Discovery Center Research Articles

Abstract A02: Expanding tumor chemical-genetic interaction map using next-generation cancer models

Abstract The development of new cancer therapeutics requires sufficient genetic and phenotypic diversity of cancer models. Current collections of human cancer cell lines are limited and for many rare cancer types, zero models exist that are broadly available. Here, we report results from the pilot phase of the Cancer Cell Line Factory (CCLF) project that aims to overcome this obstacle by systematically creating next-generation in vitro cancer models from adult and pediatric cancer patients' specimens and making these models broadly available. We first developed a workflow of laboratory, genomics and informatics tools that make it possible to systematically compare published ex vivo culture conditions for each individual tumor to enable the scientific community to iterate towards disease-specific culture recipes. Based on sample volume and rarity, 4-100 conditions were applied to each sample and all data was captured in a custom Laboratory Information Management System to enhance subsequent predictions. We developed a $150, 5-day turnaround genomics panel to validate cultures based on genomics. Importantly, we show that tumor genomics can be retained in such patient-derived models and tumor genomics are generally stable across 20 passages. Since the inception of this project, we have processed over 600 patient cancer specimens from 450 patients across 16 tumor types and report the successful generation of over 100 genomically characterized adult and pediatric cancer and normal models. We next hypothesized that novel patient-derived cell models could be used to enhance dependency predictions. To do so, we tested 72 cell lines against the informer set of 440 compounds developed by the Broad Cancer Target Discovery and Development (CTD2) Center. We show that generating cell lines and testing their sensitivities within 3 months is feasible and the high-throughput drug responses are reproducible. Moreover, to strengthen relationships between drug sensitivities and cellular features, we compared results with recently published data on the identical compounds tested against 860 existing cell lines. With this approach, we show that many chemical-genetic interaction vulnerabilities can be rapidly assessed. Importantly, adding more cancer models with the dimensions of quantity and diversity increases the predictive power of chemical-genetic interaction map. We are currently evaluating these drug sensitivity predictors for novel co-dependencies. Overall, our proof-of-concept framework demonstrates initial feasibility of rapidly generating cancer models at scale and expanding the chemical-genetic interaction map to identify new cancer vulnerability. Citation Format: Yuen-Yi (Moony) Tseng, Andrew Hong, Shubhroz Gill, Paula Keskula, Srivatsan Raghavan, Jaime Cheah, Aviad Tsherniak, Francisca Vazquez, Sahar Alkhairy, Anson Peng, Abeer Sayeed, Rebecca Deasy, Peter Ronning, Philip Kantoff, Levi Garraway, Mark Rubin, Calvin Kuo, Sidharth Puram, Adi Gazdar, Nikhil Wagle, Adam Bass, Keith Ligon, Katherine Janeway, David Root, Stuart Schreiber, Paul Clemons, Todd Golub, William Hahn, Jesse Boehm. Expanding tumor chemical-genetic interaction map using next-generation cancer models [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr A02.

Rocky River Wetland Usage for Education and Recreation: Early Planning and Implementation in Anderson County, South Carolina

The Rocky River Conservancy, Anderson University, the City and County of Anderson, SC, and local environmental groups are working in partnership to rehabilitate, preserve, and develop ∼200 ha of forested and emergent wetland and contiguous upland located within the city limits of Anderson, SC. The goal of the project is to provide a natural resource usable by the local community for education, and passive and active recreation, while safeguarding this unique and dwindling natural habitat. The environmental advocacy organization, Upstate Forever (Greenville, SC), secured an EPA grant for a hydrology assessment and long-range planning for the site. The long-range vision includes plans for construction of boardwalks, observation platforms, and a discovery center. Anderson University faculty and students have been surveying the site's flora and fauna and collecting water-quality data. Vertebrates documented include 21 species of fishes, 18 species of amphibians and reptiles, 120 species of birds, and 11 species of mammals. A tree-frog mark—recapture program has begun. Clearing of overgrown trails, opening sites for access to wetland margins, removal of trash, addition of trail signage, and trail enhancement are underway. Community and civic groups such as local garden clubs are being made aware of the resources available to them. The Anderson University Life-long Learning program, and local teachers have visited and used the site. Fund-raising, stepwise development without harming or altering the flora and fauna, and continuing to raise community awareness and buy-in of the value of this resource represent ongoing challenges.

I6 Natural product-based protein amyloid inhibitors

Toxic protein amyloid formation has been implicated in more than a dozen protein misfolding diseases such as Alzheimer’s disease, Parkinson’s disease, and type 2 diabetes. Currently there are no effective disease-modifying drugs available. One common therapeutic strategy is to discover and develop protein amyloid inhibitors that can slow down, prevent, or remodel toxic amyloids. Natural products are a major class of amyloid inhibitors, and several dozens of natural product-based amyloid inhibitors have been identified and characterized in recent years. Using amyloidogenic proteins amylin, amyloid beta-peptide, and tau as model systems, we screened libraries of natural compounds used in Complementary and Alternative Medicine. We identified multiple potent inhibitors, including rosmarinic acid and baicalein (200 nM and 1 μM respectively in apparent IC 50 ) [1] . These compounds disaggregate amyloidogenic protein fibrils, significantly reduce protein amyloid-induced cytotoxicity and toxic amyloid oligomers in circulating sera and/or cerebrospinal fluid from diseased animal models. Dissecting the functional groups of these compounds, we demonstrated, for the first time to our knowledge, that the vicinal hydroxyl groups of the catechol groups played key functional roles in amyloid inhibition in more than two dozen catechol-containing compounds, including many plant- and fruit-derived flavonoids and other phenolic compounds [2] . Compounds with multiple catechol groups, such as rosmarinic acid, exhibited additive effects. We provided further mass spectrometric evidence that incubating several of these catechol-containing inhibitors with amyloidogenic proteins leads to covalent adducts consistent with Schiff base conjugation mechanism to interfere with toxic amyloid formation. Consistent with forming covalent adducts via the mechanism of quinone intermediates, we demonstrated that many catechol-containing natural products significantly increase amyloid inhibition effects under autooxidation or oxidizing conditions. Lastly, I will discuss our approach to enhance certain natural product solubility/bioavailability by engineering natural compound-incorporating nanoparticles [3] . Acknowledgement This work is in part supported by Virginia Tech new faculty start-up funds, Commonwealth Health Research Board (CHRB), Alzheimer’s and Related Diseases Research Award Fund (ARDRAF) from Virginia Center on Aging, Diabetes Action Research and Education Foundation (DAREF), and Virginia Tech Center for Drug Discovery (VTCDD).

Analogue Three-Dimensional Memory Game for Teaching Reflection, Symmetry, and Chirality to High School Students

This interdisciplinary analogue 3D Memory Game is a version of a card-based memory game, developed to encourage high school students to use deductive reasoning skills and to understand reflection (mirror images), symmetry, and chirality. Instead of cards, three-dimensional pieces are used in order to facilitate the understanding of the spatial arrangement of things, both geometric objects and organic compounds. Correlating geometric objects with the simple molecular model representation of organic compounds, the game promotes knowledge transposition to spatial recognition of chemical structures and chirality in formal education, classrooms, or nonformal educational settings (e.g., a science center or discovery center or university outreach setting). The game was used in 2016 in a classroom with 16 students in a high school in Sao Goncalo, Rio de Janeiro, Brazil, as well as at a science fair in 2015. The game lasts 15–25 min when played by 5 or 3 groups of 2 students, respectively. On the basis of the feed...

New strategies for the expression of human P‐glycoprotein (MDR1) in the yeast Pichia pastoris

P‐glycoprotein (P‐gp) overexpression is often correlated with multidrug‐resistance (MDR) of cancer. The search for P‐gp inhibitors as co‐therapeutics to combat MDR has had little success after decades of studies. We previously used high‐throughput in silico ligand docking studies and identified drug‐like compounds that reversed MDR in human cancer cells in culture. Effects on P‐gp ATPase hydrolysis activity was used as an initial biochemical screen for inhibitor effectiveness followed by assays of MDR‐reversal of a prostate cancer cell line ((Brewer et al. in Mol Pharmacol. 2014; Follit et al in Pharmacol Res Perspect. 2015). More recently, computationally identified compounds were shown to reverse MDR in cancer cells, but did not appear to inhibit ATP hydrolysis by isolated P‐gp. One reason may be that mouse P‐gp rather than human P‐gp was previously used in our biochemical tests. Expression of human P‐gp in Pichia pastoris in a biologically active form was previously reported, but unfortunately, we experienced very modest expression levels of the human P‐gp expression construct for P. pastoris available in our lab. Codon optimization of mouse P‐gp was previously shown by others to result in increased protein yield, therefore a gene for human P‐gp was designed with optimized codon usage for translation in P. pastoris. A strong Kozak sequence was incorporated at the 5′ end of the coding frame. Unique internal restriction sites were incorporated that allow subcloning of individual sections of the gene, if necessary for troubleshooting and future mutagenesis. The DNA was synthesized using standard Gibson assembly methods and cloned into a pUC57 cloning vector. When transformed into E. coli, DNA rearrangement was observed. To identify whether a specific section of the insert was the cause of counter‐selection in E. coli, the insert DNA was digested into 5 component pieces and each one was subcloned. One of the sections was found to be more susceptible to rearrangements. We report here our attempts at constructing a stable, codon‐optimized, human P‐gp gene for high yield protein production in Pichia pastoris.Support or Funding InformationThis work is supported by NIH NIGMS [R15GM094771‐02] to JGW/PDV, SMU University Research Council, SMU Engaged Learning program, the SMU Center for Drug Discovery, Design and Delivery, the Communities Foundation of Texas, and a private gift from Ms. Suzy Ruff of Dallas, Texas.

Improving the Sensitivity of P‐Glycoprotein to Drug‐Like Inhibitors in ATPase Assays and ESR Studies

Multidrug resistance (MDR) in cancers is frequently associated with transmembrane efflux proteins including P‐glycoprotein (P‐gp), multidrug resistance associated protein (MRP1), and breast cancer resistance protein (BCRP). Over‐expression of these transporters in cancer cells increases efflux of therapeutic drugs rendering them ineffective. In order to re‐sensitize multidrug resistant cancers to chemotherapy, we have found inhibitors of P‐gp by in silico screening methods (Brewer et al, Mol. Pharmacol. 2014). To investigate the mechanism underlying the inhibition, we have employed biochemical assays and electron spin resonance spectroscopy (ESR), and have established nanodisc technologies that incorporate and stabilize P‐gp in native‐like phospholipid bilayer environments for our drug finding and mechanistic studies. In ATP hydrolysis assays using P‐gp in micelles, we found that the concentration of detergents used to solubilize P‐gp during purification had a significant impact on the sensitivity of P‐gp to the putative inhibitors. We hypothesized that partitioning of the compounds into empty micelles may decrease the effective concentration of the potential inhibitors. Carefully decreasing the amount of detergents used during purification resulted in significantly increased sensitivity of P‐gp to the inhibitors, while overall protein activity and stability were not affected. Similarly, excess lipids used during reconstitution of P‐gp into nanodisc may cause partitioning of inhibitors into empty nanodiscs or empty lipid vesicles, resulting in lowered sensitivity of P‐gp to the inhibitors. By optimizing the amount of lipids used during nanodisc assembly, we restored the sensitivity of P‐gp to the inhibitory compounds. Biophysical studies using ESR and a spin‐labeled analog of ATP showed that the computationally identified compounds inhibited P‐gp by binding to the ATP binding domain of P‐gp, which was consistent with our predictions by in silico screening method.Support or Funding InformationThis work is supported by NIH NIGMS [R15GM09477102] to JGW/PDV, SMU University Research Council, SMU Engaged Learning program, the SMU Center for Drug Discovery, Design and Delivery, the Communities Foundation of Texas, and a private gift from Ms. Suzy Ruff of Dallas, Texas.

Transport of the Alzheimer's Disease Associated Amyloid‐Beta Peptide by P‐Glycoprotein

The broad range of substrates that can be transported by the transmembrane protein, P‐glycoprotein (P‐gp), has been well established. While best known for the ability to confer general multidrug resistance to a population of cancer cells and for its pharmacokinetic implications in being a critical transporter in the blood brain barrier (BBB), P‐gp action has also been implicated in Alzheimer's disease (AD). One clearance pathway across the BBB for amyloid‐β, which is thought to be a causative agent in neurodegeneration and symptom onset in AD, was hypothesized to be catalyzed by P‐gp. A dynamic P‐gp model similar to that used in McCormick et al. (Biochemistry 2015) was used here to allow docking of amyloid‐β and an unrelated peptide of the same size to P‐gp. Simulations of the catalytic cycles through four different crystallographic conformations of P‐gp‐related proteins using targeted molecular dynamics (TMD) were performed. Even though movement of amyloid‐β was not targeted by the method, transport of amyloid‐β through the membrane was observed during the putative catalytic cycles. These simulations started with amyloid‐β bound to P‐gp in conformations that were open to the cytoplasm and ended with amyloid‐β bound to P‐gp in conformations that would allow amyloid‐β access to the extracellular space. In simulations using a control peptide of the same length, no transport was observed. In experiments to physically evaluate the computational results, synthetic amyloid‐β 42 was fluorescently labeled with carboxyfluorescein and incubated with cells having P‐gp overexpressed. The experiments showed that cell lines with high levels of P‐gp had measurably less accumulation of the fluorescent amyloid‐β 42 than cells with low expression levels of P‐gp. Amyloid‐β accumulation was inhibited in the presence of P‐gp specific inhibitors, supporting the hypothesis that P‐gp plays a role in the clearance of amyloid‐β 42 from the brain.Support or Funding InformationThis work is supported by NIH NIGMS [R15GM09477102] to JGW/PDV, SMU University Research Council, SMU Engaged Learning program, the SMU Center for Drug Discovery, Design and Delivery, the Communities Foundation of Texas, and a private gift from Ms. Suzy Ruff of Dallas, Texas.

Weibull Distribution: User Performance Analyses for Telerobotics System Interface

When aiming to improve interfaces for remote devices, methods are required for assessing them and comparing the effect of changes. Distributions provide a means of summarizing data and a model that produces a particular distribution is known, so that if the data is found to match a known distribution a useful model is available for interpreting the data. This paper presents the analysis using the Weibull distribution to evaluate the user performance of the prototype telerobotics user interface. This prototype was deployed for public testing at an exhibition in the CSIRO Discovery Centre, Canberra, Australia, over three months. An investigation of operator requests to three models of telerobotics control from a total of 6139 total user sessions was found to fit Weibull distributions. All of the devices offered operators the opportunity to manipulate wooden blocks through the application with three model controls. Usage patterns were quite different on the different control models, but operator behavior could be characterized by the two parameters of the Weibull distribution. One of the parameters, the shape parameter, was found to be nearly invariant so the comparison could be reduced to the scale parameter. This meant interfaces can be compared with a single value calculated from automatically captured data during use of the interface.

In search of stability

Craig Lindsley flew out to Tulsa in November 2012 to give a talk about the research in his labs at the Vanderbilt Center for Neuroscience Drug Discovery (VCNDD) in Nashville. His host was William K. Warren Jr., a businessperson and philanthropist who had endowed the medicinal chemist’s chair at Vanderbilt University. Lindsley walked his audience through what was then a six-year effort to develop compounds that address the cognitive challenges and tough-to-treat symptoms of schizophrenia. When he wrapped up his talk, he opened the floor for questions. What happened next changed the course of VCNDD. “Bill stood up and said, ‘I have some questions for you,’ ” Lindsley recalls. “What would you do if I gave you a million dollars?” “What about $5 million?” “What about $10 million?” Warren wasn’t throwing around theoretical money. His foundation was prepared to make a major investment in VCNDD’s efforts to move a drug candidate

116.2 Discovery and Development of Novel M1 and M4 PAMs for the Treatment of Schizophrenia.

Abstract Background: Multiple lines of evidence indicate that development of selective positive allosteric modulators (PAMs) of the M1 and M4 muscarinic acetylcholine receptor subtypes (mAChR) represent important novel therapeutic approaches for the complex symptoms associated schizophrenia. Over the last decade, Dr. Jones and colleagues at the Vanderbilt Center for Neuroscience Drug Discovery (VCNDD) have disclosed the discovery of several, selective mAChR PAMs, as represented by the M1 PAM VU6004256 and M4 PAM VU0467154. This presentation will focus on recent findings demonstrating the ability of M1 and M4 PAMs to reverse abnormalities in prefrontal cortical-mediated physiology, behaviors, and/or cognitive functions observed across preclinical models of N-methyl-D-aspartate subtype of the glutamate receptor (NMDAR) hypofunction, which are thought to underlie many of the symptoms observed in schizophrenia. Methods: Medicinal chemistry and high throughput screening methods were utilized to identify two different series of selective M1 and M4 PAMs, represented by VU6004256 and VU0467154. Disposition was determined in mouse and rat pharmacokinetic studies using LC/MS/MS quantitation. In vivo efficacy was determined across several mouse and rat models predictive of antipsychotic-like activity and enhancement of cognitive function, in particular using the genetic mouse model of global reduction in the NR1 subunit of the NMDAR (NR1 knockdown [KD]). Results: In vitro both VU6004256 and VU0467154 exhibit low nanomolar potency at M1 or M4, respectively, with no activity at the other mAChR subtypes up to 30 μM or significant off target activity at other GPRCs at 10 µM. These ligands are also highly brain penetrant with suitable pharmacokinetic properties for in vivo dosing. Both VU6004256 and VU0467154 produced dose-dependent reductions in preclinical models predictive of antipsychotic-like activity, including reversal of hyperlocomotion in the NR1 KD mice. In addition, the M1 PAM VU6004256 decreased excessive pyramidal neuron firing in layer V of the prefrontal cortex (PFC) in awake, freely moving NR1 KD mice, as well as reversed impairments in two PFC-mediated learning tasks observed in these mice. Interestingly, the M4 PAM VU0467154 also enhanced performance in preclinical models of associative learning and memory functions after acute and chronic dosing and induced state-dependent alterations in sleep architecture and arousal. Conclusion: Collectively, these findings indicate that VU6004256 and VU0467154 represent highly optimized M1 and M4 PAM tool compounds for the evaluation of the respective roles of these mAChR subtypes in vivo and provide further validation for the development of selective M1 and M4 PAMs for the treatment of the psychotic symptoms and cognitive impairments observed in schizophrenia.

Role of Academic Drug Discovery in the Quest for New CNS Therapeutics.

There was a greater than 50% decline in central nervous system (CNS) drug discovery and development programs by major pharmaceutical companies from 2009 to 2014. This decline was paralleled by a rise in the number of university led drug discovery centers, many in the CNS area, and a growth in the number of public-private drug discovery partnerships. Diverse operating models have emerged as the academic drug discovery centers adapt to this changing ecosystem.

How Much Longer Will We Put Up With $100,000 Cancer Drugs?

The spiraling cost of new drugs mandates a fundamentally different approach to keep lifesavingtherapies affordable for cancer patients. We call here for the formation of new relationships between academic drug discovery centers and commercial partners, which can accelerate the development of truly transformative drugs at sustainable prices.

China’s ”New Normal”: An Interpretation from Institutional and Marxian Views

ABSTRACTChina is approaching towards a new phase of economic development which is frequently termed as the “new normal”. The paper aims to interpret China’s “new normal” from the New Institutional Economics and Marxian viewpoints. The former school is primarily concerned with the “supply-side” driver of increasing economic output and efficiency. It advocates for free and open markets for ideas to sustain China’s economic growth or advance itself into a global centre of technological innovation or scientific discovery. The Marxian view, on the other hand, shares the concern of “demand-side” driver of increasing economic output. Also, it calls for the shift from consumption-led to investment-led strategy while maintaining an egalitarian pattern of income distribution for successful transition. The paper argues that China is gradually advancing its capacity for innovation facilitated by in-house and foreign investments. However, the growing income inequality may pose a threat to its soft landing.

Measuring Complexity for Autism Interventions: Tcfd’s Inventory of Neuroeducational Complexity

Autism is a complex condition, whether viewed from etiology, comorbidities, functioning, or interventions. There are numerous approaches for measuring complexity in children and adolescents with neurodevelopmental or medical diagnoses. Interventions, however, create the need for broader and deeper assessment—including the environments in which the young person lives. The Center for Discovery, New York state’s Center of Excellence for Developmental Disabilities, (TCFD) implemented an Assessment, Support, Education and Training (ASSET) grant from the New York Office for People with Developmental Disabilities. This paper will describe the Assessment activity. A major goal was to develop a tool for assessing the characteristics of the young person and pivotal environments. The objective was to promote the delay of or prevent movement to a more restrictive placement including residential placement. The pilot tool was developed over nine months and includes six areas for evaluation—medical/ impairments (8 items), functional profile (11 items), educational profile (5 items), home/family environment (9 items), school environment (6 items), and community environment (4 items). Implementation of CfD’s Inventory of Neuro-educational Complexity (INC) was able to distinguish among 30 pilot subjects those likely to use family and school interventions to maintain family living from those most likely needing at least short term residential placement. The INC is of substantial heuristic value in this time of great interest in effective and resource focused interventions with this population.

Wearable Stress Sensors for Children With Autism Spectrum Disorder With In Situ Alerts to Caregivers via a Mobile Phone

Background: Children with autism spectrum disorder (ASD) often exhibit unexpected and difficult to manage self-injurious, aggressive, and/or disruptive and challenging behaviors. These behaviors can lead to restrictive care settings including hospitalizations and lifelong residential care placement. Because children with ASD have significant impairments in social communication skills including lack of facial expression, an inability to clearly articulate feelings, and atypical body language, caregivers could benefit tremendously by knowing when a child is becoming stressed. Objective: To develop a set of customized features in a wearable sensor and mobile app that monitors stress reactivity of children with autism in real time and automatically triggers in situ alerts to a caregiver via a mobile handheld device. Methods: The Center for Discovery (CFD) is a not-for-profit internationally recognized service provider for people with complex developmental disabilities, including a large population of children and adults with autism. Neumitra Inc., is a start-up technology vendor specializing in wearable stress monitoring. Neumitra’s wearable sensor called neuma featured an embedded system with automated scoring of electrodermal activity, a well-established method for recording physiological stress responses. The sensor was accompanied by a mobile app for users to self-monitor their own stress levels. The app provided a 10-point color gradient scale as an interpretation of real-time stress and arousal levels. CFD collaborated with Neumitra’s development team to develop a set of customized features amenable to the use case presented by caring for children with autism. The research team at CFD trialed the neuma system extensively, developed use case scenarios, and identified the features necessary to successfully implement in situ alerts to caregivers and track stress events to review for patterns of stress. Results: The resulting system is neuma-CFD, a coordinated technological system for in situ monitoring of stress levels to identify correlations in the user’s stress increases and contextual events. The system delivers in situ alerts to caregivers via a smartphone or similar handheld devices. A new interface for the mobile app was customized to minimize user burden. The home screen now allows users to create high-frequency calendar events in only two taps. These events include common challenging behaviors and common intervention techniques. Thus, upon review, stress responses can be viewed relevant to both challenging behavioral episodes and intervention techniques. To enhance clinical review, the app now logs the detection of stress events into the calendar. Users can also access an increased granular review of electrodermal activity within a calendar event, such as behavior episodes or classroom routines. Conclusions: In field testing, in situ alerts were reported by caregivers to be beneficial. Furthermore, the integration of color-coding calendar events and routines in an intuitive interface allows multiple users to review the contextual events correlated to stress responses with minimal training. Wear tolerance, a challenging human factor common in ASD, can be addressed through behavioral shaping protocols. The hardware form factor was not amenable to this population due impulsive behaviors including pulling on the device to remove it, causing hardware damage. Exposure to water during handwashing was another challenge in hardware. These concerns are being revised in future versions of hardware. This system can also benefit other healthcare populations, such as patients with anxiety, posttraumatic stress disorder or any other condition for which understanding patterns of stress offers improved health outcomes.

What's New in Orthopaedic Basic Science.

1Surgical Discovery Centre, Department of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom aE-mail: [email protected]

Vanderbilt neuroscience drug advances to clinic

In a first for an academic drug discovery group, the Vanderbilt Center for Neuroscience Drug Discovery has received FDA approval to put a treatment for brain disorders into the clinic without any help from the pharmaceutical industry. A study assessing the safety of the compound, a positive allosteric modulator of muscarinic acetylcholine receptor 1 (M1) for Alzheimer’s disease and schizophrenia, will begin early next year. Academic drug discovery centers such as VCNDD typically focus on generating early-stage compounds that are spun off into companies or licensed to partners with the cash and experience to push them into clinical studies. Since it was established in 2008, VCNDD has secured several drug discovery partnerships with big pharma firms for preclinical compounds developed in its labs. But with many drug firms exiting neuroscience research, some of those programs have stalled. Big pharma’s waning commitment to neuroscience prompted a shift in strategy at VCNDD.

The third annual BRDS on research and development of nucleic acid-based nanomedicines.

The completion of human genome project, decrease in the sequencing cost, and correlation of genome sequencing data with specific diseases led to the exponential rise in the nucleic acid-based therapeutic approaches. In the third annual Biopharmaceutical Research and Development Symposium (BRDS) held at the Center for Drug Discovery and Lozier Center for Pharmacy Sciences and Education at the University of Nebraska Medical Center (UNMC), we highlighted the remarkable features of the nucleic acid-based nanomedicines, their significance, NIH funding opportunities on nanomedicines and gene therapy research, challenges and opportunities in the clinical translation of nucleic acids into therapeutics, and the role of intellectual property (IP) in drug discovery and development.

GREEN APPROACH TOWARDS SYNTHESIS OF 3-SUBSTITUTED-5-CARBONYLMETYL-1,2,4-OXADIAZOLES WITHOUT ANY SOLVENT AND CATALYST VIA TRANSAMIDOXIMATION.

17Sep 2016 GREEN APPROACH TOWARDS SYNTHESIS OF 3-SUBSTITUTED-5-CARBONYLMETYL-1,2,4-OXADIAZOLES WITHOUT ANY SOLVENT AND CATALYST VIA TRANSAMIDOXIMATION. G. B. Dharma Rao and Ravi Gujjula. Discovery Centre, Process Technology Development Division, Defence R. & D. Establishment, Jhansi Road, Gwalior – 474002 (M.P), India. Department of Chemistry, Kommuri Pratap Reddy Institute of Technology, Hyderabad - 501301 (TS), India.

Abstract B26: Accelerating prediction of tumor vulnerabilities using next-generation cancer models

Abstract The development of new cancer therapeutics requires sufficient genetic and phenotypic diversity of cancer models. Current collections of human cancer cell lines are limited and for many rare cancer types, zero models exist that are broadly available. Here, we report results from the pilot phase of the Cancer Cell Line Factory (CCLF) project that aims to overcome this obstacle by systematically creating next-generation in vitro cancer models from adult and pediatric cancer patients' specimens and making these models broadly available. We first developed a workflow of laboratory, genomics and informatics tools that make it possible to systematically compare published ex vivo culture conditions for each individual tumor to enable the scientific community to iterate towards disease-specific culture recipes. Based on sample volume and rarity, 4-100 conditions were applied to each sample and all data was captured in a custom Laboratory Information Management System to enhance subsequent predictions. We developed a $150, 5-day turnaround genomics panel to validate cultures based on genomics. Importantly, we show that tumor genomics can be retained in such patient-derived models and tumor genomics are generally stable across 20 passages. Since the inception of this project, we have processed over 650 patient cancer specimens from 450 patients across 16 tumor types and report the successful generation of over 100 genomically characterized adult and pediatric cancer and normal models. We next hypothesized that novel patient-derived cultures could be used to enhance dependency predictions. To do so, we tested 65 cell lines against the “informer” set of 440 compounds developed by the Broad Cancer Target Discovery and Development (CTD2) Center. We show that generating cell lines and testing their sensitivities within 3 months is feasible and the drug responses are reproducible. Moreover, to strengthen relationships between drug sensitivities and cellular features, we compared results with recently published data on the identical compounds tested against 860 existing cell lines. With this approach, we are able to identify many known drug dependencies in these novel models and exhibit the consistency sensitivities compared to existing cell lines. We are also evaluating drug sensitivity predictors for novel dependencies. Overall, our proof-of-concept framework demonstrates initial feasibility of rapidly generating cancer models and assessing drug sensitivities at scale. Citation Format: Yuen-Yi Tseng, Paula Keskula, Andrew L. Hong, Shubhroz Gill, Jaime H. Cheah, Gregory V. Kryukov, Aviad Tsherniak, Francisca Vazquez, Glenn Cowley, Coyin Oh, Anson Peng, Abeer Sayeed, Rebecca Deasy, Peter Ronning, Philip Kantoff, Levi Garraway, Mark A. Rubin, Calvin Kuo, Sidharth Puram, Adi Gazdar, Filemon S. Dela Cruz, Jr., Adam Bass, Jr., Nikhil Wagle, Keith L. Ligon, Katherine Janeway, David Root, Stuart L. Schreiber, Paul A. Clemons, Aly Shamji, William C. Hahn, Todd R. Golub, Jesse S. Boehm. Accelerating prediction of tumor vulnerabilities using next-generation cancer models. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr B26.