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1. A first-in-class pan-lysyl oxidase inhibitor impairs stromal remodeling and enhances gemcitabine response and survival in pancreatic cancer

Author

Chitty, Jessica L., Yam, Michelle, Perryman, Lara, Parker, Amelia L., Skhinas, Joanna N., Setargew, Yordanos F. I., Mok, Ellie T. Y., Tran, Emmi, Grant, Rhiannon D., Latham, Sharissa L., Pereira, Brooke A., Ritchie, Shona C., Murphy, Kendelle J., Trpceski, Michael, Findlay, Alison D., Melenec, Pauline, Filipe, Elysse C., Nadalini, Audrey, Velayuthar, Sipiththa, Major, Gretel, Wyllie, Kaitlin, Papanicolaou, Michael, Ratnaseelan, Shivanjali, Phillips, Phoebe A., Sharbeen, George, Youkhana, Janet, Russo, Alice, Blackwell, Antonia, Hastings, Jordan F., Lucas, Morghan C., Chambers, Cecilia R., Reed, Daniel A., Stoehr, Janett, Vennin, Claire, Pidsley, Ruth, Zaratzian, Anaiis, Da Silva, Andrew M., Tayao, Michael, Charlton, Brett, Herrmann, David, Nobis, Max, Clark, Susan J., Biankin, Andrew V., Johns, Amber L., Croucher, David R., Nagrial, Adnan, Gill, Anthony J., Grimmond, Sean M., Pajic, Marina, Timpson, Paul, Jarolimek, Wolfgang, and Cox, Thomas R.

Published
2023
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3. Abstract B062: CRO67 has therapeutic potential against pancreatic tumor cells and cancer associated fibroblasts

Author

Netto, Keilah Garcia, primary, Chiang, Shannon, additional, Kokkinos, John, additional, Haghighi, Koroush S., additional, Raina, Aparna, additional, Pitiyarachchi, Omali, additional, Youkhana, Janet, additional, Truong, Quach, additional, Wenholz, Daniel, additional, Li, Xiang, additional, Laczka, Olivier, additional, Kumar, Naresh, additional, Wilkinson, John, additional, Goldstein, David, additional, Sharbeen, George, additional, and Phillips, Phoebe A., additional

Published
2024
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4. Ex vivo culture of intact human patient derived pancreatic tumour tissue

Author

Kokkinos, John, Sharbeen, George, Haghighi, Koroush S., Ignacio, Rosa Mistica C., Kopecky, Chantal, Gonzales-Aloy, Estrella, Youkhana, Janet, Timpson, Paul, Pereira, Brooke A., Ritchie, Shona, Pandzic, Elvis, Boyer, Cyrille, Davis, Thomas P., Butler, Lisa M., Goldstein, David, McCarroll, Joshua A., and Phillips, Phoebe A.

Published
2021
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5. Development of a long term, ex vivo, patient-derived explant model of endometrial cancer.

Author

van der Woude, Hannah, Phan, Khoi, Kenwright, Diane N., Goossens, Louise, Hally, Kathryn Elizabeth, Currie, Margaret Jane, Kokkinos, John, Sharbeen, George, Phillips, Phoebe A., and Henry, Claire Elizabeth

Subjects
LEVONORGESTREL, ENDOMETRIAL cancer, BODY mass index
Abstract

Incidence of endometrial cancer (EC) is rising in the developed world. The current standard of care, hysterectomy, is often infeasible for younger patients and those with high body mass index. There are limited non-surgical treatment options and a lack of biologically relevant research models to investigate novel alternatives to surgery for EC. The aim of the present study was to develop a long-term, patient-derived explant (PDE) model of early-stage EC and demonstrate its use for investigating predictive biomarkers for a current non-surgical treatment option, the levonorgestrel intra-uterine system (LNG-IUS). Fresh tumour specimens were obtained from patients with early-stage endometrioid EC. Tumours were cut into explants, cultured on media-soaked gelatin sponges for up to 21 days and treated with LNG. Formalin-fixed, paraffin embedded (FFPE) blocks were generated for each explant after 21 days in culture. Tumour architecture and integrity were assessed by haematoxylin and eosin (H&E) and immunohistochemistry (IHC). IHC was additionally performed for the expression of five candidate biomarkers of LNG resistance. The developed ex vivo PDE model is capable of culturing explants from early-stage EC tumours long-term (21 Days). This model can complement existing models and may serve as a tool to validate results obtained in higher-throughput in vitro studies. Our study provides the foundation to validate the extent to which EC PDEs reflect patient response in future research. [ABSTRACT FROM AUTHOR]

Published
2024
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6. HSP47: The New Heat Shock Protein Therapeutic Target

Author

Sharbeen, George, McAlpine, Shelli, Phillips, Phoebe, Bernstein, Peter R., Series editor, Buschauer, Armin, Series editor, Georg, Gunda I., Series editor, Lowe, John A., Series editor, Meanwell, Nicholas A., Series editor, Saxena, Anil Kumar, Series editor, Stilz, Ulrich, Series editor, Supuran, Claudiu T., Series editor, McAlpine, Shelli R., editor, and Edkins, Adrienne Lesley, editor

Published
2016
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10. Data from Cancer-Associated Fibroblasts in Pancreatic Ductal Adenocarcinoma Determine Response to SLC7A11 Inhibition

Author

Sharbeen, George, primary, McCarroll, Joshua A., primary, Akerman, Anouschka, primary, Kopecky, Chantal, primary, Youkhana, Janet, primary, Kokkinos, John, primary, Holst, Jeff, primary, Boyer, Cyrille, primary, Erkan, Mert, primary, Goldstein, David, primary, Timpson, Paul, primary, Cox, Thomas R., primary, Pereira, Brooke A., primary, Chitty, Jessica L., primary, Fey, Sigrid K., primary, Najumudeen, Arafath K., primary, Campbell, Andrew D., primary, Sansom, Owen J., primary, Ignacio, Rosa Mistica C., primary, Naim, Stephanie, primary, Liu, Jie, primary, Russia, Nelson, primary, Lee, Julia, primary, Chou, Angela, primary, Johns, Amber, primary, Gill, Anthony J., primary, Gonzales-Aloy, Estrella, primary, Gebski, Val, primary, Guan, Yi Fang, primary, Pajic, Marina, primary, Turner, Nigel, primary, Apte, Minoti V., primary, Davis, Thomas P., primary, Morton, Jennifer P., primary, Haghighi, Koroush S., primary, Kasparian, Jorjina, primary, McLean, Benjamin J., primary, Setargew, Yordanos F., primary, and Phillips, Phoebe A., primary

Published
2023
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11. Figure S2 from Cancer-Associated Fibroblasts in Pancreatic Ductal Adenocarcinoma Determine Response to SLC7A11 Inhibition

Author

Sharbeen, George, primary, McCarroll, Joshua A., primary, Akerman, Anouschka, primary, Kopecky, Chantal, primary, Youkhana, Janet, primary, Kokkinos, John, primary, Holst, Jeff, primary, Boyer, Cyrille, primary, Erkan, Mert, primary, Goldstein, David, primary, Timpson, Paul, primary, Cox, Thomas R., primary, Pereira, Brooke A., primary, Chitty, Jessica L., primary, Fey, Sigrid K., primary, Najumudeen, Arafath K., primary, Campbell, Andrew D., primary, Sansom, Owen J., primary, Ignacio, Rosa Mistica C., primary, Naim, Stephanie, primary, Liu, Jie, primary, Russia, Nelson, primary, Lee, Julia, primary, Chou, Angela, primary, Johns, Amber, primary, Gill, Anthony J., primary, Gonzales-Aloy, Estrella, primary, Gebski, Val, primary, Guan, Yi Fang, primary, Pajic, Marina, primary, Turner, Nigel, primary, Apte, Minoti V., primary, Davis, Thomas P., primary, Morton, Jennifer P., primary, Haghighi, Koroush S., primary, Kasparian, Jorjina, primary, McLean, Benjamin J., primary, Setargew, Yordanos F., primary, and Phillips, Phoebe A., primary

Published
2023
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12. Supplementary Table 2 from Cancer-Associated Fibroblasts in Pancreatic Ductal Adenocarcinoma Determine Response to SLC7A11 Inhibition

Author

Sharbeen, George, primary, McCarroll, Joshua A., primary, Akerman, Anouschka, primary, Kopecky, Chantal, primary, Youkhana, Janet, primary, Kokkinos, John, primary, Holst, Jeff, primary, Boyer, Cyrille, primary, Erkan, Mert, primary, Goldstein, David, primary, Timpson, Paul, primary, Cox, Thomas R., primary, Pereira, Brooke A., primary, Chitty, Jessica L., primary, Fey, Sigrid K., primary, Najumudeen, Arafath K., primary, Campbell, Andrew D., primary, Sansom, Owen J., primary, Ignacio, Rosa Mistica C., primary, Naim, Stephanie, primary, Liu, Jie, primary, Russia, Nelson, primary, Lee, Julia, primary, Chou, Angela, primary, Johns, Amber, primary, Gill, Anthony J., primary, Gonzales-Aloy, Estrella, primary, Gebski, Val, primary, Guan, Yi Fang, primary, Pajic, Marina, primary, Turner, Nigel, primary, Apte, Minoti V., primary, Davis, Thomas P., primary, Morton, Jennifer P., primary, Haghighi, Koroush S., primary, Kasparian, Jorjina, primary, McLean, Benjamin J., primary, Setargew, Yordanos F., primary, and Phillips, Phoebe A., primary

Published
2023
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13. Supplementary Table 4 from Cancer-Associated Fibroblasts in Pancreatic Ductal Adenocarcinoma Determine Response to SLC7A11 Inhibition

Author

Sharbeen, George, primary, McCarroll, Joshua A., primary, Akerman, Anouschka, primary, Kopecky, Chantal, primary, Youkhana, Janet, primary, Kokkinos, John, primary, Holst, Jeff, primary, Boyer, Cyrille, primary, Erkan, Mert, primary, Goldstein, David, primary, Timpson, Paul, primary, Cox, Thomas R., primary, Pereira, Brooke A., primary, Chitty, Jessica L., primary, Fey, Sigrid K., primary, Najumudeen, Arafath K., primary, Campbell, Andrew D., primary, Sansom, Owen J., primary, Ignacio, Rosa Mistica C., primary, Naim, Stephanie, primary, Liu, Jie, primary, Russia, Nelson, primary, Lee, Julia, primary, Chou, Angela, primary, Johns, Amber, primary, Gill, Anthony J., primary, Gonzales-Aloy, Estrella, primary, Gebski, Val, primary, Guan, Yi Fang, primary, Pajic, Marina, primary, Turner, Nigel, primary, Apte, Minoti V., primary, Davis, Thomas P., primary, Morton, Jennifer P., primary, Haghighi, Koroush S., primary, Kasparian, Jorjina, primary, McLean, Benjamin J., primary, Setargew, Yordanos F., primary, and Phillips, Phoebe A., primary

Published
2023
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16. Abstract C073: CRO-67 is a novel therapeutic for pancreatic cancer: Implications for tumor and stromal reprogramming

Author

Kokkinos, John, primary, Sharbeen, George, additional, Haghighi, Koroush S., additional, Youkhana, Janet, additional, Raina, Aparna, additional, Pitiyarachchi, Omali, additional, Truong, Quach, additional, Wenholz, Daniel, additional, Laczka, Olivier, additional, Kumar, Naresh, additional, Goldstein, David, additional, and Phillips, Phoebe A., additional

Published
2022
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18. Cancer‐Associated Fibroblasts: Interfacial Curvature in Confined Coculture Directs Stromal Cell Activity with Spatial Corralling of Pancreatic Cancer Cells (Adv. Biology 6/2021)

Author

Nemec, Stephanie, primary, Lam, Joey, additional, Zhong, Jingxiao, additional, Heu, Celine, additional, Timpson, Paul, additional, Li, Qing, additional, Youkhana, Janet, additional, Sharbeen, George, additional, Phillips, Phoebe A., additional, and Kilian, Kristopher A., additional

Published
2021
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21. Cancer-Associated Fibroblasts in Pancreatic Ductal Adenocarcinoma Determine Response to SLC7A11 Inhibition

Author

Sharbeen, George, primary, McCarroll, Joshua A., additional, Akerman, Anouschka, additional, Kopecky, Chantal, additional, Youkhana, Janet, additional, Kokkinos, John, additional, Holst, Jeff, additional, Boyer, Cyrille, additional, Erkan, Mert, additional, Goldstein, David, additional, Timpson, Paul, additional, Cox, Thomas R., additional, Pereira, Brooke A., additional, Chitty, Jessica L., additional, Fey, Sigrid K., additional, Najumudeen, Arafath K., additional, Campbell, Andrew D., additional, Sansom, Owen J., additional, Ignacio, Rosa Mistica C., additional, Naim, Stephanie, additional, Liu, Jie, additional, Russia, Nelson, additional, Lee, Julia, additional, Chou, Angela, additional, Johns, Amber, additional, Gill, Anthony J., additional, Gonzales-Aloy, Estrella, additional, Gebski, Val, additional, Guan, Yi Fang, additional, Pajic, Marina, additional, Turner, Nigel, additional, Apte, Minoti V., additional, Davis, Thomas P., additional, Morton, Jennifer P., additional, Haghighi, Koroush S., additional, Kasparian, Jorjina, additional, McLean, Benjamin J., additional, Setargew, Yordanos F., additional, and Phillips, Phoebe A., additional

Published
2021
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22. Additional file 1 of ROR1 and ROR2 expression in pancreatic cancer

Author

Liu, Dongli, Sharbeen, George, Phillips, Phoebe, and Ford, Caroline E.

Subjects
body regions
Abstract

Additional file 1 : Supplementary Fig.S1. Correlation between mRNA and protein expression of ROR1 and ROR2 in CPTAC PDAC discovery cohort. A. ROR1 mRNA and protein expression was positively correlated (Pearson���s R=0.25, p=0.005). B. ROR2 mRNA and protein expression was positively correlated (Pearson���s R=0.48, p

Published
2021
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25. Bringing the pancreas patient back to the bench: Ex vivo culture of intact human patient derived pancreatic tumour tissue

Author

Kokkinos, John, primary, Sharbeen, George, additional, Haghighi, Koroush S., additional, Ignacio, Rosa Mistica C., additional, Kopecky, Chantal, additional, Gonzales-Aloy, Estrella, additional, Youkhana, Janet, additional, Pandzic, Elvis, additional, Boyer, Cyrille, additional, Davis, Thomas P., additional, Butler, Lisa M., additional, Goldstein, David, additional, McCarroll, Joshua A., additional, and Phillips, Phoebe A., additional

Published
2020
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27. ROR1 and ROR2 expression in pancreatic cancer.

Author

Liu, Dongli, Sharbeen, George, Phillips, Phoebe, Australian Pancreatic Cancer Genome Initiative, Johns, Amber L., Gill, Anthony J., Chantrill, Lorraine A., Timpson, Paul, Chou, Angela, Pajic, Marina, Dwarte, Tanya, Herrmann, David, Vennin, Claire, Cox, Thomas R., Pereira, Brooke, Ritchie, Shona, Reed, Daniel A., Chambers, Cecilia R., Metcalf, Xanthe, and Nobis, Max

Subjects
*GENE expression, *PANCREATIC cancer, *PROGNOSIS, *OVERALL survival, *DRUG target
Abstract

Background: The Wnt receptors ROR1 and ROR2 are generating increased interest as cancer therapeutic targets but remain understudied in pancreatic ductal adenocarcinoma (PDAC). Compared to canonical Wnt/ β-catenin signalling, the role of noncanonical Wnt signalling in PDAC remains largely unknown. Only one study has investigated the prognostic significance of the noncanonical Wnt signalling receptor, ROR2 in PDAC. No studies have investigated the prognostic role of ROR1 in PDAC.Methods: Here, we performed analysis of ROR1 and ROR2 mRNA expression in three publicly available datasets ICGC-PACA-AU (n = 81), TCGA-PAAD (n = 150) and CPTAC-PDAC (n = 137). ROR1 and ROR2 protein expression from the CPTAC-PDAC discovery cohort were also analysed. Immunohistochemistry (IHC) using the validated anti ROR1 monoclonal antibody (4A5) was performed on the Australian Pancreatic Cancer Genome Initiative (APGI) cohort of PDAC samples (n = 152). Association between ROR1 cytoplasmic staining intensity and clinicopathological parameters including stage, grade and overall survival (OS) was investigated.Results: High ROR1 mRNA expression levels correlated with a favourable OS outcome in all of the ICGC-PACA-AU, TCGA-PAAD and CPTAC-PDAC cohorts. ROR1 protein expression was not associated with stage, grade or OS in the APGI cohort.Conclusion: ROR1 and ROR2 have potential as prognostic markers when measured at the mRNA level in PDAC. Our IHC cohort did not support ROR1 protein expression in predicting OS, and highlighted the discrepancy of prognostic biomarkers when measured by MS, IHC and RNAseq. [ABSTRACT FROM AUTHOR]

Published
2021
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28. Metabolically rewiring pancreatic stromal cells in pancreatic cancer

Author

Phillips, Phoebe, Medical Sciences, Faculty of Medicine, UNSW, Sharbeen, George, Medical Sciences, Faculty of Medicine, UNSW, McCarroll, Joshua, Children's Cancer Institute, Goldstein, David, Prince of Wales Clinical School, Faculty of Medicine, UNSW, Akerman, Anouschka, Prince of Wales Clinical School, Faculty of Medicine, UNSW, Phillips, Phoebe, Medical Sciences, Faculty of Medicine, UNSW, Sharbeen, George, Medical Sciences, Faculty of Medicine, UNSW, McCarroll, Joshua, Children's Cancer Institute, Goldstein, David, Prince of Wales Clinical School, Faculty of Medicine, UNSW, and Akerman, Anouschka, Prince of Wales Clinical School, Faculty of Medicine, UNSW

Abstract

Pancreatic cancer (PC) is a lethal malignancy characterised by chemoresistance and metastatic spread. This is largely due to the presence of dense stromal fibrosis which distorts tumour vasculature. This limits nutrient, oxygen and chemotherapy perfusion into pancreatic tumours and promotes oxidative stress. The craftsmen of fibrosis are cancer-associated pancreatic stellate cells (CA-PSCs) who drive disease progression, chemoresistance and metastasis. To survive in the tumour microenvironment, CA-PSCs and PC cells undergo significant metabolic changes. A key alteration is increased expression of nutrient transporters to promote nutrient uptake. Solute carrier transporters have gained significant attention as a novel class of therapeutic targets, particularly solute carrier transporter 7A11 (SLC7A11) and solute carrier transporter 7A5 (SLC7A5), which are upregulated in PC cells and CA-PSCs. This study aimed: (1) to assess SLC7A11 inhibition in cancer-associated pancreatic stellate cells in vitro and in a clinically relevant orthotopic mouse model of PC; and (2) to investigate the function of SLC7A5 and SLC3A2 in cancer-associated pancreatic stellate cells in vitro. This study demonstrated that inhibiting SLC7A11 in CA-PSCs reduced proliferation. This limited cystine uptake, glutathione synthesis and anti-oxidant capacity of CA-PSCs and sensitised to oxidative stress. In a co-culture setting, inhibiting SLC7A11 in both PC cells and CA-PSCs significantly reduced colony number. We evaluated the therapeutic efficacy of two different SLC7A11 inhibitors, sulfasalazine and erastin. Sulfasalazine proved ineffective at reducing orthotopic pancreatic tumour growth, indicating it cannot be repurposed as PC therapy. Excitingly, erastin showed significant anti-proliferative effects in both PC cells and CA-PSCs. In CA-PSCs, the anti-proliferative effects were mediated by the induction of both ferroptosis and apoptosis. Lastly, we observed inhibition of SLC7A5 in CA-PSCs reduced p

Published
2019

29. Identification of Novel Medulloblastoma Cell-Targeting Peptides for Use in Selective Chemotherapy Drug Delivery

Author

Tjandra, Kristel C., primary, McCarthy, Nigel, additional, Yang, Lu, additional, Laos, Alistair J., additional, Sharbeen, George, additional, Phillips, Phoebe A., additional, Forgham, Helen, additional, Sagnella, Sharon M., additional, Whan, Renee M., additional, Kavallaris, Maria, additional, Thordarson, Pall, additional, and McCarroll, Joshua A., additional

Published
2019
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30. MutY-Homolog (MYH) inhibition reduces pancreatic cancer cell growth and increases chemosensitivity

Author

Sharbeen, George, Youkhana, Janet, Mawson, Amanda, McCarroll, Joshua, Nunez, Andrea, Biankin, Andrew, Johns, Amber, Goldstein, David, and Phillips, Phoebe

Abstract

Patients with pancreatic ductal adenocarcinoma (PC) have a poor prognosis due to metastases and chemoresistance. PC is characterized by extensive fibrosis, which creates a hypoxic microenvironment, and leads to increased chemoresistance and intracellular oxidative stress. Thus, proteins that protect against oxidative stress are potential therapeutic targets for PC. A key protein that maintains genomic integrity against oxidative damage is MutY-Homolog (MYH). No prior studies have investigated the function of MYH in PC cells. Using siRNA, we showed that knockdown of MYH in PC cells 1) reduced PC cell proliferation and increased apoptosis; 2) further decreased PC cell growth in the presence of oxidative stress and chemotherapy agents (gemcitabine, paclitaxel and vincristine); 3) reduced PC cell metastatic potential; and 4) decreased PC tumor growth in a subcutaneous mouse model in vivo. The results from this study suggest MYH may be a novel therapeutic target for PC that could potentially improve patient outcome by reducing PC cell survival, increasing the efficacy of existing drugs and reducing metastatic spread.

Published
2016

32. Biochemical characterization of the multidrug regulator QacR distinguishes residues that are crucial to multidrug binding and induction of qacA transcription

Author

Peters, Kate M., Sharbeen, George, Theis, Torsten, Skurray, Ronald A., and Brown, Melissa H.

Subjects
DNA-ligand interactions -- Research, Glutamine -- Chemical properties, Glutamine -- Structure, Leucine -- Chemical properties, Leucine -- Structure, Staphylococcus aureus -- Research, Tyrosine -- Chemical properties, Tyrosine -- Structure, Biological sciences, Chemistry
Abstract

The studies on functional significance of hydrophobic, aromatic, and polar residues characteristic of the rhodamine 6G pocket and the proximal [Tyr.sup.92] which facilitated the transcriptionally active conformation are reported. The results highlight the significant role of [Leu.sup.54], [Tyr.sup.93], [Gln.sup.96], and [Tyr.sup.123] residues to QacR-mediated derepression of qacA transcription following ligand binding in the distal subpocket which might be important for the general mechanism irrespective of the bound ligand.

Published
2009

34. Identification of Novel Medulloblastoma Cell-Targeting Peptides for Use in Selective Chemotherapy Drug Delivery

Author

Tjandra, Kristel C., McCarthy, Nigel, Yang, Lu, Laos, Alistair J., Sharbeen, George, Phillips, Phoebe A., Forgham, Helen, Sagnella, Sharon M., Whan, Renee M., Kavallaris, Maria, Thordarson, Pall, and McCarroll, Joshua A.

Abstract

Medulloblastoma is a malignant brain tumor diagnosed in children. Chemotherapy has improved survival rates to approximately 70%; however, children are often left with long-term treatment side effects. New therapies that maintain a high cure rate while reducing off-target toxicity are required. We describe for the first time the use of a bacteriophage-peptide display library to identify heptapeptides that bind to medulloblastoma cells. Two heptapeptides that demonstrated high [E1-3 (1)] or low [E1-7 (2)] medulloblastoma cell binding affinity were synthesized. The potential of the peptides to deliver a therapeutic drug to medulloblastoma cells with specificity was investigated by conjugating E1-3 (1) or E1-7 (2) to doxorubicin (5). Both peptide–drug conjugates were cytotoxic to medulloblastoma cells. E1-3 doxorubicin (3) could permeabilize an in vitro blood–brain barrier and showed a marked reduction in cytotoxicity compared to free doxorubicin (5) in nontumor cells. This study provides proof-of-concept for developing peptide–drug conjugates to inhibit medulloblastoma cell growth while minimizing off-target toxicity.

Published
2020
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35. A Rationally Optimized Nanoparticle System for the Delivery of RNA Interference Therapeutics into Pancreatic Tumors in Vivo

Author

Teo, Joann, primary, McCarroll, Joshua A., additional, Boyer, Cyrille, additional, Youkhana, Janet, additional, Sagnella, Sharon M., additional, Duong, Hien T. T., additional, Liu, Jie, additional, Sharbeen, George, additional, Goldstein, David, additional, Davis, Thomas P., additional, Kavallaris, Maria, additional, and Phillips, Phoebe A., additional

Published
2016
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37. beta III-Tubulin: a novel mediator of chemoresistance and metastases in pancreatic cancer

Author

Erkan, Murat Mert (ORCID 0000-0002-2753-0234 & YÖK ID 214689), McCarroll, Joshua A.; Sharbeen, George; Liu, Jie; Youkhana, Janet; Goldstein, David; McCarthy, Nigel; Limbri, Lydia F.; Dischl, Dominic; Ceyhan, Gueralp O.; Johns, Amber L.; Biankin, Andrew V.; Kavallaris, Maria; Phillips, Phoebe A., School of Medicine, Department of General Surgery, Erkan, Murat Mert (ORCID 0000-0002-2753-0234 & YÖK ID 214689), McCarroll, Joshua A.; Sharbeen, George; Liu, Jie; Youkhana, Janet; Goldstein, David; McCarthy, Nigel; Limbri, Lydia F.; Dischl, Dominic; Ceyhan, Gueralp O.; Johns, Amber L.; Biankin, Andrew V.; Kavallaris, Maria; Phillips, Phoebe A., School of Medicine, and Department of General Surgery

Abstract

Pancreatic cancer is a leading cause of cancer-related deaths in Western societies. This poor prognosis is due to chemotherapeutic drug resistance and metastatic spread. Evidence suggests that microtubule proteins namely, beta-tubulins are dysregulated in tumor cells and are involved in regulating chemosensitivity. However, the role of beta-tubulins in pancreatic cancer are unknown. We measured the expression of different beta-tubulin isotypes in pancreatic adenocarcinoma tissue and pancreatic cancer cells. Next, we used RNAi to silence beta III-tubulin expression in pancreatic cancer cells, and measured cell growth in the absence and presence of chemotherapeutic drugs. Finally, we assessed the role of beta III-tubulin in regulating tumor growth and metastases using an orthotopic pancreatic cancer mouse model. We found that beta III-tubulin is highly expressed in pancreatic adenocarcinoma tissue and pancreatic cancer cells. Further, we demonstrated that silencing beta III-tubulin expression reduced pancreatic cancer cell growth and tumorigenic potential in the absence and presence of chemotherapeutic drugs. Finally, we demonstrated that suppression of beta III-tubulin reduced tumor growth and metastases in vivo. Our novel data demonstrate that beta III-tubulin is a key player in promoting pancreatic cancer growth and survival, and silencing its expression may be a potential therapeutic strategy to increase the long-term survival of pancreatic cancer patients., National Health and Medical Research Council (NHMRC); Cancer Council New South Wales; Cure Cancer Australia Foundation Grant; Cancer Institute NSW Fellowship; NHMRC CDF Fellowship; NHMRC Senior Research Fellowship

Published
2015

38. Correction to “Effective Delivery of siRNA into Cancer Cells and Tumors Using Well-Defined Biodegradable Cationic Star Polymers”

Author

Boyer, Cyrille, primary, Teo, Joann, additional, Phillips, Phoebe, additional, Erlich, Rafael B., additional, Sagnella, Sharon, additional, Sharbeen, George, additional, Dwarte, Tanya, additional, Duong, Hien T. T., additional, Goldstein, David, additional, Davis, Thomas P., additional, Kavallaris, Maria, additional, and McCarroll, Joshua, additional

Published
2015
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40. βIII-Tubulin: A novel mediator of chemoresistance and metastases in pancreatic cancer

Author

McCarroll, Joshua A., primary, Sharbeen, George, additional, Liu, Jie, additional, Youkhana, Janet, additional, Goldstein, David, additional, McCarthy, Nigel, additional, Limbri, Lydia F., additional, Dischl, Dominic, additional, Ceyhan, Güralp O., additional, Erkan, Mert, additional, Johns, Amber L., additional, Biankin, Andrew V., additional, Kavallaris, Maria, additional, and Phillips, Phoebe A., additional

Published
2014
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44. Effective Delivery of siRNA into Cancer Cells and Tumors Using Well-Defined Biodegradable Cationic Star Polymers

Author

Boyer, Cyrille, primary, Teo, Joann, additional, Phillips, Phoebe, additional, Erlich, Rafael B., additional, Sagnella, Sharon, additional, Sharbeen, George, additional, Dwarte, Tanya, additional, Duong, Hien T. T., additional, Goldstein, David, additional, Davis, Thomas P., additional, Kavallaris, Maria, additional, and McCarroll, Joshua, additional

Published
2013
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49. βIII-Tubulin: A novel mediator of chemoresistance and metastases in pancreatic cancer

Author

Amber L. Johns, Jie Liu, Dominic Dischl, Andrew V. Biankin, Joshua A. McCarroll, Janet Youkhana, David Goldstein, Lydia F. Limbri, Maria Kavallaris, Nigel McCarthy, Güralp O. Ceyhan, Phoebe A. Phillips, George Sharbeen, Mert Erkan, Erkan, Murat Mert (ORCID 0000-0002-2753-0234 & YÖK ID 214689), McCarroll, Joshua A., Sharbeen, George, Liu, Jie, Youkhana, Janet, Goldstein, David, McCarthy, Nigel, Limbri, Lydia F., Dischl, Dominic, Ceyhan, Gueralp O., Johns, Amber L., Biankin, Andrew V., Kavallaris, Maria, Phillips, Phoebe A., School of Medicine, and Department of General Surgery

Subjects
Oncology, medicine.medical_specialty, Blotting, Western, Mice, Nude, Apoptosis, macromolecular substances, Biology, Tubulin, Cell Line, Tumor, Pancreatic cancer, Internal medicine, medicine, Animals, Humans, Gene silencing, Anoikis, Pancreatic Cancer, Chemoresistance, Tumor growth, Metastases, Beta III-Tubulin, Neoplasm Metastasis, metastases, Cell Proliferation, Mice, Inbred BALB C, Reverse Transcriptase Polymerase Chain Reaction, Cell growth, Cell Cycle, chemoresistance, Cancer, Cell cycle, medicine.disease, Immunohistochemistry, Xenograft Model Antitumor Assays, βIII-tubulin, ddc, Gene Expression Regulation, Neoplastic, Pancreatic Neoplasms, tumor growth, RNAi Therapeutics, Drug Resistance, Neoplasm, Cell biology, Adenocarcinoma, RNA Interference, CA19-9, Research Paper
Abstract

Pancreatic cancer is a leading cause of cancer-related deaths in Western societies. This poor prognosis is due to chemotherapeutic drug resistance and metastatic spread. Evidence suggests that microtubule proteins namely, beta-tubulins are dysregulated in tumor cells and are involved in regulating chemosensitivity. However, the role of beta-tubulins in pancreatic cancer are unknown. We measured the expression of different beta-tubulin isotypes in pancreatic adenocarcinoma tissue and pancreatic cancer cells. Next, we used RNAi to silence beta III-tubulin expression in pancreatic cancer cells, and measured cell growth in the absence and presence of chemotherapeutic drugs. Finally, we assessed the role of beta III-tubulin in regulating tumor growth and metastases using an orthotopic pancreatic cancer mouse model. We found that beta III-tubulin is highly expressed in pancreatic adenocarcinoma tissue and pancreatic cancer cells. Further, we demonstrated that silencing beta III-tubulin expression reduced pancreatic cancer cell growth and tumorigenic potential in the absence and presence of chemotherapeutic drugs. Finally, we demonstrated that suppression of beta III-tubulin reduced tumor growth and metastases in vivo. Our novel data demonstrate that beta III-tubulin is a key player in promoting pancreatic cancer growth and survival, and silencing its expression may be a potential therapeutic strategy to increase the long-term survival of pancreatic cancer patients., National Health and Medical Research Council (NHMRC); Cancer Council New South Wales; Cure Cancer Australia Foundation Grant; Cancer Institute NSW Fellowship; NHMRC CDF Fellowship; NHMRC Senior Research Fellowship

Published
2015

50. The Use of Star Polymer Nanoparticles for the Delivery of siRNA to Mouse Orthotopic Pancreatic Tumor Models.

Author

McCarroll JA, Sharbeen G, Kavallaris M, and Phillips PA

Subjects
Animals, Cell Line, Tumor, Cell Proliferation drug effects, Gene Silencing drug effects, Humans, Mice, Nanoparticles therapeutic use, Pancreatic Neoplasms genetics, Polymers chemistry, Polymers pharmacology, RNA Interference drug effects, RNA, Small Interfering chemistry, RNA, Small Interfering pharmacology, Tubulin genetics, Tubulin Modulators chemistry, Tubulin Modulators pharmacology, Xenograft Model Antitumor Assays, Drug Delivery Systems methods, Nanoparticles chemistry, Pancreatic Neoplasms therapy, RNA, Small Interfering genetics
Abstract

Pancreatic cancer is a lethal malignancy which is refractory to most chemotherapy drugs. Recent landmark studies have shed new light on the complex genetic heterogeneity of pancreatic cancer and provide an opportunity to utilize "precision-based medicines" to target genes based on the genetic profile of an individual's tumor to increase the efficiency of chemotherapy and decrease tumor growth and metastases. Gene-silencing drugs in the form of short-interfering RNA (siRNA) have the potential to play an important role in precision medicine for pancreatic cancer by silencing the expression of genes including those considered difficult to inhibit (undruggable) using chemical agents. However, before siRNA can reach its clinical potential a delivery vehicle is needed to carry siRNA across the cell membrane and into the cytoplasm of the cell. Herein, we detail the methods required to use star polymer nanoparticles to deliver siRNA to pancreatic tumors in an orthotopic pancreatic cancer mouse model to silence the expression of an "undruggable" gene (βIII-tubulin) that regulates pancreatic cancer growth and chemosensitivity.

Published
2019
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