- Tumor Engineering: Applications for Cancer Biology and Drug Development

Colonization of distant organs by tumor cells is a critical step of cancer progression. The initial avascular stage of this process (micrometastasis) remains almost inaccessible to study due to the lack of relevant experimental approaches. Herein, we introduce an in vitro/in vivo model of organ-specific micrometastases of triple-negative breast cancer (TNBC) that is fully implemented in a cost-efficient chick embryo (CE) experimental platform. The model was built as three-dimensional (3D) tissue engineering constructs (TECs) combining human MDA-MB-231 cells and decellularized CE organ-specific scaffolds. TNBC cells colonized CE organ-specific scaffolds in 2–3 weeks, forming tissue-like structures. The feasibility of this methodology for basic cancer research, drug development, and nanomedicine was demonstrated on a model of hepatic micrometastasis of TNBC. We revealed that MDA-MB-231 differentially colonize parenchymal and stromal compartments of the liver-specific extracellular matrix (LS-ECM) and become more resistant to the treatment with molecular doxorubicin (Dox) and Dox-loaded mesoporous silica nanoparticles than in monolayer cultures. When grafted on CE chorioallantoic membrane, LS-ECM-based TECs induced angiogenic switch. These findings may have important implications for the diagnosis and treatment of TNBC. The methodology established here is scalable and adaptable for pharmacological testing and cancer biology research of various metastatic and primary tumors.

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Clinical, Pathological, and Ethical Considerations for the Conduct of Clinical Trials in Dogs with Naturally Occurring Cancer: A Comparative Approach to Accelerate Translational Drug Development

ILAR Journal ◽

10.1093/ilar/ily019 ◽

2018 ◽

Vol 59 (1) ◽

pp. 99-110 ◽

Cited By ~ 5

Author(s):

Daniel Regan ◽

Kelly Garcia ◽

Douglas Thamm

Keyword(s):

Clinical Trials ◽

Drug Development ◽

Translational Research ◽

Cancer Biology ◽

Comparative Approach ◽

Cancer Drug ◽

Comparative Oncology ◽

Pet Dogs ◽

Naturally Occurring

Abstract The role of comparative oncology in translational research is receiving increasing attention from drug developers and the greater biomedical research community. Pet dogs with spontaneous cancer are important and underutilized translational models, owing to dogs’ large size and relative outbreeding, combined with their high incidence of certain tumor histotypes with significant biological, genetic, and histological similarities to their human tumor counterparts. Dogs with spontaneous tumors naturally develop therapy resistance and spontaneous metastasis, all in the context of an intact immune system. These fundamental features of cancer biology are often lacking in induced or genetically engineered preclinical tumor models and likely contribute to their poor predictive value and the associated overall high failure rate in oncology drug development. Thus, the conduct of clinical trials in pet dogs with naturally occurring cancer represents a viable surrogate and valuable intermediary step that should be increasingly incorporated into the cancer drug discovery and development pipeline. The development of molecular-targeted therapies has resulted in an expanded role of the pathologist in human oncology trials, and similarly the expertise of veterinary pathologists will be increasingly valuable to all phases of comparative oncology trial design and conduct. In this review, we provide a framework of clinical, ethical, and pathology-focused considerations for the increasing integration of translational research investigations in dogs with spontaneous cancer as a means to accelerate clinical cancer discovery and drug development.

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Urinary Bladder Cancer in Dogs, a Naturally Occurring Model for Cancer Biology and Drug Development

ILAR Journal ◽

10.1093/ilar/ilu018 ◽

2014 ◽

Vol 55 (1) ◽

pp. 100-118 ◽

Cited By ~ 89

Author(s):

D. W. Knapp ◽

J. A. Ramos-Vara ◽

G. E. Moore ◽

D. Dhawan ◽

P. L. Bonney ◽

...

Keyword(s):

Bladder Cancer ◽

Urinary Bladder ◽

Drug Development ◽

Cancer Biology ◽

Urinary Bladder Cancer ◽

Naturally Occurring

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Chick Embryo Experimental Platform for 3D Tissue Engineering Modelling of Cancer Micrometastases for Tumor Biology, Drug Development and Nanomaterials Testing

10.20944/preprints202109.0085.v1 ◽

2021 ◽

Author(s):

Anna Guller ◽

Inga Kuschnerus ◽

Vlada Rozova ◽

Annemarie Nadort ◽

Yin Yao ◽

...

Keyword(s):

Tissue Engineering ◽

Chick Embryo ◽

Drug Development ◽

Cancer Biology ◽

Mesoporous Silica Nanoparticles ◽

Tumor Biology ◽

In Vivo Model ◽

Primary Tumors ◽

Experimental Platform ◽

Organ Specific

Colonization of distant organs by tumor cells is a critical step of cancer progression. The initial avascular stage of this process (micrometastasis) remains almost inaccessible to study due to the lack of relevant experimental approaches. Here, we introduce an in vitro/in vivo model of organ-specific micrometastases of triple-negative breast cancer (TNBC) that is fully implemented in a cost-efficient chick embryo (CE) experimental platform. The model is built as three-dimensional (3D) tissue engineering constructs (TECs) combining human MDA-MB-231 cells and decellular-ized CE organ-specific scaffolds. TNBC cells colonized CE organ-specific scaffolds in 2-3 weeks, forming tissue-like structures. The feasibility of this methodology for basic cancer research, drug development and nanomedicine was demonstrated on a model of hepatic micrometastasis of TNBC. We revealed that MDA-MB-231 differentially colonize parenchymal and stromal com-partments of the liver-specific extracellular matrix (LS-ECM) and become more resistant to the treatment with molecular Doxorubicin (Dox) and Dox-loaded mesoporous silica nanoparticles than in monolayer cultures. When grafted on CE chorioallantoic membrane, LS-ECM-based TECs induced angiogenic switch. These findings may have important implications for the diag-nosis and treatment of TNBC. The methodology established here is scalable and adaptable for pharmacological testing and cancer biology research of various metastatic and primary tumors.

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Patient-Centered Cancer Drug Development: Clinical Trials, Regulatory Approval, and Value Assessment

American Society of Clinical Oncology Educational Book ◽

10.1200/edbk_242229 ◽

2019 ◽

pp. 374-387 ◽

Cited By ~ 3

Author(s):

Bishal Gyawali ◽

Thomas J. Hwang ◽

Kerstin Noelle Vokinger ◽

Christopher M. Booth ◽

Eitan Amir ◽

...

Keyword(s):

Clinical Trials ◽

Drug Development ◽

Cancer Biology ◽

Drug Approval ◽

The United States ◽

Rapid Expansion ◽

Cancer Drug ◽

Trial Participation ◽

Value Assessment ◽

The Impact

Historically, patient experience, including symptomatic toxicities, physical function, and disease-related symptoms during treatment or their perspectives on clinical trials, has played a secondary role in cancer drug development. Regulatory criteria for drug approval require that drugs are safe and effective, and almost all drug approvals have been based only on efficacy endpoints rather than on quality-of-life (QoL) assessments. In contrast to Europe, information regarding the impact of drugs on patients’ QoL is rarely included in oncology drug labeling in the United States. Until recently, patient input and preferences have not been incorporated into the design and conduct of clinical trials. In recent years, a more in-depth understanding of cancer biology, as well as regulatory changes focused on expediting cancer drug development and approval, has allowed earlier access to novel therapeutic agents. Understanding the implications of these expedited programs is important for oncologists and patients, given the rapid expansion of these programs. In this article, we provide an overview of the role of QoL in the regulatory drug–approval process, key issues regarding trial participation from the patient perspective, and the implications of key expedited approval programs that are increasingly being used by regulatory bodies for cancer care.

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Changes in numbers of randomized (RCT) versus non-randomized (NRCT) clinical trials from 2004-2016: Evidence of shifting cancer drug development pathway.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.2543 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 2543-2543

Author(s):

Laura Vidal Boixader ◽

Kelly Kevelin Curtis ◽

Jim Wahl ◽

Nicholas Kenny ◽

Keren Rachel Moss

Keyword(s):

Clinical Trials ◽

Drug Development ◽

Cancer Biology ◽

Drug Approval ◽

Cancer Drug ◽

Phase 2 ◽

The Past ◽

Anti Cancer ◽

High Antitumor Activity ◽

Drug Approval Process

2543 Background: Trials using randomized designs have been conducted for decades to demonstrate efficacy of novel anti-cancer drugs (NACD). Recently, several NACD have shown high antitumor activity in early phase studies, prompting suggestions that NRCT could expedite drug development. We sought to determine what changes have occurred in numbers of NACD RCT vs NRCT conducted from 2004-2016. Methods: We reviewed a database of NACD clinical trials conducted by INC (excluding phase I and I/II trials) and classified them by RCT vs NRCT, grouped by year (≤ 2010 or > 2010). We queried Citeline Trialtrove database for industry sponsored, phase 2 trials (P2T) initiated from 2006-2016 and examined numbers of RCT vs NRCT by year.A more detailed analysis of non-small cell lung cancer (NSCLC) clinical trials based on drug type category - Immunooncology (IO) vs. all other mechanims of action (NIO) was performed. Results: 190 INC-conducted trials were reviewed. 58 trials (31%) were performed ≤ 2010 and 132 trials (69%) > 2010. Over this period, NRCT (n = 107, 56%) outnumbered RCT (n = 83, 44%). Whereas RCT outnumbered NRCT from 2004-2010 (74% vs 52%), after 2010, NRCT outnumbered RCT (58% vs 42%). Citeline Trialtrove search revealed 4776 industry sponsored P2T initiated from 2006-2016. The total number of P2T started annually was highest in 2007 (n = 621), decreasing to a low of 375 in 2016. The proportion of phase 2 RCT demonstrated an increase from 27% (n = 166) in 2006 to a peak plateau of 37-39% from 2011-2014, followed by a drop to 33% in 2015 and 29% in 2016. Among IO studies, RCT declined in 2015-6 vs. previous years, and a decreased for all NACD in 2016 vs. previous years also was noted. For studies in NSCLC, declines in RCT were evident from 2015-6 vs. previous years ( 45% in 2007-14 vs. 25% in 2015-6). Conclusions: Our data indicate a trend toward fewer trials of NACD using randomized designs and more studies using non-randomized designs, with overall fewer P2T initiated in the past year. This change reflects shifts in NACD development pathways, related to a better understanding of cancer biology, drive to develop personalized treatment and a more flexible regulatory drug approval process.

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Drug Development in Tissue-Agnostic Indications

Cancers ◽

10.3390/cancers13112758 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2758

Author(s):

Pauline du Rusquec ◽

Christophe Le Tourneau

Keyword(s):

Drug Development ◽

Targeted Therapies ◽

Cancer Biology ◽

Market Access ◽

Cancer Type ◽

Molecular Alterations ◽

Large Patient ◽

Cancer Types ◽

Traditional Paradigm ◽

Development Paradigm

A better understanding of cancer biology has led to the development of targeted therapies specifically designed to modulate an altered molecular pathway in the cancer cells or their microenvironment. Despite the identification of molecular targets across cancer types, most of targeted therapies were developed per cancer type. In this ancestral paradigm, randomization was the gold-standard approach for market access. Randomization of large patient populations was feasible for drugs developed in common cancer types but more challenging in rare cancer types. The traditional paradigm of drug development in oncology was further challenged by the ever-expanding molecular segmentation of cancer with ever-smaller subgroups of patients who might benefit from specific targeted therapies or immunotherapies and the identification of molecular alterations against which drugs may be effective across cancer types. In this novel drug development paradigm, novel ways of evaluating the efficacy of drugs are highly needed in these small patient populations. One approach is to use each patient as his/her own control by comparing the efficacy of a drug to the efficacy of prior treatments received. This approach allows to overcome patient heterogeneity, especially in a tissue-agnostic drug development paradigm.

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Functional information from magnetic resonance imaging

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100136799 ◽

1995 ◽

Vol 53 ◽

pp. 84-85

Author(s):

Alan P. Koretsky ◽

Afonso Costa e Silva ◽

Yi-Jen Lin

Keyword(s):

Magnetic Resonance Imaging ◽

Magnetic Resonance ◽

High Resolution ◽

Cancer Biology ◽

Imaging Modality ◽

Magnetic Resonance Images ◽

Great Success ◽

Functional Information ◽

Resonance Imaging ◽

High Resolution Mri

Magnetic resonance imaging (MRI) has become established as an important imaging modality for the clinical management of disease. This is primarily due to the great tissue contrast inherent in magnetic resonance images of normal and diseased organs. Due to the wide availability of high field magnets and the ability to generate large and rapidly switched magnetic field gradients there is growing interest in applying high resolution MRI to obtain microscopic information. This symposium on MRI microscopy highlights new developments that are leading to increased resolution. The application of high resolution MRI to significant problems in developmental biology and cancer biology will illustrate the potential of these techniques.In combination with a growing interest in obtaining high resolution MRI there is also a growing interest in obtaining functional information from MRI. The great success of MRI in clinical applications is due to the inherent contrast obtained from different tissues leading to anatomical information.

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