Cell and Animal-Based Models to Advance Cancer Health Disparity Research
Cancer health disparities (CHDs) are defined as differences in the incidence, prevalence, morbidity, and mortality that contribute to an unequal burden of cancer and represent a major public health concern both nationally and globally. In the United States, several racial/ethnic populations demonstrate increased incidence and/or more aggressive disease for numerous cancer types. The causes of these CHDs are multifactorial, including differences in access to health care, diet and lifestyle, cultural barriers, environmental exposures, and ancestry-related factors. Recent data suggest that biological factors may contribute to CHDs. The NCI specifically encourages and funds investigations of such biological factors to better understand mechanisms that contribute to CHDs. One limitation in conducting basic, translational, and clinical research investigating the causes of CHDs is a substantial lack of relevant in vitro and in vivo-based models. The development and validation of appropriate models to study underrepresented population groups would greatly advance this field of research.
The primary goal of this topic is to develop new, commercially available models relevant to diverse racial/ethnic populations. These models may be used to enhance research capabilities of basic scientists and/or provide novel tools to pharmaceutical companies for preclinical oncology studies. Establishing these novel models may influence CHD research in multiple ways including 1) attracting additional researchers to this largely underexplored area of research, 2) improving the quality and acceptance of CHD research data, and 3) improving validation and commercialization of cancer therapeutics relevant to diverse patient populations. Lastly, achieving these goals will contribute to the overarching goal of facilitating the reduction of CHDs.
Small businesses are invited to submit proposals to develop a panel of cell lines, primary cells, or patient-derived xenograft (PDX) mouse models established from racially/ethnically diverse patient populations. Additionally, competitive applications may propose novel genetically engineered mouse (GEM) models to investigate cancers or co-morbid conditions that are more frequent and aggressive amongst diverse racial/ethnic populations.
? Cancer cell lines and primary cancer cells: The scientific integrity of cancer cell lines and primary cells is critical for maintaining high standards in research. Any cells established via this solicitation must be fully confirmed through a rigorous and validated authentication and be contamination-free. Furthermore, offerors must have access to fully annotated tumor tissues from diverse racial/ethnic populations with appropriate approval(s) in place (i.e., IRB).
? PDX Mouse Models: PDX models have recently gained huge recognition in clinical and preclinical oncology research. Molecular profiling studies have shown the similarity between patient tumor and PDX models is greater than between patient tumor and traditional cell lines. Therefore, new initiatives have been proposed to use PDX models in a number of clinically relevant research areas including characterization of tumor heterogeneity, in vivo therapeutic target validation studies, clinically relevant mechanism of action studies, and sensitivity and resistance to therapy studies. Furthermore, PDX models have even been suggested to be a useful tool to mimic human clinical trials using animals. Similarly, offerors must have access to fully annotated tumor tissues from diverse racial/ethnic populations with appropriate approval(s) in place (i.e., IRB).
? GEM Models: Numerous cancer types are more prevalent in specific racial/ethnic populations. An example of one such disease is triple negative breast cancer (TNBC). Although diagnosed less often, breast cancer in African American women display different characteristics compared to breast cancer in Caucasian women, including earlier onset, less favorable clinical outcome, and an aggressive tumor phenotype. The reason for this aggressive phenotype is currently widely studied however progress is hampered by the lack of suitable TNBC model systems. Development of GEMs (including knock-in mice, knock-out mice, and mice with chemically induced mutations) to study cancers disproportionately effecting racial/ethnic populations would advance the field. Offerors must provide data or cite literature justifying the GEMs proposed and have relevant technical expertise.
Phase I Activities and Deliverables
? Establish an experimental model relevant to CHD research. This may include one of the following:
o Cancer cell line or primary cells established from racial/ethnic minorities
o PDX animal model established from racial/ethnic minorities
o GEM model
? Cancer cell line and primary cells deliverables: Establish a stable cell line from tumor cells and passage the cells in culture to determine viability.
o Detailed documentation must be provided including patient clinical characteristics, passage history, mycoplasma testing results, and appropriate growth/preparation conditions.
o Develop a standardized, working protocol for establishment of additional cell culture models.
? PDX animal model deliverables: Establish a serially transplantable, phenotypically stable, human cancer xenograft model in immunocompromised mice.
o Transplant fresh surgical tissue or biopsy (either subcutaneous or intraperitoneal) into recipient immunodeficient mice (Transplant generation 1)
o Subsequent serial transplantations must be conducted following establishment of initial xenograft outgrowths, typically >10mm in diameter (A minimum of three generations of transplantation is required to establish a stable line)
o After three generation of transplantations, confirm genetic and phenotypic heterogeneity of the tumors.
o Freeze and bank tumors.
o Develop a standardized, working protocol for establishment of additional models.
o Perform comprehensive molecular characterization of patient samples and earliest PDXs, including whole exome sequencing and mutational status analysis using a CLIA-approved panel.
? GEM model deliverables: Develop a GEM model to support investigations on cancers disproportionately effecting racial/ethnic populations.
o Develop transgenic constructs and strategy to create GEM models
o Transfer fertilized mouse embryos with transgenic constructs to foster mouse mothers
o Identify potential transgenic founders and mate to generate F1 progeny
o Analyze to identify and confirm successful transgenic mice
o Determine validation and development plan for transgenic mice
? Validate the genetic ancestry of patients (if applicable) from which a model was established using a panel of ancestry informative makers (AIMs). The AIM panel(s) selected should be relevant to the patient populations being investigated and capable of specifying admixture proportions.
Phase II Activities and Deliverables
? Cancer cell lines and primary cells: Generate a panel of no less than 50 cell lines from different patient sources.
? PDX animal models: Generate a panel of no less than 20-50 models (depending on tumor type being used) from unique patient sources using established protocols.
? GEM Models: Demonstrate preclinical utility and merit of the generated transgenic mouse model(s) by conducting sufficient experiments.
- Agency: Department of Health and Human Services,Department of Health and Human Services
- Program: SBIR
- Phase: Phase I
- Release Date: July 24, 2015
- Open Date: July 24, 2015
- Close Date: October 16, 2015
- URL: https://sbir.nih.gov/sites/default/files/PHS2016-1.pdf