Improving susceptibility of neuroendocrine tumors to radionuclide therapies: personalized approaches towards complementary treatments

Abstract

Radionuclide therapies are an important tool for the management of patients with neuroendocrine neoplasms (NENs). Especially [¹³¹I]MIBG and [¹⁷⁷Lu]Lu-DOTA-TATE are routinely used for the treatment of a subset of NENs, including pheochromocytomas, paragangliomas and gastroenteropancreatic tumors. Some patients suffering from other forms of NENs, such as medullary thyroid carcinoma or neuroblastoma, were shown to respond to radionuclide therapy; however, no general recommendations exist. Although [¹³¹I]MIBG and [¹⁷⁷Lu]Lu-DOTA-TATE can delay disease progression and improve quality of life, complete remissions are achieved rarely. Hence, better individually tailored combination regimes are required. This review summarizes currently applied radionuclide therapies in the context of NENs and informs about recent advances in the development of theranostic agents that might enable targeting subgroups of NENs that previously did not respond to [¹³¹I]MIBG or [¹⁷⁷Lu]Lu-DOTA-TATE. Moreover, molecular pathways involved in NEN tumorigenesis and progression that mediate features of radioresistance and are particularly related to the stemness of cancer cells are discussed. Pharmacological inhibition of such pathways might result in radiosensitization or general complementary antitumor effects in patients with certain genetic, transcriptomic, or metabolic characteristics. Finally, we provide an overview of approved targeted agents that might be beneficial in combination with radionuclide therapies in the context of a personalized molecular profiling approach.

Figure 1

Clinically approved targeted radionuclide theranostics in NENs mediated by somatostatin receptor type 2 (SSTR2, A) or norepinephrine transporter (NET, B). Panel C shows representative ⁶⁸Ga-DOTATATE PET/CT images of an 83-year old male patient presenting with a well-differentiated neuroendocrine tumor of the pancreas with peritoneal, lymph node and hepatic metastases at baseline. After 4 cycles of PRRT, a good partial response with shrinkage of the pancreatic tumor, peritoneal metastases and the lymph node metastasis inguinal left was observed. Abbreviations: DOTA - tetraxetan, TATE - (Tyr3)octreotate, TOC - (Tyr3)octreotide, MIBG - meta-iodobenzylguanidine

Figure 2

Radioresistance pathways in NENs: pharmacological targeting sensitizes to radiotherapy. A tick under radiosensitization indicates that preclinical evidence for radiosensitization exists, the citations specify that evidence was given specifically in NEN models. *HIFα degradation can be perturbed by pathogenic variants in several genes or through metabolic effects of oncometabolites. Abbreviations: SHH-sonic hedgehog, PTCH-patched, SMO-smoothened, GLI-glioma-associated oncogene, FZD-frizzled, Me-methylation, Ac-acetylation, ROS-reactive oxygen species, SOD-superoxide dismutase, CAT-catalase, GPX-glutathione peroxidase, TRX-thioredoxin, PI3K-phosphatidylinositol 3-kinases, AKT-serine/threonine-protein kinase, PTEN-phosphatase and tensin homolog, TSC-tuberous sclerosis complex, mTOR-mammalian target of rapamycin, HIF-hypoxia inducible factor.

Figure 3

Personalized evaluation of promising radiosensitizers for combination therapy with PRRT in NENs. Omics studies on gene mutations, transcriptional and metabolic pathways in the primary tumor or biopsy material should lead the selection of adjuvant therapies for NENs eligible for PRRT. Clinical trials using such a personalized approach could evaluate agents that have been FDA-approved for use in other cancers. Especially compounds with preclinical evidence for radiosensitization effects together [¹⁷⁷Lu]Lu-DOTA-TATE (marked with ◄) and those with evidence for anti-tumor effects in NENs (marked with #) should be prioritized.