According to the National Institutes of Health’s definition, translational research aims to treat human disease via utilization of existing knowledge from both basic and patient-oriented research. Translational research forms the bridge between “bench (preclinical and basic research) and bedside (clinical research),” where exciting discoveries at the bench are delivered to patients in need and, through reverse feedback, clinical questions and needs arising from patient care go back to the bench to inspire mechanistic research and new solutions.
While it sounds simple, there are multiple barriers in the field of translational research in the clinical environment. In particular, the speed of early novel drug development is hindered by lack of development strategies based on true understanding of the drugs’ mechanism, lack of high-quality hypothesis-based clinical trial designs that can test the applicability of novel drugs, and lack of solid preclinical testing to define the best synergistic existing therapies to combine with new drugs to induce true efficacy in patients.
There is an urgent demand from academic translational/clinical researchers and Pharma for a robust preclinical system to test novel drugs’ best application strategies via a dedicated preclinical team prior to, or in parallel with, the actual testing of the drug in patients.
A new program in the Department of Breast Medical Oncology at The University of Texas MD Anderson Cancer Center seeks to address these challenges.
It is becoming clear that simply validating the drug toxicity, pharmacokinetic and pharmacodynamic marker monitoring, and biomarker development is not sufficient to launch a successful novel drug in this modern era. Instead, preclinical testing can support the rationale of each drug to reduce the current risk of development based on tight collaboration among academic, clinical, and translational investigators.
For example, screening to discover the best synergistic partner for a drug (via RNA interference or the new CRISPR/cas9 gene-knockout system), drug testing in clinically relevant animal models (patient-derived xenograft and immunocompetent tumor models based on mice or a genetic engineering model), and integration of bioinformatics analysis of patient sample-based omics data will all contribute to the likelihood of the clinical success of a drug.
In the end, the goal is to reduce the risk of the project by expanding disease indications of the drug of interest, identifying clinically relevant predictive biomarkers, understanding resistance mechanisms, and designing novel combination therapies. These approaches will successfully bring a clear path for the drug development complement of the results of Phase I or II study.
But how many clinical investigators do we have in the USA, not just engaged, but truly understanding these technologies and application to the clinic? Unfortunately, even in a very large cancer center, the number of such clinical investigators is limited because of the lack of education opportunities and the limited time to commit to translational research-oriented drug development.
To address these issues, we have established an innovative preclinical research platform: Enhanced Drug-development Guidance and Evaluation (EDGE) Preclinical Solutions. Our mission is to reduce the suffering of breast cancer patients through preclinical operations dedicated to discovering and developing targeted therapies and molecular biomarkers for patient-centered, hypothesis-driven translational/clinical research through extensive collaboration with industry and academia.
EDGE Preclinical Solutions will serve clinicians, basic scientists, and pharmaceutical companies who have a plan to develop promising drugs in breast cancer that can further guide the launch of investigator-initiated clinical trials.
EDGE Preclinical Solutions consists of a dedicated professional multidisciplinary team, including six research faculty members, three clinical faculty members, seven trainees, and six administrative research staff members.
Our unique strength is that we have the capability to align with five goals of the National Center for Advancing Translational Sciences (NCATS):
(1) We have the skills and knowledge needed for translational research;
(2) We are engaging others and forming collaborations;
(3) We are integrating the multiple disciplines, phases of research, and populations addressed;
(4) We are developing robust scientific hypothesis-based proposals that will enable significant advances in translation; and
(5) We are using innovative informatics solutions to advance translational research, with maximal speed that overcomes the hurdles originating from the traditional slow academic approach.
We provide one-stop service, using in-house high-quality in vitro and in vivo experimental resources. Because we have a comprehensive understanding of all the tools and core facilities available inside MD Anderson, we can coordinate all experimental planning for the investigators who come to us.
If investigators need help in planning and contracting with Pharma, the EDGE faculty and staff can assist. If a company desires a full strategic alliance working with clinical investigators and preclinical development, EDGE Preclinical Solutions can be the matchmaker and can execute the research plan.
The hypothesis-driven preclinical data produced by these activities will be quickly translated into a clinic that is run by world-expert breast cancer clinical investigators. The advantage of this system for clinical investigators is that they can develop preclinical data that will support their clinical strategy, without needing their own bench space or extensive experience in conducting bench research. The advantage for basic researchers is that they do not have to put effort into preclinical data-generation projects that are commonly considered unsuitable for postdoctoral fellows and graduate students.
Currently, 12 investigator-initiated preclinical studies supported by various pharmaceutical companies are being managed by EDGE Preclinical Solutions. Two early-phase clinical trials (NCT01434303 and NCT00921336) based on our preclinical studies have launched, with more to come.
During the development of the EDGE Preclinical Solutions platform, our team learned that translational research in drug development can be divided into two stages:
· The first stage is to facilitate early translation by bringing new compounds or biomarkers to lead to the initial phase drug. This is a critical step for translation of any new cancer drugs, which is well recognized by cancer centers and Pharma.
· The second stage is to select the best translatable molecules or compounds that can benefit the patients by meeting certain milestones as stability, safety, and efficacy, and further develop pre-clinically. This is the area that remains underdeveloped by many cancer centers or that Pharma may not have full access to, and this is where EDGE Preclinical Solutions can contribute significantly to early drug development.
In summary, EDGE Preclinical Solutions will provide rapid translation of clinical and preclinical findings via a comprehensive preclinical research platform. In contrast to the conventional academic approach to drug development, which may focus on more mechanistic work that will lead to high-impact publications, our strategy of creating a dedicated preclinical platform will help speed up drug development, skipping the possibly redundant experiment just to perfect publication that requires sometimes years of basic work that may still lack a translatable path to efficacious therapy.
We are confident that this change will result in the rapid development of novel drugs that will benefit both industry and academia by arming us with more innovative therapies. But most importantly, this rapid translational approach to developing novel drugs will benefit patients who are in desperate need of better treatment options.
Jangsoon Lee, PhD, is Clinical Research Scientist in the Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, Enhanced Drug Development Guidance and Evaluation Preclinical Solutions, at The University of Texas MD Anderson Cancer Center.
Bora Lim, MD, is Assistant Professor of Medicine in the Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, Enhanced Drug Development Guidance and Evaluation Preclinical Solutions, at The University of Texas MD Anderson Cancer Center.
Naoto T. Ueno, MD, PhD, FACP, is Professor of Medicine, the Nylene Eckles Distinguished Professor in Breast Cancer Research, and Chief of the Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, Enhanced Drug Development Guidance and Evaluation Preclinical Solutions, at The University of Texas MD Anderson Cancer Center.