Annual Summit on Cell Therapy and Molecular Medicine September 27-28, 2017
(10 Plenary Forums - 1Event)
Chicago, Illinois, USA

Biography:

Jindan Yu is a member of Department of Biochemistry and Molecular Genetics. She is currently working in Northwestern University as an Associate Professor in Medicine Department.

Abstract:

Signal transduction through the hormonal transcription factor Androgen Receptor (AR) is a major driver of prostate cancer initiation and progression. FOXA1, a transcription factor of the FKHD family, was recently found to be among most frequently mutated genes in both localized prostate cancer (PCa, 3.4%) and castration-resistant prostate cancer (CRPC, 12%). Further, we found that FOXA1 mRNA expression is transiently up-regulated in PCa, but ultimately down-regulated in CRPC, suggesting context dependent roles. How FOXA1 regulates hormone-naïve primary PCa and hormone-insensitive CRPC has not been carefully examined. Through genomic analysis, here we report that FOXA1 regulates two essential oncogenic processes via disparate mechanisms. FOXA1 inhibits cell motility, epithelial-to-mesenchymal transition (EMT), and tumor metastasis through modulating SLUG. On the other hand, FOXA1 regulates cell proliferation by monitoring the genomic actions of the AR; FOXA1 defines prostate-specific AR cistrome and FOXA1 loss in CRPC cells emancipates oncogenic AR activities. Moreover, FOXA1 loss in PCa leads to neuroendocrine prostate cancer, a final-stage, lethal disease with no effective treatment. This is in part mediated by the induction of interleukin 8 (IL-8) transcriptions and subsequent ERK activation. In summary, we propose a model wherein homeostasis between FOXA1 and AR levels is critical in defining prostatic AR signaling and preventing AR from oncogenic activation. FOXA1 plays important roles in maintaining the prostate lineage; therapeutic approaches that restore FOXA1 function may be useful in the treatment of late-stage CRPC patients.

Biography:

Guoan Chen is a Research Assistant Professor in the Section of Thoracic Surgery at the University of Michigan Medical School. He completed his PhD from Peking Union Medical College in 1999 and Post-doctoral training in tumor molecular biology at the University of Michigan in 2003. He has over 15 years of research experience in identification and characterization of molecular genetic alterations including protein profiles, autoantibody profiles, gene mutations, DNA copy number changes by SNP, DNA methylation, gene signatures by mRNAs, microRNA profiles, circRNAs and long non-coding RNAs in lung cancer using functional genomic, proteomics and bioinformatics approaches with more than 80 papers in reputed journals.

Abstract:

Lung cancer is a molecularly-heterogenous disease and the leading cause of cancer mortality. The molecular basis for this clinical heterogeneity remains incompletely understood. Increasing appreciation of the role of long non-coding RNAs (lncRNAs) in cancer progression has led to the identification of these molecules as a largely uncharacterized aspect of disease biology and novel prognostic/diagnostic biomarkers. We recently generated transcriptome data using next-generation RNA sequencing (RNA-Seq) to reveal lncRNA expression patterns in lung cancer. Preliminary studies have identified several novel lncRNAs which were dysregulated in lung cancer. LINC00857, as one of the top dysregulated lncRNAs, was highly expressed in lung cancer and significantly related to poor survival in patients with lung adenocarcinomas. This was verified by several lung data sets and confirmed by RT-PCR in an independent data set. Functional studies of in vitro and in vivo models indicated that LINC00857 plays an important role in lung cancer proliferation, invasion and cell cycle regulation. Mechanistic studies indicated that LINC00857 mediated tumor growth potentially through regulation of autophagy via YBX1-MET/AMPKa axis in lung cancer cell lines. The study provided a comprehensive analysis of lncRNAs in lung adenocarcinomas. It established the role of LINC00857 as a potential driver of lung cancer pathogenesis and a potentially as a new diagnostic/prognostic biomarker. Importantly this study may help identify new molecular targets or a predictive marker for lung cancer treatment in tumors with TP53, KRAS or EGFR mutations, as well as ALK fusion.

Biography:

Qi Cao earned his PhD in Pathology from the University of Michigan in 2008. He was a Research Investigator in the Department of Pathology at the University of Michigan before becoming a member of the Houston Methodist Research Institute in 2013. He is an Assistant Professor of Inflammation and Epigenetics, Institute for Academic Medicine at Houston Methodist, and Assistant Professor of Microbiology and Immunology, Weill Cornell Medical College. He has been working on the functions of polycomb group proteins in prostate and breast cancer for over 10 years.

Abstract:

Prostate cancer (PCa) is the second leading cause of cancer-related deaths in American men, excluding skin cancer. Although most cases will be effectively treated with chemotherapy and/or radiotherapy, 11% of patients diagnosed with PCa will acquire recurrent and/or metastatic disease with a mortality rate of nearly 100%. Androgen receptor (AR) signaling plays a critical role in prostate cancer progression. However, androgen depletion therapy has proven ineffective. Patients relapse and develop castration-resistance. Therefore, identification of novel molecular targets is essential for the development of new treatments. Epigenetic modifiers, such as polycomb group (PcG) proteins, are also crucial in cancer initiation, progression, and metastasis by modifying histones and non-histone proteins. Two polycomb repressive complex 1 (PRC1) proteins, RING1B and BMI1, are essential for PCa stem cell maintenance and are associated with PCa metastasis. However, the precise role of the PRC1 complex remains unclear. B lymphoma Mo-MLV insertion region 1 homolog (BMI1) has been shown associating with metastatic prostate cancer by cDNA microarray analyses and tissue microarray analysis. BMI1 is an epigenetic component of a polycomb repressive complex 1 (PRC1), maintaining gene repression. We have demonstrated that BMI1 promotes prostate cancer progression by repressing multiple tumor suppressors. Here we discovered a novel function of BMI1 in prostate cancer by regulating androgen receptor (AR) protein and pathway. Furthermore, our pre-clinical tests demonstrated that BMI1 is therapeutic target for advanced prostate cancer patients.

Biography:

Zhaoyu Li has completed his PhD from University of Alberta and Post-doctoral studies from University of Pennsylvania School of Medicine. He is an Assistant Professor of Cancer Biology at Mayo Clinic. He has published more than 20 papers in reputed journals and has been serving as an Editorial Board Member of repute.

Abstract:

A transcription factor functions differentially and/or identically in multiple cell types. However, the mechanism for cell-specific regulation of a transcription factor remains to be elucidated. We address how a single transcription factor, forkhead box protein A1 (FOXA1), forms cell-specific genomic signatures and differentially regulates gene expression in four human cancer cell lines (HepG2, LNCaP, MCF7, and T47D). FOXA1 is a pioneer transcription factor in organogenesis and cancer progression. Genomewide mapping of FOXA1 by chromatin immunoprecipitation sequencing annotates that target genes associated with FOXA1 binding are mostly common to these cancer cells. However, most of the functional FOXA1 target genes are specific to cancer cell type. Further investigations using the CRISPR-Cas9 genome editing technology indicate that cell-specific FOXA1 regulation is attributable to unique FOXA1 binding, genetic variations, and/or potential epigenetic regulation. Thus, FOXA1 controls the specificity of cancer cell types. We raise a flower-blooming hypothesis for cell-specific transcriptional regulation from these observations.

Biography:

Qiou Wei after obtaining his MD from Chongqing Medical University and PhD from the University of South Dakota, did his Post-doctoral training at Harvard Medical School and National Cancer Institute. Currently, he is a tenure-track Assistant Professor at the Department of Toxicology and Cancer Biology, and an active Member of the Markey Cancer Center, the University of Kentucky College of Medicine. He studies the fundamental mechanisms of cancer invasion and metastasis with the ultimate goal of identifying small molecules that can be used to block the process of tumorigenesis and cancer metastasis.

Abstract:

Colorectal cancer is the third most common cancer and the second leading cause of cancer death in both men and women. Sulfiredoxin (Srx) is a unique reductase that restores the peroxidase activity of peroxiredoxins (Prxs) by reducing the hyperoxidized, inactive form of Prxs back to their active, reduced form. To understand the role and mechanism of Srx in colorectal cancer development, we studied the functional significance of Srx in colon tumorigenesis, cancer invasion and metastasis using human patient primary specimens, cell culture as well as mouse models. We demonstrate that Srx is highly expressed in primary specimens of human colorectal cancer patients, and such abnormally high expression of Srx enhances cancer invasion in culture and drives cancer metastasis in a mouse orthotopical implantation model. Moreover, we also demonstrate that genetic depletion of Srx protects mouse from carcinogen-induced colon cancer development. Mechanistically, we reveal that loss of Srx sensitizes cancer cell to oxidative stress induced cell death, whereas the presence of Srx enhances the activation of mitogen activated protein kinase signaling through increasing the C-terminal tyrosine phosphorylation levels of the epidermal growth factor receptor (EGFR). This function of Srx is mediated through its inhibition of EGFR acetylation, a novel post-translational modification of EGFR in human CRC cells identified by liquid chromatography-electrospray ionization-tandem mass spectrometry analysis. Taken together, our data suggest that Srx promotes CRC cell invasion and metastasis through a novel mechanism of enhancing EGFR signaling, and it may thus be used as a potential target to develop molecular therapeutics for the treatment of colorectal cancer in patients.

Biography:

Michael J Spinella joined the Department of Comparative Biosciences and the University of Illinois at Urbana-Champaign in August 2016. After receiving his PhD in Biochemistry in 1992 from Albany Medical College, he performed training fellowships in Cancer Biology and Molecular Therapeutics at the Massey Cancer Center in Richmond, VA and at the Memorial Sloan Kettering Cancer Center in New York. He was a member of the faculty in the Department of Pharmacology at Dartmouth Medical School from 1999-2016.

Abstract:

Decitabine (5-aza), a potent inhibitor of DNA methylation, is approved for the treatment of myelodysplastic syndrome (MDS) and also shows promise for the treatment of specific leukemias. However, DNA methylation inhibitors in solid tumors have been disappointing. Testicular germ cell tumors (TGCTs) are the most common carcinomas of men of age 15-35. We describe our recent findings that TGCTs are exquisitely sensitive to 5-aza and the novel 5-aza pro-drug quadecitabine (SGI-110). Currently available cisplatin-based cytotoxic therapies result in substantial acute and life-long side effects that impact quality of life. In addition, 15-20% of cases is refractory or relapses despite cisplatin therapy and is in many cases fatal. Our novel findings that extend to animal studies strongly suggest that pluripotent embryonal carcinoma (EC), the stem cells of TGCTs, are uniquely vulnerable to very low doses of 5-aza and SGI-110. The dose is 100-1000 fold lower than those needed to cause cytotoxicity in somatic cancers and normal cells. Notably, hypersensitivity to 5-aza also occurs in EC cells resistant to cisplatin. Further, low dose 5-aza can restore cisplatin sensitivity to cisplatin resistant EC cells. These findings suggest that cisplatin sensitivity of TGCTs may be related to their DNA methylation status. The hypersensitivity was also associated with high levels of the pluripotency marker, DNMT3B. Knockdown of DNMT3B results in resistance to 5-aza suggesting that 5-aza sensitivity is mechanistically linked to high levels of DNMT3B. Together, this work provided the rationale for our recently initiated and promising phase I clinical trial using SGI-110 to treat cisplatin refractory TGCT patients. We discuss our recent genome-wide molecular studies aimed to identify potential mechanism(s) to account for the hypersensitivity of TGCTs to 5-aza including promoter demethylation, p53 activation, dsRNA MDA5/MAVS/IRF7 viral mimicry and pluripotency-specific non-CpG gene body methylation. We also discuss preliminary findings from our ongoing trial.

Biography:

Sarah Freemantle, Ph.D. is a new faculty member in the Department of Comparative Bioscience at the University of Illinois College of Veterinary Medicine.  She received her Ph.D. degree from the University of Newcastle-upon-Tyne, England where she examined resistance to antimetabolite-based chemotherapy agents. She continued her work on folate-based chemotherapeutics in her post-doctoral studies at the Medical College of Virginia before taking a position at Dartmouth Medical School in 1998.  At Dartmouth she worked on genes involved in chemoprevention and developed several mouse models for lung cancer and knockouts of key genes. More recent work has examined genes involved in chemotherapy response and chemoprevention which include the G0S2 gene.  

Abstract:

G0/G1 switch gene 2 (G0S2) is a direct retinoic acid target gene widely expressed in many cell types and implicated in cancer based on frequent methylation-mediated silencing in diverse solid tumors. We recently reported high levels of G0S2 expression in breast cancer, particularly estrogen receptor-positive (ER⁺) breast cancer that strongly correlates with survival, suggesting that G0S2 plays a role in breast cancer progression. However, the function(s) and mechanism(s) of G0S2 tumor suppression remain unclear. We hypothesize that G0S2 represses proliferation and oncogenic signaling in ER⁺ breast cancer cells and promotes more effective responses to existing therapies targeting ER⁺ breast cancer, leading to inhibition of recurrence. In order to determine potential mechanisms of G0S2 anti-oncogenic activity, we performed genome-wide expression analysis that revealed an enrichment of gene signatures related to PI3K/mTOR pathway activation in G0S2-null MEFs. G0S2-null MEFs also exhibited decreased sensitivity to PI3K/mTOR pathway inhibitors. Overexpression of G0S2 in human ER⁺ breast cancer cells decreased basal mTOR signaling and sensitized the cells to pharmacologic mTOR pathway inhibitors. These findings indicate that G0S2 functions as a tumor suppressor in part by repressing PI3K/mTOR activity and may enhance therapeutic response to PI3K/mTOR inhibitors. Recent studies have suggested that hyper activation of PI3K/mTOR signaling promotes escape from hormone dependence in ER+ breast cancer. Our data implicates G0S2 in opposing this form of antiestrogen resistance, prompting further investigation of the potential role of G0S2 as an antineoplastic breast cancer target and biomarker for recurrence and therapy response.

Biography:

P Charles Lin received his PhD in Cell and Molecular Biology (1988) at the Peking Union Medical College, Institute of Chinese Medical Sciences, Beijing, China. In 1992, he joined the Department of Medicine, Duke University Medical Center as a Research Associate. In 1999, he was appointed as Assistant Professor at Vanderbilt University Medical Center. In 2005, he became Associate Professor with Tenure at the Department of Radiation Oncology, Department of Cancer Biology, and Department of Cell & Development Biology at Vanderbilt University School of Medicine. He established the Vascular Biology Section at the Center for Cancer Research in August, 2010.

Abstract:

Vascular endothelial cells and Gr-1+CD11b+ myeloid derived suppressor cells (MDSCs) are two important components that constitute the tumor microenvironment. Targeting these cells offers the potential to halt tumor growth. In this study, we report a common mediator in C/EBP-d that regulates both components and aids in tumor development. C/EBP-d is elevated in tumor derived MDSCs. Interestingly, genetic deletion of C/EBP-d in mice significantly impaired MDSC expansion in response to tumor progression, but it had no effect on Gr-1+CD11b+ cell production in normal development. It suggests a specific role of C/EBP-d in emergency myelopoiesis under tumor conditions. Consistent with the pro tumor functions of MDSCs, loss of C/EBP-d resulted in reduced tumor angiogenesis and tumor growth. Moreover, we found expression of C/EBP-d in vascular endothelial cells. C/EBP-d regulated cell motility, endothelial network formation and vascular sprouting. Notably, inactivation of C/EBP-d in endothelial cells specifically inhibited the expression of VEGFR2 but not VEGFR1. Ectopic expression of C/EBP-d increased and knockdown of the gene decreased VEGFR2 expression. C/EBP-d is recruited to the promoter region of VEGFR2, indicative of transcriptional regulation. Collectively, this study has identified a positive mediator in C/EBP-d, which regulates tumor induced MDSC expansion and VEGFR2 expression in endothelium. Considering the importance of MDSCs and endothelial cells in tumor progression, targeting C/EBP-d may provide an interesting means for cancer therapy, killing two birds with one stone. 

Biography:

Sudha Bansode is an Associate Professor in Zoology at Shankarrao Mohite College, Akluj, Maharashtra State, India. Recently she was a Visiting Scholar at University of California, Riverside, USA. She is active researcher & passionate teacher in India. Still she has been published above 20 research papers in International Journals & she is interested on Bone Research. Also she has honor of Distinguished Editorial Board Member of several International Journals. She is a own author of “Textbook Histological Techniques” & “Outlines of Physiology”. She was a invited Indian Speaker of “OXFORD SYMPOSIUM” on 27-29 August, 2014 at Balliol College, Oxford, United Kingdom. 

Abstract:

Cancer is uncontrolled growth of abnormal cells in the body concern develops when the body’s normal control mechanism stops working. Old cells do not die and cells grow out of control, forming new abnormal cells. Then extra cells may form a mass of tissues called a tumor and some such as leukemia do not form tumors. During the course of tumor progression cancer cells acquire a number of characteristics alterations. These include the capacities to proliferate independently exogenous growth promoting or growth inhibitory signals to invade surrounding tissue and metastasize to distant sites to elicit an antigenic response and to evade mechanisms that limit of cell proliferation, such apoptotic and explicative se scene. These properties reflect alterations in the cellular signaling pathways that in normal cells control cell proliferation, motility and survival many of the proteins currently under investigation as possible target for cancer therapy is signaling proteins that are components of these pathways.

Biography:

Yuru Liu has completed her PhD from John Hopkins University School of Medicine and Post-doctoral studies from Duke University. She is an Assistant Professor in Department of Pharmacology, School of Medicine, University of Illinois at Chicago. She has established her own research group and uses state-of-the-art genetic models to identify the signaling mechanisms of alveolar regeneration after lung injury. She has published 15 papers in reputed journals and has been serving as Councilor in American Society for Pharmacology and Experimental Therapeutics, the Great Lakes Chapter.

Abstract:

The alveolar epithelium is composed of type I cells covering most of the gas-blood exchange surface and type II cells secreting surfactant that lowers surface tension of alveoli to prevent alveolar collapse. Here we have identified a subgroup of type II cells expressing higher level of cell surface molecule CD44 (CD44^high type II cells) that comprised ~3% of total type II cells in 5-10 week old mice. These cells were preferentially apposed to lung capillaries. They displayed a higher proliferation rate and augmented differentiation capacity into type I cells and the ability to form alveolar organoids compared to CD44^low type II cells. Moreover, in aged mice of 18-24 months old, the percentage of CD44^high type II cells among all type II cells was increased but these cells showed decreased progenitor properties. Thus, CD44^high type II cells likely represent a type II cell sub-population important for constitutive regulation of alveolar homeostasis. Since CD44 is considered as a marker for cancer stem cells in lung cancer, it is important to further characterize the signaling of CD44^high type II cells in lung homeostasis, regeneration and aging, as disregulation of the CD44^high type II cells is likely to contribute to the cancer initiation.

Biography:

Frank Eckerdt is currently working as Research Assistant Professor of Neurological Surgery in Northwestern Medicine Feinberg School of Medicine. He has done his Post-doctoral Fellowship from J. W. Goethe University, Obstetrics Gynecology (2004) and PhD from J. W. Goethe University, Biology (2003).

Abstract:

Glioblastoma (GBM) and Medulloblastoma (MB) are deadly brain tumors in adults and children, respectively. Most patients still succumb to these diseases due to relapse, which is caused by a subpopulation of therapy resistant brain cancer stem cells (CSCs). The PI3K pathway promotes cancer cell survival and might stimulate chemotherapy resistance in solid tumors. We employed analysis of gene expression data and found that expression of PIK3CA (p110alpha) correlates with stem cell markers in MB and GBM patient samples, respectively, suggesting important roles in CSCs. Using 3-D neurosphere cultures, we show that the PI3K/AKT pathway is activated in stem-like cancer cells and inhibition of PI3K blocked kinase signaling and neurosphere growth in these CSCs. Of all class I PI3K catalytic isoforms, only knockdown of p110alpha disrupted cancer stem cell frequencies, indicating a pivotal role for this isoform in CSCs. Inhibition of the PI3K pathway in combination with inhibitors targeting protein kinases known to be important for survival signaling enhanced these antineoplastic effects in CSCs. In summary, the p110alpha isoform is a promising target for MB and GBM. The striking effects on stem-like cancer cells and neurospheres is particularly interesting as it suggests enhanced vulnerability of the therapy-resistant, tumor-initiating CSC population to PI3K-p110alpha inhibition in MB and GBM.

Biography:

Christina Coughlin joined Immunocore as Chief Medical Officer in April 2015. She has extensive experience in Oncology Drug Development, with expertise in both clinical development and translational medicine. Prior to joining Immunocore, she led two early development programs at Novartis in checkpoint inhibition and PI3 kinase inhibition. She has also served as International Project Team Leader at Morphotek Inc., the monoclonal antibody company acquired by Eisai Co. Ltd in 2007, where she led the early clinical development team responsible for monoclonal antibody development against novel targets. She graduated with an MD and PhD from the University of Pennsylvania, where she studied patient responses to tumour antigens with Dr. Robert Vonderheide in the division of Translational Research under the direction of Dr. Carl June.

Abstract:

Uveal melanoma (UM) is characterized by low PD-L1 expression, low mutational burden and limited efficacy with checkpoint inhibition. IMCgp100 is a bispecific T cell redirector with an affinity-­enhanced TCR recognizing gp100 and an anti-CD3 scFV. Two phase 1 trials evaluated safety, pharmacokinetics, pharmacodynamics and efficacy for IMCgp100 administered IV weekly in HLA-A2 patients: a first in human study enrolling patients with melanoma including a cohort with advanced UM (n=16) and a second study of an intra-patient dose escalation (IE) regimen for pts with advanced UM (n=19). The intra-patient escalation regimen was designed during the course of the FIH Phase 1 study to mitigate T cell-mediated toxicities that were observed. Endpoints of the two studies included overall response rate by RECISTv1.1, progression free survival, and overall survival. The safety profile of IMCgp100 was consistent between trials with the most frequent adverse events including rash, pruritus, and edema. Durable, objective responses were observed in both trials. Within 3 doses of IMCgp100, immunofluorescence studies reveal an influx of PD-1+/CD8+ T cells in the tumor bed with PD-L1 expression. Peripheral cytokines indicate activation of immune responses within 24 hours of the first dose. These studies demonstrate preliminary immune biology, safety and promising efficacy in advanced UM.

Biography:

Pengda Liu has completed his PhD from East Carolina University and Post-doctoral studies from Duke University Medical Center and BIDMC, Harvard Medical School. He is currently an Assistant Professor in the Department of Biochemistry and Biophysics at UNC-Chapel Hill. He has published more than 38 papers in peer-reviewed journals and has been serving as an ad hoc reviwers for many reputed journals. 

Abstract:

Hyperactivation of the PI3K-Akt pathway is observed in virtually all solid tumors. Multiple genetic events such as PTEN loss and PIK3CA amplification partially account for the increase in the pathway activation. In addition to genetic changes, dysregulation of post-translational modifications of Akt, including phosphorylation, acetylation, hydroxylation, methylation and others, that are necessary for Akt activation is also frequently observed in various types of cancers. However, whether and how Akt is regulated by its binding partners are minimally understood. To this end, through a proteomic approach, we have identified the tumor suppressor SAV1 as a novel Akt interacting partner to suppress Akt activation. Furthermore, we found that phosphorylaton of Akt1-Y26 disrupts SAV1 binding and subsequently activate Akt, which is large mediated by TAM kinases. Mechanistically, TAM-mediated Akt1-Y26 phosphorylation facilitates Akt plasma membrane recruitment by PI(3,4,5)P3 to promote Akt activation. On the other hand, TAM inhibition leads to enhanced SAV1 binding and reduced Akt activity. Importantly, cancer patient-derived SAV1 mutants and Akt1 mutants were identified to exert elevated oncogenicity by bypassing SAV1 binding and suppression, further supporting a pathophysiological role of the identified TAM/Akt/SAV1 signaling in tumorigenesis and the potential to target this Akt regulatory axis for inhibition to combat cancer.

Biography:

Carla Mattos received her PhD at MIT and did Post-doctoral work at Harvard University and at Brandeis University. She is a recipient of the Boroughs Wellcome Fund New Investigator Award in the Pharmacological Sciences, the CAREER award from the NSF and the Presidential Early Career Award for Scientists and Engineers. She uses a combination of biophysical and biochemical approaches to study Ras structure, dynamics and allosteric connections to infer and test hypothesis associated with function. She is actively engaged in the Ras initiative at the NCI through her collaborations at the Frederick National Laboratory for Cancer Research.

Abstract:

Ras is found mutated in about 20% of human cancers, associated with poor prognosis due to a lack of drugs able to deter uncontrolled signaling through multiple pathways in the cell. There are three isoforms: H-, K-, and N-Ras. The G-domain, which catalyzes GTP hydrolysis and mediates downstream signaling, is 95% conserved between the Ras proteins. To date, biochemical studies done on H-Ras have been considered representative of all three Ras proteins. We have recently shown, using a combination of X-ray crystallography, NMR spectroscopy, enzyme kinetic assays and molecular dynamics simulations, that the three isoforms are biochemically distinct due to allosteric effects of isoform-specific residues on the population of conformational states. Furthermore, oncogenic mutations also affect conformational states in the particular isoforms. An engineered high-affinity binder shows a modest specificity toward K-RasG12D over the wild type protein and crystal structures of the complexes reveal allosteric effects on conformational states induced by the mutation, providing a view of specificity features that may be further developed to direct targeting of oncogenic mutants of K-Ras. 

Biography:

Sweta Srivastava has her expertise in Cancer Biology and has been working towards understanding the molecular mechanisms involved in regulating therapy response. Her research activities include understanding the role of small molecule GTPases and their effector kinases in tumor progression.

Abstract:

Therapy resistance and tumor recurrence severely affects therapy outcome. Colossal efforts have gone into understanding radio-resistance in various tumors, however; there is no definitive study to exemplify the molecular mechanisms of radio-resistance in cervical carcinoma. In our previous report we have shown that RhoC regulates cervical carcinoma tumor progression. In this study we extend the role of RhoC to therapy resistance. We also suggest that Rock2, a downstream effector of RhoC, modulates radio-resistance in cervical carcinoma. Using CaSki and SiHa cell lines, our observations suggested that increased expression of RhoC and nuclear Rock2 (Rock2_nu) confer therapy resistance to cervical cancer cells and inhibition of RhoC and Rock2 results in increased sensitization to radiation. Interestingly high Rock2_{nu ­}cells also co-express increased CDK1, indicative of potential to progress in cell division. Additionally flow cytometric live sorting of Rock2_high cells and further cell survival analysis showed that Rock2_high cells have better cell survival ability as compared to Rock2_low cells. The interaction between Rock2 and BRCA2 has also been observed in the resistant cells suggesting its crosstalk with the DNA damage response machinery. Inhibition of Rock2 in cervical cancer resulted in disruption of DNA repair machinery. We extended our finding to other cell lines including Detroit 562 and patient biopsies derived cells and observed increased radio-sensitization upon irradiation in vitro. Our observations thus suggest that RhoC-Rock2 signaling pathway is a novel mechanism of regulation of radiation resistance in cervical cancer.

Biography:

Stephen S Lin is a Senior Science Officer at California’s Stem Cell Agency, CIRM. He joined the Agency in 2015 to oversee its $32M initiative to create a repository of iPSCs from over 2800 individuals covering both genetically complex and rare diseases, as well as a $40M genomics initiative that applies cutting edge genomics and bioinformatic approaches to stem cell research and therapeutic development. He is also Program Lead on a $15M award to create a preclinical research organization termed the Translating Center that focuses on preparing stem cell therapy candidates for clinical trials through support with process development, safety/toxicity studies, and manufacturing. From 2012, he had been a Staff Scientist and Team Lead at Thermo Fisher Scientific (formerly Life Technologies) prior to that he was a Scientist since 2006 at StemCells Inc., of California in the area of liver cell therapeutics. He received his PhD from Washington University in St. Louis in 2002 under Jeffrey Gordon and did his Post-doctoral research at Harvard University under Stanley Korsmeyer.

Abstract:

The mission of the California Institute for Regenerative Medicine (CIRM) is to accelerate stem cell treatments to patients with unmet medical needs. With $3 billion in funding and 300 active programs, it is the world’s largest institution dedicated to helping people by developing cell therapies. To accomplish its mission, CIRM has funded a breadth of activities spanning from basic research to translation to clinical trials. In addition to individual grants, CIRM has created resources to help the stem cell community worldwide. Some resources promote research and drug development using stem cells. CIRM has established an iPSC Repository maintained by the Coriell Institute that is currently the largest publically accessible pluripotent stem cell bank in the world. CIRM also has a genomics research initiative that applies cutting edge sequencing and bioinformatics approaches to stem cell research and therapeutic development. Other resources established at CIRM promote the acceleration of stem cell discoveries into therapeutic development, including: the Stem Cell Center, which supports preclinical IND-enabling and clinical trial management activities related for stem cell therapies, and an Alpha Clinics network that conducts clinical trials for stem cell related therapies. CIRM supports additional activities that promote standardization, clarity, and speed to this emerging therapeutic area. In total, these resources are designed to catalyze the flow of stem cell discoveries to the clinic, which can come from both inside and outside of California. 

Biography:

Alexander Kazansky is working as Associate Professor from 2014 to present at the Dept. of Health and Biomedical Sciences, University of Texas Rio Grande Valley (UTRGV); Associate Professor at the Dept. of Biomedicine, University of Texas Brownsville (UTB) 2011-2014 and; Associate Professor at the Department of Biological Science, University of Texas at Brownsville, Texas (2006-2011) Adjunct Associate Professor, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas (2006-present). He served as Assistant Professor at the Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas (2003-2006). He served as a Post-doctoral Fellow, Department of Cell Biology, Baylor College of Medicine, Houston, Texas; Research Associate, Laboratory of Molecular Genetics of Cell Differentiation, Institute of Gene Biology, Moscow, Russia and; Graduate Student, Institute of General Genetics and Koltzov Institute of Developmental Biology, Moscow, Russia.

Abstract:

Prostate cancer remains one of the most common and potentially lethal neoplastic manifestations among men. In many cases, malignant transformation can be directly linked to activation of the STAT family of transcription factors. STAT5B, a specific member of the STAT family is intimately associated with prostate tumor progression. While the full form of STAT5B is thought to promote tumor progression, a naturally occurring truncated isoform acts as a tumor suppressor. We previously demonstrated that truncated STAT5 is generated by insertion of an alternatively spliced exon and results in the introduction of an early termination codon. In this report we demonstrate a new approach aimed at inhibition the expression of full-length STAT5B (a proto-oncogene) while simultaneously enhancing the expression of STAT5∆B (a tumor suppressor). The presented work combines the actions of steric-blocking splice-switching oligonucleotides (SSOs) and a novel nanotechnology-based approach for targeted delivery of DNA to tumor cells. We were able to block alternative splicing of STATs mRNA applying conjugates of SSO with pH insertion peptide (pHLIP). Our data demonstrates the functional effect of the intron/exon proportional tuning toward anti-cancer activity. A common feature of most STATs is alternative splicing, which leads to generation of a dominant-negative isoform. STAT proteins are involved in wide variety of physiological processes including immune response and tumor progression. Ability to modulate their actions and specifically switch function from tumor activating to tumor suppressing would be highly beneficial in many areas of biomedical research. In conclusion we developed and confirmed a novel method to implement steric-blocking splice-switching oligonucleotides for targeted delivery towards the development of novel therapeutic strategies.

Biography:

Abstract:

MicroRNAs (miRs) have potential as non-invasive biomarkers, but their relevance as biomarkers is limited by inconsistent results, and their regulatory mechanisms remain elusive. In the present study, our results show that the levels of miR-200c and 141 in tumor cells and in circulation differ for mice and for humans between cases with metastatic breast cancer, cases with localized breast cancer, and healthy female controls. The levels of miR-200c and 141 are low in primary tumor cells but are high in the circulation of patients with metastatic breast cancer. Further, we suggest the potential cell origin of circulating miR-200c and 141 and describe their transcriptional regulation in cultured cells and during tumor progression in animal models of spontaneous breast cancer. These results could provide useful insights in early prediction of tumor metastasis and influence treatment strategies for patients at high risk of developing metastatic breast cancer.