Nurturing Connections: From Preclinical Imaging to Diagnosis to Therapy
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The bridge from preclinical research and imaging to human treatment can be fragile, but a strong relationship between the University of Wisconsin-Madison and Siemens Medical Solutions demonstrates the power of partnerships and the potential of therapeutic agents. Molecular imaging promises to forge stronger connections between diagnosis and treatment, expanding options for cancer treatment. Although it is several years from general human applications, a molecular imaging compound that finds, treats and follows malignant cells provides a perfect example of a multi-purpose agent.
Cellectar’s CLR1404 is poised to enter the lengthy clinical trials process as an anti-cancer therapy agent. In preclinical imaging evaluations, CLR1404 appears to have characteristics that overcome the shortcomings associated with FDG-PET scanning. This preclinical imaging research led to subsequent therapeutic research and ultimately convinced Cellectar to shift their strategy to therapeutic applications due to the agent’s significant promise as a therapy, particularly for hard-to-treat metastatic disease. The therapeutic mechanism is straightforward and the agent can be labeled with a variety of therapeutic radioactive isotopes to treat malignant lesions.
“We see four potential uses for CLR1404, and we are starting with therapy,” says Jamey Weichert, PhD, associate professor of Radiology, Medical Physics and Pharmaceutics at the University of Wisconsin-Madison and founder and chief scientific officer at Cellectar. Purposes include:
- Initial detection and characterization of malignant lesions
- Disease staging
- Therapeutic applications
- Therapeutic response monitoring
Treatment & monitoring applications
In many types of cancer, treatment remains inexact and difficult. Patients with only a few metastatic lesions can be effectively treated with external beam radiation therapy, but as the number and location of metastases grows, it becomes increasingly difficult to treat the patient with radiotherapy. “Patients like these frequently receive a systemic chemotherapy agent,” notes Weichert.
Researchers can label CLR1404 with a radioactive isotope that can irradiate and destroy malignant cells from the inside. In preclinical testing, it was shown that the agent is taken up by and retained in malignant cells, with the treatment isotope then destroying the malignant cells. A specific search-and-destroy mechanism such as this is particularly important for widespread metastatic diseases, which can’t be effectively treated surgically or with externally applied radiation therapy.
As with the staging of cancer, if the current mechanism that is seen in the preclinical work functions similarly in clinical practice, physicians could monitor the patient’s response to treatment via a CLR1404 PET scan. “If the treatment destroys the cells, then we shouldn’t see the tumor uptake on the scan,” explains Weichert. Although the model could be particularly useful for CLR1404-based treatments, it may have more widespread applications. “We could potentially use the agent after treatment to monitor patient response in any therapeutic regimen,” says Weichert.
Disease detection & staging
FDG opened the door and remains the gold standard for current oncology PET applications. It is approved for diagnosis and staging for a variety of types of cancer. But FDG also is associated with some shortcomings that make it a less than ideal tracer. For example, FDG is not a highly specific tracer. It does not always discriminate malignant from benign tumors, and uptake can be high in areas of inflammation. Consequently, it can be difficult for physicians to detect initial and recurrent disease in some patients, particularly those with inflammatory disease or scar tissue. In some cases, radiation therapy can produce scar tissue, decreasing the utility of FDG PET for disease monitoring as the tissue can obscure lesions.
CLR1404 behaves differently than FDG and other tracers by biochemically locking into cancer cells. Weichert explains, “Every piece of evidence indicates that if CLR1404 enters a tumor and stays there, the lesion is malignant.” Equally important, preclinical research indicates that CLR1404 is a versatile agent, detecting a broad variety of cancer types including cancers of the lung, prostate, brain, pancreas and melanoma. In fact, this research hints of broad detection capabilities, with CLR1404 detecting 43 out of 43 cancer types that have been investigated to date. In addition, the compound can be deployed in both PET and SPECT imaging, depending on which radioactive isotope of iodine is used to label CLR1404.
While researchers have not fully detailed the mechanism, they believe that malignant cells underexpress key metabolic phospholipase enzymes. CLR1404 is retained in malignant cells regardless of location in the body. “It undergoes prolonged selective retention in tumor cells. Once it’s in, it doesn’t apparently come out,” explains Weichert. Eventually, if CLR1404 enters the clinical arena, this mechanism could aid detection and characterization of specific lesions such as colon polyps that can turn malignant. Because the agent will not enter premalignant polyps, but enters and is retained by malignant colon tumor cells, it may afford physicians a non-invasive way of determining whether a colon tumor is malignant or benign. This approach may therefore bring us closer to the concept of imaging-based virtual biopsy.
Weichert and the preclinical research team employ many of the same tools as clinical oncologists. “Just as state-of-the-art hybrid PET/CT scanning is the gold standard in clinical diagnosis and staging of cancer, hybrid microPET/CT is our gold standard for preclinical studies…Utilizing a micro PET/CT scanner like the Siemens Inveon multimodal system is extremely powerful because it permits direct three-dimensional mapping of biochemical or functional information provided by the tracer onto the precise anatomic structure provided by CT,” he says. In other words, scanning with the multimodal imaging system allows researchers to see the exact location of tumors and their metabolic activity in preclinical research animals.
Staging cancer partially hinges on quantifying the spread of metastatic lesions. CLR1404 appears to be ideally suited to staging because it is taken up by and retained in malignant lesions regardless of location in the body. If the current mechanism that is seen in the preclinical work functions similarly in clinical practice, an oncologist could order a CLR1404 PET scan for a recently diagnosed breast cancer patient. If metastases exist in the brain, bones, lungs or another area, the scan will show CLR1404 uptake in those areas to provide precise staging data. The agent could improve the current FDG staging protocol because it appears to be more specific than FDG and without the complications or confusion caused by the presence of inflammation or scar tissue.
Partnerships, process & progress
“The arrangement between University of Wisconsin-Madison and Siemens provides a good opportunity to move ideas off the bench and toward the bedside,” says Weichert, “but also extends it to commercialization whereupon it will hopefully be more beneficial to the general population.” The primary focus of university or laboratory bench research is on the molecular imaging process. University researchers are exploring the agent in conjunction with PET/CT and SPECT scanning. Cellectar, which holds the license to CLR1404, emphasizes the therapeutic development, focusing on labeling the agent with radioactive isotopes for treatment. Siemens’ broad range of imaging tools helps facilitate the transfer from preclinical animal research to human trials and clinical practice. The preclinical Inveon PET/CT scanner operates on the same principles as clinical systems like the Biograph PET•CT family of solutions, offering researchers the resolution and sensitivity necessary to help nurture the development of new agents.
Note: As a founder of Cellectar, which licenses the rights to CLR1404, Jamey Weichert, MD, has a financial interest in this agent.