Screening and Monitoring Response to Treatment Using Subsecond Molecular Imaging and Hyperpolarized Contrast Agents

Principal Investigator: CHEKMENEV, EDUARD Y
Program: BCRP
Proposal Number: BC112431
Award Number: W81XWH-12-1-0159
Funding Mechanism: Era of Hope Scholar Award
Partnering Awards:
Award Amount: $3,747,439.00


Currently there is no cure for advanced breast cancer. Moreover, there is a significant percentage of 0-3 stage breast cancer patients who will progress to stage 4 even if they were treated by surgery, radiation, and chemotherapy. Nevertheless, there are doctors and scientists who believe that we already have a sufficient range of therapies to cure and possibly eradicate breast cancer. However, as long as the response to treatment is measured by tumor size or by earlier reporters such as positron emission tomography (PET) and/or dynamic contrast enhanced (DCE)-MRI exams, the patients are faced with the lag period of several weeks to several months to determine the efficacy of their treatment. As a result, valuable time is depleted and oncologists can try only a limited range of therapies and/or their combinations before (in most cases) the patient progresses to the point when therapeutic focus is shifted to the palliative care rather than combating the deadly disease. In addition, a potentially looming challenge with so many therapies becoming available and many more in the pipeline is that the oncologists and patients will be faced with having too little time to try all therapeutic options.

Population screening for breast cancer potentially allows catching the disease earlier, when it is curable. While mammographic screening is a cost-effective imaging modality for breast cancer that examines the breast for any uncharacteristic masses, mammography has a false-negative (missed cancer) rate of at least 10 percent, and it also results in unnecessary surgery, anxiety, and radiation exposure. MRI has been shown to detect cancers not visible on mammograms. The main strength of breast MRI is its very high negative predictive value. However, breast MRI has disadvantages of being more false-positive than mammography and significantly more expensive imaging modality. The latter stems from relatively long scan time/low-throughput and high cost of high-field MRI scanners. Moreover, currently available imaging technologies are not taking advantage of current knowledge about breast cancer genetics, phenotype, and metabolism. Rather, a safer, faster, more accurate and cost-effective molecular imaging method is clearly needed to dramatically improve breast cancer prevention through population screening and monitoring response to treatment.

Hyperpolarized, i.e., more sensitive MRI offers an increase in sensitivity by 4-6 orders of magnitude over conventional MRI. This sensitivity and signal increase of exogenous contrast agent is generated temporarily and can last only minutes, but can be used to significantly increase image quality. More importantly, once injected into a living organism, these agents allow for molecular imaging of the parent hyperpolarized contrast agent and its metabolic products at physiological concentrations. Hyperpolarized MRI contrast agents are similar to PET tracers in that they allow for imaging of specific biochemical pathways significantly elevated in cancer. However, there are several key advantages to these new agents: (i) they are non-radioactive, (ii) they allow for sub-second imaging speed, (iii) they exhibit a fast uptake, which translates to short wait time, (iv) and they exhibit rapid clearance, so there is the potential for same-day follow-up scan(s). Hyperpolarized MRI contrast agents have relatively low or no toxicity, and many are already approved for use in their non-hyperpolarized form. These contrast agents hold great promise as a game-changing technology that could significantly increase the quality of life for all breast cancer patients through efficient population screening and monitoring response to treatment.

We plan developing hyperpolarized MRI allowing for sub-second molecular imaging of breast cancer with specificity similar to or greater than that of PET, but significantly lower cost than conventional MRI due to much higher patient throughput/much faster exams and the use of low-field = low-cost MRI. Specifically, we will develop (i) pure hyperpolarized metabolic contrast agents suitable for human use and will validate these contrast agents in animal models of human breast cancer, (ii) high speed production (up to 100 doses/hour) of hyperpolarized contrast agents, (iii) investigate and optimize transportation of metabolic hyperpolarized contrast agents over long distances, and (iv) develop and optimize low field (low-cost) ultrafast in vivo metabolic imaging suitable for preclinical models of breast cancer and future clinical trials.

The overall goal of this 5-year work is to develop technologies and metabolic contrast agents that should enable efficient imaging of hyperpolarized contrast agents for sensitive, economical, and sub-second imaging of breast cancer metabolic biomarkers. This should enable future clinical trial(s) for population screening and monitoring response to treatment. If successful, this could also fundamentally change the development of new therapies by accelerating clinical trials and preclinical work from years to potentially weeks and providing true hope for current breast cancer patients that new advances in biomedical sciences will actually reach them rather than the next generations of cancer patients.