Day 2 :
- Track 5: Novel Approaches to Cancer Therapeutics
Track 6: Cancer Therapy and Clinical Cancer Research
Deakin University, Australia
Title: Multifunctional Locked Nucleic Acid Modified Chimeric Survivin Targeted Nano-bullets Against Cancer Stem Cells
Time : 09:00-09:25
Jagat Kanwar is group leader and head of the Nanomedicine and Laboratory of Immunology and Molecular Biomedical Research has an international reputation in investigating fundamental and applied molecular aspects of cancer and chronic inflammation. Our nanomedicine laboratory of immunology and molecular biomedical research (NLIMBR) is discovering the novel and safe targeted nanomedicine based nano-nutraceuticals for cancers, autoimmune disorders and inflammatory diseases. We also vested the molecular diagnosis including role of a non-invasive exosomes in blood, inflammatory sites and cancer tissues. Our research focused on cancer and inflammatory autoimmune diseases aims to investigate the underlying mechanisms involved in apoptosis, autophagy and inflammation by targeting the production of cytokines, chemokines, oxygen radicals and matrix metalloproteinase.
Theranostics, the combination of diagnostics and therapies is a new concept in cancer management. Our published work strongly suggests that orally administered multifunctional targeted “nano-bullets” (nanocarriers; NCs) with iron saturated bovine lactoferrin (Fe-bLf) were able to kill tumours. Here for the first time, we are developed multifunctional-targeted nanocapsules conjugated with stably modified aptamers to target and kill cancer as well as cancer stem cells. These nanocapsules labeled with biosensors, will deliver anti-cancer molecules to colon tumours and help to monitor the therapy in real-time imaging. A cell permeable dominant negative mutant form of survivin (dNSurR9C84A), dNSurR9C84A has shown promising anticancer properties by inhibition of survivin and reduces the chance of side effects since survivin is not expressed in normal cells in an adult. However due to short half-life of dNSurR9C84A a drug delivery system based on low molecular weight chitosan was used which could prolong the bioavailability of dNSurR9C84A. These chitosan nanoparticles were well characterized before examining effects on colon cancer cells (Caco-2). The nanoparticle transport studies were carried out both in vitro and ex vivo in order to understand the mechanism of low molecular weight chitosan nanoparticles with intestinal cells. The in vivo Biodistribution studies showed a highly selective and specific patter of uptake of the targeted nanocarriers or “nanobullets” (CHNP-dNSurR9C84A-LNA-Nu+Ep) in the tumour. The targeted nanocarriers were also able to significantly inhibit the tumour volume up to a period of 95 days. These nanobullets showed specific internalization in cancer stem cells and led to cancer stem cells specific apoptosis, thus proved to be appropriate for oral administration in colon cancer
University of New South Wales, Australia
Title: The BET bromodomain inhibitor JQ1 and the histone deacetylase inhibitor panobinostat induce synergistic anticancer effects by repressing LIN28B and N-Myc expression
Time : 09:25-09:50
Jeyran Shahbazi is working as a Research Officer at Children's Cancer Institute, Lowy Cancer Research Centre, UNSW. Her research interests include Cell Biology, Cancer Research, Molecular Biology.
Patients with neuro blastoma associated with MYCN oncogene amplification experience a very poor prognosis. BET bromodomain inhibitors are emerging as one of the most promising novel classes of anticancer agents by blocking the BET bromodomain proteins BRD3 and BRD4 from activating transcription of oncogenes such as MYC and MYCN. However, treatment with BET bromodomain inhibitors alone does not result in cancer remission. Here we show that BRD3 and BRD4 directly bound to the LIN28B gene promoter and activated LIN28B gene transcription, and that knocking down LIN28B expression reduced the expression of N-Myc protein, but not N-Myc mRNA. Combination therapy with the BET bromodomain inhibitor JQ1 and the histone deacetylase inhibitor panobinostat synergistically suppressed LIN28B gene expression, reduced N-Myc mRNA expression to the same extent as JQ1 treatment alone, but considerably and synergistically reduced N-Myc protein expression. JQ1 and panobinostat induced synergistic growth inhibition and apoptosis in neuroblastoma cells, but not normal non-malignant cells in vitro. Importantly, in neuroblastoma-bearing mice, JQ1 and panobinostat combination therapy synergistically and considerably reduced N-Myc protein expression in tumor tissues and blocked tumor progression. Our findings have therefore identified a potential strategy to reduce N-Myc onco-protein expression and a novel therapeutic approach for the treatment of aggressive neuroblastoma.
Zhejiang University, China
Title: Dual inhibition of Cdc7 and Cdk9 by PHA-767491 suppresses hepatocarcinoma synergistically with 5-fluorouracil
Time : 09:50-10:15
Xi Chen got her MD degree from Peking University Health Science Center, China and later a PhD degree in Biochemistry from King’s College London, UK. Her Postdoctoral training was received in the University of Pittsburgh, USA. She started working as an Associate Professor in Zhejiang University since 2011. She is also the Deputy Director of the central lab of the Children’s Hospital, Zhejiang University School of Medine. She has published 15 peer-reviewed papers in scientific journals and presented in several international conferences. Her current research interest focuses on the treatment of cancer.
Activation of checkpoint kinase 1 (Chk1) is essential in chemo resistance of hepatocarcinoma (HCC) to5-fluorouracil (5-FU) and other anti metabolite family of drugs. In this study, we demonstrated that PHA-767491, a dual inhibitor of two cell cycle checkpoint kinases, cell division cycle kinase 7 (Cdc7) and cyclin-dependent kinase 9 (Cdk9) has synergistic antitumor effect with 5-FU to suppress human HCC cells both in vitro and in vivo. Compared with the sole use of each agent, PHA-767491 in combination with 5-FU exhibited much stronger cytotoxicity and induced significant apoptosis manifested by remarkably increased caspase 3 activation and poly (ADP-Ribose) polymerase (PARP) fragmentation in two HCC cell lines BEL-7402 and Huh7. PHA-767491 directly counteracted the 5-FU-induced phosphorylation of Chk1, a substrate of Cdc7 and decreased the expression of the anti-apoptotic protein myeloid leukemia cell 1 (Mcl1), a downstream target of Cdk9. In tumor tissues sectioned from nude mice HCC xenografts, administration of PHA-767491 also decreased Chk1 phosphorylation and increased in situ cell apoptosis. Our study suggests that PHA-767491 could enhance the efficacy of 5-FU by inhibiting Chk1 phosphorylation and down-regulating Mcl1 expression through inhibition of Cdc7 and Cdk9, thus combinational administration of PHA-767491 with 5-FU could be potentially beneficial to patients with advanced and resistant HCC.
University of Queensland, Australia
Title: Controlling the calcium to phosphate ratio in preparation of lipid coated calcium phosphate nanoparticles to enhance gene delivery to breast cancer cells
Time : 10:15-10:40
Jie Tang completed her MPhil from West China School of Pharmacy, Sichuan University. She is now studying as a PhD candidate sponsored by Chinese Scholarship Council and UQI scholarship in Australian Institute for Bioengineering and Nanotechnology, the University of Queensland. She has published more than 5 papers in high impact journals in the field of cancer therapy.
Lipid-coated calcium phosphate (LCP) nanoparticles (NPs) remain an attractive option for siRNA systemic delivery for anti-cancer treatment. Previous researchers revealed the influence of the stoichiometry of reactants on the size and morphology of nanostructured calcium phosphate (CaP) particles. There are very few reportson investigating the influence of synthesis parameters such as the Ca/P molar ratio and mixing style on the siRNA loading onto LCP NPs and protection by LCP NPs and subsequent siRNA delivery efficiency. Thus in this research, we examined the effect of Ca/P molar ratio on the size, zeta potential, dispersion and siRNA loading onto LCP NPs and optimized the Ca/P molar ratio in terms of the siRNA loading efficiency and siRNA protection from enzyme degradation. Our data indicated that the particle size and zeta potential of LCP NPs decreased with an increase of the Ca/P molar ratio from 25 to 100 and was maintained at 40 nm and -20 mV when the ratio was over 100. Interestingly, LCP particles synthesized at a lower Ca/P ratio exhibited higher gene encapsulated efficiency (i.e., higher percentage of gene loaded from reaction solution) and provided more effective protection of siRNA from degradation by serum-derived nucleases but had a decreased gene loading capacity per particle. LCP NPs synthesized at the optimized Ca/P ratio (100) had a hollow, spherical structure with an average size of about 40 nm and were able to maintain their stability in serum containing media and PBS for over 24 hours. Moreover, LCP NPs exhibited a growing dissolution in aqueous solutions with a lower pH value indicating that the siRNA release from LCP NPs is pH sensitive. The superior ability of optimized LCP NPs to maintain the integrity of encapsulated siRNA and the colloidal stability in culture medium of the nanoparticles allow this formulation to achieve improved cellular accumulation of siRNA and enhanced growth inhibition (a two-fold high than OligofectamineTM) of human breast cancer cells in vitro.
University of California, USA
Title: Pilot study comparing the Pharmacokinetics of Sorafenib in the Asian-American population vs. Non-Asian Population in the Treatment of Hepatocellular Carcinoma
Time : 10:40-11:05
David K Imagawa is a Professor of Clinical Surgery and Chief in the Division of Hepatobiliary and Pancreas Surgery/Islet Cell Transplantation in the University of California. His research interest are Liver and pancreatic diseases, bile duct and pancreatic tumor resections, bile duct injuries, biliary reconstruction, minimal invasive treatment of advanced liver tumors, laparascopic, ultrasound guided radiofrequency ablation, biliary reconstruction, pathogenesis of chronic rejection, liver cancer, hepatocellular carcinoma, liver tumor, post transplant hyperlipidemia, clinical trials of novel chemotherapeutic agents, Therasphere, Cirtex, Metabasis, gene therapy for immunosuppression, reperfusion injury in transplantation, islet cell transplantation for complicated Diabetes Mellitus Type I, mechanism of immunomodulation, hepatitis screening, organ donation.
Sorafenib is the only FDA approved agent that has been shown to prolong survival in unresectable hepatocellular carcinoma (HCC). The recommended dose is 400mg BID. Our anecdotal experience has shown that the majority of our Asian-American patient populations are unable to tolerate this recommendation. This is a pilot study aimed at evaluating a potential difference in pharmacokinetics (PK) of Sorafenib metabolism between the Asian-American (AA) and Non-Asian (NA) patient population. A cohort of 23 patients completed the study. The PK of Sorafenib and its main metabolite M-2 were analyzed at 0, 1, 2, 4, 9 and 12 hours respectively. A subset analysis comparing high dose (>400mg daily) vs. low dose (≤400mg daily), high body surface area (BSA>1.9) vs. low body surface area (BSA≤1.9) and AA vs. NA patients was preformed. 18 patients were in the low dose cohort with 2 mortalities (749 and 283 days) and 1 patient achieving complete response (201 days). There were no deaths in the high dose group. There were no significant differences in the PK of Sorafenib and M-2 between the high and low dose groups nor the high and low BSA groups. Despite the difference in dose, the mean Sorafenib AUC and Cmax of the low dose group was at least 70% of the high dose group at steady state. Furthermore, the mean Sorafenib AUC and Cmax of the low BSA cohort was at least 75% of the high BSA group at steady state. There were no significant differences in the PK between the AA and NA groups. Our analysis reveals a trend towards comparable PK of Sorafenib and M-2 metabolite despite lower doses and lower BSA. These findings suggest that a lower, more tolerable dose of Sorafenib in AA patients may not compromise drug efficacy. Large, population based studies are needed to validate these findings.
University of Queensland, Australia
Title: Using layered double hydroxides nanoparticle conjugated with CpG to polarise immune responses from Th2 to Th1 bias
Time : 11:20-11:45
Zhi Ping (Gordon) Xu is an Australian Research Council (ARC) Future Fellow (2013-2016). Since 2004, He has received a number of fellowships and awards, including an ARC Australian Postdoctoral Fellowship (2005-2007), ARC Australian Research Fellowship (2008-2012), and UQ Foundation’s Research Excellence Award (2009). Associate Professor Xu and his colleagues have received funding from the ARC and National Health and Medical Research Council (NHMRC) totalling more than $5 million. Associate Professor Xu is an ARC and NHMRC referee.
Vaccine is one of the promising treatments in cancer therapy. Modulation of immune response is very important in the induction of humoral or cellular immunity, which will affect vaccine efficiency. Here we have tailored an anionic clay nanomaterial to specifically load the model antigen obalbumin (OVA) and the toll-like receptor ligand CpG in combination to modulate the immune response from Th2 bias towards the preferred polarity Th1 for anti-cancer purpose. Alum is a vaccine adjuvant approved for human use by FDA, while it has a severe inflammatory response and cannot modulate the immune response. The anionic clay, MgAl-layered double hydroxide (LDH) nanomaterial, has a similar chemical composition to Alum, but distinct properties. For example, MgAl-LDH nanoparticles can strongly interact with and carry proteins and gene materials for cellular delivery. In this research, using MgAl-LDH to carry OVA induced a comparable antibody response to Alum. In sharp contrast, combination of CpG to LDH-OVA resulted in much higher IgG2a:IgG1 ratio than that in the case of Alum, demonstrating polarisation of the immune response from Th2 towards Th1. Moreover, CpG-OVA-loaded LDH retarded tumour growth in vivo, further confirming LDH-CpG adjuvant activity. Therefore, MgAl-LDH nanomaterial has the great potency to be a vaccine adjuvant for switching Th2 to Th1 dominant immune responses.
The Chinese University of Hong Kong, China
Title: Mechanistic studies on the anti-tumor effects of indirubin-3’-oxime on human neuroblastoma cells
Time : 11:45-12:10
K.N. Leung graduated with a B.Sc. Degree in Biochemistry (First Class Honors) from The Chinese University of Hong Kong (CUHK) and obtained a Ph.D. Degree in Microbiology and Immunology from the John Curtin School of Medical Research, Australian National University. After two years of postdoctoral work at the Pathology Department of the University of Cambridge, he returned to the CUHK as a Lecturer in the Department of Biochemistry in 1983. K.N. Leung is now a Professor in the School of Life Sciences, CUHK and was appointed as Assistant Dean of the Faculty of Science in 2007, and then Associate Dean (Education) of the Faculty of Science in 2014. He was the chairman of the Hong Kong Society for Immunology from 2000-2002. He has served the Editorial Boards of several international journals and as a peer reviewer for 15 journals. He has over 30 years of experience in teaching and research in Immunology and Cancer Biochemistry. His main research interests include immunopharmacological studies of food components, natural products and Chinese medicinal herbs, cancer immunotherapy, and molecular studies of leukemic cell proliferation, differentiation and apoptosis..
Neuroblastoma is the most common extracranial solid tumor found in infancy and childhood and accounts for ~15% of all childhood cancer-related deaths. Naturally-occurring compounds that can inhibit neuroblastoma cell proliferation or trigger them to undergo apoptosis have attracted increasing interest as an alternative therapy for human neuroblatoma. Indirubin-3’-oxime (I3M), an indigo alkaloid, was found to exhibit potent anti-tumor activities on various types of cancer cells. However, its modulatory effects on human neuroblastoma and the underlying mechanisms remain poorly understood. Our results showed that I3M inhibited the growth of the human neuroblastoma LA-N-1, SH-SY5Y and SK-N-DZ cells in a concentration- and time-dependent manner with minimal cytotoxicity on normal cells. Mechanistic studies showed that I3M specifically decreased the expression of mitochondrial regulators ERR and PGC-1 and resulted in decreased mitochondrial mass and mitochondrial membrane potential in LA-N-1 cells. I3M also increased the level of CDK inhibitor p27Kip1 and reduced the levels of CDK2 and cyclin E in LA-N-1 cells, leading to cell cycle arrest at the G0/G1 phase. Studies on the anti-angiogenic activities showed that I3M inhibited the in vitro proliferation, migration, and tube formation of the human microvascular endothelial HMEC-1 cells in a concentration-dependent manner and significantly suppressed the in vivo angiogenesis in Matrigel plugs in mice. Moreover, I3M also down-regulated the expression of Ang-1 and MMP2 genes and up-regulated the expression of Ang-2 gene in HMEC-1 cells. Collectively, our results indicate that I3M might exert its anti-tumor activity by causing mitochondrial dysfunction which led to cell cycle arrest in LA-N-1 cells or through expression of its anti-angiogenic activities. Therefore, I3M might be exploited as a potential therapeutic candidate for the treatment of some forms of human neuroblastomas
Advanced Centre for Treatment Research and Education in Cancer, India
Title: Inverse regulatory role of p53 modulating human sodium iodide symporter gene expression in breast cancer
Time : 12:10-12:35
Madhura G Kelkar has completed her Master’s degree in Life Sciences from Mumbai University. She has cleared national level entrance exams including GATE and CSIR-UGC-NET. Currently, she is enrolled to Homi Bhabha National Institute (HBNI) for the Doctorate study. During her PhD course, she has published papers in peer-reviewed reputed journals like Current Opinion in Pharmacology and Cell. She had also attended national and international conferences
Human Sodium Iodide Symporter mediated (NIS) radio iodide accumulation is the basis of effective targeted radio iodide therapy in differentiated thyroid cancers. NIS is aberrantly expressed in majority of the breast cancer (BC) subtypes although its relevance and regulation is poorly understood. To get an insight on NIS transcriptional regulation, we have identified the presence of three putative regulatory p53-binding sites on full-length human NIS promoter by genome wide in silico analysis. Since p53 mutations in BC are frequently observed, we have investigated the role of p53 in NIS regulation. Over expression of wild type p53 as a transgene or activation of endogenous p53 by doxorubicin (DR) treatment in BC cell lines results in significant reduction of promoter activity. Further the siRNA-mediated p53 knockdown effect shows reversal on reduced transcript (p<0.005). Abrogation of p53 binding sites by site directed mutagenesis also results in significant increase in promoter activity (p<0.05) indicating NIS-promoter repression is p53-dependent. Further, direct binding of p53 to human NIS promoter is also confirmed by chromatin immunoprecipitation analysis. As a result of endogenous p53 activation by DR, cellular NIS protein content is also reduced and thus impacting NIS-mediated iodide uptake significantly (p<0.05). Further, DR drug effect is validated in breast cancer xenograft model by optical bioluminescence imaging. This study provides novel information revealing complete biochemical and functional basis to show that human NIS is a direct target of p53 in BC cells. Our study opens up a scope for establishing link between aberrant NIS expression and p53 mutations in BC patients.
University of Queensland, Australia
Title: Layered double hydroxide (LDH) nanoparticles are developed as highly efficient siRNAs carriers
Time : 12:35-13:00
Yanheng Wu is a recipient of UQ international PhD scholarship at the Australian Institute of Bioengineering and Nanotechnology of the University of Queensland.
RNA interference (RNAi) is mediated by small RNAs including small interfering RNAs (siRNAs) that direct the sequence-specific degradation of the target mRNA, making it a powerful tool for the treatment of various genetic disorders, viral infections and cancers. One of the major impediments to the clinical application of RNAi-based therapy is the need to deliver these molecules into targeted cells. Although a variety of packaging particles are currently under development as siRNA delivery systems, application of these technologies has been hindered by their high cytotoxicity, low drug loading capacity, inefficient release in cells and poor ability to penetrate cell membranes. Layered double hydroxide (LDH) nanoparticles, a family of anionic clay materials are now emerging as a potential new gene delivery system as they exhibit low cytotoxicity and high biocompatibility. In this study, we prepared LDH nanoparticles with the average particle size of 110 nm and investigated the loading capacity of oligo dsDNA (a mimic of siRNA) by LDH nanoparticles at the dsDNA:LDH mass ratios from 1:1 to 1:40. We further examined the LDH-mediated siRNA delivery to nasopharyngeal cancer cell line CNE2. In particular, we showed the effect of the dsDNA:LDH mass ratio on the dsDNA delivery efficiency to the cells. We found that the cell line took up the most dsDNA via the LDH nanoparticles at the dsDNA:LDH mass ratio between 1:10 and 1:30. The optimized mass ratio is probably resulted from the tradeoff between the loading amount and the carrier dose effect. We finally demonstrated that the use of the optimized ratio to deliver functional siRNA to treat cancer cells (CNE2) was highly efficient. This work proves convincing evidence that LDH nanoparticles can be used as an efficient siRNA delivery vector.
Tan Shian Ming completed his MBBS in 2003 from National University of Singapore and attained his Masters of Medicine (Psychiatry) Postgraduate degree in 2013. He is currently an Associate Consultant Psychiatrist in Singapore General Hospital, a tertiary hospital with a designated oncology center. He has published papers on psycho-oncology and had previously presented in local and international conferences.
Despite the advances in medical treatment, receiving a diagnosis of cancer conjures up in many, the spectre of morbidity and mortality. Often viewed as a death sentence, grappling with the challenges of living with cancer sits uncomfortably in most individuals and evokes a vast range of overwhelming emotions. These psychological responses may sometimes manifest as depression and anxiety disorders; conditions that oncologists may not be confident in addressing. This oral presentation gives an overview of the common psychiatric conditions arising in oncology patients including clinical presentation and general management considerations. At the same time, it provides insight to the challenges in determining the fine line that separates psychiatric illness from normal psychological reactions in oncology patients and suggests answers to mitigate this conundrum.