Peering into the Future: Why We Need New Imaging Biomarkers
New imaging biomarkers could play several critical roles in molecular imaging in the next decade. The development of more specific biomarkers is expected to deliver improvements on a number of fronts, says Hartmuth Kolb, PhD, vice president of Siemens Medical Solutions Biomarker Research, including:
Biomarkers: A short history
The primary molecular imaging modalities—PET and SPECT—rely on biomarkers, or tracers, to help detect and localize disease. Current biomarkers, primarily FDG-based, which are used in oncologic and Alzheimer’s applications, and cardiac tracers like 99mTc-Sestamibi, Rubidium-82 and N13-Ammonia, demonstrate the potential of molecular imaging.
Used in conjunction with PET, FDG indicates metabolic activity associated with malignancies and is used in diagnose, staging and monitoring treatment of various cancers. FDG also helps physicians detect areas of decreased metabolic activity in the brain to diagnose Alzheimer’s disease. 99mTc-Sestamibi and other cardiac biomarkers help physicians evaluate coronary perfusion.
Despite their proven utility, there are limits to the currently available tracers. FDG uptake can be increased in benign disorders such as inflammation or infection potentially resulting in false positive results for cancer. Conversely, some malignancies do not exhibit markedly increased FDG uptake, or, as is the case in malignant brain tumors, normal glucose metabolic activity is high resulting in low tumor to background ratios of FDG. Similarly, there are unfilled cardiac imaging needs. Myocardial infarction remains unpredictable; the current biomarker/imaging combinations do not allow physicians to determine which patients will develop an infarct. “The molecular imaging field is waiting for the next generation of biomarkers,” says Kolb.
This month, Molecular Imaging Insight peers into the future of biomarkers. New biomarkers will have a broad impact in the practice, as well as the business of medicine, delivering improved diagnosis, treatment and monitoring in neurology, oncology, cardiology and radiation oncology.
Snapshot of the future: Neurology
Research into new neurologic biomarkers is quite broad. Some researchers are exploring biomarkers for malignant brain tumors, while others develop novel imaging biomarkers for neuron-degenerative diseases such as Alzheimer’s or Parkinson’s disease.
Of the various target diseases, current PET protocols are most robust in Alzheimer’s disease. FDG-PET scanning can detect early stages of Alzheimer’s disease before patients demonstrate clinically significant symptoms. FDG meets current clinical needs, says Dan Silverman, MD, PhD, associate professor of molecular and medical pharmacology at the David Geffen School of Medicine at University of California Los Angeles (UCLA). Physicians need to determine if there is a functional deficit, and FDG-PET scanning fits the bill. FDG uptake in affected areas of the brain highlights any functional deficits. Consequently, FDG is nearly universally accepted; in fact, the Centers for Medicare and Medicaid Services (CMS) in the United States, have reimbursed PET studies for patients referred for Alzheimer’s disease for four years.
Alzheimer’s research, however, continues on a number of fronts. Future biomarkers could target the disease state via a number of different avenues including amyloid plaque or neurotransmitters. Amyloid plaque biomarkers hold the long-term potential to expand treatment options and broaden the utility of PET in Alzheimer’s disease; however, advances could follow a circuitous route beginning with drug development rather than clinical diagnosis.
The accumulation of amyloid plaque is one of the primary indicators of Alzheimer’s disease. The utility of amyloid biomarkers in diagnosis of Alzheimer’s disease, however, is questionable. In fact, Silverman says current research does not provide compelling evidence showing that amyloid plaque biomarkers, which bind to extracellular amyloid plaque, are more than or even as useful as FDG in the diagnosis and prognosis of Alzheimer’s disease. Still, amyloid plaque biomarkers could play a critical role in the drug development process.
If a pharmaceutical company develops a drug aimed at reducing amyloid plaque, the biomarker could be deployed to assess the effectiveness of the drug. “If the biomarker proves to be useful in drug development, then it could be used to monitor the effectiveness of the therapy in a clinical setting,” explains Silverman.
Similarly, biomarkers that target neurotransmittors are less biochemically specific for Alzheimer’s disease than FDG. On the other hand, agents that target neurotransmittors are diagnostically useful in Parkinson’s disease. For example, FDOPA (6-fluoro-L-dopa) PET scans identity deficits in FDOPA transmission that characterize Parkinson’s disease. The imaging biomarker can yield a diagnosis for patients who present with both dementia and motor symptoms, helping physicians determine appropriate diagnosis and treatment.
Snapshot of the future: Oncology
New oncology biomarkers are rampant with possibility. In the next decade, FDG could be joined by a host of other biomarkers that address a broad range of targets and processes. “FDG is quite useful, but it only measures one process—glucose metabolism,” explains Wolfgang Weber, MD, professor and chair of nuclear medicine at the University of Freiburg, Germany. In many cases, FDG helps physicians answer a critical question; it provides a yes or no answer to the presence of cancer. But high-tech biomarkers in the development pipeline will speak in shades of gray. That is, they will provide data about the heterogeneity of a tumor or measure the aggressiveness of a malignancy. The information can be used to personalize treatment and gauge therapeutic success, says Kolb.
State-of-the-art PET/CT technologies, like Siemens HD•PET will multiply the impact of new biomarkers. HD•PET improves the resolution of standard PET and delivers more uniform resolution. “Improved resolution is especially important with new, high-tech biomarkers,” indicates Kolb. That’s because the new biomarkers provide much more specific, nuanced information about cancerous cells. Several new biomarkers in preclinical and clinical trials could offer improvements in therapeutic monitoring.
Take for example FLT (18F-3’-fluoro-3’-deoxy-L-thymidine). The biomarker measures cell proliferation or cancer growth. Several studies comparing FLT and FDG indicate FLT is a better marker for tumor proliferation than FDG. Research does point to a downside to FLT; its uptake in cancer cells is lower than that of FDG. “The comparatively low uptake of FLT indicates that it is less useful for staging than FDG; however, it appears to be useful for treatment monitoring,” says Weber. Although FDG is an early marker for cell death, it does not measure tumor growth. FLT could help fill the gap. The mechanism is fairly simple. Physicians could analyze FLT in successive PET scans to see changes in tumor proliferative activity over time. Biomarkers like FLT that provide a measure of tumor proliferation could prove particularly useful in monitoring the effectiveness of drugs that target tumor growth. An FLT-PET scan could provide the data needed to discontinue or support specific therapies targeting tumor growth.
Another biomarker in development targets angiogenesis, or blood vessel development. The biomarker, and others in the same class, measures the process of angiogenesis. Unlike normal, quiescent endothelial cells, endothelial cells within malignant tumors frequently express a specific substance (alpha-v beta-3 integrin) on the surface. A biomarker that binds to that could measure changes in angiogenetic activity in response to therapies that target angiogenesis. “There’s a good chance this information could be used to develop a marker to examine treatment-induced anti-angiogenetic activity,” says Weber. The proposed approach is similar to FLT treatment monitoring PET scans. If the scan does not show a decrease in angiogenesis, physicians could discontinue the therapy and pursue a different treatment option.
Hypoxia is a critical measure in radiation oncology. One of the biological properties of tumor cells is low oxygen tension, or hypoxia. Uptake of the current tracer used to assess hypoxia, F-MISO (18F-fluoromisonidazol), correlates with the amount of oxygen in the tissue. But F-MISO has several drawbacks. The agent is slow to clear, which requires sites to wait to image patients. What’s more, its signal uptake is low, resulting in poor contrast and difficult-to-read images.
“There is great interest among researchers in imaging hypoxia,” Weber says. Hypoxic cells are clinically problematic. The amount of hypoxia is inversely related to the effectiveness of radiation therapy. Tumor cells with more hypoxia tend to be less responsive to treatment. Plus, hypoxia leads tumor cells to invade other tissues. A probe that measures hypoxia with a contrast comparable to FDG-PET scanning could prove quite useful for oncologists. “Assessing hypoxia is especially critical with new radiation therapy treatment devices that allow physicians to increase the dose to more aggressive cells like those with low oxygen tension,” explains Weber. The marker could help radiation oncologists pinpoint areas of tumor that require higher doses.
Another approach to image hypoxia is to target a protein developed in response to hypoxia called carbonic anhydrase IX (CA-9). CA-9 is clinically linked to poor survival, indicating a need for aggressive treatment. A biomarker that measures the presence of CA-9 would provide critical data about hypoxia and the aggressiveness of a tumor. In turn, oncologists could use the information to amplify treatment to areas of highly aggressive activity.
Other researchers are trying to extend the principles of peptide-labeled probes currently used in Europe. The radioisotopes bind to specific receptors in cancer cells. Currently, the primary target is somotostatin, a receptor expressed in several fairly uncommon tumors including endocrine cancer. In addition to measuring the receptor, the peptide can be labeled with other radioisotopes and used for treatment. For example, DOTATOC, a peptide that binds to the somotostatin receptor in endocrine tumors, can be radiolabeled for PET imaging with Galium-68 and for radionuclide therapy with Yttrium 90. Weber explains the process. “If the initial PET scan with Galium-68 DOTATOC shows high uptake, the patient can be treated with Yttrium 90 DOTATOC. Follow-up PET scans using Galium-68 DOTATOC monitor the tumor’s response to treatment.” Researchers aim to use the protocol as a model for other tracer/isotope combinations that target different types of tumors.
Snapshot of the future: Cardiology
Although several biomarker options exist for cardiac PET and SPECT imaging, each is associated with multiple shortfalls. Current biomarkers for myocardial perfusion imaging include N13-ammonia, oxygen-15-labelled water and Rubidium 82.
The use of both N13-ammonia and oxygen-15 is limited to university medical centers and very large sites because both compounds require an on-site cyclotron, an investment beyond the reach of most hospitals, cardiology practices and imaging centers. But there are challenges beyond initial investment. Oxygen-15 is rarely used in clinical settings because it results in relatively poor image quality caused by an inadequate myocardial perfusion to background ratio. Its use is relegated to the research realm by experts who can overcome the image quality challenge. N13 is somewhat less problematic as it does provide acceptable image quality.
Unlike other current tracers, Rubidium-82 does not require an onsite cyclotron. It does, however, require a generator with a fairly hefty price tag. Monthly operational costs for a Rubidium-82 generator stretch into the $30,000 (€20,000) range. “Rubidium-82 only makes sense for sites with a large volume of studies that can justify the cost of a generator,” says Jamshid Maddahi, MD, professor of molecular and medical pharmacology at David Geffen School of Medicine at UCLA. In addition, the extraction fraction of Rubidium-82 is less than Oxygen-15 and N13-ammonia, which translates into the possibility of missing mild defects or ischemia. Rubidium also offers less than ideal resolution; the positron associated with the marker typically travels eight or nine millimeters before emitting energy, so it does not pinpoint the exact location of a defect. Finally, the tracer has a short half-life. Patients must be injected in the scanner, eliminating the option of exercise imaging.
Consequently, the cardiac imaging community is searching for a better solution. Maddahi identifies characteristics of an ideal agent:
“DMS747158 could fulfill the well-recognized need for a radiopharmaceutical that broadens the use of PET technology as a major modality for myocardial perfusion imaging,” sums Maddahi.
Imaging biomarkers at a glance
Researchers are exploring and developing a broad range of new biomarkers that could bolster molecular imaging in multiple areas including neurology, oncology, cardiology and radiation oncology. New biomarkers promise to expand applications and offer more specific information than current tracers like FDG, Rubidium and N-15 ammonia. Some tracers under development could be linked with specific treatments for Alzheimer’s disease or cancer, providing physicians a razor-sharp mechanism for monitoring the effectiveness of certain therapies. Others could play a critical role in the drug development process, providing pharmaceutical companies a mechanism for viewing the effectiveness of experimental treatments. Some new tracers simplify molecular imaging, erasing hurdles associated with current biomarkers and opening the field to more sites. A final group of new biomarkers will measure features of malignant cells, arming physicians with a wealth of data about the heterogenity and aggressiveness of tumors.
Biomarkers will play a central role in the future of molecular imaging, fostering evolutions in drug development, diagnosis and therapeutic monitoring.
- Earlier diagnosis of cancer
- More specific oncologic therapeutic response monitoring
- Expanded cardiac PET applications
- Aid in the drug development processes for Alzheimer’s disease and oncology
Biomarkers: A short history
The primary molecular imaging modalities—PET and SPECT—rely on biomarkers, or tracers, to help detect and localize disease. Current biomarkers, primarily FDG-based, which are used in oncologic and Alzheimer’s applications, and cardiac tracers like 99mTc-Sestamibi, Rubidium-82 and N13-Ammonia, demonstrate the potential of molecular imaging.
Used in conjunction with PET, FDG indicates metabolic activity associated with malignancies and is used in diagnose, staging and monitoring treatment of various cancers. FDG also helps physicians detect areas of decreased metabolic activity in the brain to diagnose Alzheimer’s disease. 99mTc-Sestamibi and other cardiac biomarkers help physicians evaluate coronary perfusion.
Despite their proven utility, there are limits to the currently available tracers. FDG uptake can be increased in benign disorders such as inflammation or infection potentially resulting in false positive results for cancer. Conversely, some malignancies do not exhibit markedly increased FDG uptake, or, as is the case in malignant brain tumors, normal glucose metabolic activity is high resulting in low tumor to background ratios of FDG. Similarly, there are unfilled cardiac imaging needs. Myocardial infarction remains unpredictable; the current biomarker/imaging combinations do not allow physicians to determine which patients will develop an infarct. “The molecular imaging field is waiting for the next generation of biomarkers,” says Kolb.
This month, Molecular Imaging Insight peers into the future of biomarkers. New biomarkers will have a broad impact in the practice, as well as the business of medicine, delivering improved diagnosis, treatment and monitoring in neurology, oncology, cardiology and radiation oncology.
Snapshot of the future: Neurology
Research into new neurologic biomarkers is quite broad. Some researchers are exploring biomarkers for malignant brain tumors, while others develop novel imaging biomarkers for neuron-degenerative diseases such as Alzheimer’s or Parkinson’s disease.
Of the various target diseases, current PET protocols are most robust in Alzheimer’s disease. FDG-PET scanning can detect early stages of Alzheimer’s disease before patients demonstrate clinically significant symptoms. FDG meets current clinical needs, says Dan Silverman, MD, PhD, associate professor of molecular and medical pharmacology at the David Geffen School of Medicine at University of California Los Angeles (UCLA). Physicians need to determine if there is a functional deficit, and FDG-PET scanning fits the bill. FDG uptake in affected areas of the brain highlights any functional deficits. Consequently, FDG is nearly universally accepted; in fact, the Centers for Medicare and Medicaid Services (CMS) in the United States, have reimbursed PET studies for patients referred for Alzheimer’s disease for four years.
Alzheimer’s research, however, continues on a number of fronts. Future biomarkers could target the disease state via a number of different avenues including amyloid plaque or neurotransmitters. Amyloid plaque biomarkers hold the long-term potential to expand treatment options and broaden the utility of PET in Alzheimer’s disease; however, advances could follow a circuitous route beginning with drug development rather than clinical diagnosis.
The accumulation of amyloid plaque is one of the primary indicators of Alzheimer’s disease. The utility of amyloid biomarkers in diagnosis of Alzheimer’s disease, however, is questionable. In fact, Silverman says current research does not provide compelling evidence showing that amyloid plaque biomarkers, which bind to extracellular amyloid plaque, are more than or even as useful as FDG in the diagnosis and prognosis of Alzheimer’s disease. Still, amyloid plaque biomarkers could play a critical role in the drug development process.
If a pharmaceutical company develops a drug aimed at reducing amyloid plaque, the biomarker could be deployed to assess the effectiveness of the drug. “If the biomarker proves to be useful in drug development, then it could be used to monitor the effectiveness of the therapy in a clinical setting,” explains Silverman.
Similarly, biomarkers that target neurotransmittors are less biochemically specific for Alzheimer’s disease than FDG. On the other hand, agents that target neurotransmittors are diagnostically useful in Parkinson’s disease. For example, FDOPA (6-fluoro-L-dopa) PET scans identity deficits in FDOPA transmission that characterize Parkinson’s disease. The imaging biomarker can yield a diagnosis for patients who present with both dementia and motor symptoms, helping physicians determine appropriate diagnosis and treatment.
Snapshot of the future: Oncology
New oncology biomarkers are rampant with possibility. In the next decade, FDG could be joined by a host of other biomarkers that address a broad range of targets and processes. “FDG is quite useful, but it only measures one process—glucose metabolism,” explains Wolfgang Weber, MD, professor and chair of nuclear medicine at the University of Freiburg, Germany. In many cases, FDG helps physicians answer a critical question; it provides a yes or no answer to the presence of cancer. But high-tech biomarkers in the development pipeline will speak in shades of gray. That is, they will provide data about the heterogeneity of a tumor or measure the aggressiveness of a malignancy. The information can be used to personalize treatment and gauge therapeutic success, says Kolb.
State-of-the-art PET/CT technologies, like Siemens HD•PET will multiply the impact of new biomarkers. HD•PET improves the resolution of standard PET and delivers more uniform resolution. “Improved resolution is especially important with new, high-tech biomarkers,” indicates Kolb. That’s because the new biomarkers provide much more specific, nuanced information about cancerous cells. Several new biomarkers in preclinical and clinical trials could offer improvements in therapeutic monitoring.
Take for example FLT (18F-3’-fluoro-3’-deoxy-L-thymidine). The biomarker measures cell proliferation or cancer growth. Several studies comparing FLT and FDG indicate FLT is a better marker for tumor proliferation than FDG. Research does point to a downside to FLT; its uptake in cancer cells is lower than that of FDG. “The comparatively low uptake of FLT indicates that it is less useful for staging than FDG; however, it appears to be useful for treatment monitoring,” says Weber. Although FDG is an early marker for cell death, it does not measure tumor growth. FLT could help fill the gap. The mechanism is fairly simple. Physicians could analyze FLT in successive PET scans to see changes in tumor proliferative activity over time. Biomarkers like FLT that provide a measure of tumor proliferation could prove particularly useful in monitoring the effectiveness of drugs that target tumor growth. An FLT-PET scan could provide the data needed to discontinue or support specific therapies targeting tumor growth.
Another biomarker in development targets angiogenesis, or blood vessel development. The biomarker, and others in the same class, measures the process of angiogenesis. Unlike normal, quiescent endothelial cells, endothelial cells within malignant tumors frequently express a specific substance (alpha-v beta-3 integrin) on the surface. A biomarker that binds to that could measure changes in angiogenetic activity in response to therapies that target angiogenesis. “There’s a good chance this information could be used to develop a marker to examine treatment-induced anti-angiogenetic activity,” says Weber. The proposed approach is similar to FLT treatment monitoring PET scans. If the scan does not show a decrease in angiogenesis, physicians could discontinue the therapy and pursue a different treatment option.
Hypoxia is a critical measure in radiation oncology. One of the biological properties of tumor cells is low oxygen tension, or hypoxia. Uptake of the current tracer used to assess hypoxia, F-MISO (18F-fluoromisonidazol), correlates with the amount of oxygen in the tissue. But F-MISO has several drawbacks. The agent is slow to clear, which requires sites to wait to image patients. What’s more, its signal uptake is low, resulting in poor contrast and difficult-to-read images.
“There is great interest among researchers in imaging hypoxia,” Weber says. Hypoxic cells are clinically problematic. The amount of hypoxia is inversely related to the effectiveness of radiation therapy. Tumor cells with more hypoxia tend to be less responsive to treatment. Plus, hypoxia leads tumor cells to invade other tissues. A probe that measures hypoxia with a contrast comparable to FDG-PET scanning could prove quite useful for oncologists. “Assessing hypoxia is especially critical with new radiation therapy treatment devices that allow physicians to increase the dose to more aggressive cells like those with low oxygen tension,” explains Weber. The marker could help radiation oncologists pinpoint areas of tumor that require higher doses.
Another approach to image hypoxia is to target a protein developed in response to hypoxia called carbonic anhydrase IX (CA-9). CA-9 is clinically linked to poor survival, indicating a need for aggressive treatment. A biomarker that measures the presence of CA-9 would provide critical data about hypoxia and the aggressiveness of a tumor. In turn, oncologists could use the information to amplify treatment to areas of highly aggressive activity.
Other researchers are trying to extend the principles of peptide-labeled probes currently used in Europe. The radioisotopes bind to specific receptors in cancer cells. Currently, the primary target is somotostatin, a receptor expressed in several fairly uncommon tumors including endocrine cancer. In addition to measuring the receptor, the peptide can be labeled with other radioisotopes and used for treatment. For example, DOTATOC, a peptide that binds to the somotostatin receptor in endocrine tumors, can be radiolabeled for PET imaging with Galium-68 and for radionuclide therapy with Yttrium 90. Weber explains the process. “If the initial PET scan with Galium-68 DOTATOC shows high uptake, the patient can be treated with Yttrium 90 DOTATOC. Follow-up PET scans using Galium-68 DOTATOC monitor the tumor’s response to treatment.” Researchers aim to use the protocol as a model for other tracer/isotope combinations that target different types of tumors.
Snapshot of the future: Cardiology
Although several biomarker options exist for cardiac PET and SPECT imaging, each is associated with multiple shortfalls. Current biomarkers for myocardial perfusion imaging include N13-ammonia, oxygen-15-labelled water and Rubidium 82.
The use of both N13-ammonia and oxygen-15 is limited to university medical centers and very large sites because both compounds require an on-site cyclotron, an investment beyond the reach of most hospitals, cardiology practices and imaging centers. But there are challenges beyond initial investment. Oxygen-15 is rarely used in clinical settings because it results in relatively poor image quality caused by an inadequate myocardial perfusion to background ratio. Its use is relegated to the research realm by experts who can overcome the image quality challenge. N13 is somewhat less problematic as it does provide acceptable image quality.
Unlike other current tracers, Rubidium-82 does not require an onsite cyclotron. It does, however, require a generator with a fairly hefty price tag. Monthly operational costs for a Rubidium-82 generator stretch into the $30,000 (€20,000) range. “Rubidium-82 only makes sense for sites with a large volume of studies that can justify the cost of a generator,” says Jamshid Maddahi, MD, professor of molecular and medical pharmacology at David Geffen School of Medicine at UCLA. In addition, the extraction fraction of Rubidium-82 is less than Oxygen-15 and N13-ammonia, which translates into the possibility of missing mild defects or ischemia. Rubidium also offers less than ideal resolution; the positron associated with the marker typically travels eight or nine millimeters before emitting energy, so it does not pinpoint the exact location of a defect. Finally, the tracer has a short half-life. Patients must be injected in the scanner, eliminating the option of exercise imaging.
Consequently, the cardiac imaging community is searching for a better solution. Maddahi identifies characteristics of an ideal agent:
- Unit dose availability. Centers could order one or two doses a day that could be shipped from a centrally located, third-party radiopharmacy.
- Longer half-life. All current agents have a short half-life, which poses geographic limits because sites must operate an on-site cyclotron or generator.
- High extraction fraction with resolution similar to N13-ammonia or Oxygen-15.
- Appropriate for rest and exercise imaging.
- Reliable absolute quantification of blood flow.
“DMS747158 could fulfill the well-recognized need for a radiopharmaceutical that broadens the use of PET technology as a major modality for myocardial perfusion imaging,” sums Maddahi.
Imaging biomarkers at a glance
Researchers are exploring and developing a broad range of new biomarkers that could bolster molecular imaging in multiple areas including neurology, oncology, cardiology and radiation oncology. New biomarkers promise to expand applications and offer more specific information than current tracers like FDG, Rubidium and N-15 ammonia. Some tracers under development could be linked with specific treatments for Alzheimer’s disease or cancer, providing physicians a razor-sharp mechanism for monitoring the effectiveness of certain therapies. Others could play a critical role in the drug development process, providing pharmaceutical companies a mechanism for viewing the effectiveness of experimental treatments. Some new tracers simplify molecular imaging, erasing hurdles associated with current biomarkers and opening the field to more sites. A final group of new biomarkers will measure features of malignant cells, arming physicians with a wealth of data about the heterogenity and aggressiveness of tumors.
Biomarkers will play a central role in the future of molecular imaging, fostering evolutions in drug development, diagnosis and therapeutic monitoring.