Day 2 :
Keynote Forum
Al Charest
Beth Israel Deaconess Medical Center Cancer Center, USA
Keynote: PDGFRα signaling strength confers sensitivity to vinblastine in glioblastoma
Biography:
Alain Charest, MSc, PhD is an Associate Professor in the Department of Medicine at Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA. Dr. Charest received his postgraduate degrees at McGill University, Montreal, Canada. The focus of the Charest laboratory is on leveraging clinically relevant genetically engineered mouse models of primary malignant brain cancer to study central aspects of gliomagenesis and molecular responses to therapeutic interventions. Recent work from the Charest lab involves studies on how PDGFRa signaling strength confers sensitivity to chemotherapeutic agents in Glioblastoma Multiforme.
Abstract:
The PDGF Receptor alpha is overexpressed and activated in a substantial number of Glioblastoma (GBM) tumors. Although the activation of PDGFRα in GBM is chronic in nature, our knowledge of PDGFR signaling pathways is largely derived from acute stimulation studies, which are less representative of the clinical setting. In order to decipher the identity and clinical significance of sustained PDGFRα signaling during tumorigenesis and to reveal therapeutic vulnerabilities, we created a novel genetically engineered conditional mouse model based on genomic events that are observed in patients, that is the overexpression of PDGFRα and its chronic activation by PDGF-A ligand in the context of loss of function of the p53 tumor suppressor gene. To broaden its clinical relevance, we created our model system with a titratable expression of PDGF-A, which is specific for PDGFRα homodimers. De novo intracranial PDGF-A;PDGFRα tumors arise in these mice with full penetrance and short latency and display histological and molecular features that are consistent with Proneural GBMs. Tumor growth in animals was intimately related to the levels of PDGF-A ligand expression, suggesting differences in cellular signaling in tumors with low and high levels of activated receptors. Indeed, global phospho- (pTyr, pSer/pThr) and total proteomic analyses on cells derived from PDGFRα-positive GBMs revealed that the strength and utilization of specific signaling pathways are dependent on the levels of PDGFRα activation. Further investigation of these pathways unveiled a role for the microtubule binding protein Stathmin 1 (STMN1) in the vulnerability of these GBM cells to the microtubule-disrupting drug vinblastine. Our results open the possibility that GBM patients whose tumors express active PDGFRα could benefit from treatments with vinca alkaloid type of therapeutic agents. Our observations also argue strongly for the development of inhibitors of STMN1 function for the treatment of PDGFRα positive GBMs.
Keynote Forum
Jianyu Rao
David Geffen School of Medicine-UCLA, USA
Keynote: Nanocytology as a novel biomarker for cancer
Biography:
JianYu Rao is an Professor of Pathology and epidemiology, Chief of Cytopathology and Director of Gynecological Pathology. He is a surgical pathologist and cytopathologist specialized in genitourinary tract and gynecological pathology. He is also a molecular epidemiologist and cancer cell biologist. He did his training of Anatomic and Clinical pathology as well as Cytopathlogy here at UCLA from 1994 to 1999. He became the faculty at Department of Pathology and Lab Med since 1999.
Abstract:
The hallmark of cancer is the invasive and metastatic nature of the disease. Cancer cell invasion and metastasis are partly regulated by altered cytoskeletal structures that result from the complex interplay of activation/inactivation of multiple signaling pathways regulating these cellular events, which can occur at either the genetic or epigenetic level. Thus, attempts to accurately assess these physiologically relevant mechanical properties of cancer cells using single, or even multiple marker profiles at the DNA, RNA, or protein level, may not be effective. Recently, we showed that cancer cell mechanical properties, or mechanotypic biomarkers, including cell elasticity and deformability can be directly and accurately measured by state of the art, label-free technologies at the single cell level. These mechanical properties of cells can be a marker for cancer cell behavior including invasion, metastasis and drug response. We developed an approach that uses mechanotypic profiling to complement morphological and molecular analyses, a process called “Nanocytology” which collectively enable robust and high throughput measurements and can potentially be implemented even in resources poor areas. The nanocytology approach combined with targeted delivery of nanoparticles with molecular-tailored anti-cancer agents may provide a more effective alternative for cancer detection and management.
Keynote Forum
Andrea Nicolini
University of Pisa, Italy
Keynote: Immunotherapy in endocrine dependent metastatic breast cancer
Biography:
Nicolini graduated (summa cum laude) at School of Medicine, University of Pisa in 1974. He received postgraduate diplomas at University of Pisa in Internal Medicine (1980), Pneumology (1984), and Nuclear Medicine (1986). His research interests include breast and gastrointestinal cancer and their metastases, tumour markers, post-operative follow-up, physiopathology, immunology and immunotherapy of cancer, and thyroid tumours.
Abstract:
Hormone therapy is advised for ER+ metastatic breast cancer patients due to its efficacy concomitant with low toxicity; however, in most patients the occurrence of resistance is a not well yet understood hurdle to overcome. In these patients, during clinical benefit (CB) from conventional anti-estrogens, the addition of cycles of sequential immunotherapy could prolong the benefit and delay the arising of acquired hormone resistance. In order to validate this hypothesis, in 1992 we started an open exploratory clinical trial. Forty-two (42) of these patients in CB during first line anti-estrogen salvage therapy also received beta-interferon (INF-beta) 3,000,000 IU i.m./day 3 days/week, weeks 1-4 and successively recombinant interleukin-2 (IL-2) 3,000,000 IU s.c./day 3 days/week, weeks 5-8 until progression. The immunotherapy cycle lasted 10 weeks and the patient continued anti-estrogen alone during weeks 9-10, the 11th week being the first week of the successive cycle. At each control visit, routine laboratory examinations and serum measurement of a CEA-TPA-CA15.3 tumor marker (TM) panel were carried out, and an immunological assessment was made (total lymphocytes, CD4+, CD8+, NK cells, T-reg, IL-6, IL-10, IL-12, TNFa, TGFbeta1 and IFN-gamma.). The addition of INF-beta-IL-2 sequence significantly prolonged clinical benefit and overall survival from conventional anti-estrogens. During CB as opposed to progression, a significant immune stimulation was observed. During CB also a significant CEA, TPA, CA15.3 decrease occurred 24–72 h after interleukin-2 administration. At the progression a significant increase for CEA and for all 3 markers (standardized values) was found 24–72 h after interleukin-2 administration. In patients who survived less than 5 years, the Treg cell increase occurred at a significantly shorter time interval than in those who survived longer than 5 years (20 vs. 45.5 months, respectively; P=0.001). To further confirm these promising results, a multicenter prospective phase II trial is going to be launched by the Cancer Center Institute of Tuscany in Italy.