U01CA282109

A patient-centric approach to advance functional precision oncology - project summary/abstract

The development of drug resistance is a major cause of cancer treatment failure and mortality. Although much is known about the mechanisms by which tumor cells can become resistant to a given drug, translating this into effective therapeutic solutions remains an unmet clinical need.

Here we propose to pioneer the use of patient derived tumor organoids (PDTOs) as a platform to identify and validate novel targets and effective drugs to overcome drug resistance in ovarian cancer, pancreatic cancer, and other tumor types. In our preliminary studies, we show that PDTOs genetically and phenotypically match the tumor from which they were derived and can be used to study the phenotypic consequences of tumor heterogeneity, tumor evolution, and drug resistance.

Using a Clinical Laboratory Improvement Amendments (CLIA) approved high complexity assay, we show that PDTO drug sensitivities are highly concordant with known genetic biomarkers, retrospective treatment history and prospective patient responses. Tumor organoids derived from patients who developed in situ drug resistance demonstrate ex vivo resistance to those same drugs but also demonstrate sensitivity to other alternative oncology drugs. Additional preliminary studies show stable disease or tumor regression in patients treated with drugs identified from organoid drug screens.

Here, we propose to combine drug screening and molecular profiling of PDTOs derived from a given patient from different anatomic tumor sites and before and after therapy to elucidate the mechanistic basis for drug sensitivity or resistance and to identify novel targets and effective drugs to treat metastatic, drug resistant cancers. Accompanying computational prediction models that integrate large public datasets as well as innovative methods of mechanistic target validation including CRISPR, targeted protein degradation technologies, and epigenetic profiling, will be used to prioritize and advance targets and associated biomarkers with greatest clinical potential.

The rationale behind our approach is that identifying targets and effective drugs directly in patient derived samples with known clinical history and outcomes will significantly enhance translation of our findings. This proposal is significant because it will demonstrate the utility of PDTOs as both a research tool for target discovery and validation but also as a clinically useful platform to guide functional precision medicine. The findings and methods developed can be readily applied to other cancer types and clinical challenges, will accelerate preclinical drug and drug target development, and will translate to clinical studies.

The models, approaches, and expected outcomes of this proposal are highly responsive to the requirements of PAR-21-274.

Fred Hutchinson Cancer Center

TO IMPROVE SCREENING AND EARLY DETECTION STRATEGIES AND TO DEVELOP ACCURATE DIAGNOSTIC TECHNIQUES AND METHODS FOR PREDICTING THE COURSE OF DISEASE IN CANCER PATIENTS. SCREENING AND EARLY DETECTION RESEARCH INCLUDES DEVELOPMENT OF STRATEGIES TO DECREASE CANCER MORTALITY BY FINDING TUMORS EARLY WHEN THEY ARE MORE AMENABLE TO TREATMENT. DIAGNOSIS RESEARCH FOCUSES ON METHODS TO DETERMINE THE PRESENCE OF A SPECIFIC TYPE OF CANCER, TO PREDICT ITS COURSE AND RESPONSE TO THERAPY, BOTH A PARTICULAR THERAPY OR A CLASS OF AGENTS, AND TO MONITOR THE EFFECT OF THE THERAPY AND THE APPEARANCE OF DISEASE RECURRENCE. THESE METHODS INCLUDE DIAGNOSTIC IMAGING AND DIRECT ANALYSES OF SPECIMENS FROM TUMOR OR OTHER TISSUES. SUPPORT IS ALSO PROVIDED FOR ESTABLISHING AND MAINTAINING RESOURCES OF HUMAN TISSUE TO FACILITATE RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.394 - Cancer Detection and Diagnosis Research

National Cancer Institute (NCI) [HHS - NIH]

Seattle, Washington 981094433 United States

Single Zip Code

Cancer Target Discovery and Development (CTD2) (U01 Clinical Trial Not Allowed) (PAR-21-274)

Amendment Since initial award the total obligations have increased 188% from $1,098,796 to $3,167,627.