Radionuclide Controlled Image-Guided Spatiotemporal Therapy of Metastatic Breast Cancer
Abstract
Overarching Challenge: Revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival. Metastatic breast cancer represents a devastating eventuality affecting breast cancer patients with high relapse and mortality rates for which there are currently no effective therapies. Despite the introduction of novel therapies, many patients still succumb to the disease. The major limiting factors for the effective use of therapies in treating metastatic breast cancer is development of acquired resistance and the serious side effects caused by these drugs. Due to widespread location of breast cancer cells, particularly in the bone marrow, which harbors the tumor cells as well as vital stem cells, the risk of off-target toxicity is even higher with conventional therapeutics. Therefore, new therapeutic strategies that selectively destroys tumor cells, increases treatment efficacy, prevents relapse, provides a cure and reduces side effects by sparing the resident stem cells is needed. Light-mediated therapies such as photodynamic therapy (PDT) offers high degree of control that is effectively used to manage cancer in different stages – early to advanced. It operates on a simple principle, where a light-sensitive drug, which is otherwise nontoxic, when introduced in the tissue of interest causes cell death only when excited by light. Despite the promise of PDT, the shallow penetration of light in tissue confines its use to superficial and endoscope-accessible diseases. A second level of complexity arises from the fact that the current light-sensitive drugs require oxygen to be effective. However, many tumors including breast cancer have pockets of low oxygen or grow in regions where oxygen is either low or absent. This feature precludes the effective application of PDT in the treatment of many tumors. We recently discovered a two-prong approach to address the issue of shallow penetration of light by employing ultraviolet (UV) light from radionuclides and oxygen dependence by using metal based light-sensitive drugs for depth- and oxygen-independent PDT. Essentially, by replacing external light source, such as lasers and lamps, with light from radionuclides as “internal” light source enables high degree of controlled therapy anywhere in the body. This would translate to more effective therapy with minimal toxicity to vital organs and tissues. Since radionuclides are used in imaging and locating tumors, we can now simultaneously image and treat breast cancer metastasis using the same radionuclide. We propose to take advantage of this novel therapeutic and imaging platform, which for the first time allows phototherapy of metastatic cancer in a depth-independent fashion. This proposal will test the hypothesis that radionuclide-mediated activation of tumor-targeted, light-sensitive drugs using light from radionuclides will selectively destroy metastatic cancer cells, including drug-resistant types. Since the mode of cell killing is not dependent on a certain molecular pathway, the technology platform is applicable to treat a wide variety of breast cancers, irrespective of the subtype. It, therefore, has the potential to be a common image-guided treatment strategy to treat patients in early as well as advanced stages of the disease. Because of the safety of this treatment strategy, it can be effectively used along with other treatment modalities, such as chemotherapy and immunotherapy, without the risk of additional toxicity. This will tremendously benefit patients as it could potentially improve therapeutic outcomes dramatically and also lead to a complete cure. It will also set a precedent to tailor other Food and Drug Administration-approved light-sensitive drugs as radionuclide-activated drugs to expand the scope and range of the diseases these drugs currently encompass. We anticipate rapid turnover of this highly modular and adaptable technology in 5-10 ye
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810609
Entities
People
- Nalinikanth Kotagiri
Organizations
- United States Army
- University of Cincinnati