Breast cancer is the second most common and the major cause of cancer-related death of women in the USA.The last decade has witnessed major advancement of therapeutic drugs and tools, while noninvasive diagnosticimaging tools to measure interventions received much less attention. Currently, the mainstay of noninvasiveimaging in breast cancer relies primarily on anatomic imaging. Metabolic imaging using FDG PET is asuccessful diagnostic tool in several types of cancer, but not in the setting of breast cancer. The last decade hasalso witnessed the revival of interest in the role of mitochondria in tumor invasiveness, and as regulators ofcytotoxicity of first-line chemotherapy agents. Yet, current tools for noninvasive investigations and diagnosticsof the mitochondrial function in cancer patients are limited to SPECT imaging agents. Our recent preclinicalstudies provided compelling evidence for the capacity of the PET imaging voltage sensor 18F-fluorobenzyltriphenylphosphonium (FBnTP), developed by the PI laboratory, to potentially improvemanagement of breast cancer. This includes: (1) improved early detection of early-stage, small, vascularizedbreast lesion with better functional and spatial resolution compared to FDG PET and SPECT imaging;(2) Accurate 3D mapping of tumor proliferation, an important prognostic factor in the clinical setting; and(3) very early molecular-level detection of treatment response, directly at the core mechanism of cytotoxicity offirst-line chemotherapy agents. The technology supporting these utilities is based on our studies whichdemonstrate that cellular uptake of FBnTP is directly proportional to the mitochondrial membrane potential(??m) of a cell. ??m is the most comprehensive physiological endpoint of the organelle bioenergetics. ??mis a unique target that enables attaining the above goals. ??m is significantly greater in certain types ofmalignant cells, including those of breast origin, compared to normal cells, resulting in a preferentialaccumulation of FBnTP in tumor mass, compared to healthy parenchyma. ??m increases in highlyproliferating breast cancer cells, whereas collapse of ??m coincides with the initiation of the irreversible phaseof the apoptotic cell death as induced by many first-line chemotherapy agents in the breast cancer setting. Thegoal of this STTR Phase 1 study is to establish proof of concept in patient samples under the approved IRB thatFBnTP is an effective imaging technology to detect breast lesions in women; a prerequisite for future feasibilitystudies of FBnTP as a surrogate marker of breast tumor invasiveness and response to therapeuticinterventions. To improve commercial competitiveness, FBnTP imaging will be carried out using breast-dedicated positron emission mammogram (PEM), a less costly technology, compared to PET, CT and MRI andof better spatial resolution than PET.
Breast cancer is most widespread and the second cause of cancer related mortality with an estimated ~230;000new diagnoses of advanced breast cancer in the USA in 2015; most of which will undergo chemotherapy; butonly a minority will obtain complete response. In recent years our laboratory focused on developing novelimaging methods that will greatly improve management of breast cancer; by predicting tumor response tochemotherapy before treatment; and determining the extent of response to chemotherapy; shortly (few days)after the start of the treatment regimen. The present proposal aims at obtaining proof-of-principle in a smallcohort of patients of the capacity of the imaging biomarker to detect breast lesion in women; a prerequisite forfuture feasibility studies of the imaging method as a surrogate marker of breast tumor prognosis and responseto therapeutic interventions.
