Research Project: Theranostics Targeting Metastatic Breast Cancer
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Imagine an Army, Navy, and Air Force that each used incompatible equipment where operations of each branch were uncoordinated; contemporary breast cancer care is a bit like that. Diagnostic agents used to test biopsies do not target the same property as the imaging compounds used to visualize tumors and metastases in PET (positron emission tomography) scans; hence, they bind different tissues. Similarly, chemotherapeutic agents are not designed to find their way to tumors in the same way as the diagnostic or imaging agents, so these also bind different tissues. For instance, diagnosis of breast cancer sub-types may involve testing for high levels of estrogen or progesterone receptors, but imaging usually involves an agent that binds the glucose receptor. Some breast cancer subtypes may not image well with agents that adhere to the glucose receptor, and this problem is exasperated because some healthy tissue expresses high levels of glucose receptor and this lowers contrast and sensitivity in the PET scan. Finally, the type of therapy selected will tend to involve a compound that does not accumulate in cells because of overexpression of the estrogen, progesterone, or glucose receptors; it equally likely to accumulate healthy cells leading to toxicity.
We hypothesize that strategies for diagnosis, imaging, and therapy of people with metastatic breast cancer (that overexpresses the TrkC receptor on the surface of these cells) could be far more effective than the strategy outlined above. The key discovery on which is this proposal is based is that we have a novel molecular fragment that binds TrkC.
The following hypothetical situation illustrates how a coordinated strategy for care of TrkC+ breast cancer patients (i.e., at least a large proportion of patients with metastatic breast cancer) could work. Biopsies of all patients with breast tumors would be tested for overexpression of TrkC; this could be done conveniently and economically using a fluorescent (glows under UV light) agent we have developed to bind TrkC. Patients with TrkC- tumors may not have metastatic cancer, and in any case would be advised to follow some other course to avoid overdiagnosis and -treatment. Patients who do have TrkC+ breast cancer, however, would be encouraged to take a PET imaging scan using our novel imaging agent that selectively binds tissue that overexpresses TrkC. We hypothesize that imaging agent would highlight TrkC-expressing primary tumors and their metastases with better contrast than ones with affinity for the glucose receptor (the most widely used target for PET imaging). Using information from this targeted PET scan, a surgeon might attempt to locate and remove the primary tumors and their metastases. This task could be made easier using the fluorescent TrkC-selective agent that could localize in TrkC+ tumor cells making them glow under a sunlamp during surgery. A second TrkC-selective PET scan using our novel imaging agent that selectively binds tissue that overexpresses TrkC would then reveal the degree of post-operative success. Subsequently, chemotherapy might be ordered to eliminate micrometastases that could not be removed surgically; this would involve the same agent used for PET imaging but this time for photodynamic therapy (PDT, relying on light to activate our drug which binds to the TrkC+ tumors); the chemotherapy would localize in exactly the same places as the PET agent images. Overall, this strategy is coordinated or coherent: what is diagnosed and located, is treated.
In preliminary studies, we have identified first-generation agents that bind TrkC, can be labeled for PET imaging, and completely destroy tumors in a mouse model, preventing metastases, after only one injection and illumination with light for 30 minutes. These first-generation agents are not ideal for use in humans, however, just because the light they absorb does not have a long enough wavelength. It is known that a simple change in the molecular structure of these agents (BODIPY to aza-BODIPY) can cause them to absorb the right type of light, and therefore they are clinical candidates. We want to prepare these and prove they work. If only one of the several structures proposed does work, the proposed study will open the door to a "Phase 0" investigation to test the agent for imaging and preclinical investigations to evaluate it as a therapeutic. We have made contacts with three key collaborators who can help with this process: two clinicians and a researcher with technology to accurately place a fiber optic laser next to micrometastases located via PET.
If this study is successful, it will serve as a model for development of agents for coherent diagnosis, imaging, and treatment of breast cancer types that involve expression of receptors other than TrkC.
Overall, this work addresses issues that relate to (i) revolutionary treatment regimens replacing drugs that have life-threatening toxicities with safe and effective interventions, (ii) elimination of mortality associated with metastatic breast cancer, and (iii) distinguishing aggressive breast cancer from indolent forms to avoid overdiagnosis and -treatment.
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