- Email: [email protected]
414 A Novel Small Molecule Inhibitor of Protein Kinase D Blocks Pancreatic Cancer Growth Both In Vitro and In Vivo
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PKD1/2) are significantly upregulated in PaCa as compared to normal ducts (91% vs 22%; p<0.001) and western analyses showed that PKD1/2 are expressed in multiple PaCa celllines. Using Panc-1 as a model system, we demonstrated that CRT0066101 increased apoptosis, reduced BrdU incorporation (IC50=1 μM), blocked PKD1/2 activation, and attenuated PKD1/2-induced NF-κB activation. We showed that CRT0066101 given orally (80 mg/ kg/day) for 4 weeks significantly abrogated PaCa growth in a subcutaneous Panc-1 xenograft model (n=8; p<0.01). The expression of activated PKD1/2 in the treated tumor explants was significantly inhibited (p<0.05) with peak plasma concentration (12 μM) of CRT0066101 achieved within 2 hours after oral administration. Further, we showed that CRT0066101 given orally (80 mg/kg/day) for 21 days in an orthotopic model potently blocked Panc-1 tumor growth In Vivo (n=7; p<0.01). CRT0066101 significantly reduced Ki-67+ proliferation index (p<0.01), increased apoptosis (measured by in situ TUNEL assay) of PaCa tumors (p<0.05) and potently abrogated expression of multiple NF-κB-dependent proliferative and pro-survival proteins including Cyclin D1, survivin, Bcl-2, Bcl-xL, and IAP-1. Conclusion: Our results demonstrate for the first time that PKD-specific small molecule inhibitor CRT0066101 blocks PaCa growth both In Vitro and In Vivo and validates the role of PKD1/ 2 in PaCa tumorigenesis. We showed that CRT0066101 was orally bioavailable and blocked tumor growth in two distinct PaCa animal models. Thus, PKD is a novel therapeutic target in PaCa.
AGA Abstracts
Neuroplastic Changes in a Mouse Model of Pancreatic Ductal Adenocarcinoma (PDAC) Rachelle E. Stopczynski, Ronald A. DePinho, Haoqiang Ying, Erica S. Schwartz, Kathryn M. Albers, Brian M. Davis, Klaus Bielefeldt Perineural tumor invasion of intrapancreatic nerves and extrapancreatic nerve plexuses is a key feature of pancreatic malignancies and is thought to play an important role in pancreatic cancer-related pain and cancer spread. Here we provide a preliminary description of changes in pancreatic innervation in a mouse model of PDAC that will allow us to examine the mechanisms underlying cancer-induced pathophysiology of the peripheral nervous system. Several neurotrophic factors, including nerve growth factor (NGF) and members of the glial cell line-derived neurotrophic factor (GDNF) family of growth factors, and their receptors can be found in the pancreas and are increased in human pancreatic tumors. These growth factors are capable of inducing neuronal outgrowth and may contribute to sprouting and hypertrophy of pancreatic nerves, which is one of the hallmarks of human PDAC. We hypothesized that artemin, a member of the GDNF family of growth factors, and NGF play a central role in this cross-talk between cancer cells and pancreatic nerves. Experiments were performed with transgenic mice with pancreas-specific expression of the mutated Kras oncogene and heterozygous deletion of the p53 tumor suppressor (Kras). Animals were sacrificed at time points ranging from 13.9-17.4 weeks and tissue was retrieved for histological analysis and assessment of growth factor expression using real time PCR. All Kras mice had developed multifocal pancreatic cancer (by week 13) as evidenced by large masses, obstruction of the biliary tree (by week 17) and a strong desmoplastic reaction. Normal pancreatic innervation was altered with hypertrophied nerves running along blood vessels and extending into the pancreatic parenchyma and tumor nodules, but not into the fibrous tissue. Immunohistochemical experiments showed prominent expression of tyrosine hydroxylase and the artemin receptor GFRα3 on nerve fibers. Compared to wildtype mice, the expression of NGF and its receptor trkA was increased 3.22-fold and 8.85-fold, respectively, in cancer animals. While not statistically significant, a 1.99-fold increase in artemin expression was measured in the Kras animals. Finally, a 2.27-fold decrease in the expression of GFRα3 in cancer animals was observed. These data indicate significant neuroplastic changes occur in the Kras model of pancreatic cancer and these changes correlate with altered expression of growth factors, mimicking data obtained in human resection specimens. Thus, this animal model will enable us to systemically study the impact of changes in trophic factor signaling on cancer growth and animal behavior.
415 Liver Histology of IBD Patients Who are Treated With 6-Thioguanine Due to Failure of Conventional Thiopurines Reveals Very Few Cases of Nodular Regenerative Hyperplasia Dirk P. van Asseldonk, Bindia Jharap, Nanne K. de Boer, Pieter E. Zondervan, Elisabeth Bloemena, Gijsbert den Hartog, Dik B. Westerveld, Jeroen J. Kolkman, Leopold G. Engels, Adriaan A. van Bodegraven, Chris J. Mulder AIM: 6-Thioguanine (6-TG) has been proposed as a rescue drug in patients with inflammatory bowel disease (IBD) who fail to tolerate or are refractory to conventional thiopurines. However, the use of 6-TG has mainly been discarded due to previous reported hepatotoxicity, which may be class or dose-dependent. The aim of this study was to assess short-term hepatotoxicity of 6-TG therapy in a large population of IBD patients previously failing conventional thiopurines. MATERIALS AND METHODS: A national prospective cross-sectional multi-center cohort study was performed including IBD patients who were treated with 6-TG in an aimed dose of 0.3mg/kg for at least six months and who underwent a liver biopsy for safety assessment according to European consensus guidelines. The liver specimens were stained with H&E, trichrome and reticuline and were scored by experienced liver pathologists. RESULTS: From 99 patients with a mean age of 43.8 years (SD 12.0) a total of 99 liver biopsy specimens were obtained. Thirty six patients (36%) were male. Sixty-one patients (62%) had Crohn's disease and 38 (38%) had ulcerative colitis. Median duration of IBD before initiation of 6-TG was 9 years (range 1-54). Except for two patients, all were pretreated with azathioprine and/or 6-mercaptopurine. Ninety-three percent of these patients had been intolerant to previous thiopurine treatment, of which the median treatment duration was six weeks (range 1-780). Mean 6-TG dose was 0.28mg/kg (SD 0.07) and median 6-TG treatment duration, from initiation up to the first liver biopsy, was 25 months (range 665). Liver histology revealed no abnormalities in 51 specimens (51.5%); mild steatosis in 14 (14.1%); mild fibrosis in 3 (3.0%); severe steatosis in 2 (2.0%); steatohepatitis in 2 (2.0%) sinus dilatation in 8 (8.1%); cholangitis/PSC in 4 (4.0%); aspecific regeneration in 11 (11.1%) and nodular regenerative hyperplasia (NRH) in 4 (4.0%). CONCLUSION: This large, prospective study reveals very few cases of NRH (4%) in a specific IBD population who had been failing conventional thiopurine therapy and were subsequently treated with 6-TG. This is in contrast to some previous studies (up to 62%), but corresponding with the prevalence of NRH in thiopurine naïve IBD patients (6%). Aspecific findings with unknown clinical implications were observed in about half of the patients.
413 Age is not Associated With Adverse Events From Biologic Therapy in Patients With Inflammatory Bowel Disease Anita Bhushan, Darrell S. Pardi, Edward V. Loftus, William J. Tremaine, Patricia P. Kammer, Prabin Thapa, William S. Harmsen, Alan R. Zinsmeister, William J. Sandborn Introduction: Biologic therapy has become an important part of the treatment of patients with inflammatory bowel disease (IBD). A significant proportion of patients with IBD are elderly. However, relatively little is known about the safety profile of biologic therapy in older IBD patients. Aim: To perform a matched cohort study to assess the association of age with adverse events of biologics (infliximab and adalimumab) among IBD patients. Methods: All IBD (Crohn's disease and ulcerative colitis) patients aged ≥ 60 years (older cohort) at the start of biologic therapy who were seen at Mayo Clinic Rochester between 1998 and 2008 were included. Each patient from the older cohort was matched to two IBD patients < 60 years (younger cohort) at the start of biologic therapy. Patients referred for complications of biologic therapy and those who started biologics at another facility were excluded. The two cohorts were matched for gender, geography (to control for referral bias), IBD subtype, and type and duration of biologic therapy. Their medical records were abstracted for disease severity, comorbidities, and adverse events (AEs) while on biologic therapy. Results: 89 older patients and 178 younger patients were identified. 91% of patients had Crohn's disease and 9% had ulcerative colitis. 83% of patients received infliximab and 17% received adalimumab. The median age at the start of biologic therapy for the older cohort was 66 years (range 60-86) and 35 years (range 18-59) for the younger cohort. The median duration of follow up for the two cohorts was 10.3 months (range 5 days - 105 months). Statistical modeling showed that, after adjusting for gender and geography, age was not significantly associated with the risk of AEs (hazard ratio 1.1, 95% CI 0.9 - 1.26; p = 0.17). Furthermore, age was also not associated with the risk of AEs after additional adjusting for confounders such as disease extent, disease severity and comorbidities. The cumulative probability of first AE at 6 months and 1 year was 4% and 7% in the older cohort compared to 3% and 6% in the younger cohort. Conclusion: In this matched cohort study, age greater than 60 years was not an independent risk factor for first AE among IBD patients on biologic therapy after a median follow up of 10.3 months.
475a A Randomized, Double-Blind, Placebo-Controlled Study of Oral Viscous Budesonide (OVB) in Children With Eosinophilic Esophagitis (EoE) Ranjan Dohil, Robert Newbury, Lyman Fox, John F. Bastian, Seema Aceves Background. Eosinophilic esophagitis is a clinicopathologic disorder caused by immunologic reactions to ingested/inhaled allergens. Diagnosis is dependent upon finding ≥15 eosinophils/ hpf in mucosal biopsies. Untreated EoE may cause GERD-like symptoms and strictures. A previously reported retrospective study has shown OVB to be effective therapy for EoE in children but no placebo-controlled studies have yet been conducted. Aims. Evaluate the safety and efficacy of OVB in the treatment of EoE in children. Method. Children, age ≥1y, with EoE (>20 eos/hpf) were randomized (2:1) into OVB+PPI and placebo+PPI groups, respectively. OVB consisted of budesonide suspension (Pulmicort™, 0.5mg/ 2ml) mixed with Splenda™ (10g sucralose per 1 mg budesonide). Patients <5ft and ≥5ft tall received 1mg and 2mg OVB once daily, respectively, and lansoprazole 15mg and 30mg bid, respectively. Treatment duration was 3m, followed by repeat endoscopy and biopsies. Distal, mid and proximal esophageal biopsies were taken. Response was determined by measuring peak eosinophil count and patients were classified as responders ≤6, partial-responders 7-19, and non-responders >20 eos/hpf. Baseline and post-treatment symptoms and endoscopic features were scored using previously reported tools. Results. 24 children (20 males, 1-17y, mean 7.8y, 11 food-sensitized/allergic) completed the study. 13 of 15 (86.7%) receiving OVB were responders (p<0.0001), 1 partial-responder, 1 non-responder. None of the 9 subjects in the placebo group were responders. Mean pre/post-treatment peak eosinophil counts with OVB were 66.7 and 4.8 eos/hpf (p<0.0001), respectively, and with placebo 83.9 and 65.6 eos/hpf (p=0.3), respectively. Within the OVB group, the fall from baseline, in proximal (p<0.003), mid (p=0.0003) and distal (p=0.001) esophageal eosinophilia, was significant. Within the placebo group, the fall from baseline, in proximal (p=0.96), mid (p= 0.57) and distal (p=0.34) esophageal eosinophilia, was not significant. 4 of 6 food-sensitized/ allergic children receiving OVB were responders. In the OVB group, the mean symptom (p=0.0007) and endoscopy (p=0.0005) scores improved significantly compared with baseline. Analysis of key safety variables was unremarkable. Conclusions. OVB with PPI is safe,
414 A Novel Small Molecule Inhibitor of Protein Kinase D Blocks Pancreatic Cancer Growth Both In Vitro and In Vivo Christopher R. Ireson, Kuzhuvelil B. Harikumar, Ajaykumar B. Kunnumakkara, Amit Deorukhkar, Zhimin Tong, Dipen Maru, Parmeswaran Diagaradjane, Nobuo Ochi, Sunil Krishnan, Bharat B. Aggarwal, Enrique Rozengurt, Sushovan Guha Background: Protein kinase D (PKD) is a new family of serine/threonine kinases comprised of PKD1, PKD2, and PKD3 with diverse biological functions including cell proliferation and growth. Pancreatic Cancer (PaCa) is a devastating disease with few therapeutic options. We showed earlier that PKD signaling pathways promote mitogenesis in multiple PaCa cell lines. However, nothing is known about targeting biological functions of PKD in PaCa. Using a high-throughput screening strategy, we discovered a small molecule inhibitor CRT0066101 that specifically blocks activation of PKD family. Aim: The aim of our study was to determine the effects of CRT0066101 in PaCa, both In Vitro and In Vivo. Methods and Results: Our immunohistochemical analysis showed that autophosphorylated PKD1 and PKD2 (activated
AGA Abstracts
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PKD1/2) are significantly upregulated in PaCa as compared to normal ducts (91% vs 22%; p<0.001) and western analyses showed that PKD1/2 are expressed in multiple PaCa celllines. Using Panc-1 as a model system, we demonstrated that CRT0066101 increased apoptosis, reduced BrdU incorporation (IC50=1 μM), blocked PKD1/2 activation, and attenuated PKD1/2-induced NF-κB activation. We showed that CRT0066101 given orally (80 mg/ kg/day) for 4 weeks significantly abrogated PaCa growth in a subcutaneous Panc-1 xenograft model (n=8; p<0.01). The expression of activated PKD1/2 in the treated tumor explants was significantly inhibited (p<0.05) with peak plasma concentration (12 μM) of CRT0066101 achieved within 2 hours after oral administration. Further, we showed that CRT0066101 given orally (80 mg/kg/day) for 21 days in an orthotopic model potently blocked Panc-1 tumor growth In Vivo (n=7; p<0.01). CRT0066101 significantly reduced Ki-67+ proliferation index (p<0.01), increased apoptosis (measured by in situ TUNEL assay) of PaCa tumors (p<0.05) and potently abrogated expression of multiple NF-κB-dependent proliferative and pro-survival proteins including Cyclin D1, survivin, Bcl-2, Bcl-xL, and IAP-1. Conclusion: Our results demonstrate for the first time that PKD-specific small molecule inhibitor CRT0066101 blocks PaCa growth both In Vitro and In Vivo and validates the role of PKD1/ 2 in PaCa tumorigenesis. We showed that CRT0066101 was orally bioavailable and blocked tumor growth in two distinct PaCa animal models. Thus, PKD is a novel therapeutic target in PaCa.
AGA Abstracts
Neuroplastic Changes in a Mouse Model of Pancreatic Ductal Adenocarcinoma (PDAC) Rachelle E. Stopczynski, Ronald A. DePinho, Haoqiang Ying, Erica S. Schwartz, Kathryn M. Albers, Brian M. Davis, Klaus Bielefeldt Perineural tumor invasion of intrapancreatic nerves and extrapancreatic nerve plexuses is a key feature of pancreatic malignancies and is thought to play an important role in pancreatic cancer-related pain and cancer spread. Here we provide a preliminary description of changes in pancreatic innervation in a mouse model of PDAC that will allow us to examine the mechanisms underlying cancer-induced pathophysiology of the peripheral nervous system. Several neurotrophic factors, including nerve growth factor (NGF) and members of the glial cell line-derived neurotrophic factor (GDNF) family of growth factors, and their receptors can be found in the pancreas and are increased in human pancreatic tumors. These growth factors are capable of inducing neuronal outgrowth and may contribute to sprouting and hypertrophy of pancreatic nerves, which is one of the hallmarks of human PDAC. We hypothesized that artemin, a member of the GDNF family of growth factors, and NGF play a central role in this cross-talk between cancer cells and pancreatic nerves. Experiments were performed with transgenic mice with pancreas-specific expression of the mutated Kras oncogene and heterozygous deletion of the p53 tumor suppressor (Kras). Animals were sacrificed at time points ranging from 13.9-17.4 weeks and tissue was retrieved for histological analysis and assessment of growth factor expression using real time PCR. All Kras mice had developed multifocal pancreatic cancer (by week 13) as evidenced by large masses, obstruction of the biliary tree (by week 17) and a strong desmoplastic reaction. Normal pancreatic innervation was altered with hypertrophied nerves running along blood vessels and extending into the pancreatic parenchyma and tumor nodules, but not into the fibrous tissue. Immunohistochemical experiments showed prominent expression of tyrosine hydroxylase and the artemin receptor GFRα3 on nerve fibers. Compared to wildtype mice, the expression of NGF and its receptor trkA was increased 3.22-fold and 8.85-fold, respectively, in cancer animals. While not statistically significant, a 1.99-fold increase in artemin expression was measured in the Kras animals. Finally, a 2.27-fold decrease in the expression of GFRα3 in cancer animals was observed. These data indicate significant neuroplastic changes occur in the Kras model of pancreatic cancer and these changes correlate with altered expression of growth factors, mimicking data obtained in human resection specimens. Thus, this animal model will enable us to systemically study the impact of changes in trophic factor signaling on cancer growth and animal behavior.
415 Liver Histology of IBD Patients Who are Treated With 6-Thioguanine Due to Failure of Conventional Thiopurines Reveals Very Few Cases of Nodular Regenerative Hyperplasia Dirk P. van Asseldonk, Bindia Jharap, Nanne K. de Boer, Pieter E. Zondervan, Elisabeth Bloemena, Gijsbert den Hartog, Dik B. Westerveld, Jeroen J. Kolkman, Leopold G. Engels, Adriaan A. van Bodegraven, Chris J. Mulder AIM: 6-Thioguanine (6-TG) has been proposed as a rescue drug in patients with inflammatory bowel disease (IBD) who fail to tolerate or are refractory to conventional thiopurines. However, the use of 6-TG has mainly been discarded due to previous reported hepatotoxicity, which may be class or dose-dependent. The aim of this study was to assess short-term hepatotoxicity of 6-TG therapy in a large population of IBD patients previously failing conventional thiopurines. MATERIALS AND METHODS: A national prospective cross-sectional multi-center cohort study was performed including IBD patients who were treated with 6-TG in an aimed dose of 0.3mg/kg for at least six months and who underwent a liver biopsy for safety assessment according to European consensus guidelines. The liver specimens were stained with H&E, trichrome and reticuline and were scored by experienced liver pathologists. RESULTS: From 99 patients with a mean age of 43.8 years (SD 12.0) a total of 99 liver biopsy specimens were obtained. Thirty six patients (36%) were male. Sixty-one patients (62%) had Crohn's disease and 38 (38%) had ulcerative colitis. Median duration of IBD before initiation of 6-TG was 9 years (range 1-54). Except for two patients, all were pretreated with azathioprine and/or 6-mercaptopurine. Ninety-three percent of these patients had been intolerant to previous thiopurine treatment, of which the median treatment duration was six weeks (range 1-780). Mean 6-TG dose was 0.28mg/kg (SD 0.07) and median 6-TG treatment duration, from initiation up to the first liver biopsy, was 25 months (range 665). Liver histology revealed no abnormalities in 51 specimens (51.5%); mild steatosis in 14 (14.1%); mild fibrosis in 3 (3.0%); severe steatosis in 2 (2.0%); steatohepatitis in 2 (2.0%) sinus dilatation in 8 (8.1%); cholangitis/PSC in 4 (4.0%); aspecific regeneration in 11 (11.1%) and nodular regenerative hyperplasia (NRH) in 4 (4.0%). CONCLUSION: This large, prospective study reveals very few cases of NRH (4%) in a specific IBD population who had been failing conventional thiopurine therapy and were subsequently treated with 6-TG. This is in contrast to some previous studies (up to 62%), but corresponding with the prevalence of NRH in thiopurine naïve IBD patients (6%). Aspecific findings with unknown clinical implications were observed in about half of the patients.
413 Age is not Associated With Adverse Events From Biologic Therapy in Patients With Inflammatory Bowel Disease Anita Bhushan, Darrell S. Pardi, Edward V. Loftus, William J. Tremaine, Patricia P. Kammer, Prabin Thapa, William S. Harmsen, Alan R. Zinsmeister, William J. Sandborn Introduction: Biologic therapy has become an important part of the treatment of patients with inflammatory bowel disease (IBD). A significant proportion of patients with IBD are elderly. However, relatively little is known about the safety profile of biologic therapy in older IBD patients. Aim: To perform a matched cohort study to assess the association of age with adverse events of biologics (infliximab and adalimumab) among IBD patients. Methods: All IBD (Crohn's disease and ulcerative colitis) patients aged ≥ 60 years (older cohort) at the start of biologic therapy who were seen at Mayo Clinic Rochester between 1998 and 2008 were included. Each patient from the older cohort was matched to two IBD patients < 60 years (younger cohort) at the start of biologic therapy. Patients referred for complications of biologic therapy and those who started biologics at another facility were excluded. The two cohorts were matched for gender, geography (to control for referral bias), IBD subtype, and type and duration of biologic therapy. Their medical records were abstracted for disease severity, comorbidities, and adverse events (AEs) while on biologic therapy. Results: 89 older patients and 178 younger patients were identified. 91% of patients had Crohn's disease and 9% had ulcerative colitis. 83% of patients received infliximab and 17% received adalimumab. The median age at the start of biologic therapy for the older cohort was 66 years (range 60-86) and 35 years (range 18-59) for the younger cohort. The median duration of follow up for the two cohorts was 10.3 months (range 5 days - 105 months). Statistical modeling showed that, after adjusting for gender and geography, age was not significantly associated with the risk of AEs (hazard ratio 1.1, 95% CI 0.9 - 1.26; p = 0.17). Furthermore, age was also not associated with the risk of AEs after additional adjusting for confounders such as disease extent, disease severity and comorbidities. The cumulative probability of first AE at 6 months and 1 year was 4% and 7% in the older cohort compared to 3% and 6% in the younger cohort. Conclusion: In this matched cohort study, age greater than 60 years was not an independent risk factor for first AE among IBD patients on biologic therapy after a median follow up of 10.3 months.
475a A Randomized, Double-Blind, Placebo-Controlled Study of Oral Viscous Budesonide (OVB) in Children With Eosinophilic Esophagitis (EoE) Ranjan Dohil, Robert Newbury, Lyman Fox, John F. Bastian, Seema Aceves Background. Eosinophilic esophagitis is a clinicopathologic disorder caused by immunologic reactions to ingested/inhaled allergens. Diagnosis is dependent upon finding ≥15 eosinophils/ hpf in mucosal biopsies. Untreated EoE may cause GERD-like symptoms and strictures. A previously reported retrospective study has shown OVB to be effective therapy for EoE in children but no placebo-controlled studies have yet been conducted. Aims. Evaluate the safety and efficacy of OVB in the treatment of EoE in children. Method. Children, age ≥1y, with EoE (>20 eos/hpf) were randomized (2:1) into OVB+PPI and placebo+PPI groups, respectively. OVB consisted of budesonide suspension (Pulmicort™, 0.5mg/ 2ml) mixed with Splenda™ (10g sucralose per 1 mg budesonide). Patients <5ft and ≥5ft tall received 1mg and 2mg OVB once daily, respectively, and lansoprazole 15mg and 30mg bid, respectively. Treatment duration was 3m, followed by repeat endoscopy and biopsies. Distal, mid and proximal esophageal biopsies were taken. Response was determined by measuring peak eosinophil count and patients were classified as responders ≤6, partial-responders 7-19, and non-responders >20 eos/hpf. Baseline and post-treatment symptoms and endoscopic features were scored using previously reported tools. Results. 24 children (20 males, 1-17y, mean 7.8y, 11 food-sensitized/allergic) completed the study. 13 of 15 (86.7%) receiving OVB were responders (p<0.0001), 1 partial-responder, 1 non-responder. None of the 9 subjects in the placebo group were responders. Mean pre/post-treatment peak eosinophil counts with OVB were 66.7 and 4.8 eos/hpf (p<0.0001), respectively, and with placebo 83.9 and 65.6 eos/hpf (p=0.3), respectively. Within the OVB group, the fall from baseline, in proximal (p<0.003), mid (p=0.0003) and distal (p=0.001) esophageal eosinophilia, was significant. Within the placebo group, the fall from baseline, in proximal (p=0.96), mid (p= 0.57) and distal (p=0.34) esophageal eosinophilia, was not significant. 4 of 6 food-sensitized/ allergic children receiving OVB were responders. In the OVB group, the mean symptom (p=0.0007) and endoscopy (p=0.0005) scores improved significantly compared with baseline. Analysis of key safety variables was unremarkable. Conclusions. OVB with PPI is safe,
414 A Novel Small Molecule Inhibitor of Protein Kinase D Blocks Pancreatic Cancer Growth Both In Vitro and In Vivo Christopher R. Ireson, Kuzhuvelil B. Harikumar, Ajaykumar B. Kunnumakkara, Amit Deorukhkar, Zhimin Tong, Dipen Maru, Parmeswaran Diagaradjane, Nobuo Ochi, Sunil Krishnan, Bharat B. Aggarwal, Enrique Rozengurt, Sushovan Guha Background: Protein kinase D (PKD) is a new family of serine/threonine kinases comprised of PKD1, PKD2, and PKD3 with diverse biological functions including cell proliferation and growth. Pancreatic Cancer (PaCa) is a devastating disease with few therapeutic options. We showed earlier that PKD signaling pathways promote mitogenesis in multiple PaCa cell lines. However, nothing is known about targeting biological functions of PKD in PaCa. Using a high-throughput screening strategy, we discovered a small molecule inhibitor CRT0066101 that specifically blocks activation of PKD family. Aim: The aim of our study was to determine the effects of CRT0066101 in PaCa, both In Vitro and In Vivo. Methods and Results: Our immunohistochemical analysis showed that autophosphorylated PKD1 and PKD2 (activated
AGA Abstracts
S-62