Novel radiotracer shows potential to identify prostate cancer at all stages

A novel dual-receptor target radiotracer successfully diagnosed prostate cancer at all stages while reducing the number of medical scans a patient normally would have to undergo, according to study results published in The Journal of Nuclear Medicine.

“We are far from finding one method to diagnose and monitor prostate cancer, but this is a step in that direction,” Xiaoyuan Chen, PhD, chief of the laboratory of molecular imaging and nanomedicine at National Institute of Biomedical Imaging and Bioengineering, said in a press release. “Targeting multiple biomarkers could potentially allow us to identify prostate cancer at its early stages, as well as after metastasis, in only one scan.”

Xiaoyuan Chen

Various imaging techniques and tests are used to diagnose and monitor prostate cancer, but no single method can identify and monitor primary tumors, metastatic lymph nodes and bone lesions in one scan.

The radiotracer MDP with a SPECT scanner typically is used to identify bone lesions, but this method often results in false positives and is not equipped to identify primary tumors.

Consequently, Chen and colleagues sought to develop a radiotracer that could target multiple biomarkers and identify prostate cancer at all stages. Results showed the radiotracer successfully identified three of four primary tumors, all 14 metastatic lymph nodes, and all 20 bone lesions in the study cohort.

HemOnc Today spoke with Chen about how the technique works, as well as some of the challenges that must be overcome prior to widespread use.

Question: How did this technique come about?

Answer: Radiolabeled bombesin (BBN) peptides have successfully detected gastrin-releasing peptide receptor (GRPR)–positive prostate cancer. However, such radiotracers had a relatively low tumor accumulation and retention, as well as unfavorable hepatobiliary excretion. Therefore, modifications are necessary to obtain a better tumor-targeting effect and imaging quality. Most solid tumors, including prostate cancer, are angiogenesis-dependent, and integrin is a key player. As androgen-independent prostate cancer expresses both GRPR and integrin alpha-v beta-3, we hypothesize that a peptide ligand recognizing both receptors would be advantageous over a single receptor-binding probe. The first use of such RGD-BBN heterodimer was published in 2008 in Journal of Nuclear Medicine.

Q: How does the technique work?

A: A polypeptide that binds to two different types of proteins specifically expressed on prostate cancer cells is synthesized and labeled with a positron-emitting radioisotope gallium-68. The radiotracer, or imaging probe, is injected intravenously for prostate cancer diagnosis to identify both the primary tumor in the prostate gland and the metastases in distal organs, such as bone. This new tracer targets two biomarkers, GRPR and integrin alpha-v beta-3, which often indicate prostate cancer. Previous tracers have targeted GRPR, but this new tracer is one of the first dual-receptor target tracers, or tracers that target more than one biomarker to be studied in humans.

Q: What are some of the benefits observed with the technique?

A: This technique has performed better than prostate biopsy, MRI and PET using 18F-FDG.

Our pilot study showed the ability of this new tracer to bind to both early and metastatic stages of prostate cancer, creating the possibility for a more prompt and accurate diagnostic profile for both the primary and metastatic tumors.

Q: What new options does a technique like this offer?

A: Even though this study used RGD-BBN peptide heterodimer to target both GRPR and integrin in prostate cancer, dual receptor binding in general results in more than an additive effect in terms of tumor uptake and retention. The synergistic effect observed for GRPR and integrin targeting may also be applicable to other peptide systems designed for dual- or multiple-receptor targeting.

Q: You and your colleagues have emphasized that this technique is far from perfect. What are some of the challenges that still must be overcome before the radiotracer is used more often?

A: One limitation of this study is the lack of histologic confirmation of the detected bone metastasis. Thus, the GRPR and integrin alpha-v beta-3 expression status in these metastases are unknown. The accurate diagnostic and prognostic value of 68Ga-BBN-RGD will need larger-scale clinical investigations.

Q: What are your next steps?

A: This initial study was done in Peking Union Medical College Hospital, a research hospital in China. With the dosimetry, safety and preliminary diagnostic value of this tracer, we can use several mechanisms to perform clinical studies in the United States (eg, RDRC or IND). We will further improve the structure of this heterodimeric peptide to improve the pharmacokinetics and also adjust the structure to allow internal radiotherapy and, thus, radiotheranostics.

Q: Can you describe this technique’s potential impact?

A: It will be ready for prime time after multicenter trials of patients with prostate cancer provide enough statistics to demonstrate the sensitivity, specificity and accuracy of this technique in staging and detecting prostate cancer. This technique, along with other imaging tools, likely will be able to provide guidance for internal radiation therapy using the same peptide labeled with therapeutic radionuclides.

Q: Is there anything else that you would like to mention?

A: This study indicates the safety and efficacy of 68Ga-BBN-RGD, a heterodimeric PET tracer that targets both GRPR and integrin alpha-v beta-3. 68Ga-BBN-RGD PET/CT would have great value in discerning both primary prostate cancers and metastases in lymph nodes and skeleton, providing tumor staging information and monitoring response of bone metastases to therapy. Industrial partnership is needed to push this and other novel molecular imaging probes into commercial development. – by Jennifer Southall

References:

Chen X, et al. J Nucl Med. 2017;doi:10.2967/jnumed.116.177048.

Li ZB, et al. J Nucl Med. 2008;doi:10.2967/jnumed.107.048009.

For more information:

Xiaoyuan Chen, PhD, can be reached at National Institute of Biomedical Imaging and Bioengineering, 9000 Rockville Pike, Building 31, Room 1C14, Bethesda, MD 20892;email: chenx5@mail.nih.gov.

Disclosure: Chen reports no relevant financial disclosures.

A novel dual-receptor target radiotracer successfully diagnosed prostate cancer at all stages while reducing the number of medical scans a patient normally would have to undergo, according to study results published in The Journal of Nuclear Medicine.

“We are far from finding one method to diagnose and monitor prostate cancer, but this is a step in that direction,” Xiaoyuan Chen, PhD, chief of the laboratory of molecular imaging and nanomedicine at National Institute of Biomedical Imaging and Bioengineering, said in a press release. “Targeting multiple biomarkers could potentially allow us to identify prostate cancer at its early stages, as well as after metastasis, in only one scan.”

Xiaoyuan Chen

Various imaging techniques and tests are used to diagnose and monitor prostate cancer, but no single method can identify and monitor primary tumors, metastatic lymph nodes and bone lesions in one scan.

The radiotracer MDP with a SPECT scanner typically is used to identify bone lesions, but this method often results in false positives and is not equipped to identify primary tumors.

Consequently, Chen and colleagues sought to develop a radiotracer that could target multiple biomarkers and identify prostate cancer at all stages. Results showed the radiotracer successfully identified three of four primary tumors, all 14 metastatic lymph nodes, and all 20 bone lesions in the study cohort.

HemOnc Today spoke with Chen about how the technique works, as well as some of the challenges that must be overcome prior to widespread use.

Question: How did this technique come about?

Answer: Radiolabeled bombesin (BBN) peptides have successfully detected gastrin-releasing peptide receptor (GRPR)–positive prostate cancer. However, such radiotracers had a relatively low tumor accumulation and retention, as well as unfavorable hepatobiliary excretion. Therefore, modifications are necessary to obtain a better tumor-targeting effect and imaging quality. Most solid tumors, including prostate cancer, are angiogenesis-dependent, and integrin is a key player. As androgen-independent prostate cancer expresses both GRPR and integrin alpha-v beta-3, we hypothesize that a peptide ligand recognizing both receptors would be advantageous over a single receptor-binding probe. The first use of such RGD-BBN heterodimer was published in 2008 in Journal of Nuclear Medicine.

Q: How does the technique work?

A: A polypeptide that binds to two different types of proteins specifically expressed on prostate cancer cells is synthesized and labeled with a positron-emitting radioisotope gallium-68. The radiotracer, or imaging probe, is injected intravenously for prostate cancer diagnosis to identify both the primary tumor in the prostate gland and the metastases in distal organs, such as bone. This new tracer targets two biomarkers, GRPR and integrin alpha-v beta-3, which often indicate prostate cancer. Previous tracers have targeted GRPR, but this new tracer is one of the first dual-receptor target tracers, or tracers that target more than one biomarker to be studied in humans.

PAGE BREAK

Q: What are some of the benefits observed with the technique?

A: This technique has performed better than prostate biopsy, MRI and PET using 18F-FDG.

Our pilot study showed the ability of this new tracer to bind to both early and metastatic stages of prostate cancer, creating the possibility for a more prompt and accurate diagnostic profile for both the primary and metastatic tumors.

Q: What new options does a technique like this offer?

A: Even though this study used RGD-BBN peptide heterodimer to target both GRPR and integrin in prostate cancer, dual receptor binding in general results in more than an additive effect in terms of tumor uptake and retention. The synergistic effect observed for GRPR and integrin targeting may also be applicable to other peptide systems designed for dual- or multiple-receptor targeting.

Q: You and your colleagues have emphasized that this technique is far from perfect. What are some of the challenges that still must be overcome before the radiotracer is used more often?

A: One limitation of this study is the lack of histologic confirmation of the detected bone metastasis. Thus, the GRPR and integrin alpha-v beta-3 expression status in these metastases are unknown. The accurate diagnostic and prognostic value of 68Ga-BBN-RGD will need larger-scale clinical investigations.

Q: What are your next steps?

A: This initial study was done in Peking Union Medical College Hospital, a research hospital in China. With the dosimetry, safety and preliminary diagnostic value of this tracer, we can use several mechanisms to perform clinical studies in the United States (eg, RDRC or IND). We will further improve the structure of this heterodimeric peptide to improve the pharmacokinetics and also adjust the structure to allow internal radiotherapy and, thus, radiotheranostics.

Q: Can you describe this technique’s potential impact?

A: It will be ready for prime time after multicenter trials of patients with prostate cancer provide enough statistics to demonstrate the sensitivity, specificity and accuracy of this technique in staging and detecting prostate cancer. This technique, along with other imaging tools, likely will be able to provide guidance for internal radiation therapy using the same peptide labeled with therapeutic radionuclides.

Q: Is there anything else that you would like to mention?

PAGE BREAK

A: This study indicates the safety and efficacy of 68Ga-BBN-RGD, a heterodimeric PET tracer that targets both GRPR and integrin alpha-v beta-3. 68Ga-BBN-RGD PET/CT would have great value in discerning both primary prostate cancers and metastases in lymph nodes and skeleton, providing tumor staging information and monitoring response of bone metastases to therapy. Industrial partnership is needed to push this and other novel molecular imaging probes into commercial development. – by Jennifer Southall

References:

Chen X, et al. J Nucl Med. 2017;doi:10.2967/jnumed.116.177048.

Li ZB, et al. J Nucl Med. 2008;doi:10.2967/jnumed.107.048009.

For more information:

Xiaoyuan Chen, PhD, can be reached at National Institute of Biomedical Imaging and Bioengineering, 9000 Rockville Pike, Building 31, Room 1C14, Bethesda, MD 20892;email: chenx5@mail.nih.gov.

Disclosure: Chen reports no relevant financial disclosures.