The purpose of this Funding Opportunity Announcement (FOA) is to support research projects that delineate and compare the underlying biological mechanisms that drive cancer phenotype and response to perturbations between two or more patient-derived models of cancer originating from a common patient sample.
Awardees are expected to form a patient-derived models of cancer (PDMC) consortium and participate in activities as appropriate to their projects that will provide a framework to accelerate multidisciplinary efforts to address compelling fundamental cancer biology questions through PDMC comparisons.
The oncology community has recently focused on the development of patient-derived models of cancer (PDMC) platforms including, but not limited to, patient-derived xenografts (PDXs), organoids, spheroids, induced pluripotent stem cells (iPSC), conditionally-reprogrammed cells (CRCs). Each of these platforms has both merits and drawbacks with regard to their utility and in faithful representation of tumor architecture, microenvironment, cellular composition and heterogeneity, stem-differentiation states, growth patterns and responses to perturbagens, with respect to the patient specimen from which the model was initially derived. Researchers often optimize methodologies or interpret data for a single PDMC platform in isolation of other PDMC approaches. This barrier has hampered investigation of fundamental cancer biology questions that address how basic phenotypic features and processes present in the original patient specimen are either preserved or become altered by the environment and growth conditions that are unique to each specific PDMC platform. These distinctions are critical in deciphering applicability of PDMC as a representation of the intrinsic cancer biology in the original tumor. Systematic comparisons of PDMC parameters related to biological and physical microenvironment that impact cancer phenotype(s) and responsiveness to therapeutics or stressors are needed. This FOA encourages researchers to combine expertise in specific PDMC platforms and collaboratively study cancer biology across these PDMC approaches. It is anticipated that this “PDMC comparison approach” can reveal new mechanistic understanding of basic cancer biology and be complementary to translational application of PDMC aimed at drug screening, target identification, and biomarker discovery.
A major goal of this FOA is to stimulate research that will broaden our understanding of how key cancer biology features, processes, and/or responses to perturbagens are influenced by the respective environments and growth conditions of specific PDMC platforms. This FOA seeks applications describing research that systematically examines cancer cell biology and phenotypes using investigator-identified approaches and techniques, wherein individual tumor specimens are respectively studied in the context of two or more types of PDMC platforms.
Tumor specimens proposed for examination may represent any type and stage of cancer. It is anticipated that investigators will systematically examine a number of different tumor specimens that are collectively representative of tumors in a particular cancer cohort. The objective of the FOA is to stimulate research where cancer biology is compared between pairings of PDMC platforms, wherein each PDMC comparison set is derived from a single tumor specimen from the same patient. The scope of proposed studies should balance a sufficient number of PDMC comparison sets to achieve a meaningful interpretation of cancer biology similarities and differences across the PDMC platform types under study, as guided by biostatical methodology.
Ideally, one tumor specimen would be split to concurrently generate PDMC of two (or more) PDMC platform types, which would constitute a single PDMC comparison set. Alternatively, a PDMC comparison set could be the result of inter-conversion of a single existing PDMC specimen of one type to another type of PDMC. In either case, the number of PDMC comparison sets would be proportionate to the number of original tumor specimens that represent the cancer cohort. A series of PDMC comparison sets may be generated in the project period or derived from existing specimen stocks.
Examples of a respective PDMC comparison set that would be considered appropriate for this FOA include, but are not limited to the following:
- Concurrent allocation of a single tumor specimen into two or more discrete PDMC platform types (e.g., organoid and PDX; CRC and PDX; organoid and CRC; PDX, organoid, and CRC).
- Orthotropic engraftment and expansion in mice (PDX) of a previously established and characterized organoid or CRC line originally derived from a single tumor specimen.
- Expansion of an organoid or CRC line from a previously established and characterized PDX model originally derived from a single tumor specimen.
- Generation of an organoid from cancer stem cells derived from a human tumor specimen and the relevant cell-type specific iPSCs derived from the same patient.
- Expansion of previously established and characterized cancer stem cell spheroids originally derived from a single tumor specimen as PDX in mice.
- Generation of two or more discrete PDMC types (e.g., PDX, organoid, and CRC) derived from the same circulating tumor cell clone.
Deadlines: letters of intent are due 30 days before full proposal deadlines; September 14, 2016; March 1, 2017; September 6, 2017; March 7, 2018; September 6, 2018; March 6, 2019 (full proposals)
Filed Under: Funding Opportunities