Novel Imaging Tools and Therapeutics Take Advantage of Prostate Cancer Biomarker

A new way to detect metastatic prostate tumors using molecular imaging has shown promise in an early phase clinical trial. The noninvasive technique takes advantage of a prostate cancer-specific marker on the surface of prostate cancer cells.

Results of the phase I trial showed that the imaging molecule, called tc-99m MIP-1404, could be distributed throughout the body, allowing for imaging within 1 hour of injection. Tumors in soft tissue, lymph nodes, and in the bone were detected with specificity. And compared to standard bone imaging, tc-99m MIP-1404 identified more potentially cancerous lesions. The results were presented at the Society of Nuclear Medicine and Molecular Imaging’s (SNMMI) 2013 Annual Meeting held in Vancouver, Canada, in early June.

The novel imaging agent consists of two molecules bound together. MIP-1404 is a small molecule that binds to prostate-specific membrane antigen (PSMA), a protein found on prostate epithelial cells. Technetium-99m (tc-99m) is a radioactive molecule commonly used in medical settings. It can be visualized using nuclear imaging devices that are already in use in most hospitals, such as single-photon emission computerized tomography (SPECT). After an intravenous injection, tc-99m MIP-1404 circulates in the bloodstream. MIP-1404 guides the molecule to bind specifically to cells with PSMA on their surface, then nuclear imaging devices detect the attached radioactive tc-99m. The result is a full-body map of tumor sites. The image provides enough detail to show the relative concentration of tumor cells at each detected tumor site.

Since prostate cancer predominantly metastasizes to the bone, bone scans are the most common method to diagnose metastatic prostate cancer. However, bone scans are not specific to bone metastasis per se—they use only tc-99m—which acts as a nonspecific marker that collects at bone tumors, fractures, and sites of inflammation in the bone. Linking tc-99m to MIP-1404 (or, potentially, another small molecule that specifically bind to PSMA) makes the imaging specific to prostate cells.

“I believe that the small molecule agents have great promise for imaging, but we need more clinical trials,” says Scott Tagawa, MD, of the Weill Cornell Medical College in New York City, who was involved in the trial.

A previous prostate cell-specific imaging approach attempted to use an anti-PSMA antibody, rather than a small molecule, against PSMA linked to tc-99m. But the antibody-based imaging was a much longer process compared to using the small molecule MIP-1404, since the antibodies took awhile to circulate and bind to cells throughout the body.

The MIP 1404 approach is more efficient than antibody techniques and fulfills the main goal for any new prostate cancer imaging method: to be sensitive enough to detect new metastatic or recurrent cancer early on. It also gives clinicians the ability to distinguish between high-risk, fast-growing disease versus indolent disease, which does not need to be treated aggressively.

In the phase I trial presented at SNMMI, the new imaging tool was tested on 6 patients who had evidence of metastatic prostate cancer, and 10 earlier-stage patients who were scheduled for a prostatectomy and lymph node dissection. In a majority of cases, Tc-99m MIP-1404 pointed out more lesions than standard bone imaging.

In most patients, more potentially cancerous lesions were demonstrated with Tc-99m MIP-1404 than with bone scan. In the advanced prostate cancer patients, the imaging tool identified prostate cancer metastases that had been confirmed by other methods.

“This agent could one day be a molecular-imaging biomarker not just for screening patients with prostate cancer and metastases, but also for monitoring their response to subsequent treatment,” said Shankar Vallabhajosula, PhD, a professor of radiochemistry in the department of radiology at Weill Cornell Medical College, in a statement. “In time, it could also be formulated as a therapeutic radioactive drug.” Vallabhajosula is one of the authors of the phase I clinical trial.

The imaging molecule is being developed by Massachusetts-based Molecular Insight Pharmaceuticals, Inc. A phase II trial using tc-99m MIP-1404 as a diagnostic imaging tool in high-risk prostate cancer patients is underway (link). The trial will compare the ability of the imaging diagnostic to detect prostate cancer within the prostate to standard pathology analysis using biopsied tissue.

Although the technique relies on MIP 1404’s ability to detect PSMA, the role of PSMA in prostate cancer is not yet clear. But, because the protein is highly expressed on more than 95% of prostate cancer cells (both in the initial prostate tumor and in metastasized tumors), and is not found on other cells in the body, it has so far been a reliable way to detect prostate cancer in patients.

Drugs for prostate cancer that target PSMA have also been developed. Called antibody-drug conjugates (ADCs), these drugs consist of antibody ‘guides’ attached to cancer-treating molecules. They function similarly to tc-99m MIP-1404; however, instead of using an antibody to guide an imaging molecule, the antibody delivers the cancer-killing drug directly to prostate cancer cells that express PSMA on their surface. This minimizes the toxicity patients experience when chemotherapy is administered throughout the entire body.

An antibody against PSMA, called J591, conjugated to lutetium-177 (a short-range energy particle that has previously been used to treat cancer) was recently tested in a phase II trial in men with castration-resistant prostate cancer (CRPC). Patients treated with 177-Lu-J591 experienced decreases in prostate-specific antigen (PSA) levels; the still-early results suggest that patients may live longer following therapy with the PSMA-targeted antibody.

J591 is also being tested in trials as an imaging tool. Tagawa, who is involved in the trials, says that, thus far, patients whose tumors cannot be imaged well using J591 (patients without PSMA-expression) have responded poorly to treatment with 177-Lu-J591. An international phase III trial with 177-Lu-J591 is currently being planned (the drug is being called ATL-101 in the trial). According to Tagawa, 177-Lu-J591 may work best for smaller metastatic tumors that are typically not visible on standard bone scans. But this still needs to be confirmed with a national randomized, phase II study in men with nonmetastatic CRPC, which is in progress.

Another PSMA-based therapy links an antibody against PSMA to a toxin (monomethyl-auristatin-E, or MMAE) that inhibits cell proliferation. This ADC is being tested in metastatic CRPC patients as part of a phase II trial.