Development and application of two novel monoclonal antibodies against overexpressed CD26 and integrin α3 in human pancreatic cancer.

Monoclonal antibody (mAb) technology is an excellent tool for the discovery of overexpressed cell surface tumour antigens and the development of targeting agents. Here, we report the development of two novel mAbs against CFPAC-1 human pancreatic cancer cells. Using ELISA, flow cytometry, immunoprecipitation, mass spectrometry, Western blot and immunohistochemistry, we found that the target antigens recognised by the two novel mAbs KU44.22B and KU44.13A, are integrin α3 and CD26 respectively, with high levels of expression in human pancreatic and other cancer cell lines and human pancreatic cancer tissue microarrays. Treatment with naked anti-CD26 mAb KU44.13A did not have any effect on the growth and migration of cancer cells nor did it induce receptor downregulation. In contrast, treatment with anti-integrin α3 mAb KU44.22B inhibited growth in vitro of Capan-2 cells, increased migration of BxPC-3 and CFPAC-1 cells and induced antibody internalisation. Both novel mAbs are capable of detecting their target antigens by immunohistochemistry but not by Western blot. These antibodies are excellent tools for studying the role of integrin α3 and CD26 in the complex biology of pancreatic cancer, their prognostic and predictive values and the therapeutic potential of their humanised and/or conjugated versions in patients whose tumours overexpress integrin α3 or CD26

Targeting ROCK activity to disrupt and prime pancreatic cancer for chemotherapy

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease; the identification of novel targets and development of effective treatment strategies are urgently needed to improve patient outcomes. Remodeling of the pancreatic stroma occurs during PDAC development, which drives disease progression and impairs responses to therapy. The actomyosin regulatory ROCK1 and ROCK2 kinases govern cell motility and contractility, and have been suggested to be potential targets for cancer therapy, particularly to reduce the metastatic spread of tumor cells. However, ROCK inhibitors are not currently used for cancer patient treatment, largely due to the overwhelming challenge faced in the development of anti-metastatic drugs, and a lack of clarity as to the cancer types most likely to benefit from ROCK inhibitor therapy. In 2 recent publications, we discovered that ROCK1 and ROCK2 expression were increased in PDAC, and that increased ROCK activity was associated with reduced survival and PDAC progression by enabling extracellular matrix (ECM) remodeling and invasive growth of pancreatic cancer cells. We also used intravital imaging to optimize ROCK inhibition using the pharmacological ROCK inhibitor fasudil (HA-1077), and demonstrated that short-term ROCK targeting, or ‘priming’, improved chemotherapy efficacy, disrupted cancer cell collective movement, and impaired metastasis. This body of work strongly indicates that the use of ROCK inhibitors in pancreatic cancer therapy as ‘priming’ agents warrants further consideration, and provides insights as to how transient mechanical manipulation, or fine-tuning the ECM, rather than chronic stromal ablation might be beneficial for improving chemotherapeutic efficacy in the treatment of this deadly disease

A current perspective on stereotactic body radiation therapy for pancreatic cancer.

Pancreatic cancer is a formidable malignancy with poor outcomes. The majority of patients are unable to undergo resection, which remains the only potentially curative treatment option. The management of locally advanced (unresectable) pancreatic cancer is controversial; however, treatment with either chemotherapy or chemoradiation is associated with high rates of local tumor progression and metastases development, resulting in low survival rates. An emerging local modality is stereotactic body radiation therapy (SBRT), which uses image-guided, conformal, high-dose radiation. SBRT has demonstrated promising local control rates and resultant quality of life with acceptable rates of toxicity. Over the past decade, increasing clinical experience and data have supported SBRT as a local treatment modality. Nevertheless, additional research is required to further evaluate the role of SBRT and improve upon the persistently poor outcomes associated with pancreatic cancer. This review discusses the existing clinical experience and technical implementation of SBRT for pancreatic cancer and highlights the directions for ongoing and future studies

TEAD and YAP regulate the enhancer network of human embryonic pancreatic progenitors.

The genomic regulatory programmes that underlie human organogenesis are poorly understood. Pancreas development, in particular, has pivotal implications for pancreatic regeneration, cancer and diabetes. We have now characterized the regulatory landscape of embryonic multipotent progenitor cells that give rise to all pancreatic epithelial lineages. Using human embryonic pancreas and embryonic-stem-cell-derived progenitors we identify stage-specific transcripts and associated enhancers, many of which are co-occupied by transcription factors that are essential for pancreas development. We further show that TEAD1, a Hippo signalling effector, is an integral component of the transcription factor combinatorial code of pancreatic progenitor enhancers. TEAD and its coactivator YAP activate key pancreatic signalling mediators and transcription factors, and regulate the expansion of pancreatic progenitors. This work therefore uncovers a central role for TEAD and YAP as signal-responsive regulators of multipotent pancreatic progenitors, and provides a resource for the study of embryonic development of the human pancreas

Prkci Regulates Autophagy and Pancreatic Tumorigenesis in Mice

Protein kinase C iota (PKCι) functions as a bonafide human oncogene in lung and ovarian cancer and is required for Kras(G12D)-mediated lung cancer initiation and progression. PKCι expression is required for pancreatic cancer cell growth and maintenance of the transformed phenotype; however, nothing is known about the role of PKCι in pancreas development or pancreatic tumorigenesis. In this study, we investigated the effect of pancreas-specific ablation of PKCι expression on pancreatic cellular homeostasis, susceptibility to pancreatitis, and Kras(G12D)-mediated pancreatic cancer development. Knockout of pancreatic Prkci significantly increased pancreatic immune cell infiltration, acinar cell DNA damage, and apoptosis, but reduced sensitivity to caerulein-induced pancreatitis. Prkci-ablated pancreatic acinar cells exhibited P62 aggregation and a loss of autophagic vesicles. Loss of pancreatic Prkci promoted Kras(G12D)-mediated pancreatic intraepithelial neoplasia formation but blocked progression to adenocarcinoma, consistent with disruption of autophagy. Our results reveal a novel promotive role for PKCι in pancreatic epithelial cell autophagy and pancreatic cancer progression

High Volume, Top Quality, and Rigorous Research: Jefferson Sets New Standards in Pancreatic Cancer Care

Each year, Jefferson surgeons perform over 200 pancreatic resections, including more than 130 “Whipple procedures” — making the hospital #1 in surgical volume for pancreatic cancer and related diseases in the tristate region of Pennsylvania, New Jersey and Delaware. “While we are very proud of what we have achieved, there are always opportunities for improvement,” says Charles J. Yeo, MD, FACS, Samuel D. Gross Professor and Chair of Surgery, who has personally performed more than 1,400 Whipple procedures and treated thousands of patients with pancreatic cancer and related diseases. Beyond the impressive numbers, the Jefferson Pancreas, Biliary and Related Cancer Center offers much more: multidisciplinary diagnosis and treatment, groundbreaking clinical research, and active involvement in community events — such as Amy’s Ride/Run/Walk in Quakertown (May 20) and Pancreatic Cancer Action Network’s PurpleStride (November 4). New Multidisciplinary Pancreatic Cancer Clinic When pancreatic cancer is suspected, many patients and their families feel overwhelmed. In addition to the emotional impact, patients may have to schedule several appointments to see primary doctors and gastroenterologists, as well as surgeons, medical oncologists and radiation oncologists. At our Multidisciplinary Pancreatic Cancer Clinic, all relevant clinicians gather each Monday afternoon to review cases and see patients — providing the convenience of multiple appointments during a single visit. Development of a National Cancer Institute Funded Research Program Since his recruitment in 2006, Jonathan Brody, PhD, Vice Chair for Research in the Department of Surgery, has been building a worldclass pancreatic cancer research program. Dr. Brody specializes in studying the molecular basis of cancer development and progression, targeted therapy and personalized medicine. As a translational researcher, he steers the research trajectory of the Brody Laboratory while serving as an advisor/collaborator to all levels of trainees as well as our practicing surgeons, including Drs. Harish Lavu and Jordan Winter. Ongoing Clinical Trials Harish Lavu, MD, FACS, is leading the Whipple Accelerated Recovery Pathway (WARP) trial aimed at supporting faster recovery from pancreatic surgery. In 2007, the team conducted a similar study that established the seven-day “Critical Pathway” standard at Jefferson. The WARP trial — initiated in late 2015 and with nearly 70 patients enrolled to date — is testing a five-day pathway. The protocol incorporates in-hospital physical therapy, specific dietary recommendations and rigorous monitoring following discharge. Meanwhile, Jordan M. Winter, MD, FACS, is tackling a perennial patient query: “Can pancreatic surgery make the cancer ‘spread’?” To explore this topic, Dr. Winter is leading the Water or Saline at High Volumes (WASH) trial that is testing the use of 10 liters of plain water or salt water for abdominal washing immediately following removal of the tumor. Current practice uses just one or two liters of saline at the conclusion of the procedure. The study, started in April 2016 with more than 100 patients enrolled to date, aims to expand to other sites and enroll 800 patients. For more information, go to Jefferson.edu/Pancreas. “In Asia, average hospital stay for pancreatic surgery patients is 21 days. In Europe, it’s 14 days. In most U.S. hospitals, it’s 12 to 14 days. Here at Jefferson, our current seven-day stay requires tremendous coordination across the Surgery, ICU and Nursing teams. With the WARP trial, we are trying to do something few others have consistently been able to do: improve outcomes by safely discharging Whipple procedure patients after just 5 days. “Why are shorter hospital stays better? Research has shown that being in a hospital when you aren’t critically ill actually delays healing and exposes patients to hospital-acquired infections. We want to prepare our patients to leave the hospital as quickly as possible so they can recover safely and more rapidly in the comfort of their own homes.” Harish Lavu, MD, FACS Associate Professor and Chief, Section of Hepatopancreatobiliary Surgery “Lymphatics, nerves, small blood vessels and tumor margins frequently have cancer in them, which can only be appreciated at the microscopic level. As we’re dividing these structures, can some of these cells be spilled? It isn’t inconceivable. The hypothesis of the WASH study is that this high-volume washing may remove those kinds of free-floating cancer cells present after the tumor is resected – ultimately helping to prolong survival. “Very few surgical cancer studies have looked specifically at pancreatic cancer outcomes. This trial points to the potential for surgical oncologists to affect cancer outcomes with an inexpensive intervention: high-volume abdominal washing. If we can use it to improve survival even by a few months, we’re accomplishing the same thing as a billion-dollar drug.”-Jordan Winter, MD, FACS Associate Professor For more information, go to Jefferson.edu/Pancreas

Prkci Regulates Autophagy and Pancreatic Tumorigenesis in Mice

Protein kinase C iota (PKCι) functions as a bonafide human oncogene in lung and ovarian cancer and is required for Kras(G12D)-mediated lung cancer initiation and progression. PKCι expression is required for pancreatic cancer cell growth and maintenance of the transformed phenotype; however, nothing is known about the role of PKCι in pancreas development or pancreatic tumorigenesis. In this study, we investigated the effect of pancreas-specific ablation of PKCι expression on pancreatic cellular homeostasis, susceptibility to pancreatitis, and Kras(G12D)-mediated pancreatic cancer development. Knockout of pancreatic Prkci significantly increased pancreatic immune cell infiltration, acinar cell DNA damage, and apoptosis, but reduced sensitivity to caerulein-induced pancreatitis. Prkci-ablated pancreatic acinar cells exhibited P62 aggregation and a loss of autophagic vesicles. Loss of pancreatic Prkci promoted Kras(G12D)-mediated pancreatic intraepithelial neoplasia formation but blocked progression to adenocarcinoma, consistent with disruption of autophagy. Our results reveal a novel promotive role for PKCι in pancreatic epithelial cell autophagy and pancreatic cancer progression

Small molecule tyrosine kinase inhibitors in pancreatic cancer

Pancreatic cancer has proven to be chemo-resistant, with gemcitabine being the only cytotoxic agent approved for advanced pancreatic cancer since 1996. Tyrosine kinase inhibitors represent a newer generation of chemotherapeutic agents targeting specific tumor pathways associated with carcinogenesis including cell cycle control, signal transduction, apoptosis and angiogenesis. These agents present a more selective way of treating pancreatic cancer. Erlotinib is the prototype of the tyrosine kinase inhibitors with proven efficacy in advanced pancreatic cancer and has been recently approved in that setting. Multiple other tyrosine kinase inhibitors targeting the VEGFR, PDGFR, and Src kinases are in various phases of clinical trials testing. The preliminary results of these trials have been disappointing. Current challenges in pancreatic cancer clinical trials testing include improving patient selection, identifying effective combinations, improving the predictive value of current preclinical models and better study designs. This review summarizes the present clinical development of tyrosine kinase inhibitors in pancreatic cancer and strategies for future drug development