What peptides have shown promise in treating cancer?

Peptides Showing Promise in Cancer Treatment

Peptide receptor-targeted radiotherapy (PRRT) using radiolabeled somatostatin analogues has shown the most promising results in treating cancer, particularly neuroendocrine tumors, with objective response rates ranging between 20% and 40%. 1

Most Promising Peptide-Based Cancer Therapies

Peptide Receptor-Targeted Radiotherapy (PRRT)

• PRRT using 90Yttrium and 177Lutetium labeled DOTATOC or DOTATATE has demonstrated significant efficacy in treating neuroendocrine tumors (NETs) with liver metastases 1
• Based on phase II trials involving over 1000 patients in Europe, PRRT shows objective response rates of 20-40% 1
• Higher response rates are observed in pancreatic NETs compared to small intestinal NETs 1
• The highest objective response rate has been documented in metastatic rectal NETs 1
• PRRT can be considered for both functioning and nonfunctioning NETs with positive somatostatin receptor scintigraphy regardless of primary tumor site 1

Key PRRT Peptides and Radioisotopes

• DOTATOC: A derivatized somatostatin analogue peptide with high affinity for somatostatin receptor subtype 2 (sstr2) 1
• DOTATATE: Shows 6-9 fold higher affinity for sstr2 than DOTATOC 1
• 90Yttrium: Pure β-emitting isotope with 64-hour half-life and tissue penetration depth of 11mm maximum 1
• 177Lutetium: β- and γ-emitting radionuclide with 162-hour half-life and lower tissue penetration (1.7mm maximum), allowing for post-treatment imaging and dosimetry 1

Neoantigen-Based Peptide Vaccines

• Personalized neoantigen-based vaccines have shown encouraging results in early clinical trials for melanoma and glioblastoma patients 1
• These vaccines can boost pre-existing memory or effector T-cell responses and induce new T-cell responses against tumor-specific neoantigens 1
• In melanoma patients, synthetic long peptides representing 20 MHC class-I restricted neoantigens have shown clinical benefit 1
• RNA vaccines encoding up to 10 individual mutations have demonstrated efficacy in melanoma patients 1
• Some patients who progressed on neoantigen vaccination achieved complete responses when subsequently treated with immune checkpoint inhibitors 1

Cell-Penetrating Peptides (CPPs)

• CPPs can transport a wide variety of biologically active conjugates into cancer cells 2
• Notable examples include TAT and Penetratin, which can penetrate the central nervous system and target glioblastoma 2
• When conjugated with traditional chemotherapeutics like Doxorubicin and Paclitaxel, these peptides have induced apoptosis in breast, liver, and lung cancer cells 2
• Other promising CPPs include:
  • Magainin 2 attached to Bombesin (MG2B) for esophageal cancer 2
  • CopA3 for gastric cancer 2
  • p28, which has shown efficacy against breast, prostate, ovarian cancer, and melanoma cells by promoting p53 expression and cell cycle arrest 2

Advantages of Peptide-Based Cancer Therapies

• High selectivity and specificity for cancer cells 3, 4
• Small dimensions allowing better tissue penetration 3
• High biocompatibility and low immunogenicity 4, 5
• Ease of modification and synthesis 4
• Ability to carry various cargoes without limitations 4
• Lower cost of production compared to antibodies 5
• Potential for targeted drug delivery with minimal toxicity to normal tissues 5

Challenges in Peptide-Based Cancer Therapies

• Poor aqueous solubility limiting bioavailability 2
• Immunogenicity issues in some cases 2
• Dose-limiting toxicity 2
• Limited clinical efficacy despite promising preclinical results 2
• For PRRT specifically, potential renal or hematological toxicities including irreversible renal toxicity in 9.2% of patients 1

Emerging Peptide Applications in Cancer Diagnostics

• Extracellular vesicle (EV)-associated peptides and proteins show promise for early cancer detection 1
• Fibronectin on the surface of EVs from breast cancer patient plasma is elevated at all stages, including early stages 1
• Proteoglycan glypican-1 in serum-derived EVs can distinguish early from late-stage pancreatic cancer 1
• Serum EV levels of specific proteins (alpha-2-HS-glycoprotein, extracellular matrix protein 1, carcinoembryonic antigen) show high diagnostic accuracy for early non-small cell lung cancer 1

Future Directions

• Development of improved computational pipelines for neoantigen prediction to enhance peptide vaccine efficacy 1
• Integration of additional features like variant allele fraction, gene expression, and clonality of mutations in neoantigen prediction 1
• Exploration of neoantigens in cancers with both high and low tumor mutation burden 1
• Combination of peptide-based therapies with immune checkpoint inhibitors to enhance efficacy 1
• Advancement of peptide-based drug delivery systems for targeted cancer therapy 5, 6