Research Grants Awarded
Multi-parameter molecular imaging of tumor susceptibility and early evaluation of therapeutic response
Background: The use of molecularly targeted therapies in the treatment of breast cancer continues to expand. The introduction of molecular imaging techniques has increasingly allowed specific abnormalities to be examined individually. However, most breast cancers have abnormalities in multiple pathways and targeting more than one abnormality may have a synergistic effect. Moreover, many of the abnormally regulated pathways in cancer are interconnected. Objective/Hypothesis: We hypothesize that simultaneous noninvasive measurements of three different abnormalities that occur in individual breast cancers to various degrees provide useful quantitative characterization regarding appropriateness of therapy. Moreover, we hypothesize that imaging these parameters after single or combination therapy can alter treatment based on adequacy of pathway modulation through direct inhibition or indirectly as a downstream effect of inhibition of an interconnected but primarily separate pathway. Specific Aims: Three specific aims are proposed. First, we plan to simultaneously evaluate HER2/neu expression, vascular volume fraction as a surrogate of angiogenesis, and cathepsin protease expression. Second, we will determine the change in these pathways on over-expressing tumors after single and combination therapy. Third, we will extend these studies to a multimodality approach by evaluating proliferation changes with FLT PET and by imaging of HER2/neu expression using MRI. Study Design: Using orthotopically implanted breast cancer lines with known alterations in these pathways and fluorescent agents that either target HER2/neu, change their fluorescence properties with cathepsin protease interaction, or remain in the blood pool during imaging, we will image these properties simultaneously and independently. Clinical preparations of trastuzumab and bevacizumab, and in vivo inhibitors of cathepsin proteases will be administered singly and in combination to evaluate changes on the multiple parameters we are monitoring, with special attention to the modulation of other pathways when targeted therapy is given. Finally, using trastuzumab conjugated nanoparticles, we will create an MR imaging analogue to the fluorescent HER2/neu imaging agent. We will perform FLT PET imaging to determine additional information it provides on therapeutic efficacy, confirmed by cell cycle and apoptosis analysis, beyond that determined by the other imaged parameters. Potential Outcomes and Benefits of the Research: This research potentially provides a route to closer coupling of molecular medicine?s specificity with the wide variation in individual breast cancer. Specifically, we will evaluate the ability to non-invasively determine three central factors that can be targeted with therapies. We think that there is a benefit from such a multi-parameter clinically translatable imaging approach that will help further the goal of individualized medicine.
Cancer therapy historically has been relatively nonspecific in targeting disease. Fortunately, over the last number of years, as we gain a better understanding of the molecular pathways involved in allowing breast cancer to grow and spread, treatment has become more specific in targeting these abnormalities. Because these treatments are less likely to provide a benefit in patients whose tumors do not have the specific pathway abnormalities, optimal therapy in one patient with breast cancer may not be optimal for another patient. Imaging the degree of these molecular alterations may help provide a basis for individualized treatment. In this preclinical/translational proposal, we will utilize the ability to independently evaluate multiple molecular targets simultaneously using near infrared (NIR) light and novel fluorescent imaging agents to characterize tumors with respect to several major pathways that are often mis-regulated in breast cancer. In particular, we will assess levels of HER2/neu, levels of proteases, and levels of angiogenesis in various tumor models in rodents. HER2/neu is a growth factor receptor which can help breast cancers grow, proteases are enzymes that in some cases help cancers spread, and angiogenesis is a process of new blood vessel growth that allow tumors to get nutrients required for growth. All of these may be targeted with specific therapies to alter the course of the disease. A second aim of this proposal is to determine which combination of these imaging markers are most helpful in defining appropriate therapy, including determining drug dosing, when all or a subset of these molecular targets are at inappropriate levels. Finally, a third aim is to extend our ability to non-invasively characterize disease by combining multi-parameter fluorescence imaging with other imaging technologies that may provide complementary information. These include positron emission tomography (PET) imaging, which allows imaging of the growth rate of tumors, and magnetic resonance imaging (MRI), which can assess some of the same parameters measured by fluorescence, thereby allowing additional parameters, such as effectiveness of tumor cell killing, to be measured by fluorescence as well. Potential benefits to patients in the future may include imaging methods that allow oncologists to tailor therapies more accurately for individual patients. Such individualized medicine may result in better tumor control, fewer unwarranted side effects, and decreased inappropriate utilization of molecularly targeted therapies.