Pancreatic Cancer Center: Providing the Research Tools Necessary to Advance Pancreatic Cancer Patient Care

poster abstractThere were approximately 43,000 new cases of pancreatic ductal adenocarcinoma (PDAC) in the U.S. in 2010, and approximately 37,000 deaths. PDAC thus constitutes the fourth leading cause of cancer deaths, and PDAC patients have a dismal 5-year survival rate of 6%; approximately 75% of patients die within the first year after diagnosis. PDAC is notoriously resistant to chemotherapy and radiation and even with our best treatment options, a complete margin-negative surgical resection, few patients achieve long-term survival. Despite these statistics, surprisingly only a small number of NCI-designated cancer centers have a specialized pancreatic cancer program. The creation of the IUPUI Signature Center for Pancreatic Cancer Research has been the foundation for putting IUPUI, the IU School of Medicine, Purdue University and the IU Simon Cancer Center at the forefront of pancreatic cancer treatment and research across the nation. The Signature Center, comprised of basic, translational and clinical researchers, represents the continuum of the disease from biological / molecular investigation to clinical trials. Funding from the Signature Center Initiative is being utilized to develop genetically engineered mouse models, generate orthotopic pancreatic cancer mouse models as well as provide funding for peer reviewed pilot projects. Establishment and characterization of these in vivo models provides the groundwork to be used by all members in their translational research projects; support of pilot projects provides preliminary data and identification of projects to be used in a SPORE application. Additionally, work has begun on a web portal to promote and educate both patients and clinicians about the IUSCC Pancreas Cancer Clinic which became operational in 2010. Taken together these activities provide the infrastructure to support pancreas cancer research at IU across the continuum of bench to bedside to practice. The availability of these resources to all members promotes inter-disciplinary collaborations aimed at increasing our understanding of pancreatic cancer so that advancements can be made in diagnosis, prevention and treatment of this malignancy

DNA Repair Proteins as Molecular Targets for Cancer Therapeutics

Cancer therapeutics include an ever-increasing array of tools at the disposal of clinicians in their treatment of this disease. However, cancer is a tough opponent in this battle and current treatments which typically include radiotherapy, chemotherapy and surgery are not often enough to rid the patient of his or her cancer. Cancer cells can become resistant to the treatments directed at them and overcoming this drug resistance is an important research focus. Additionally, increasing discussion and research is centering on targeted and individualized therapy. While a number of approaches have undergone intensive and close scrutiny as potential approaches to treat and kill cancer (signaling pathways, multidrug resistance, cell cycle checkpoints, anti-angiogenesis, etc.), much less work has focused on blocking the ability of a cancer cell to recognize and repair the damaged DNA which primarily results from the front line cancer treatments; chemotherapy and radiation. More recent studies on a number of DNA repair targets have produced proof-of-concept results showing that selective targeting of these DNA repair enzymes has the potential to enhance and augment the currently used chemotherapeutic agents and radiation as well as overcoming drug resistance. Some of the targets identified result in the development of effective single-agent anti-tumor molecules. While it is inherently convoluted to think that inhibiting DNA repair processes would be a likely approach to kill cancer cells, careful identification of specific DNA repair proteins is increasingly appearing to be a viable approach in the cancer therapeutic cache

Pancreatic Cancer Signature Center: Providing the Research Tools Necessary to Advance Pancreatic Cancer Patient Care

There were approximately 45,000 new cases of pancreatic ductal adenocarcinoma (PDAC) in the U.S. in 2013, and approximately 38,500 deaths. PDAC thus constitutes the fourth leading cause of cancer deaths in adults, and PDAC patients have a dismal 5-year survival rate of 6%. Moreover, approximately 75% of patients die within the first year after diagnosis. PDAC is notoriously resistant to chemotherapy and radiation and even with our best treatment options, a complete margin-negative surgical resection, few patients achieve long-term survival. Despite these statistics, surprisingly only a small number of NCI-designated cancer centers have a specialized pancreatic cancer program. The creation of the IUPUI Signature Center for Pancreatic Cancer Research has been the foundation for putting IUPUI, the IU School of Medicine, Purdue University and the IU Simon Cancer Center at the forefront of pancreatic cancer treatment and research across the nation. The Signature Center, comprised of basic, translational and clinical researchers, represents the continuum of the disease from biological / molecular investigation to clinical trials. Funding from the Signature Center Initiative is being utilized to develop genetically engineered mouse models, generate orthotopic pancreatic cancer mouse models, develop cancer associated fibroblast lines to be used as a shared resource as well as provide funding for peer reviewed pilot projects led by young investigators. Establishment and characterization of these cell lines and in vivo models provides the groundwork for these resources to be used by all members in their translational research projects. Support of pilot projects provides preliminary data and identification of projects to be ultimately used in a SPORE application. Additionally, work has begun on a web portal to promote and educate both patients and clinicians about the IUSCC Pancreas Cancer Clinic which became operational in 2010. Taken together, these activities provide the infrastructure to support pancreas cancer research at IU across the continuum of bench to bedside to practice. The availability of these resources to all members promotes inter-disciplinary collaborations aimed at increasing our understanding of pancreatic cancer so that advancements can be made in early diagnosis, prevention and multi-modality targeted treatment of this malignancy

Role of Ape1 and Base Excision Repair in the Radiation Response and Heat-radiosensitization of HeLa Cells

Background: The mechanism by which heat sensitizes mammalian cells to ionizing radiation remains to be elucidated. We determined whether base excision repair (BER) is involved in heat-radiosensitization and report novel findings that provide insight regarding the role of BER in the radiation response of HeLa cells. Materials and Methods: An siRNA approach was utilized to suppress expression of AP endonuclease (Ape1), a critical enzyme of BER. Clonogenic survival curves were obtained for HeLa cells expressing normal or reduced Ape1 content and which had been irradiated, and these were compared to survival curves from cells that were irradiated prior to hyperthermia treatment. Results: The amount of heat-radiosensitization observed in Ape1-suppressed cells was similar to or slightly greater than that observed in cells expressing near-normal levels of Ape1. Interestingly, we also found that for unheated HeLa cells, suppressed expression of Ape1 resulted in enhanced resistance to X-rays. Conclusion: The data suggest that Ape1, and therefore BER, is not involved in heat-radiosensitization. However, the observation that suppressed expression of Ape1 results in enhanced radioresistance supports the notion that BER may be detrimental to the survival of irradiated cells

Targeting DNA repair pathways for cancer treatment: what's new?

Disruptions in DNA repair pathways predispose cells to accumulating DNA damage. A growing body of evidence indicates that tumors accumulate progressively more mutations in DNA repair proteins as cancers progress. DNA repair mechanisms greatly affect the response to cytotoxic treatments, so understanding those mechanisms and finding ways to turn dysregulated repair processes against themselves to induce tumor death is the goal of all DNA repair inhibition efforts. Inhibition may be direct or indirect. This burgeoning field of research is replete with promise and challenge, as more intricacies of each repair pathway are discovered. In an era of increasing concern about healthcare costs, use of DNA repair inhibitors can prove to be highly effective stewardship of R&D resources and patient expenses

Small-molecule inhibitors of proteins involved in base excision repair potentiate the anti-tumorigenic effect of existing chemotherapeutics and irradiation

There has been a recent upsurge in the development of small-molecule inhibitors specific to DNA repair proteins or proteins peripherally involved in base excision repair and the DNA damage response. These specific, nominally toxic inhibitors are able to potentiate the effect of existing cancer cell treatments in a wide array of cancers. One of the largest obstacles to overcome in the treatment of cancer is incomplete killing with initial cancer treatments, leading to resistant cancer. The progression of our understanding of cancer and normal cell responses to DNA damage has allowed us to develop biomarkers that we can use to help us predict responses of cancers, more specifically target cancer cells and overcome resistance. Initial successes using these small-molecule DNA repair inhibitors in target-validation experiments and in the early stages of clinical trials indicate an important role for these inhibitors, and allow for the possibility of a future in which cancers are potentially treated in a highly specific, individual manner

Pancreatic Cancer Signature Center: Providing the Research Tools Necessary to Advance Pancreatic Cancer Patient Care

poster abstractThere were approximately 43,000 new cases of pancreatic ductal adenocarcinoma (PDAC) in the U.S. in 2010, and approximately 37,000 deaths. PDAC thus constitutes the fourth leading cause of cancer deaths, and PDAC patients have a dismal 5-year survival rate of 6%. PDAC is notoriously resistant to chemotherapy and radiation and even with our best treatment options, a complete margin-negative surgical resection, few patients achieving long-term survival. Despite these statistics, surprisingly only a small number of NCI-designated cancer centers have a specialized pancreatic cancer program. The creation of the IUPUI Signature Center for Pancreatic Cancer Research has been the foundation for putting IUPUI, the IU School of Medicine, Purdue University and the IU Simon Cancer Center at the forefront of pancreatic cancer treatment and research across the nation. The Signature Center, comprised of basic, translational and clinical researchers, represents the continuum of the disease from biological / molecular investigation to clinical trials. Funding from the Signature Center Initiative is being utilized to develop genetically engineered mouse models, orthotopic pancreatic cancer models as well as a human pancreatic cancer xenograft model. Establishment and characterization of these in vivo models provides the groundwork to be used by all members in their translational research projects. Additionally, work has begun on a web portal to promote and educate both patients and clinicians about the IUSCC Pancreas Cancer Clinic which became operational in 2010. Taken together the development of these in vivo models as well as web support of the Pancreas Cancer Clinic provides the infrastructure to support pancreas cancer research across the continuum of bench to bedside to practice. The availability of these resources to all members promotes inter-disciplinary collaborations aimed at increasing our understanding of pancreatic cancer so that advancements can be made in diagnosis, prevention and treatment of this malignancy

Implications of Ape1 in reactive oxygen signaling response following cisplatin treatment of dorsal root ganglion neurons

Peripheral neuropathy is one of the major side-effects of the anticancer drug, cisplatin. Although previous work suggests that this neuropathy correlates with formation of DNA adducts in sensory neurons, growing evidence suggests that cisplatin also increases the generation of reactive oxygen species (ROS), which could cause DNA damage. Apurinic/apyrimidinic endonuclease/redox factor-1 (Ape1/Ref-1) is a multifunctional protein involved in DNA base excision repair (BER) of oxidative DNA damage and in redox regulation of a number of transcription factors. Therefore, we asked whether altering Ape1 functions would influence cisplatin induced neurotoxicity. Sensory neurons in culture were exposed to cisplatin for 24 hrs and several endpoints of toxicity were measured including production of ROS, cell death, apoptosis, and release of the immunoreactive calcitonin gene-related peptide (iCGRP). Reducing expression of Ape1 in neuronal cultures using siRNA enhances cisplatin-induced cell killing, apoptosis, ROS generation and the cisplatin-induced reduction in iCGRP release. Overexpressing wild-type (WT)-Ape1 attenuates all the toxic effects of cisplatin in cells containing normal endogenous levels of Ape1 and in cells with reduced Ape1 levels following Ape1siRNA treatment. Overexpressing the redox deficient/repair competent C65-Ape1 provides partial rescue, while the repair deficient Ape1 (N226A+R177A) does not protect neurons from cisplatin toxicity. We also observe an increase in phosphorylation of p53 following a decrease in Ape1 levels in sensory neuronal cultures. These results strongly support the notion that Ape1 is a potential translational target such that protecting Ape1 levels and particularly its DNA repair function could reduce peripheral neuropathy in patients undergoing cisplatin treatment