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.