Description:
355 Cell and Animal-Based Models to Advance Cancer Health Disparity Research
Fast-Track proposals will be accepted.
Direct-to-Phase II be will accepted.
Number of anticipated awards: 2-3
Budget (total costs, per award):
Phase I: $300,000 for up to 9 months;
Phase II: $2,000,000 for up to 2 years
PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED.
Summary
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 globally. In the United States, several racial/ethnic populations demonstrate increased incidence, mortality 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. A growing body of evidence suggests that biological factors may contribute to CHDs. The NCI specifically encourages and funds investigations of biological factors to better understand mechanisms that contribute to CHDs. One limitation in conducting basic, translational, and clinical research investigating the underlying biological causes of CHDs is a substantial lack of relevant in vitro and in vivo-based models. The development and validation of appropriate cell and animal-based models to study underrepresented population groups would greatly advance this field of research.
Project Goals
The primary goal of this topic is to develop new, commercially available models relevant to diverse racial/ethnic populations including American Indians, Alaska Natives, Asians, African Americans, Pacific Islanders, and Hispanic/Latinos. Solicited models include patient-derived cell lines, patient-derived xenograft (PDX) mouse models, and 3D human tissue model culture systems established from racially/ethnically diverse patient 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) benefiting investigators in 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 long-term, overarching goal of reducing CHDs.
Cancer cell lines: The use of immortalized cell lines in cancer research has been standard practice for decades. Notably, the scientific integrity of cancer cell lines is critical for maintaining high standards in research. Any cell lines established via this solicitation must be fully confirmed through a rigorous and validated authentication and be contamination-free. Notably, offerors proposing to generate conditionally reprogrammed cells (CRCs) or cell lines matched to PDX animal models will be preferred. CRCs have marked benefits over traditional immortalized cell lines as they are generated using special in vitro conditions that permit cells to pharmacologically bypass replicative senescence without any detectable cell crisis.
PDX Mouse Models: PDX models are commonly used in many clinically relevant research applications including characterization of tumor heterogeneity, in vivo therapeutic target validation studies, therapeutic mechanism of action studies, and therapeutic sensitivity and resistance studies. Furthermore, PDX models are suggested to be a useful tool to mimic human clinical trials using animals.
3D human tissue model culture systems: While immortalized cell lines have been standard practice in cancer research for decades, adequate modeling of the heterogeneity of human cancer is an unmet need. Newly emerging 3D cell culture technologies enable the propagation of normal and malignant epithelial cells, as well as more
Page 70
accurately mimicking the in vivo tumor microenvironment (e.g. organoid, spheroid, and organ-on-a-chip models). These 3D model systems need to be previously developed (preferably with validation studies) and either derived from diverse racial/ethnic populations or applicable to the study of CHDs in general.
Phase I Activities and Deliverables
Offerors must clearly demonstrate access to human samples from racial/ethnic minority populations, with appropriate informed consent in place.
Establish an experimental model derived from a racial/ethnic minority population and/or relevant to CHD research. This may include one of the following:
• Human derived cancer cell line
• PDX animal model
• 3D human tissue model culture system
Cancer cell line deliverables: Establish a stable cell line from human tumor cells and passage the cells in culture to determine viability and experimental relevance.
• Detailed documentation must be provided including patient clinical characteristics, passage history, mycoplasma testing results, Identifiler/STR profile of early and late passage showing concordance, and appropriate growth/preparation conditions.
• Develop a standardized, working protocol for establishment of additional cell culture models.
• Demonstrate utility in pre-clinical assays and technical validly for the proposed cell line
o Perform comprehensive and robust studies to confirm model system is phenotypically stable.
o Use a standard chemotherapeutic agent to confirm model system is appropriate to perform drug response assays (e.g. measure cell proliferation, cell death, migration, and/or invasion).
• Applications proposing CRCs or cell lines matched to PDX animal models are preferred due to the increased innovation and potential research applications of the models.
PDX animal model deliverables: Establish a serially transplantable, phenotypically stable, human cancer xenograft model in immunocompromised mice.
• Transplant fresh surgical tissue or biopsy (either subcutaneous or orthotopic) into recipient immunodeficient mice (Passage generation 1).
• Subsequent serial transplantations must be conducted following establishment of initial xenograft outgrowths, typically >10mm in diameter. A minimum of three generations (to passage generation 4) of transplantation is required to establish a stable line.
• Confirm genetic and phenotypic concordance of the tumors in passage generation 4 versus passage generation 1 and patient material (when available).
• Confirm percent human versus mouse DNA in each passage and confirm histopathology of each passage phenotypically matches the patient diagnoses.
• Cryopreserve and bank tumor fragments. Confirm re-growth success rate from a minimum of 5 cryopreserved tumor fragments.
• Develop a standardized, working protocol for establishment of additional models.
• Perform comprehensive molecular characterization of patient samples and earliest PDXs, including whole exome sequencing and mutational status analysis using a CLIA-approved panel.
• Demonstrate utility in pre-clinical assays and technical validly for the proposed model system
o Perform comprehensive and robust studies to confirm model system is phenotypically stable.
o Use a standard chemotherapeutic agent to confirm model system is appropriate to perform drug response assays (e.g. measure tumor growth, angiogenesis, cell proliferation, cell death, migration, and/or invasion).
Page 71
3D human tissue model culture system: Establish a 3D culture that mimics the tumor microenvironment. Note that all proposed model systems must be using established technologies with previously demonstrated reproducibility in pre-clinical or chemo-sensitivity assays.
• The model system must address the following requirements:
o Human tumor cells must be derived from a diverse racial/ethnic population
o Heterogeneous population of cell types must be represented
o Structural components that mimic the in vivo tumor microenvironment should be incorporated
• Demonstrate utility in pre-clinical assays and technical validly for the proposed model system
o Perform comprehensive and robust studies to confirm model system is phenotypically stable.
o Use a standard chemotherapeutic agent to confirm model system is appropriate to perform drug response assays (e.g. measure tumor growth, angiogenesis, cell proliferation, cell death, migration, and/or invasion).
All human tissues and cells used to generate the abovementioned models must be well characterized including validation of the genetic ancestry of patients (if applicable) 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.
Preferences will be placed on proposals that generate models for indications that have clearly demonstrated cancer health disparities and a paucity of models available to study.
Phase II Activities and Deliverables
Cancer cell lines: It is expected that a panel of cell lines be established from different patient sources. The exact number of cell lines will depend on technique used for establishing the lines (i.e. CRCs or cell lines matched to PDX-models) and the tumor type proposed.
PDX animal models: It is expected that multiple PDX models be established from unique patient sources using established protocols. The exact number of models will depend on the tumor type proposed and any known technical/biological limitations.
3D human tissue model culture system: Further demonstrate pre-clinical utility of the generated 3D model system, with a particular emphasis on the relevancy to CHD research. Furthermore, additional 3D models must be developed derived from diverse racial/ethnic populations and prepared for commercialization.
