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Mapping biologically active chemical space to accelerate drug discovery.Sittampalam S, Rudnicki D, Tagle D, Simeonov A, Austin CNat Rev Drug Discov , (18), 83-84, 2019. Article Pubmed |
Metastatic Tumor-In-A-Dish, A Novel Multi-Cellular Organoid to Study Lung Colonization and Predict Therapeutic Response.Ramamoorthy P, Thomas SM, Kaushik G, Subramaniam D, Chastain KM, Dhar A, Tawfik O, Kasi A, Sun W, Ramalingam S, Gunewardena S, Umar S, Mammen JMV, Padhye SB, Weir SJ, Jensen RA, Sittampalam S, Anant SCancer Res. , 2019. Article Pubmed Metastasis is a major cause of cancer-related deaths. A dearth in preclinical models that recapitulates the metastatic microenvironment has impeded the development of therapeutic agents that are effective against metastatic disease. Since the majority of solid tumors metastasize to the lung, we developed a multi-cellular lung organoid that mimics the lung microenvironment with air sac like structures and production of lung surfactant protein. We used these cultures called primitive lung-in-a-dish (PLiD), to recreate metastatic disease using primary and established cancer cells. The metastatic tumor-in-a-dish (mTiD) cultures resemble the architecture of metastatic tumors in the lung including angiogenesis. Pretreating PLiD with tumor exosomes enhanced cancer cell colonization. We next tested the response of primary and established cancer cells to current chemotherapeutic agents and an anti-VEGF antibody in mTiD against cancer cells in 2-dimensional (2D) or 3D cultures. The response of primary patient-derived colon and ovarian tumor cells to therapy in mTiD cultures matched the response of the patient in the clinic, but not 2D or single cell type 3D cultures. The sensitive mTiD cultures also produced significantly lower circulating markers for cancer similar to that seen in patients that responded to therapy. Thus, we have developed a novel method for tumor colonization in vitro, a final stage in tumor metastasis. Moreover, the technique has significant utility in precision/personalized medicine, wherein this phenotypic screen can be coupled with current DNA pharmacogenetics to identify the ideal therapeutic agent, thereby increasing the probability of response to treatment while reducing unnecessary side effects.
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Translational in vitro research: integrating 3D drug discovery and development processes into the drug development pipeline.Kelm JM, Lal-Nag M, Sittampalam S, Ferrer-Alegre MDrug Discov. Today , 2018. Article Pubmed As we witness steady progress towards the development of robust, scalable, and reproducible 3D tissue models for preclinical drug testing, there is a need for systematic physiological and pharmacological validation and benchmarking. Ongoing and future studies should generate evidence as to whether 3D tissue models are more predictive, help reduce the risk of failure rate, and can be used for decision making in the drug discovery and development pipeline. Here, we discuss the importance of harmonizing the validation of these models based on throughput capacity and physiological complexity as a requirement to establish their true translational capacity. We also outline our strategy for a novel 3D-tailored holistic drug discovery concept rather than piecemeal integration of 3D models into the current process.
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The Assay Guidance Manual: Quantitative Biology and Pharmacology in Preclinical Drug Discovery.Coussens NP, et al.Clin Transl Sci , 2018. Article Pubmed The Assay Guidance Manual (AGM) is an eBook of best-practices for the design, development, and implementation of robust assays for early drug discovery. Initiated by pharmaceutical company scientists, the manual provides guidance for designing a "testing funnel" of assays to identify genuine hits using high-throughput screening (HTS) and advancing them through pre-clinical development. Combined with a workshop/tutorial component, the overall goal of the AGM is to provide a valuable resource for training translational scientists. This article is protected by copyright. All rights reserved.
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Small-Molecule Screens: A Gateway to Cancer Therapeutic Agents with Case Studies of Food and Drug Administration-Approved Drugs.Coussens NP, Braisted J, Peryea T, Sittampalam S, Simeonov A, Hall MPharmacol. Rev. , (69), 479-496, 2017. Article Pubmed High-throughput screening (HTS) of small-molecule libraries accelerates the discovery of chemical leads to serve as starting points for probe or therapeutic development. With this approach, thousands of unique small molecules, representing a diverse chemical space, can be rapidly evaluated by biologically and physiologically relevant assays. The origins of numerous United States Food and Drug Administration-approved cancer drugs are linked to HTS, which emphasizes the value in this methodology. The National Institutes of Health Molecular Libraries Program made HTS accessible to the public sector, enabling the development of chemical probes and drug-repurposing initiatives. In this work, the impact of HTS in the field of oncology is considered among both private and public sectors. Examples are given for the discovery and development of approved cancer drugs. The importance of target validation is discussed, and common assay approaches for screening are reviewed. A rigorous examination of the PubChem database demonstrates that public screening centers are contributing to early-stage drug discovery in oncology by focusing on new targets and developing chemical probes. Several case studies highlight the value of different screening strategies and the potential for drug repurposing.
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Novel Phenotypic Outcomes Identified for a Public Collection of Approved Drugs from a Publicly Accessible Panel of Assays.Lee JA, Shinn P, Jaken S, Oliver S, Willard FS, Heidler S, Peery RB, Oler J, Chu S, Southall N, Dexheimer TS, Smallwood J, Huang R, Guha R, Jadhav A, Cox K, Austin C, Simeonov A, Sittampalam S, Husain S, Franklin N, Wild DJ, Yang JJ, Sutherland JJ, Thomas CPLoS ONE , (10), e0130796, 2015. Article Pubmed Phenotypic assays have a proven track record for generating leads that become first-in-class therapies. Whole cell assays that inform on a phenotype or mechanism also possess great potential in drug repositioning studies by illuminating new activities for the existing pharmacopeia. The National Center for Advancing Translational Sciences (NCATS) pharmaceutical collection (NPC) is the largest reported collection of approved small molecule therapeutics that is available for screening in a high-throughput setting. Via a wide-ranging collaborative effort, this library was analyzed in the Open Innovation Drug Discovery (OIDD) phenotypic assay modules publicly offered by Lilly. The results of these tests are publically available online at www.ncats.nih.gov/expertise/preclinical/pd2 and via the PubChem Database (https://pubchem.ncbi.nlm.nih.gov/) (AID 1117321). Phenotypic outcomes for numerous drugs were confirmed, including sulfonylureas as insulin secretagogues and the anti-angiogenesis actions of multikinase inhibitors sorafenib, axitinib and pazopanib. Several novel outcomes were also noted including the Wnt potentiating activities of rotenone and the antifolate class of drugs, and the anti-angiogenic activity of cetaben.
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Three-Dimensional Cell Culture Assays: Are They More Predictive of In Vivo Efficacy than 2D Monolayer Cell-Based Assays?Sittampalam S, Eglen R, Ferguson S, Maynes JT, Olden K, Schrader L, Shelper T, Ferrer-Alegre MAssay Drug Dev Technol , (13), 254-61, 2015. Article Pubmed |
A multicenter pilot study examining the role of circulating tumor cells as a blood-based tumor marker in patients with extensive small-cell lung cancer.Huang CH, Wick JA, Sittampalam S, Nirmalanandhan VS, Ganti AK, Neupane PC, Williamson SK, Godwin AK, Schmitt S, Smart NJ, Spencer S, Van Veldhuizen PJFront Oncol , (4), 271, 2014. Article Pubmed BACKGROUND: Small-cell lung cancer (SCLC), a variant of lung cancer marked by early metastases, accounts for 13% of all lung cancers diagnosed in US. Despite high response rates to treatment, it is an aggressive disease with a median survival of 9-11 months for patients with extensive stage (EX-SCLC). Detection of circulating tumor cells (CTCs) is a novel laboratory technique currently in use to determine response to therapy and to predict prognosis in breast, colorectal, and prostate cancer. We initiated a pilot study to analyze the role of CTCs as a biomarker of response and relapse in patients with EX-SCLC.
METHODS: We collected blood samples from chemotherapy naïve patients with EX-SCLC prior to initiation of therapy, after completion of systemic therapy, and follow-up every 6-8 weeks and at relapse. The number of CTCs was determined using the cell search system in a central laboratory. The study was conducted in four different sites, and it was reviewed and approved by respective research review committees and IRBs.
RESULTS: We enrolled 26 patients with EX-SCLC, 1 was excluded due to ineligibility, all were treated with platinum and etoposide. We observed partial response in 16 patients, stable disease in 3 patients, 1 patient with disease progression, and 6 patients were not assessed (5 deceased, 1 not available). The overall median number of CTCs in 24 patients measured at baseline and post-tx was 75 (range 0-3430) and 2 (range 0-526), respectively. A significant reduction in CTCs from baseline to post-treatment was identified for 15 subjects; the median reduction was 97.4% (range -100 to +100%, p < 0.001). Higher baseline CTCs and percentage change in post-treatment CTCs were associated with decreased survival.
CONCLUSION: We demonstrated that it is feasible to detect CTCs in EX-SCLC. If validated in other prospective studies, CTCs could be a useful biomarker in the management of EX-SCLC by predicting patients' clinical responses to therapy.
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Impact of high-throughput screening in biomedical research.Macarron R, Banks MN, Bojanic D, Burns DJ, Cirovic DA, Garyantes T, Green DV, Hertzberg RP, Janzen WP, Paslay JW, Schopfer U, Sittampalam SNat Rev Drug Discov , (10), 188-95, 2011. Article Pubmed High-throughput screening (HTS) has been postulated in several quarters to be a contributory factor to the decline in productivity in the pharmaceutical industry. Moreover, it has been blamed for stifling the creativity that drug discovery demands. In this article, we aim to dispel these myths and present the case for the use of HTS as part of a proven scientific tool kit, the wider use of which is essential for the discovery of new chemotypes.
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