Radiopharmaceutical Imaging and Therapy of Cancer

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

Here is a summary of the accomplishments over the last year: 1. Multiple myeloma is a cancer of bone marrow. Although much progress in treating multiple myeloma has occurred in the past 10 years there are still major limitations in imaging and still some gaps in therapy. Our team has developed a targeted molecular imaging probe, capable of both imaging and therapy, that relies on B cell maturation antigen (BCMA). We linked a nanobody ( an ultrasmall antibody found in llamas and other camelids) to a radioisotope (F-18) using pyriidine (Py) chemistry to create F-18 Py-BCMA. This probe was tested in animal models of multiple myeloma and showed high sensitivity and specificity for disease. Moreover, we next labeled it with I-131 which is a beta emitter that can be used to treat cancers. We found that mice with systemic multiple myeloma can be apparently cured of the disease using I-131-BCMA therapy. This work is currently undergoing refinement in preparation for translation to the clinic. We collaborate with multiple myeloma researchers at the University of Miami as well as our own in house myeloma experts within CCR. 2. Triple negative breast cancer is a relatively common and aggressive breast cancer that shows none of the hallmarks of typical breast cancer, i.e. estrogen receptor, progesterone receptor and HER2 receptor. The absence of these receptors makes triple negative breast cancer difficult to treat because of the lack of targets. We have identified a marker of triple negative breast cancer, B7H4 that is highly expressed in tumor but not in surrounding normal tissue. We have developed an imaging agent for B7H4 that potentially could allow for the detection of triple negative disease non invasively. Moreover, early results suggest B7H4 could be used to deliver radiopharmaceutical therapy to the tumors. This work is on going with hopes to translate clinically in 2026-7. 3. Immune checkpoint inhibitors are an important therapeutic class of agents for cancer. However, it is difficult to predict which patients will respond to this therapy. The hallmark of success in immunotherapy such as immune checkpoint inhibition is activation of T cells within the tumor. We have developed an imaging agent targeting CXCL9. CXCL9 (and its partners CXCL10, CXCL11) are known markers of T cell activation. Activated T cells lay down CXCL9 as a chemokine to attract more T cells to the area. Thus, CXCL9 could be an early marker of T cell activation. We developed a nanobody that binds to CXCL9 and labeled it with F-18. This probe was used to detect very early T cell activation after immunotherapy. This agent has potential for clinical translation and could be used in patients undergoing checkpoint therapy. 4. As explained before, multiple myeloma is an important bone marrow disease. We are using F-18 Fluciclovine to image multiple myeloma in patients. This agent is approved for use in prostate cancer but we recently became aware of its potential utility in multiple myeloma. F-18 fluciclovine is a radioanalog of leucine. It has been noted that some multiple myeloma cells have mutations in the RAS gene. These are associated with more aggressive phenotypes and have been noted to increase uptake of some amino acids including leucine. We have scanned 23 patients with multiple myeloma and compared the findings with FDG PET. To date, F18 fluciclovine generally shows lesions that are different from those shown on FDG PET. We are similarly exploring the use of Ga-68 Pentixafor (see below) in an upcoming clinical trial in multiple myeloma. 5. Endocrine cancers of the adrenal such as Cushings or aldosterinomas can produce high blood pressure, electrolyte abnormalities and other specific symptoms. However, it is difficult to distinguish the common non functional adrenal adenoma from functional adrenal adenomas. We have found that Ga-68 Pentixafor which is based on the CXCR4 receptor can be used to identify functional adenomas vs. non functional adenomas. This is very useful because verifying this often involves adrenal venous sampling which is technically difficult, invasive and costly. We are investigating whether this new agent could replace the more invasive AVS test. 6. Fibroblasts are commonly found within tumors and are known as Cancer Associated Fibroblasts (CAFs). CAFs are thought to be immunosuppressive and therefore, support tumor growth. We are working with a small molecule agent that targets fibroblast activating protein (FAP). In collaboration with an industry partner we have brought F-18 FAPi to the clinic and are currently scanning patients with a variety of illnesses. This agent may be more sensitive than FDG PET for many different tumor types, particularly those involving the GI track such as stomach, pancreas, biliary tree and small bowel. Thus, the MIB has an active preclinical and clinical translation pipeline of agents which are either in the clinic or poised to be launched to the clinic in the coming years.