Theranostics Targeting Metastatic Breast Cancer
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Background: Care of breast cancer patients currently involves using different agents for diagnosis, location, and treatment. For instance, biopsies may reveal cell surface receptors overexpressed on that particular patient''s cancer type, but this information is not used to target PET (positron emission tomography) imaging agents; instead, the PET agent that targets the glucose receptor is used. Personalized PET agents, which track the particular cancer type the patient has, obviously should be superior for locating micrometastases. Similarly, the therapeutics and PET imaging agents used in contemporary care tend to localize in different regions of the body. If it were possible to use the same targeted agent to locate and treat solid tumors and their metastases, then the physician would know where the cancer tissue is, where the therapeutic will go, and, after another round of imaging, what effect the therapeutic had. This is not possible in contemporary, clinical oncology; we would like to develop agents to make it possible.Overarching Challenges: This proposal outlines how to develop agents to diagnose, locate, and treat metastatic breast cancer, thereby impacting three overarching challenges: (i) replacing drugs having life-threatening toxicities with targeted forms to increase their therapeutic indices leading to safer and more effective interventions; (ii) elimination of mortality associated with metastatic breast cancer by more effectively imaging primary tumors and their micrometastases; and (iii) distinguishing aggressive breast cancer from indolent forms, based on their response to targeted agents for biopsies, to identify patients who will respond while avoiding overdiagnosis and inappropriate treatments of others.Objective/Hypothesis: This proposal is based on preliminary results that feature a small-molecular targeting fragment that adheres to, and is internalized by, the cell surface receptor TrkC (overexpressed in metastatic breast cancer). These targeting fragments are bound to a dye (BODIPY) that can be fluorescent, a PET imaging agent, and a sensitizer for photodynamic therapy (PDT). PDT involves activating agents with light so that they destroy (cancer) tissue. This agent was used to identify metastatic breast cancer in histology, can be made to incorporate 18F for PET imaging, and completely ablated tumors in mice after one dose and illumination, preventing metastatic spread.There is just one obvious problem with the agent developed for the preliminary work: it absorbs light at a short wavelength, making it difficult to activate at a tissue depth of more than a few mm. The central hypothesis of this proposal is that a very similar agent can be made by replacing the BODIPY with an aza-BODIDY dye, and this will retain the desirable attributes of the first-generation agent except it will absorb at >700 nm and be excitable at a tissue depth of several cm, and our objective is to do that. There are several possible molecular designs for achieving this, and it will be necessary to make several to identify one with optimal properties, but this application is not speculative: it is just a case of funding to get the work done. The deliverable will be a lead to develop into a clinical candidate for coherent breast cancer diagnosis, imaging, and treatment.Specific Aims: Our aims are to (1) develop second-generation, actively targeted agents (as described above) and validate their chemical properties in vitro and toxicities in vivo; (2) validate the actively targeted fluorescent agents for histochemistry and surgical staining; and (3) validate the actively targeted PET/PDT agents in vivo.Study Design: Controls in this work establish the differences in staining, imaging, and therapy for targeted and non-targeted agents. Two approaches are used to do this: (i) use of agents with fragments that are isomers of the targeting fragment, but do not target; and (ii) use of tumors that do and do not express the targeted receptor, TrkC. Thus, PET and PDT effects can be compared with and without targeting the TrkC receptor.Impact: A clinical candidate theranostic for coherent breast cancer diagnosis, imaging, and treatment.
