Applications of organoid technology in peptide drug screening
Peptide-based radiopharmaceutical therapy
Radiopharmaceutical therapy (RPT) is a novel treatment for cancer patients, involving the targeted delivery of radionuclides to tumors by conjugating to small molecules, peptides or antibodies60-71. RPT has advantages over existing therapeutic modalities, which makes it a safe, precise and effective option to treat many kinds of diseases, especially cancers72, 73. Unlike traditional radiotherapy, the radiation administered from radionuclides inside the tumor microenvironments minimizes the injury of normal tissues60. Importantly, by combining with molecular imaging, including positron emission tomography (PET) and single-photon emission computed tomography (SPECT), RPT allows diagnosis of the whole-body tumor status and effects of therapy in a non-invasive way, which is rapid and precise74-76. To our knowledge, organoid models used in RPT were mostly generated from three-dimensional cultures of tumor cell lines, which are mostly like tumor spheroids77-94. Due to the limited cell types, the cell line-derived tumor spheroids cannot present the characteristics of the corresponding tumors. Despite this, they also display some spatial features compared to monolayer cultured cell lines. Most of these studies focused on investigating the therapeutic efficacy on combination with radionuclide-conjugated drugs and potential radiosensitizers. For example, Rea et al. investigated whether disulfiram could promote the anti-cancer effect of 131I-metaiodobenzylguanidine (131I-MIBG) using tumor spheroids derived from human neuroblastoma and glioma cells. The results suggested that disulfiram facilitated the killing function of 131I-MIBG to noradrenaline transporter-positive tumor spheroids, which could serve as a radiosensitizer91.
Recently, 177Lu-DOTATATE, a peptide receptor radionuclide therapy (PRRT), was approved by USA and European Union (EU) for the treatment of somatostatin-receptor (SSTR)-positive neuroendocrine tumors (NETs)65, 95, 96. Meanwhile,68Ga-DOTATATE, 64Cu-DOTATATE (US) and 68Ga-DOTATOC (EU) were also approved as companion diagnostic agents for PET imaging of tumors in patients with SSTR-positive NETs, enabling the combination of diagnostic imaging with targeted therapy60. 177Lu-DOTATATE is the only peptide-conjugated radionuclide applied in tumor spheroid study. Tesson et al. used tumor spheroids to evaluate the effectiveness of radiosensitizer drugs when combined with177Lu-DOTATATE, and demonstrated a significantly increased cytotoxicity after combined treatment, indicated by the reduced tumor spheroid growth97. Similarly, Lundsten et al. cultured NET cell line-derived tumor spheroids to examine whether the heat shock protein 90 (HSP90) inhibitor onalespib could enhance the efficacy of 177Lu-DOTATATE93. The results indicated that the combination of onalespib and177Lu-DOTATATE significantly reduced spheroid growth compared to monotherapies. A p53-stabilizing peptide VIP116 was defined as a radiosensitizer to inhibit neuroblastoma growth and enhanced177Lu-DOTATATE treatment. These results were also observed in tumor spheroid model systems98. Radiotracers can also be used to monitor the status of tumor spheroids. Seifert et al. incubated 68Ga-DOTATATE with mCherry-transgenic mouse pheochromocytoma (MPCmCherry) derived tumor spheroids to study the morphologic and metabolic characteristics after HIF2α expression84. The reduced cellular uptake of 68Ga-DOTATATE demonstrated the decreased expression level of SSTR2, suggesting that radiotracers can also be used to measure therapeutic effects in organoid-based drug screens.
Multiple potential peptide-conjugated radionuclides are undergoing preclinical tests, such as 177Lu-FAP-2286. Thus, there is a huge gap in introducing patient-derived organoids to RPT, which may enable the discovery of more efficient modalities for the treatment of refractory diseases.