The goal of this proposal is to understand the mechanisms of differential signaling among receptors important for the development of cancer, and to use this knowledge to design strategies to suppress malignant disease. Cancers often highjack the signaling logic of embryonic development for growth and metastasis and bypass natural regulatory controls. This allows receptors on cancer cells to remain in a perpetual ?on-state?. Current therapeutic approaches therefore attempt to prevent receptor activation by promoting non-signaling competent receptor ?off-states?. This, however, produces an enormous selective pressure that drives the rapid outgrowth of resistance. Recent findings suggest that receptors important for oncogenesis actually allow for diverse signaling outputs rather than just discrete on/off states ? functioning more like a rheostat than a digital convertor. This newly discovered property opens the possibility of actively `tuning' tumor signaling away from metastasis. This proposal investigates the mechanisms that control receptor signal bias in developmental and disease models using an array of techniques that span the relevant length and time scales necessary to reveal receptor and cellular signaling dynamics. My approach incorporates cutting-edge biophysical technologies (including cryo-EM and interferometry) that will help decipher the `logic' governing signal bias among oncogenic receptors. A quantitative and high-resolution view of the differential signaling process will provide important fundamental insight into cancer receptor biology and should open new avenues for the design of modulatory therapeutics that limit disease progression.
Current therapeutics for solid tumors largely attempt to completely inhibit receptor signaling relays found on the cancer cell's extracellular membrane. Yet this targeted inhibition, often by monoclonal antibodies or small molecule kinase inhibitors, typically leads to rapid resistance and only modest clinical benefit. Successful completion of my proposed research will inform the development of new strategies to modulate ? rather than inhibit ? receptor activation away from metastases.
