Bombesin related peptides/receptors and their promising therapeutic roles in cancer imaging, targeting and treatment

Abstract

Introduction Despite remarkable advances in tumor treatment, many patients still die from common tumors (breast, prostate, lung, CNS, colon, and pancreas), and thus, new approaches are needed. Many of these tumors synthesize bombesin (Bn)-related peptides and over-express their receptors (BnRs), hence functioning as autocrine-growth-factors. Recent studies support the conclusion that Bn-peptides/BnRs are well-positioned for numerous novel antitumor treatments, including interrupting autocrine-growth via the use of over-expressed receptors for imaging and targeting cytotoxic-compounds, either by direct-coupling or combined with nanoparticle-technology. Areas covered The unique ability of common neoplasms to synthesize, secrete, and show a growth/proliferative/differentiating response due to BnR over-expression, is reviewed, both in general and with regard to the most frequently investigated neoplasms (breast, prostate, lung, and CNS). Particular attention is paid to advances in the recent years. Also considered are the possible therapeutic approaches to the growth/differentiation effect of Bn-peptides, as well as the therapeutic implication of the frequent BnR over-expression for tumor-imaging and/or targeted-delivery. Expert opinion Given that Bn-related-peptides/BnRs are so frequently ectopically-expressed by common tumors, which are often malignant and become refractory to conventional treatments, therapeutic interventions using novel approaches to Bn-peptides and receptors are being explored. Of particular interest is the potential of reproducing BnRs in common tumors, such as the recent success of utilizing overexpression of somatostatin-receptors by neuroendocrine-tumors to provide the most sensitive imaging methods and targeted delivery of cytotoxic-compounds.

Bombesin-Targeted PET of Prostate Cancer

“…GRPR expression was identified on the messenger RNA level as well as on the protein level of primary PC and metastases. Markwalder and Reubi (6) showed that GRPR expression depended on the Gleason score, with higher receptor levels at low Gleason scores (3)(4)(5)(6) and lower receptor levels at high Gleason scores (7)(8)(9). Early GRPR ligand developments and studies in preclinical models focused on agonists because of their known property of internalization when bound to the receptors.…”

“…In this review, we discuss the preclinical and clinical work already done or under evaluation for the use of gastrin-releasing peptide receptors (GRPRs) as targets for the imaging of PC, with a focus on the development of PET tracers for the imaging of GRPRpositive tumors. Comprehensive recent reviews have discussed tracers for use in SPECT and therapy (2,3).…”

Synthesis, radiolabeling, and evaluation of gastrin releasing peptide receptor antagonist 68Ga‐HBED‐CC‐RM26

“…The elevated expression of gastrin releasing peptide receptors (GRPrs) in prostate cancer, breast cancer, and small‐cell and non‐small‐cell lung carcinomas has explicitly favored designing of radiolabeled peptides as GRPr‐specific probes . The enormous presentation of GRP receptors, especially in prostate and breast cancer specimens, has ensured GRPr to be a prospective target for imaging and therapy of these cancers.…”

Comparison of biological properties of [177Lu]Lu‐ProBOMB1 and [177Lu]Lu‐NeoBOMB1 for GRPR targeting

“…[1][2][3][4][5] BBN, a peptide isolated from the frog, Bombina bombina, has a mammalian ortholog named the gastrin-releasing peptide (GRP) and both bind GRPR. 7,[9][10][11][12] 13,14 In a previous article, we modified a sequence initially published by the Schally group, RC-3950-II, to adapt it for theranostic application yielding DOTA-pABzA-DIG-D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-ψ-Pro-NH 2 (ProBOMB1), which we characterized after labeling with nat/68 Ga. 8,15 The radiotracer, [ 68 Ga]Ga-ProBOMB1, had excellent characteristics for imaging GRPR. In nuclear medicine, the use of peptides as delivery vectors is an effective strategy for targeting GPCRs (ie, somatostatin, CXC chemokine receptor 4, cholecystokinin-2, and substance P).…”

“…7,[9][10][11][12] Examples of agents tested in the clinic include [ 68 Ga]Ga-NeoBOMB1, [ 68 Ga]Ga-RM2, [ 68 Ga]Ga-SB3, [ 64 Cu]Cu-CB-TE2A-AR06, [ 68 Ga]Ga-NOTA-Aca-BBN, and [ 99m Tc]Tc-demobesin-4. 13,14 In a previous article, we modified a sequence initially published by the Schally group, RC-3950-II, to adapt it for theranostic application yielding DOTA-pABzA-DIG-D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-ψ-Pro-NH 2 (ProBOMB1), which we characterized after labeling with nat/68 Ga. 8,15 The radiotracer, [ 68 Ga]Ga-ProBOMB1, had excellent characteristics for imaging GRPR. In particular, contrast between tumor tissue and healthy tissue was better than that of other leading compounds that have been trialed in clinical settings.…”