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Research Agenda
ACCRF´s Research Agenda and Projects (September 2007)
ACCRF´s Research Agenda represents the best efforts of the best minds at the best cancer institutions in the world to find a cure for ACC.
Rather than focus on just one approach to improving therapies, ACCRF is making progress in multiple areas and ensuring that they link together into
a flexible, logically-sequenced plan of action.
Guiding Principles
Certain principles underlie the manner in which ACCRF has developed the overall Research Agenda as well
as the individual research projects:
- Multi-Institutional Cooperation – No single institution has the resources or the expertise to carry out all the necessary research projects for
ACC. The specimens and models are too rare, the technology platforms are too expensive, and the leading experts are too dispersed for any one
institution to carry the burden alone. ACCRF´s greatest impact is in fostering multi-institutional cooperation.
- Proactive Project Selection – ACCRF is fortunate to benefit from the insights of an exceptional Scientific Advisory Board. It would be foolish to
limit its participation to the passive review of investigator-initiated proposals (the traditional model for most foundations in which researchers tell
project funders what they would like to study). Instead, in consultation with top researchers from around the world, ACCRF´s Scientific Advisory Board
proactively drives the Research Agenda, suggesting high-impact projects and identifying the leading researchers with the capacity and interest to carry
them out. Certainly, ACCRF welcomes investigator-initiated proposals, but does not rely upon them as the primary engine of progress.
- Accelerating Practices – The need for rigor and validation in scientific research often obscures and occasionally blunts the sense of urgency
among researchers. However, ACCRF believes that there are ways the research process may be accelerated responsibly:
- ACCRF pushes for rapid and wide dissemination of research findings to avoid unnecessarily
duplicative work and to attract new researchers to the field.
- ACCRF delineates expectations for deliverables and timeframes in each project, and uses
contracts in place of grants, where appropriate.
Based upon these principles, and benefitting from the input of many researchers at numerous scientific meetings, ACCRF has created this Research
Agenda. It is a living document that will change as circumstances and feedback warrant.
Project Categories
The projects supported by ACCRF fall into three broad categories:
- Specimens & Models – Researchers investigating ACC need certain building blocks as the foundation of their experiments.
Biobanks (repositories for tumor specimens), cell lines (tumors grown in dishes) and animal models (tumors grown typically in mice) are readily
available for researchers looking at common cancers. Unfortunately, these specimens and models are very difficult to obtain for researchers
looking at rare cancers. ACCRF is committed to increasing the availability of – and access to – these crucial building blocks of research.
- Basic Research – In order to accelerate the development of improved therapies, it is prudent to invest in projects that reveal the mechanisms of
action that are driving the development and progression of ACC. By understanding which genes, proteins and/or environmental factors are leading to the
cancer, researchers will be in a better position to propose and develop effective treatments. ACCRF and its Scientific Advisory Board believe that
supporting basic research actually may be the quickest route to improved therapies.
- Translational Research – The eventual goal of all research is to get treatment ideas from "the bench" (basic research) to "the
bedside" (translational research). Before a novel therapy can reach the bedside, however, it must pass many tests of safety and efficacy. ACCRF is
preparing the infrastructure to conduct high-throughput cell line and animal model screening of compounds. In addition, ACCRF is exploring
ways to support clinical trials for ACC patients, whether for novel compounds or drugs already approved for other indications.
In summary, the Research Agenda´s focus is on putting in place the building blocks of research and then finding the most capable
researchers with the available capacity to carry out the highest-impact basic and translational research projects rapidly. The various
components are depicted below and described thereafter.
Tumor Donations
The entire research endeavor is based upon the support of patients. By consenting to provide tumor specimens, patients jumpstart
the entire process of developing biobanks, animal models and cell lines – the building blocks upon which improved therapies may be discovered.
Indeed, tumor donations permit patients to take an active role in eventually helping other patients – and perhaps themselves.
The most useful specimens for research are those that are made available to researchers within hours of surgery (fresh or frozen). So
it is imperative that patients inform their surgeons ahead of time that they would like to donate for research any excess tumor that won´t
be required for their own follow-up care. If a patient´s surgical hospital does not have an active research or biobanking program (most do not),
then the following services are available at no cost to the patient:
Biobanks and Patient Databases
Biobanks are crucial to the research endeavor in two ways. First, they provide the inputs for the gene-based and protein-based studies
that are involved in developing targeted therapies and improved diagnostics. Second, if they are combined with patient records, they provide
an invaluable resource from which to undertake correlative studies on patient outcomes.
- ACCRF has provided the M.D. Anderson Cancer Center with support for a Lab Technician to harvest, process and distribute
ACC samples. In addition, pathologic, clinical and follow-up information on ACC cases are maintained. Specimens are actively
being banked.
- ACCRF has provided the University of Virginia with support for a Lab Technician to harvest, process and distribute ACC samples.
Specimens are actively being banked.
Cell Lines
Cell lines (human tumor cells grown in dishes) are helpful to researchers in understanding the basic biology of a disease as well as for
initial screening of drugs. Unfortunately, researchers have found it to be very difficult to create ACC cell lines. Until recently, only one
ACC cell line was available in the United States and Europe.
- ACCRF has identified additional ACC cell lines that have been created globally, and has worked with researchers to make them
more widely available. ACCRF-affiliated researchers now have access to nine cell lines.
- ACCRF supports the efforts of researchers at the University of Virginia, the Dana Farber Cancer Institute, the M.D. Anderson Cancer Center and Johns
Hopkins University to grow new ACC cell lines from fresh tumor donations and animal models.
Animal Models
Animal models (typically mice with implanted human tumors, called xenografts) help researchers better understand the mechanisms of
action, effectiveness, dosing and toxicity of new treatments. In addition, they facilitate the creation of new cell lines.
- ACCRF supports the efforts of researchers at the University of Virginia, the Dana Farber Cancer Institute, the M.D. Anderson Cancer Center
and Johns Hopkins University to create new animal models of ACC. Several xenografts have been created, and more are under development.
Genomic & Proteomic Studies
Genomics and proteomics involve the study of genes, RNA and proteins in living cells. Genetic mutations are often implicated in the
development and progression of cancer. In addition, the RNA and protein products of those genes may be different in tumors than in normal
tissues. By identifying the mutated genes, RNA and proteins that are peculiar to ACC, researchers may be able to diagnose patients better
and use targeted treatments more effectively.
- ACCRF has a Research Collaboration Agreement with the Wellcome Trust Sanger Institute (WTSI) in the United Kingdom to sequence
many genes across many DNA samples in the search for mutations associated with ACC. The initial list of genes is heavily weighted
toward those that have been drugged or are easily druggable (protein kinases). WTSI was the leading contributor of finished sequence
to the Human Genome Project, and its Cancer Genome Project maintains the pre-eminent public database of cancer genes and somatic
mutations. For more information on WTSI, please click here:
http://www.sanger.ac.uk/genetics/CGP/
- ACCRF supports the efforts at the University of Virginia to create a transgenic mouse model of ACC that would identify a key
biological pathway in the development of the disease, and would be invaluable in testing new therapies. For the latest update,
please click here:
http://www.accrf.org/pdf/UVA_ProgressReportMay2006.pdf
- ACCRF supported the expansion of an aCGH (array comparative genomic hybridization) study to identify genetic imbalances and novel
target genes in ACC. The study is being conducted at the Sahlgrenska Academy at Goteborg University in Sweden.
Correlative Studies
By combining patient histories with genomic analyses of their tumors, researchers may learn key lessons about the linkages
between certain tumor profiles and patient outcomes. The result may be optimal treatments for individual patients.
- ACCRF is supporting biobanking efforts that are well-designed and robust at both MD Anderson and UVA. Gradually, over the
next few years, sufficient specimens and patient histories will be gathered to conduct correlative studies with potentially
powerful conclusions.
Drug Screening and Development
Before a new treatment for ACC may reach patients through clinical trials, it must be subjected to rigorous
screening for safety, toxicity and efficacy in vitro (in cell line dishes) and in vivo (in animal models). Screens may be
conducted with libraries of a million compounds or merely those that are clinically-relevant (currently available to patients).
- ACCRF is facilitating the provision of ACC cell lines to the Center for Molecular Therapeutics at the Massachusetts General
Hospital. High Throughput Screening (HTS) with clinically-relevant compounds will be carried out on the cell lines, providing
information on the functioning of the cells and perhaps leading to the optimization of molecularly-targeted therapies for ACC.
For more information, please click here:
http://www.massgeneral.org/cancer/research/basic/ccr/molecular_therapeutics.asp
- ACCRF is consolidating the animal models developed by its affiliated researchers at one research institution, permitting
cost-effective drug screening that will be made available to all researchers, whether from academic or private institutions.
The information gleaned from the genomic, proteomic and HTS studies will help researchers decide upon the best compounds to screen in the
animal models.
Clinical Trials
The goal of the Research Agenda is to get effective drugs to patients. Clinical trials are the testing ground for effectiveness
(and toxicity) in humans. They may involve a drug that has already been approved for another cancer or condition, or a novel drug
that has yet to receive regulatory approval for any indication.
Clinical trials are particularly difficult to organize for rare conditions such as ACC because multiple institutions must coordinate
in order to enroll sufficient patients. It is far simpler to plan the scientific, logistical, regulatory and statistical elements of
a clinical trial within one institution. And private firms may not be willing to finance the high cost of clinical trials for a small
patient population that may not generate much revenue.
- ACCRF communicates regularly with the medical oncologists at the leading head & neck cancer institutions who treat most ACC patients.
These relationships will be crucial as multi-institutional groups are formed to push clinical trials forward for ACC patients.
- By supporting the generation of data on mechanisms of action and pre-clinical drug efficacy, ACCRF will provide medical oncologists with
the rationale for designing ACC-specific clinical trials that are more likely to yield improved therapies. Patients are more likely to enroll
in such trials, and the NIH and private pharmaceutical firms are more likely to sponsor such clinical trials.
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