ABSTRACT Genome sequencing technology has been transformative in the analysis of cancer. From genomic, transcriptomic, and epigenetic data, researchers are making new discoveries about the mechanisms of cancer development that are leading to new therapies and diagnostic tests. Accelerating these discoveries, genomic analysis is being applied to a wide variety of analytes such as cell-free DNA and single cells from tissue biopsies. However, given the increasing range of available genomic sequencing assays available for cancer genomic studies, a major challenge comes from the limited amounts of clinical tumor samples. Tissue biopsies and samples oftentimes provide a small amount of genomic analyte. As a result, only one or two genomic sequencing experiments can be performed, which leads to a less than complete picture of features of a patient tumor. To address this issue, we developed and validated a technology called APEX – this sequencing technology enables repeated use of the same nucleic acid analytes derived from a variety of clinical samples relevant for cancer translational research and clinical studies. As a result, researchers have the opportunity to conduct many types of genomic analyses on the same sample and genomic material. APEX technology is based on the covalent attachment of nucleic acid analytes to a solid support, so that the original genomic material is permanently retained, can be subject to a variety of sequencing assays and as a result, can be analyzed through many iterations. The use of multiple iterations also offers an opportunity to improve the delineations of critical genomic aberrations that occur in only a small fraction of the tumor cells. We propose the development of APEX for integrated multi-modal and iterative genomic analyses of primary cancer biopsies and cell free DNA from patients. Aim 1 focuses on cell-free DNA analytes, and Aim 2 focuses on single-cell transcriptome sequencing. Overall, our proposed APEX technology will broadly impact the field of translational cancer research by providing a new platform whereby clinical samples can be used as a renewable resource for subsequent genomic sequencing. It removes constraints afforded by limited amounts of tissue samples from translational clinical studies. With these improvements, APEX will improve the assessment of somatic genomic alterations in cancer cells, integration of multi-modal sequencing technologies, and offer personalized molecular analyses for each cancer patient.