m2 of irinotecan hydrochloride, 400 mg/m2 of leucovorin calcium, and then 2400 mg/m2 of 5-fluorouracil for 4 cycles) followed by 5.5 weeks of external-beam radiation (50.4 Gy delivered in 28 daily fractions) with capecitabine (825 mg/m2 orally twice daily) prior to pancreatectomy. MAIN OUTCOMES AND MEASURES: Feasibility, defined by the accrual rate, the safety of the preoperative regimen, and the pancreatectomy rate. RESULTS: The accrual rate of 2.6 patients per month was superior to the anticipated rate. Although 14 of the 22 patients (64% [95% CI, 41%-83%]) had grade 3 or higher adverse events, 15 of the 22 patients (68% [95% CI, 49%-88%]) underwent pancreatectomy. Of these 15 patients, 12 (80%) required vascular resection, 14 (93%) had microscopically negative margins, 5 (33%) had specimens that had less than 5% residual cancer cells, and 2 (13%) had specimens that had pathologic complete responses. The median overall survival of all patients was 21.7 months (95% CI, 15.7 to not reached) from registration. CONCLUSIONS AND RELEVANCE: The successful completion of this collaborative study demonstrates the feasibility of conducting quality-controlled trials for this disease stage in the multi-institutional setting. The data generated by this study and the logistical elements that facilitated the trial's completion are currently being used to develop cooperative group trials with the goal of improving outcomes for this subset of patients. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01821612.

14 Clinical Trial Dual blockade of epidermal growth factor receptor and insulin-like growth factor receptor-1 signaling in metastatic pancreatic cancer: phase Ib and randomized phase II trial of gemcitabine, erlotinib, and cixutumumab versus gemcitabine plus erlotinib (SWOG S0727). 2014

Philip, Philip A / Goldman, Bryan / Ramanathan, Ramesh K / Lenz, Heinz-Josef / Lowy, Andrew M / Whitehead, Robert P / Wakatsuki, Takeru / Iqbal, Syma / Gaur, Rakesh / Benedetti, Jacqueline K / Blanke, Charles D. ·Wayne State University, Karmanos Cancer Institute, Detroit, Michigan. ·Cancer · Pubmed #25041791.

ABSTRACT: BACKGROUND: Targeting a single pathway in pancreatic adenocarcinoma (PC) is unlikely to affect its natural history. We tested the hypothesis that simulataneous targeting of the epidermal growth factor receptor (EGFR) and insulin-like growth factor receptor-1 (IGF-1R) pathways would significantly improve progression-free survival (PFS) by abrogating reciprocal signaling that promote drug resistance METHODS: This was a phase Ib/II study testing cixutumumab, combined with erlotinib and gemcitabine (G) in patients with untreated metastatic PC. The control arm was erlotinib plus G. The primary end point was PFS. Eligibility included performance status 0/1 and normal fasting blood glucose. Polymorphisms in genes involved in G metabolism and in the EGFR pathway were also studied RESULTS: The phase I results (n = 10) established the safety of cixutumumab 6 mg/kg/week intravenously, erlotinib 100 mg/day orally, and G 1000 mg/m(2) intravenously on days 1, 8, and 15 of a 28-day cycle. In the RP2 portion (116 eligible patients; median age, 63), the median PFS and overall survival (OS) were 3.6 and 7.0 months, respectively, on the cixutumumab arm, and 3.6 and 6.7 months, respecively, on the control arm. Major grades 3 and 4 toxicities with cixutumumab and control were elevation of transaminases, 12% and 6%, respectively; fatigue, 16% and 12%, respectively; gastrointestinal, 35% and 28%, respectively; neutropenia, 21% and 10%, respectively; and thrombocytopenia, 16% and 7%, respecively. Grade 3/4 hyperglycemia was seen in 16% of patients on cixutumumab. Grade 3 or 4 skin toxicity was similar in both arms of the study (< 5%). No significant differences in PFS by genotype were seen for any of the polymorphisms. CONCLUSIONS: Adding the IGF-1R inhibitor cixutumumab to erlotinib and G did not lead to longer PFS or OS in metastatic PC.

15 Article GPR68, a proton-sensing GPCR, mediates interaction of cancer-associated fibroblasts and cancer cells. 2018

Wiley, Shu Z / Sriram, Krishna / Liang, Wenjing / Chang, Sarah E / French, Randall / McCann, Thalia / Sicklick, Jason / Nishihara, Hiroshi / Lowy, Andrew M / Insel, Paul A. ·Department of Pharmacology, University of California, San Diego, La Jolla, California, USA. · The Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan, China. · Moores Cancer Center, University of California, San Diego, La Jolla, California, USA. · Division of Surgical Oncology, Department of Surgery, University of California, San Diego, La Jolla, California, USA. · Division of Clinical Cancer Genomics, Hokkaido Cancer Center, Shiroishi-ku, Sapporo, Japan. · Department of Medicine, University of California, San Diego, La Jolla, USA. ·FASEB J · Pubmed #29092903.

ABSTRACT: The microenvironment of pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense fibrotic stroma (desmoplasia) generated by pancreatic cancer-associated fibroblasts (CAFs) derived from pancreatic stellate cells (PSCs) and pancreatic fibroblasts (PFs). Using an unbiased GPCRomic array approach, we identified 82 G-protein-coupled receptors (GPCRs) commonly expressed by CAFs derived from 5 primary PDAC tumors. Compared with PSCs and PFs, CAFs have increased expression of GPR68 (a proton-sensing GPCR), with the results confirmed by immunoblotting, The Cancer Genome Atlas data, and immunohistochemistry of PDAC tumors. Co-culture of PSCs with PDAC cells, or incubation with TNF-α, induced GPR68 expression. GPR68 activation (by decreasing the extracellular pH) enhanced IL-6 expression via a cAMP/PKA/cAMP response element binding protein signaling pathway. Knockdown of GPR68 by short interfering RNA diminished low pH-induced production of IL-6 and enhancement of PDAC cell proliferation by CAF conditioned media. CAFs from other gastrointestinal cancers also express GPR68. PDAC cells thus induce expression by CAFs of GPR68, which senses the acidic microenvironment, thereby increasing production of fibrotic markers and IL-6 and promoting PDAC cell proliferation. CAF-expressed GPR68 is a mediator of low-pH-promoted regulation of the tumor microenvironments, in particular to PDAC cell-CAF interaction and may be a novel therapeutic target for pancreatic and perhaps other types of cancers.-Wiley, S. Z., Sriram, K., Liang, W., Chang, S. E., French, R., McCann, T., Sicklick, J., Nishihara, H., Lowy, A. M., Insel, P. A. GPR68, a proton-sensing GPCR, mediates interaction of cancer-associated fibroblasts and cancer cells.

16 Article Reprogramming pancreatic stellate cells via p53 activation: A putative target for pancreatic cancer therapy. 2017

Saison-Ridinger, Maya / DelGiorno, Kathleen E / Zhang, Tejia / Kraus, Annabelle / French, Randall / Jaquish, Dawn / Tsui, Crystal / Erikson, Galina / Spike, Benjamin T / Shokhirev, Maxim N / Liddle, Christopher / Yu, Ruth T / Downes, Michael / Evans, Ronald M / Saghatelian, Alan / Lowy, Andrew M / Wahl, Geoffrey M. ·Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California, United States of America. · Clayton Foundation Peptide Biology Lab, Helmsley Center for Genomic Medicine, Salk Institute for Biological Studies, La Jolla, California, United States of America. · Department of Surgery, Division of Surgical Oncology, Moores Cancer Center, University of California, San Diego, La Jolla, California, United States of America. · Integrative Genomics and Bioinformatics Core, Salk Institute for Biological Studies, La Jolla, California, United States of America. · Huntsman Cancer Institute, Department of Oncologic Sciences, University of Utah, Salt Lake City Utah, United States of America. · Storr Liver Centre, Westmead Institute for Medical Research and Sydney Medical School, University of Sydney, Westmead Hospital, Westmead, New South Wales, Australia. ·PLoS One · Pubmed #29211796.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is characterized by an extremely dense fibrotic stroma, which contributes to tumor growth, metastasis, and drug resistance. During tumorigenesis, quiescent pancreatic stellate cells (PSCs) are activated and become major contributors to fibrosis, by increasing growth factor signaling and extracellular matrix deposition. The p53 tumor suppressor is known to restrict tumor initiation and progression through cell autonomous mechanisms including apoptosis, cell cycle arrest, and senescence. There is growing evidence that stromal p53 also exerts anti-tumor activity by paracrine mechanisms, though a role for stromal p53 in PDAC has not yet been described. Here, we demonstrate that activation of stromal p53 exerts anti-tumor effects in PDAC. We show that primary cancer-associated PSCs (caPSCs) isolated from human PDAC express wild-type p53, which can be activated by the Mdm2 antagonist Nutlin-3a. Our work reveals that p53 acts as a major regulator of PSC activation and as a modulator of PDAC fibrosis. In vitro, p53 activation by Nutlin-3a induces profound transcriptional changes, which reprogram activated PSCs to quiescence. Using immunofluorescence and lipidomics, we have also found that p53 activation induces lipid droplet accumulation in both normal and tumor-associated fibroblasts, revealing a previously undescribed role for p53 in lipid storage. In vivo, treatment of tumor-bearing mice with the clinical form of Nutlin-3a induces stromal p53 activation, reverses caPSCs activation, and decreases fibrosis. All together our work uncovers new functions for stromal p53 in PDAC.

17 Article TGFβ engages MEK/ERK to differentially regulate benign and malignant pancreas cell function. 2017

Principe, D R / Diaz, A M / Torres, C / Mangan, R J / DeCant, B / McKinney, R / Tsao, M-S / Lowy, A / Munshi, H G / Jung, B / Grippo, P J. ·University of Illinois College of Medicine, Chicago, IL, USA. · Department of Medicine, University of Illinois, Chicago, IL, USA. · Ontario Cancer Institute/Princess Margaret Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada. · Department of Surgery, University of California San Diego, San Diego, CA, USA. · Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. ·Oncogene · Pubmed #28368414.

ABSTRACT: While TGFβ signals are anti-proliferative in benign and well-differentiated pancreatic cells, TGFβ appears to promote the progression of advanced cancers. To better understand dysregulation of the TGFβ pathway, we first generated mouse models of neoplastic disease with TGFβ receptor deficiencies. These models displayed reduced levels of pERK irrespective of KRAS mutation. Furthermore, exogenous TGFβ led to rapid and sustained TGFBR1-dependent ERK phosphorylation in benign pancreatic duct cells. Similar to results that our group has published in colon cancer cells, inhibition of ERK phosphorylation in duct cells mitigated TGFβ-induced upregulation of growth suppressive pSMAD2 and p21, prevented downregulation of the pro-growth signal CDK2 and ablated TGFβ-induced EMT. These observations suggest that ERK is a key factor in growth suppressive TGFβ signals, yet may also contribute to detrimental TGFβ signaling such as EMT. In neoplastic PanIN cells, pERK was not necessary for either TGFβ-induced pSMAD2 phosphorylation or CDK2 repression, but was required for upregulation of p21 and EMT indicating a partial divergence between TGFβ and MEK/ERK in early carcinogenesis. In cancer cells, pERK had no effect on TGFβ-induced upregulation of pSMAD2 and p21, suggesting the two pathways have completely diverged with respect to the cell cycle. Furthermore, inhibition of pERK both reduced levels of CDK2 and prevented EMT independent of exogenous TGFβ, consistent with most observations identifying pERK as a tumor promoter. Combined, these data suggest that during carcinogenesis pERK initially facilitates and later antagonizes TGFβ-mediated cell cycle arrest, yet remains critical for the pathological, EMT-inducing arm of TGFβ signaling.

18 Article Characterization of RON protein isoforms in pancreatic cancer: implications for biology and therapeutics. 2016

Chakedis, Jeffery / French, Randall / Babicky, Michele / Jaquish, Dawn / Mose, Evangeline / Cheng, Peter / Holman, Patrick / Howard, Haleigh / Miyamoto, Jaclyn / Porras, Paula / Walterscheid, Zakk / Schultz-Fademrecht, Carsten / Esdar, Christina / Schadt, Oliver / Eickhoff, Jan / Lowy, Andrew M. ·Department of Surgery, Division of Surgical Oncology, Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA. · Lead Discovery Center GmbH, Dortmund, Germany. · Merck KGaA, Darmstadt, Germany. ·Oncotarget · Pubmed #27323855.

ABSTRACT: The RON tyrosine kinase receptor is under investigation as a novel target in pancreatic cancer. While RON mutations are uncommon, RON isoforms are produced in cancer cells via a variety of mechanisms. In this study we sought to: 1) characterize RON isoform expression in pancreatic cancer, 2) investigate mechanisms that regulate isoform expression, and 3) determine how various isoforms effect gene expression, oncogenic phenotypes and responses to RON directed therapies. We quantified RON transcripts in human pancreatic cancer and found expression levels 2500 fold that of normal pancreas with RON isoform expression comprising nearly 50% of total transcript. RNA seq studies revealed that the short form (sfRON) and P5P6 isoforms which have ligand independent activity, induce markedly different patterns of gene expression than wild type RON. We found that transcription of RON isoforms is regulated by promoter hypermethylation as the DNA demethylating agent 5-aza-2'-deoxycytidine decreased all RON transcripts in a subset of pancreatic cancer cell lines. The viability of sfRON-expressing HPDE cells was reduced by a RON specific small molecule inhibitor, while a therapeutic monoclonal antibody had no demonstrable effects. In summary, RON isoforms may comprise half of total RON transcript in human pancreatic cancer and their expression is regulated at least in part by promoter hypermethylation. RON isoforms activate distinct patterns of gene expression, have transforming activity and differential responses to RON directed therapies. These findings further our understanding of RON biology in pancreatic cancer and have implications for therapeutic strategies to target RON activity.

19 Article Image-based detection and targeting of therapy resistance in pancreatic adenocarcinoma. 2016

Fox, Raymond G / Lytle, Nikki K / Jaquish, Dawn V / Park, Frederick D / Ito, Takahiro / Bajaj, Jeevisha / Koechlein, Claire S / Zimdahl, Bryan / Yano, Masato / Kopp, Janel / Kritzik, Marcie / Sicklick, Jason / Sander, Maike / Grandgenett, Paul M / Hollingsworth, Michael A / Shibata, Shinsuke / Pizzo, Donald / Valasek, Mark / Sasik, Roman / Scadeng, Miriam / Okano, Hideyuki / Kim, Youngsoo / MacLeod, A Robert / Lowy, Andrew M / Reya, Tannishtha. ·Departments of Pharmacology and Medicine, University of California San Diego School of Medicine La Jolla, CA. · Sanford Consortium for Regenerative Medicine, La Jolla, CA. · Moores Cancer Center, University of California San Diego School of Medicine, La Jolla, CA. · Department of Surgery, Division of Surgical Oncology, University of California San Diego School of Medicine, La Jolla, CA. · Department of Medicine, Division of Gastroenterology, University of California San Diego School of Medicine, La Jolla, CA. · Department of Physiology, Graduate School of Medicine, Keio University, Keio, Japan. · Department of Cellular and Molecular Medicine, University of California San Diego School of Medicine, La Jolla, CA. · Eppley Institute For Research in Cancer and Allied Diseases, Department of Pathology, University of Nebraska Medical Center, Omaha, NE. · Department of Pathology, University of California San Diego School of Medicine, La Jolla, CA. · Center for Computational Biology and Bioinformatics, University of California San Diego School of Medicine, La Jolla, CA. · Department of Radiology, University of California San Diego School of Medicine, La Jolla, CA. · Department of Oncology Drug Discovery, Ionis pharmaceuticals, Carlsbad, CA. ·Nature · Pubmed #27281208.

ABSTRACT: Pancreatic intraepithelial neoplasia is a pre-malignant lesion that can progress to pancreatic ductal adenocarcinoma, a highly lethal malignancy marked by its late stage at clinical presentation and profound drug resistance. The genomic alterations that commonly occur in pancreatic cancer include activation of KRAS2 and inactivation of p53 and SMAD4 (refs 2-4). So far, however, it has been challenging to target these pathways therapeutically; thus the search for other key mediators of pancreatic cancer growth remains an important endeavour. Here we show that the stem cell determinant Musashi (Msi) is a critical element of pancreatic cancer progression both in genetic models and in patient-derived xenografts. Specifically, we developed Msi reporter mice that allowed image-based tracking of stem cell signals within cancers, revealing that Msi expression rises as pancreatic intraepithelial neoplasia progresses to adenocarcinoma, and that Msi-expressing cells are key drivers of pancreatic cancer: they preferentially harbour the capacity to propagate adenocarcinoma, are enriched in circulating tumour cells, and are markedly drug resistant. This population could be effectively targeted by deletion of either Msi1 or Msi2, which led to a striking defect in the progression of pancreatic intraepithelial neoplasia to adenocarcinoma and an improvement in overall survival. Msi inhibition also blocked the growth of primary patient-derived tumours, suggesting that this signal is required for human disease. To define the translational potential of this work we developed antisense oligonucleotides against Msi; these showed reliable tumour penetration, uptake and target inhibition, and effectively blocked pancreatic cancer growth. Collectively, these studies highlight Msi reporters as a unique tool to identify therapy resistance, and define Msi signalling as a central regulator of pancreatic cancer.

20 Article Macrophage PI3Kγ Drives Pancreatic Ductal Adenocarcinoma Progression. 2016

Kaneda, Megan M / Cappello, Paola / Nguyen, Abraham V / Ralainirina, Natacha / Hardamon, Chanae R / Foubert, Philippe / Schmid, Michael C / Sun, Ping / Mose, Evangeline / Bouvet, Michael / Lowy, Andrew M / Valasek, Mark A / Sasik, Roman / Novelli, Francesco / Hirsch, Emilio / Varner, Judith A. ·Moores Cancer Center, University of California, San Diego, La Jolla, California. · Center for Experimental Research and Medical Studies (CeRMS), Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Turin, Italy. Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy. · Moores Cancer Center, University of California, San Diego, La Jolla, California. Department of Pathology, Mudanjiang Medical University, Mudanjiang, China. · Moores Cancer Center, University of California, San Diego, La Jolla, California. Department of Surgery, University of California, San Diego, La Jolla, California. · Moores Cancer Center, University of California, San Diego, La Jolla, California. Department of Pathology, University of California, San Diego, La Jolla, California. · Center for Computational Biology and Bioinformatics, University of California, San Diego, La Jolla, California. · Center for Experimental Research and Medical Studies (CeRMS), Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Turin, Italy. Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy. jvarner@ucsd.edu franco.novelli@unito.it emilio.hirsch@unito.it. · Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy. Molecular Biotechnology Center, Torino, Italy. jvarner@ucsd.edu franco.novelli@unito.it emilio.hirsch@unito.it. · Moores Cancer Center, University of California, San Diego, La Jolla, California. Department of Pathology, University of California, San Diego, La Jolla, California. jvarner@ucsd.edu franco.novelli@unito.it emilio.hirsch@unito.it. ·Cancer Discov · Pubmed #27179037.

ABSTRACT: SIGNIFICANCE: We report here that PI3Kγ regulates macrophage transcriptional programming, leading to T-cell suppression, desmoplasia, and metastasis in pancreas adenocarcinoma. Genetic or pharmacologic inhibition of PI3Kγ restores antitumor immune responses and improves responsiveness to standard-of-care chemotherapy. PI3Kγ represents a new therapeutic immune target for pancreas cancer. Cancer Discov; 6(8); 870-85. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 803.

21 Article PEDF inhibits pancreatic tumorigenesis by attenuating the fibro-inflammatory reaction. 2016

Principe, Daniel R / DeCant, Brian / Diaz, Andrew M / Mangan, Riley J / Hwang, Rosa / Lowy, Andrew / Shetuni, Brandon B / Sreekumar, Bharath K / Chung, Chuhan / Bentrem, David J / Munshi, Hidayatullah G / Jung, Barbara / Grippo, Paul J / Bishehsari, Faraz. ·University of Illinois College of Medicine, Champaign, IL, USA. · Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA. · Department of Surgical Oncology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Surgery, University of California San Diego, San Diego, CA, USA. · Northwestern Medicine, Central DuPage Hospital, Winfield, IL, USA. · Department of Medicine, Yale University School of Medicine, New Haven, CT, USA. · Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. · Department of Medicine, Rush University Medical Center, Chicago, IL, USA. ·Oncotarget · Pubmed #27058416.

ABSTRACT: Pancreatic cancer is characterized by a pronounced fibro-inflammatory reaction that has been shown to contribute to cancer progression. Previous reports have demonstrated that pigment epithelium-derived factor (PEDF) has potent tumor suppressive effects in pancreatic cancer, though little is known about the mechanisms by which PEDF limits pancreatic tumorigenesis. We therefore employed human specimens, as well as mouse and in vitro models, to explore the effects of PEDF upon the pancreatic microenvironment. We found that PEDF expression is decreased in human pancreatic cancer samples compared to non-malignant tissue. Furthermore, PEDF-deficient patients displayed increased intratumoral inflammation/fibrosis. In mice, genetic ablation of PEDF increased cerulein-induced inflammation and fibrosis, and similarly enhanced these events in the background of oncogenic KRAS. In vitro, recombinant PEDF neutralized macrophage migration as well as inhibited macrophage-induced proliferation of tumor cells. Additionally, recombinant PEDF suppressed the synthesis of pro-inflammatory/pro-fibrotic cytokines both in vivo and in vitro, and reduced collagen I deposition and TGFβ synthesis by pancreatic stellate cells, consistent with reduced fibrosis. Combined, our results demonstrate that PEDF limits pancreatic cancer progression by attenuating the fibro-inflammatory reaction, and makes restoration of PEDF signaling a potential therapeutic approach to study in pancreatic cancer.

22 Article FRAX597, a PAK1 inhibitor, synergistically reduces pancreatic cancer growth when combined with gemcitabine. 2016

Yeo, Dannel / He, Hong / Patel, Oneel / Lowy, Andrew M / Baldwin, Graham S / Nikfarjam, Mehrdad. ·Department of Surgery, Austin Health, University of Melbourne, Heidelberg, VIC, Australia. yeod@student.unimelb.edu.au. · Department of Surgery, Austin Health, University of Melbourne, Heidelberg, VIC, Australia. hong.he@unimelb.edu.au. · Department of Surgery, Austin Health, University of Melbourne, Heidelberg, VIC, Australia. patelo@unimelb.edu.au. · Department of Surgery, Division of Surgical Oncology, University of California at San Diego, Moores Cancer, La Jolla, CA, USA. alowy@ucsd.edu.au. · Department of Surgery, Austin Health, University of Melbourne, Heidelberg, VIC, Australia. grahamsb@unimelb.edu.au. · Department of Surgery, Austin Health, University of Melbourne, Heidelberg, VIC, Australia. mehrdad.nikfarjam@gmail.com. ·BMC Cancer · Pubmed #26774265.

ABSTRACT: BACKGROUND: Pancreatic ductal adenocarcinoma remains one of the most lethal of all solid tumours. Treatment options are limited and gemcitabine-based chemotherapy remains the standard of care. Although growing evidence shows that p21-activated kinase 1 (PAK1) plays a crucial role in pancreatic cancer, its role has not been fully elucidated. This study aimed to characterise the expression and functional relevance of PAK1 in pancreatic cancer. METHODS: PAK1 expression was measured in pancreatic cancer specimens by immunohistochemistry and in pancreatic cancer cell lines by western blotting. The effect of inhibition of PAK1 by either shRNA knock-down (KD), or by a selective inhibitor, FRAX597, alone or in combination with gemcitabine, on cell proliferation and migration/invasion was measured by thymidine uptake and Boyden chamber assays, respectively. The effect on tumour growth and survival was assessed in orthotopic murine models. RESULTS: PAK1 was expressed in all human pancreatic cancer samples tested, an7d was upregulated in all pancreatic cancer cell lines tested. PAK1 KD inhibited pancreatic cancer cell growth and survival, and increased sensitivity to gemcitabine treatment. AKT activity and HIF1α expression were also inhibited. FRAX597 inhibited pancreatic cancer cell proliferation, survival, and migration/invasion. When combined with gemcitabine, FRAX597 synergistically inhibited pancreatic cancer proliferation in vitro and inhibited tumour growth in vivo. CONCLUSIONS: These results implicate PAK1 as a regulator of pancreatic cancer cell growth and survival. Combination of a PAK1 inhibitor such as FRAX597 with cytotoxic chemotherapy deserves further study as a novel therapeutic approach to pancreatic cancer treatment.

23 Article A novel protein isoform of the RON tyrosine kinase receptor transforms human pancreatic duct epithelial cells. 2016

Chakedis, J / French, R / Babicky, M / Jaquish, D / Howard, H / Mose, E / Lam, R / Holman, P / Miyamoto, J / Walterscheid, Z / Lowy, A M. ·Department of Surgery, Division of Surgical Oncology, Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA. ·Oncogene · Pubmed #26477314.

ABSTRACT: The MST1R gene is overexpressed in pancreatic cancer producing elevated levels of the RON tyrosine kinase receptor protein. While mutations in MST1R are rare, alternative splice variants have been previously reported in epithelial cancers. We report the discovery of a novel RON isoform discovered in human pancreatic cancer. Partial splicing of exons 5 and 6 (P5P6) produces a RON isoform that lacks the first extracellular immunoglobulin-plexin-transcription domain. The splice variant is detected in 73% of xenografts derived from pancreatic adenocarcinoma patients and 71% of pancreatic cancer cell lines. Peptides specific to RON P5P6 detected in human pancreatic cancer specimens by mass spectrometry confirm translation of the protein isoform. The P5P6 isoform is found to be constitutively phosphorylated, present in the cytoplasm, and it traffics to the plasma membrane. Expression of P5P6 in immortalized human pancreatic duct epithelial (HPDE) cells activates downstream AKT, and in human pancreatic epithelial nestin-expressing cells, activates both the AKT and MAPK pathways. Inhibiting RON P5P6 in HPDE cells using a small molecule inhibitor BMS-777607 blocked constitutive activation and decreased AKT signaling. P5P6 transforms NIH3T3 cells and induces tumorigenicity in HPDE cells. Resultant HPDE-P5P6 tumors develop a dense stromal compartment similar to that seen in pancreatic cancer. In summary, we have identified a novel and constitutively active isoform of the RON tyrosine kinase receptor that has transforming activity and is expressed in human pancreatic cancer. These findings provide additional insight into the biology of the RON receptor in pancreatic cancer and are clinically relevant to the study of RON as a potential therapeutic target.

24 Article Tumor radiosensitization by monomethyl auristatin E: mechanism of action and targeted delivery. 2015

Buckel, Lisa / Savariar, Elamprakash N / Crisp, Jessica L / Jones, Karra A / Hicks, Angel M / Scanderbeg, Daniel J / Nguyen, Quyen T / Sicklick, Jason K / Lowy, Andrew M / Tsien, Roger Y / Advani, Sunil J. ·Department of Radiation Medicine and Applied Sciences. · Department of Pharmacology. · Department of Pathology Department of Surgery. · Division of Head and Neck Surgery. · Division of Surgical Oncology. · Howard Hughes Medical Institute. · Center for Advanced Radiotherapy Technologies University of California San Diego. ·Cancer Res · Pubmed #25681274.

ABSTRACT: Intrinsic tumor resistance to radiotherapy limits the efficacy of ionizing radiation (IR). Sensitizing cancer cells specifically to IR would improve tumor control and decrease normal tissue toxicity. The development of tumor-targeting technologies allows for developing potent radiosensitizing drugs. We hypothesized that the anti-tubulin agent monomethyl auristatin E (MMAE), a component of a clinically approved antibody-directed conjugate, could function as a potent radiosensitizer and be selectively delivered to tumors using an activatable cell-penetrating peptide targeting matrix metalloproteinases and RGD-binding integrins (ACPP-cRGD-MMAE). We evaluated the ability of MMAE to radiosensitize both established cancer cells and a low-passage cultured human pancreatic tumor cell line using clonogenic and DNA damage assays. MMAE sensitized colorectal and pancreatic cancer cells to IR in a schedule- and dose-dependent manner, correlating with mitotic arrest. Radiosensitization was evidenced by decreased clonogenic survival and increased DNA double-strand breaks in irradiated cells treated with MMAE. MMAE in combination with IR resulted in increased DNA damage signaling and activation of CHK1. To test a therapeutic strategy of MMAE and IR, PANC-1 or HCT-116 murine tumor xenografts were treated with nontargeted free MMAE or tumor-targeted MMAE (ACPP-cRGD-MMAE). While free MMAE in combination with IR resulted in tumor growth delay, tumor-targeted ACPP-cRGD-MMAE with IR produced a more robust and significantly prolonged tumor regression in xenograft models. Our studies identify MMAE as a potent radiosensitizer. Importantly, MMAE radiosensitization can be localized to tumors by targeted activatable cell-penetrating peptides.

25 Article Single-incision laparoscopic surgery through an ostomy site: a natural approach by an unnatural orifice. 2015

Lopez, Nicole E / Peterson, Carrie Y / Ramamoorthy, Sonia L / McLemore, Elisabeth C / Sedrak, Michael F / Lowy, Andrew M / Horgan, Santiago / Talamini, Mark A / Sicklick, Jason K. ·*Division of General Surgery, Department of Surgery ‡Division of Surgical Oncology, Moores UCSD Cancer Center §Division of Minimally Invasive Surgery †Division of Colorectal Surgery, University of California, San Diego, UC San Diego Health System, La Jolla, CA. ·Surg Laparosc Endosc Percutan Tech · Pubmed #24743670.

ABSTRACT: Single-incision laparoscopic surgery (SILS) is gaining popularity for a wide variety of surgical operations and capitalizes on the benefits of traditional laparoscopic surgery without incurring multiple incision sites. Traditionally, SILS is performed by a midline periumbilical approach. However, such a minimally invasive approach may be utilized in patients who already have an abdominal incision. Our series retrospectively reviews 7 cases in which we utilized the fascial defect at the time of after ostomy reversal as our SILS incision site. In turn, we performed a variety of concurrent intra-abdominal procedures with excellent technical success and outcomes. Our study is the largest single-institution case series of this novel approach and suggests that utilizing an existing ostomy-site abdominal incision is a safe and effective location for SILS port placement and should be considered in patients undergoing concurrent procedures.

Next