Unlocking the Chemical Space of Cancer-Associated Perturbations

The prevailing approach to precision cancer medicine relies on genetic profiling of patients, followed by
identification of the malignant gene product, and delineation of the mechanisms of that protein product in causing
disease. As a result, much of the future of precision oncology is built on the hope of tailoring therapeutic
interventions based on diagnostic technologies that acquire complex genomic and transcriptomic data. Despite
the focus on cancer genetics, the unique functional capabilities acquired by normal cells during tumor
development are driven by the aberrantly activated tumor cell proteome that arises not only from gene mutations
but also from epigenetic reprogramming, post-translational alterations, or rewiring of signaling pathways.
Unfortunately, integrating traditional measurements of protein biochemistry that reflect tumor cell biology and the
therapeutics to which a tumor would respond into clinical decision-making for cancer patients is challenging due
to the uniqueness of each protein and limitations in existing technologies. Thus, our proposal focuses on
mechanism-based cancer research at the interface of chemistry and cancer biology to develop quantitative
approaches that evaluate dynamic changes in the proteome in order to characterize unique features of tumor
biology with the long-term goal of motivating novel targeted therapies. Specifically, we aim to establish an
innovative new development and discovery platform termed Probe Enabled Activity Reporting (PEAR) for tumor
proteome profiling by leveraging chemical biology approaches to understand the molecular complexity of
proteomic changes necessary for tumor cell function, as well as cellular adaptations to cancer therapy. The
foundation of our bedside-to-bench and back again approach is rooted in the hypothesis that novel chemical
probe reactomes exist in cancer cells themselves and changes in the reactome profile in response to cancer
therapeutics will reflect alterations in protein function that drive cancer cell adaptations and thus, would be ideal
for new treatment modalities in the future. In interconnected and interdisciplinary discovery and elucidation
modules, we will utilize state-of-the-art patient derived cancer models to both visualize and identify the protein
targets of chemical biology probes in pre- and post-treatment with the hypothesis that the differential reactomes
will be indicative of proteomic liabilities, therapeutic response, and unique aspects of tumor cell biology. The
major outcomes from investing in PEAR for tumor proteome profiling to enable therapeutic development will be
development of methodology to visualize reactive targets, identification of treatment induced reactive targets and
establishing their functional relevance, and unraveling unique tumor cell biology based on a novel
compartmentalized reactive target method. Taken together, our proposal will establish and validate novel
concepts and methodologies that can be applied across the broad spectrum of solid tumors and as an extension,
holds the potential to provide fundamental insights into tumor biology and transform precision oncology by
providing a platform to improve existing paradigms for drug discovery.

Grant Number: 4R01CA280833-04
NIH Institute/Center: NIH
Principal Investigator: Donita Brady