Day 2 :
1Institute of Molecular Genetics, Italy
Keynote: Tumorspheres from in vitro transformed cell lines show molecular signatures related to stemness and transformation
Time : 09:30-10:10
Chiara Mondello is Senior Researcher and Group Leader at the Institute of Molecular Genetics of the National Research Council in Pavia (Italy). Her main interests concern the study of genome instability and cellular transformation in mammalian cells. She has published more than 80 papers in peer-reviewed journals and several chapters in books. She has been the Editor of the book “Multiple Pathways in Cancer Development” (Transwell Research Network).
Evidence indicates that a subset of cells endowed with high tumorigenic potential and stemness features (cancer stem cells: CSCs) is responsible for tumor initiation and maintenance in several cancers. In this study, we used a tumor cellular model developed in our laboratory from telomerase immortalized human fibroblasts (named cen3tel) and the tumorsphere assay to possibly isolate and characterize CSCs from in vitro transformed cells. We found that cen3tel cells were able to form spheres (frequency ~ 2-10%) and sphere cells showed self renewal capacity and Sox2 overexpression, suggesting that in these populations there is a subset of cells with CSC-like features. The characterization of sphere cells revealed that they displayed the activation of pro-survival mechanisms, through the expression modulation of genes as c-MYC, GNL3 and Notch, and the tumor suppressor miR-34a, which could favor the growth of cells in suspension upon detachment from a solid support. Moreover, genome wide gene expression profiles of sphere cells relatively to adherent cells revealed an extensive transcriptional reprogramming involving several stemness and cancer-related genes, indicating that transformed cells are highly plastic entities adopting specific gene expression programs depending on different environmental conditions. However, sphere cells were only slightly more tumorigenic in vivo than adherent cells suggesting that different subpopulations can support tumorigenicity in transformed cells, highlighting a further level of complexity in tumor heterogeneity.
Gillies McIndoe Research Institute, New Zealand
Time : 10:10-10:50
Dr Tinte Itinteang serves as the current Chief Scientific Officer and the Evans Family Research Fellow of the Gillies McIndoe Research Institute (GMRI) in Wellington, New Zealand. Tinte completed medical training at the Melbourne University in 2001, and then completed his basic medical residency in New Zealand, from 2008- 2010 he completed his PhD from Victoria University of Wellington, NZ on the role of stem cells and the renin-angiotensin system (RAS) in infantile haemangioma. From 2012-2014, he was appointed as a research fellow at the Gillies McIndoe Research institute, during which time he spent six weeks at the Friedlander laboratory at The Scripps Research Institute in San Diego investigating the role of iPSCs for disease modelling. He was then appointed as the Chief Scientist of the GMRI from 2015. His work on the role of stem cells and the RAS in infantile haemangioma has been acknowledged with the International Society for the Study of Vascular Anomalies John Mulliken award as well as several national and international honours. He is the author of over 50 peer reviewed articles and over 100 presentations at international conferences.
Infantile haemangioma (IH) is the most common tumour of infancy, characterised by an initial proliferation with aggressive vasculogenesis, followed by spontaneous slow involution leaving a fibro-fatty residuum. IH affects about 10% of infants and has a predilection for female, Caucasian and premature infants. We have demonstrated the presence of embryonic-like stem cells in the endothelium of proliferating IH that express markers associated with mesenchymal and haematopoietic plasticity. These primitive cells are also the putative source of the fibro-fatty tissue that naturally occurs during involution of this tumour. This presentation focuses on the role of the primitive endothelium in the pathoetiogensis of IH and their ability to form downstream definitive mesenchymal and haematopoietic cells. It will also cover our insights into the role of the renin-angiotensin system (RAS) in the regulation of this primitive population, underscoring the novel use of RAS modulators in the treatment of problematic IH. The potential to exploit IH as a human model for directed regenerative medicine will be discussed.
Minerva Biotechnologies, USA
Keynote: Are cancer stem cells really healthy cells being reprogrammed back to a naïve stem cell state?
Time : 11:10-11:50
Cynthia Bamdad holds a BS in Physics from Northeastern University and a PhD in Biophysics from Harvard University. As a PhD candidate and without the benefit of an advisor, she invented the first electronic DNA chip that she commercialized at a California startup, which was then sold to Motorola for $300M; the chip is now the core of an FDA-approved diagnostic device marketed by Genmark. She is sole or lead inventor on over a hundred patent applications, including for novel technologies that enabled Minerva Biotechnologies’ groundbreaking discoveries in basic cancer biology.
The intersecting space between stem cells and cancer stem cells is rapidly expanding. Many of the markers, previously thought to be stem cell markers, are now being shown to be markers of metastasis as well. Similarly, metastatic markers such as CXCR4, have now been shown to be markers of the earliest stem cells, called ‘naïve’ stem cells. Here, we report the discovery of a novel stem cell growth factor, NME7-AB, that induces human stem cells to revert to the earliest naïve state. NME7-AB is naturally expressed in every cell of a human Day 3 morula, but by Day 5 is only expressed in the cells of the inner cell mass, which are naïve by definition. Although this new growth factor should be turned off for adult life, we have found it expressed in nearly every metastatic tissue we have examined. In vitro and in vivo, NME7-AB induces cancer cells to become more metastatic; they upregulate metastatic markers and form tumors in mice from as few as 50 cells. Daily injections of NME7-AB into the tumor-bearing mice caused the solid tumor cancers to metastasize. These data are consistent with the idea that cancer cells are being reprogrammed back to a stem cell-like state, wherein the metastatic cancer cells, aka cancer stem cells, are reverted all the way back to the naïve stem cell state. These data suggest that agents that inhibit naïve stem cell pluripotency or growth will also be inhibitors of cancer cells and, more particularly, cancer stem cells.
Tolero Pharmaceuticals, Inc., USA
Keynote: Defining and exploiting the clinical mechanism of activity for alvocidib in acute myeloid leukemia patients
Time : 11:50-12:30
Steven L Warner specializes in small molecule drug discovery, new screening platforms in drug discovery, and translational research focusing on cancer therapeutics. He is an expert in the discovery of novel cancer agents and has played integral roles in moving multiple compounds into clinical trials. He earned his graduate degree in Pharmaceutical Sciences at the University of Arizona. He completed a postdoctoral fellowship under the mentoring of Dan Von Hoff at the Translational Genomics Research Institute (TGen). He is currently the Vice President of Drug Discovery and Development at Tolero Pharmaceuticals.
Alvocidib drug development has largely focused on the inhibition of cell cycle regulating CDKs. However, recent clinical activity in leukemia is not fully accounted for by cell cycle inhibition. We set out to more fully understand the mechanism of alvocidib particularly in leukemia patients that were benefiting significantly from the treatment. In addition to the cell cycle regulating CDKs, alvocidib has very potent activity against CDK9 (IC50=1.5 nM). CDK9 is responsible for controlling the transcriptional pause release that is important for the expression of certain genes. One of the most universally regulated transcripts by CDK9 is the anti-apoptotic family member, MCL-1, a member of the BCL-2 family involved suppressing cell death. Alvocidib treatment results in a concentration and time-dependent inhibition of MCL-1 expression in cancer cells. To further validate the CDK9/MCL-1 axis as the therapeutic target of alvocidib in, we utilized an approach called mitochondrial profiling to interrogate the dependencies that leukemia cells have on BCL-2 family members and retrospectively screened archived patient samples from a previously completed phase II clinical trial. We discovered that the patients that had a strong dependency on MCL-1, identified by a high NOXA priming score, where those that showed profound benefits from alvocidib. These findings led us to conduct an on-going phase II prospective biomarker trial where we are prescreening patients for NOXA priming and enrolling patients with a score ³40%. Taken together, these results highly support the conclusion that alvocidib works through a mechanism that targets CDK9 activity and MCL-1 expression.