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PET Scans to Image Prostate Cancer Advance Toward Mainstream Clinical Use


This project was partially supported by a PCF Creativity Award made possible through generous support of Movember.


December 03, 2012 -- Being able to clearly “see” prostate cancer lesions that have spread throughout the body can allow doctors to treat metastatic disease earlier and with greater precision. Traditionally, bone scans or computed tomography (CT) scans have been used to visualize, or “image” prostate tumors that have metastasized away from the prostate gland. But each of those imaging techniques has drawbacks, such as inability to clearly identify lesions that are outside of bony sites, or not being able to differentiate a benign lesion from a cancerous lesion. Oncologists hunger for better pictures of metastatic tumors in patients that not only show where those tumors are at the earliest stages of development but also images that give them clues into the inner workings of those tumors that may allow them to tailor chemotherapy or other treatments to a particular tumor.

That’s where PET scans step in. The acronym stands for positron emission tomography, which is a type of nuclear imaging test that produces 3-D images of body tissues and organs and can also give clues about how those tissues are working, or functioning. Referred to as functional imaging, PET scans are used to help diagnose any number of conditions such as Alzheimer’s or heart disease or certain cancers based upon a tissue’s metabolic uptake of glucose or changes in blood flow. (More recently, PET scans report on molecular functions such as the presence of certain receptors or enzymes that can affect the disease process and PET scans are also now referred to as a molecular imaging technique.) Yet until now, PET scans have not been used routinely to diagnose prostate cancer because, while most cancers have increased glucose uptake that can readily be imaged with PET scans, prostate cancer tends to be slow growing and less likely to show changes in glucose metabolism.

“Unlike most cancers, prostate tumors are not as greedy in their use of glucose,” says Dr. Martin Pomper, a professor of radiology at Johns Hopkins University School of Medicine. “That’s why there’s been a massive effort to find agents that can better image prostate cancer on PET,” he says.

Recently, Dr. Pomper and his colleagues, have published a paper in the Journal of Nuclear Medicine that bears some fruit from this massive effort: the first-in- man clinical trial of a novel small molecule radiotracer (18F-DCFBC) that can be used in PET scans to visualize metastatic prostate tumors.

Rather than using an analogue of glucose labeled with the positron-emitting radioactive tracer, 18 F-fluorine that is used in standard PET scans to image tissues, Pomper’s group attached 18F-fluorine to their newly synthesized small-molecule compound that is targeted to a protein (prostate-specific membrane antigen--PSMA) that is found in prostate cancer as well as in the new vasculature of many other types of solid tumors.

Because the novel tracer 18F-DCFBC is targeted to tumor sites directly rather than being attracted to bony sites that are reacting to the destructive attacks by metastatic prostate cancer cells, it seems able to pick up lesions not seen by conventional bone or CT scans—lesions that have not yet caused local bone destruction. And by targeting the PSMA protruding from the tumor cellular membrane, 18F-DCFBC seems also to “light up” on PET images, soft tissues that have been invaded by metastatic cancer cells, such as lymph nodes. With several new drugs that have recently come to market for the treatment of metastatic prostate cancer, the earlier this cancer is found,the sooner such medications can be prescribed.

In their paper, the researchers performed PET scans with the radiotracer 18F-DCFBC on five patients with metastatic prostate cancer; a total of 32 suspected metastatic cancer sites were identified by the scans. Those patients also underwent conventional imaging techniques (bone and CT scans) to compare lesions found. Of the 32 lesions visualized on PET scans, only 21 were visualized by conventional imaging techniques. The authors write that the lesions not caught by conventional imaging may be metastatic cancers in their earliest stages of formation, but further studies will be needed to verify this.

In total (via both conventional imaging techniques and PET scans) a total of 42 lesions were detected. Of the 10 that were “seen” by conventional imaging, but not picked up by PET, seven were considered upon further examination to be stable, benign lesions, such as compression fractures. The remaining three lesions, not detected by PET were of indeterminate nature. The authors postulated that of the three indeterminate lesions, the one most likely positive for metastatic cancer might have been missed by their novel PET PSMA-targeted radiotracer because the patient had recently started oral treatment with anti-androgen therapy which is thought to transiently diminish PSMA expression in tumor cells that remain sensitive to androgen inhibition. Ultimately, to determine the false positive rate of their PET radiotracer, each site picked up on PET will need follow-up biopsy to histologically determine if cancer is present, or when biopsy is not an option, long-term imaging and clinical follow up in future studies.

The authors reported that the five patients tolerated the 18F-DCFBC radiotracer well at the dosage needed to conduct the PET scans.

All the better to visualize you with, dear tumor cell

While PET scans have not been an option to visualize metastatic prostate cancers in the past, a PSMA-targeted, high-molecular weight antibody called ProstaScintTM used to image tumors has been on the market for about 15 years. This antibody is used with a form of imaging called single photon emission computed tomography (SPECT) that uses a gamma radiation-emitting radiotracer and a gamma detecting camera to formulate 3-D images. However, says Pomper, there are drawbacks to this type of imaging which have limited its use. “SPECT is one to two orders of magnitude less sensitive than PET, so the images provided are generally of lower resolution than PET images,” he says. And because ProstaScintTM binds to a part of the PSMA molecule within a tumor cell, this also lessens its ability to image living tumor cells. (Tumor cells must be in a state of open decay for the ProstaScintTM antibody to bind with the intracellular portion of PSMA.)

For these and other reasons, says Dr. Pomper, the antibody (despite is utility as a target) is not often used by urologists to image prostate cancer. There are other PSMA-binding antibodies available that do bind to the extra-cellular portion of PSMA that can be used to image prostate tumors; however, because the time required to clear any non-binding PSMA antibody from the bloodstream can take several days--thus requiring a lengthy wait-time from antibody injection to image taking—there has been a massive hunt for novel low-molecular weight radiotracers like 18F-DCFBC that “quickly get to the target, bind strongly, and quickly wash away from non-target sites” to allow a PET scan to be done just a couple of hours after injection of the radiotracer, says Pomper.

Pomper says his team’s next step is to study if they can use 18F-DCFBC PET scans to find tumors that are confined within the prostate gland and use those molecular images along with conventional anatomic images to better guide localized treatments, such as the placement of radioactive beads used to kill cancer cells or high frequency ultrasound ablation. They also plan to begin a larger clinical trial that include follow-up tissue sampling to validate their findings.


PET with 18F-DCFBC for imaging Prostate Cancer Metastatic Disease

Bone Mets Visualized

PET with 18F-DCFBC
Images courtesy of Drs. Cho and Pomper and Johns Hopkins Medicine.
 

This series of images show from left to right: a PET scan of a male with prostate cancer bone metastatic sites at the T12 spinal level and the L4 spinal area as indicated by arrows; the next image is a standard CT scan with a PET overlay scan that combine to show the same cancer mets at T12 and L4 regions of the spine; and the third picture is standard CT scan in the same man that fails to clearly show these cancer bone lesions. The forth images is a frontal view bone scan in the same male patient that fails to show the L4 lesion clearly.

 

Lymph Node Mets Visualized

Lymph Node Mets Visualized

Images courtesy of Drs. Cho and Pomper and Johns Hopkins Medicine.

From top to bottom this series of cross-sectional images show a lymph node prostate cancer metastatic site in (top picture) a PET scan; (middle picture) CT scan alone, and (bottom picture) a PET/CT overlay image. The cancerous node is more easily and clearly visualized with PET images. (Arrows indicate suspect site in all three images.)


All the Better to Functionalize you with, dear tumor cell

Aside from the functionality PET scans provide in terms of indicating glucose uptake by tissues or oxygen use, a PSMA-targeted radiotracer has the potential to inform on a prostate tumor’s level of aggressiveness or its reliance on male hormones—both of which can influence the intensity or type of treatment prescribed. Prior work has suggested that advancing levels of PSMA indicate that a prostate tumor is, or about to, become far less treatable, entering what is known as an androgen-independent state. As prostate tumors advance toward an end stage of what is termed treatment-resistant prostate cancer, they begin to lose their dependence on the male androgen hormones in order to grow, becoming ever more resistant to drugs that are used to lower androgen levels in men with prostate cancer. (Using PET to determine intratumor PSMA levels has the potential to let doctors know which patients are most likely to respond to first or second line anti-androgen therapy, or even which distinct tumors inside the same patient might be best targeted, as various metastatic tumor sites express PSMA at various levels.) And potentially, PSMA PET could be used as a marker of patient response to anti-androgen drugs in real time so dosage could be adjusted or other drugs substituted or added to the treatment regimen.

This idea is bolstered by pre-clinical work out of Dr. Charles Sawyers lab at Memorial Sloan-Kettering Cancer Center, demonstrating that anti-androgen compounds increase PSMA expression at one and two weeks of exposure and this can be detected in mice by PET imaging. However, because this work has yet to be conducted on humans, clinical studies will be needed to fully characterize intatumor PSMA responses to anti-androgen therapy.

In addition to using 18F-DCFBC to report on a tumor’s state of androgen dependence or reliance on male hormones to thrive, Pomper says that, in theory, it could be used to report on individual tumor’s response to standard cytotoxic chemotherapy drugs, such as the taxane-based compounds currently used to treat metastatic prostate cancer. Pre-clinical work by Molecular Insight Pharmaceuticals, Inc. in Cambridge, MA supports this idea. In a 2011 paper in the Journal of Nuclear Medicine, researchers from the company published results demonstrating that their lead molecular imaging candidate—a radiolabeled small molecule, targeting PSMA and designed for use in SPECT imaging (123I-MIP-1072)—was able to report on mouse model response to the chemotherapeutic paclitaxel in models of prostate cancer. In the study, mice with prostate cancer were treated with paclitaxel and 123I-MIP-1072 was used to image their response to the drug. The amount of 123I-MIP-1072 taken up in the mice tumors was proportional to changes in tumor size. Because about only 50 percent of patients with prostate cancer respond to taxane-based chemotherapeutics such as paclitaxel, being able to image whether or not tumors shrink in response to these drugs could allow men to avoid the toxicities associated with the drugs or dosage to be adjusted according to individualized responses.

Next steps

18F-DCFBC is just one of several experimental new agents for imaging prostate cancer with PET,” said Pomper. He and Dr. Steve Cho (2012 PCF–Movember Creativity Award recipient), also of Johns Hopkins University School of Medicine and co-developer of 18F-DCFBC are working on a similar agent that they feel will give superior imaging via PET due to lessening the visualization of non-tumorous blood vessels. And this fall, the FDA approved the production and limited use of 11C-choline, another PET-imaging agent, for patients with recurrent prostate cancer. Clinical studies of that agent showed that it was superior to conventional imaging in finding metastatic prostate cancer, with half of the patients with suspect findings later confirmed by tissue examination to have recurrent disease. However, 11C-choline had a fairly high rate of giving false positive PET reports as well.

“Martin Pomper is a leader in the field of the development of PET for prostate cancers; his group initially described these small molecule agents for PET some 10 years ago,” says Dr. Jonathan W. Simons, President and CEO of the Prostate Cancer Foundation. “His work has propelled the field forward,” he adds. Others are now working on gallium-labeled agents, or technesium-labeled agents that can be used to visualize prostate tumors.

Applicability extends to other cancers

PET for spotting the most lethal tumors early

This fall, Dr. Sawyers and colleagues published a paper in Nature Medicine detailing the use of a new PET radiotracer (89Zr-transferrin) that can be used to report on activation of tumor oncogene pathways in prostate cancer. The MYC master gene is often aberrantly activated in many cancers, causing it to become an oncogene that increases the activity of other genes under its control. One of those genes produces a protein known as transferrin receptor 1 (TFRC). And, because cancer cells make more TFRC than normal cells, it is thought that by measuring TFRC amounts, it would indicate when cancer is present and when mutated MYC is a primary driver of the disease. This would be important not only diagnosing cancer, but potentially in using precision treatments that are targeted to MYC-driven prostate cancers, which tend to be more lethal.

The researchers tested 89Zr-transferrin in mice models of MYC-driven prostate cancer and found it was able to image via PET increased TFRC expression, showing not only fulminate prostate tumors, but also pre-cancerous lesions, known as PIN or prostatic intraepithelial neoplasia. This is particularly exciting, because while some non-lethal, slow-growing prostate cancers are overtreated, being able to identify, through non-invasive imaging, early prostatic changes that are being driven by one of the most deadly genetic drivers of this disease could allow such men to be segregated to early and aggressive life-extending treatments. The authors of the Nature Medicine paper report that “efforts toward the clinical translation of 89Zr-transferrin are currently under way.”

PSMA a target in multiple cancers

Collectively, this expansion of PET for prostate cancer visualization and annotation of molecular markers will likely benefit those who suffer from other forms of cancer as well. The MYC oncogene is implicated as a primary driver of not only certain prostate, colon, breast and pediatric cancers, it also plays a starring role in some lung, liver and ovarian cancers. And PSMA that the Pomper group is targeting with their novel radiotracer, is widely expressed in tumor tissues other than prostate. The Pomper lab plans to expand their study to PET imagining using 18F-DCFBC tracers to visualize several types of cancers, even those that light up with traditional PET imaging. The PSMA protein, despite its name (prostate-specific membrane antigen) has been shown to be present in the tumor endothelial cells that line tiny blood vessels that feed many types of tumors. For example, 85 percent of colorectal tumors make the PSMA, as do 100 percent of bladder cancers and 75 percent of breast and ovarian tumors. The hope is, by targeting their radiotracer to PSMA, they will find all sorts of nascent tumors at their earliest stage, even before they become “greedy” glucose users.

Dr. Cho, the first author on the Journal of Nuclear Medicine paper on PET and PSMA, and the recipient of the 2008 Peter and Laurie Grauer–PCF Young Investigator Award and The 2011 Movember–PCF Creativity Award based on his work developing 18F-DCFBC to target PSMA in prostate cancer says, “Much work remains before PET scans are routinely used to bring functional or molecular imaging into routine clinical care to improve prostate cancer treatment. However, ongoing collective work, here at Hopkins and other sites, is moving forward at an accelerated pace that we believe will bring this form of imaging into clinical reality for prostate cancer patients in the short-term future.”

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