Prognostic Implications, Modifications & Therapeutic Strategies Targeting Somatostatin Receptor-2 Expression in Gastroenteropancreatic Neuroendocrine Tumors

Lindsay F. Remer, M.D. ^1, Rachyl M. Shanker, M.D. ^1, James P. Madigan, Ph.D. ^2, Samira M. Sadowski, M.D. ²

1. Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA 20892.
2. Neuroendocrine Cancer Therapy Section, Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA 20892.

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PUBLISHED: 28 Febuary 2025

CITATION:REMER, Lindsay F. et al. Prognostic Implications, Modifications & Therapeutic Strategies Targeting Somatostatin Receptor-2 Expression in Gastroenteropancreatic Neuroendocrine Tumors. Medical Research Archives,  Available at: <https://esmed.org/MRA/mra/article/view/6309>.

COPYRIGHT: © 2025 European Society of Medicine. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

DOI: https://doi.org/10.18103/mra.v13i2.6309

ISSN 2375-1924

Abstract

Gastroenteropancreatic neuroendocrine tumors (GEP NETs) are a diverse group of tumors often characterized by somatostatin receptor type 2 (SSTR2) positivity. The objective of this article is to review basic information on GEP NETs and somatostatin receptors (SSTR) with a focus on SSTR2. The prognostic implications of the receptor, how epigenetic modifications play a role, and the diagnostic and therapeutic strategies available that rely on the somatostatin receptor including somatostatin analogs (SSAs), SSTR-based imaging, and peptide receptor radionuclide therapy (PRRT) are explored. While surgery is the only curative option, current therapy for SSTR2 positive GEP NETs is based on the use of SSAs which have been shown to both control symptoms and exert antiproliferative effects in SSTR2 positive GEP NETs. SSTR-based imaging offers numerous benefits over standard imaging techniques including revealing additional metastases, assessing response to therapy, and by demonstrating sufficient SSTR expression in tumors to render patients eligible for PRRT. PRRT has been shown to be an effective treatment in low grade, SSTR2 positive GEP NETs. Adjuncts are being investigated to synergize with PRRT and improve patient outcomes. Complete responses to SSA and PRRT are rare and SSTR2 negative tumors have limited treatment options. Given that GEP NETs have a low frequency of mutations and no mutations in SSTR2 have been identified, efforts are being made to investigate epigenetic regulations influencing SSTR2 expression as a future therapeutic option.

Keywords: Somatostatin receptor, somatostatin analog, neuroendocrine tumor, epigenetics

Introduction

Gastroenteropancreatic neuroendocrine tumors (GEP NETs) arise from neuroendocrine cells along the digestive tract and are the most common neuroendocrine tumor (NET) subtype 1. GEP NETs are known for their ability to produce and secrete peptides, hormones, and neuroamines, and can be functional or non-functional which often influences patient presentation 2. The majority of GEP NETs are non-functional and are thus identified at later stages secondary to tumor burden, mass effect or metastases 2. In the minority, functional tumors tend to present earlier as localized lesions in the setting of symptoms related to secretory function 2. GEP NETs can also be classified by genomic characteristics 3. These tumors arise either sporadically or in association with hereditary predisposition syndromes including multiple endocrine neoplasia type 1 (MEN1), Von Hippel-Lindau’s disease (VHL), or neurofibromatosis type 1 (NF1) 4. Using histology, mitotic count, and expression of Ki-67, they are classified as well-differentiated grade 1, 2 or 3 NETs, or poorly differentiated grade 3 neuroendocrine carcinomas (NECs) 5. Both the incidence and prevalence of these lesions have increased over time and while most possess an indolent, benign pathology there is a subset of highly proliferative, therapy-resistant tumors that still pose a challenge to clinicians and scientists 4. While surgical resection is the only curative therapy, only a small subset of patients are candidates for surgery due to the presence of metastatic disease at initial diagnosis 6. Consequently, great effort has been made into the identification of novel diagnostic and therapeutic targets for NETs.

A significant area of focus in GEP NET research is the somatostatin receptor (SSTR) family of transmembrane G-protein coupled receptors (GPCRs). Somatostatin itself is an inhibitory peptide, regulating endocrine and exocrine hormone secretion in normal physiologic states 7. Although a heterogenous group of tumors, SSTR expression is a shared feature amongst NETs and therefore a desirable candidate for diagnosis and therapy 7. High SSTR expression is associated with well-differentiated tumors and is more common amongst gastroenteric NETs than pancreatic NETs 8. Currently, there are five described subtypes of the SSTR, SSTR 1-5, which vary in structure, distribution, and signaling effects 9. Qian et al. discovered in examination of 112 small intestine NETs, 19 pancreatic NETs, and 42 NETs from other locations, that 65%, 76%, 90%, 86% and 93% of all cases were recognized by the expression of SSTR1, SSTR2, SSTR3, SSTR4, and SSTR5, respectively 10. Further evaluation showed that SSTR type-2 (SSTR2) was expressed most frequently and that 51% of examined NETs were recognized by high SSTR2 levels 10. SSTR2 subtype is prevalent amongst GEP NETs and are a particular area of clinical focus 6. Consequently, somatostatin analogs (SSAs) have become increasingly utilized to diagnose and treat SSTR expressive NETs through radiolabeling 11.

Somatostatin Signaling

Somatostatin is a cyclic neuroendocrine peptide, widely functioning as inhibitory to exocrine function and hormonal homeostasis 12. Somatostatin has two isoforms, somatostatin-14 and -28, each with 14 and 28 amino acids respectively 6. These isoforms result from post-translational modification of pro-somatostatin and have a short plasma half-life of less than three minutes 13-15. Somatostatin-14 is secreted from pancreatic β-cells, and somatostatin-28 largely from gastrointestinal D-cells, with each peptide’s functions specifically mediated by the SSTR subtype it binds to 16. Somatostatin-14 has higher affinity to SSTRs 1-4, while somatostatin-28 preferentially binds to SSTR5 17. SSTR subtypes can be co-expressed in various cell types and share common signaling pathways.

As SSTRs 1-5 are types of GPCRs, their structures and signaling are largely conserved with up to 61% of conserved amino acid identity despite being encoded for by different genes 18,19. GPCRs are the largest family of cell surface signaling receptors, and mediate most of our physiologic responses to hormones, neurotransmitters, lipids, and peptides. GPCRs play a critical role in normal cellular function, and their dysregulation has been implicated in a variety of diseases and cancers 20. Composed of a single subunit polypeptide chain, seven α-helical segments span the plasma membrane, with an extracellular component binding to an agonistic molecule 21. The intracellular component of the receptor incorporates the “G protein” portion of the receptor which upon agonistic stimulation of the extracellular receptor an alpha subunit exchanges GDP for GTP, allowing for its dissociation from beta and gamma subunits 21. The ligand-binding pockets are what make each SSTR subtype distinct, and their functionality critical to various organ processes 22. These processes result in inhibition of adenylyl cyclase, reduction of intracellular Ca2+, and inhibition of cellular proliferation and secretory signaling 23.

Somatostatin Receptors

SSTR1 is encoded by SSTR1 on chromosome 14q13 24. Compared to other SSTR subtypes, studies report SSTR1 expression is more difficult to detect through immunohistochemistry (IHC) and may be more reliably analyzed using reverse transcriptase-polymerase chain reaction (RT-PCR) 25. SSTR1 is naturally found in neuroendocrine cells 26, cerebral cortex 27, blood vessels 28, retinal cells 29, as well as normal, benign, and malignant thyroid cells 30. In the pancreas, SSTR1 has been identified on glucagon secreting α- cells and somatostatin secreting δ-cells 31. Functionally, activation of SSTR1 inhibits growth hormone (GH), prolactin (PL), and calcitonin. It has been shown to inhibit the cell cycle and angiogenesis. SSTR1 is thought to also regulate cardiac and vasomotor tone due to its presence in vascular tissue 32.

In cancer, SSTR1 has been identified as highly expressed in neuroblastomas, and correlates with improved prognosis 33. Additionally, SSTR1 is expressed in GEP NETs, and has been shown to be highly expressed in lower grade tumors 34. Pharmacologically, octreotide, a somatostatin analog used in a variety of therapeutic treatments, has no affinity for SSTR1 9. Newer agents, including pasireotide, a cyclic hexapeptide, has 30 times higher binding affinity for SSTR1 compared to octreotide, but its utility in NET treatment has yet to be demonstrated 35.

SSTR3 is encoded by SSTR3 on chromosome 22q13.1 24. It is expressed throughout the gastrointestinal tract, exocrine pancreas, salivary glands, and nervous system 36. Within the pancreas, SSTR3 is expressed mostly on δ and β -cells 37. Activation of SSTR3 inhibits cellular proliferation and induces apoptosis in various cell types, including in models of pituitary NET 38, neuronal injury 39, and breast cancer 40. Like its comparable subtypes, SSTR3’s presence in NETs has been established, albeit in lower abundance than SSTR2A and SSTR5 25. SSTR3 expression is also associated with lower grade NETs 34.

SSTR3 is highly expressed both in normal pituitary and in gonadotroph pituitary adenomas, making it of therapeutic interest in this group of neoplasms as well 41. In terms of pharmacologic targeting, octreotide has low affinity for SSTR3, while newer somatostatin analog pasireotide has a 5-fold stronger binding affinity 35.

SSTR4 is encoded by SSTR4 on chromosome 20p11.2 and found in lung, heart, placenta, and intestinal cells 42. Interestingly, SSTR4 is the most rarely expressed in NETs amongst all SSTR subtypes, and its function is less understood 25,43. SSTR4 has been shown to mediate analgesic effects by inhibiting nociceptive signaling 44, while also mediating pro-inflammatory effects of somatostatin in murine intestine 42,45,46. It is implicated in mediating neurogenic inflammatory conditions, Alzheimer’s disease, and depression, setting it apart from the other subtypes 47,48.

SSTR5 is encoded by SSTR5 on chromosome 16p13.3 49. Along with SSTR2, it is the most abundantly expressed somatostatin receptor 50. SSTR5 is highly expressed in the pituitary and has been shown to be crucial in the modulation of pituitary hormone release 51. In GEP NETs its expression is correlated with lower grade, well differentiated tumors 52. There is conflicting evidence whether SSTR5 expression is correlated with better 50,53 or worse 54 survival but it is generally regarded as a positive prognosticator. Similar to SSTR2, SSTR5 is detectable in circulating tumor cells in NET patients, proving a useful prospective biomarker 55. Additionally, SSTR5 has high binding affinity to somatostatin analogs octreotide and lanreotide, regulating symptoms from functional tumor secretion and resulting in delayed tumor proliferation 56-58.

Epigenetic and post transcriptional regulation of SSTR5 has been shown to downregulate its expression in pancreatic NETs, influencing tumor biology and treatment responsiveness 59. An alternatively spliced SSTR5 variant sst5TMD4 has been reported in glioblastoma 60, breast cancer 61, and prostate cancer 62 with overexpression associated with more aggressive disease 60.

Somatostatin Receptor 2

SSTR2 is encoded by SSTR2 located on chromosome 17q24 42. SSTR2 RNA is subject to alternative splicing which can produce two variants, SSTR2a and SSTR2b 6. SSTR2 plays a role in cell cycling, angiogenesis, apoptosis, as well as growth factor signaling via inhibition of adenylate cyclase, inhibition of calcium influx, augmentation of p53 influx and downstream signaling through kinases such as mitogen activated protein kinase (MAPK) and protein kinase B (AKT) 63. Given its upregulation in GEP-NETs and wide-reaching functions, this receptor has been the focus of research on its diagnostic and therapeutic implications.

Implications in Other Cancers

While SSTR2 is of particular interest in GEP NETs, it is also expressed in other malignancies with various functional and therapeutic implications. Small-cell lung cancer (SCLC) comprises approximately 15% of lung cancers, is highly morbid and lacks effective therapeutic treatment. Significantly, these tumors possess neuroendocrine features; and SSTR2 has been found to be most prevalent as determined by IHC and sequencing analyses 64,65. As seen in GEP NETs, decreased expression of SSTRs (except SSTR5) occurs in more poorly differentiated tumors 65. Although SSTR2 expression is correlated with worse tumor differentiation, studies have failed to demonstrate predictive capacity for overall survival (OS) or progression free survival (PFS) 66. Congruently, SSTR expression as determined by 68Ga-DOTATATE radioimaging and in vitro assays can elucidate options for treatment, including 177Lu-DOTATATE PRRT alone or in combination therapy as second- or third-line treatment options 67,68.

In meningioma, SSTR2 is widely expressed 69 and utilized as a biomarker of disease 70. While expression has not been demonstrated to correlate with meningioma grade, it has been correlated to the meningothelial subtype, which can guide prognostication and treatment 71. Like in GEP NET, 68Ga-DOTATATE-PET can be utilized for diagnosis of meningioma and has proven useful in identifying tumor recurrence versus post-treatment change 72,73. While surgery is the mainstay treatment for meningioma, the utility of somatostatin analogs and SSTR2-directed PRRT within the treatment paradigm is currently under investigation 74.

Another neurologic tumor of which SSTR2 is of significant relevance is gliomas. There are various subtypes of gliomas, of which differential SSTR2 expression has been shown 75,76. High grade gliomas (grade III and IV) are the most common primary malignant brain tumors and have poor prognosis 77. Glioblastoma (grade IV) is the most aggressive subtype of glioma and rarely expresses SSTR2, while oligodendroglioma, astrocytoma, and anaplastic oligodendrogliomas have been shown to have more significant expression 76. In addition to variable expression amongst glioma subtypes, there exists discrepancy between ability to assess glioma SSTR2 expression in vivo versus in vitro. While IHC and western blot techniques have demonstrated increased expression of SSTR1-3 75, in vivo somatostatin receptor scintigraphy has not shown clear binding of somatostatin analogs 78-80. Furthermore, there are reports of 68Ga-DOTATATE uptake misrepresenting glioma tumor recurrence in the setting of treatment related changes, which is thought to be due to SSTR2 expression in proinflammatory macrophages and other immune cell populations 81. Like in GEP NETs, a truncated alternatively spliced SSTR5 variant, sst5TMD4, has been associated with more aggressive disease in glioblastoma 60,82. Overall, SSTR2 expression is correlated with improved outcomes in glioma, while the utility of 68Ga-DOTATATE imaging amongst various glioma subtypes is still under investigation.

Head and neck squamous cell carcinoma (HNSCC) are a prevalent and heterogenous group of cancers originating from mucosal epithelium of various anatomic structures including oral cavity, oropharynx, lip, nasal cavity, sinuses, nasopharynx, and larynx 83, and caused by different inciting agents 84. In contrast to the aforementioned cancer types, SSTR2 expression is correlated with worse prognosis of HNSCC 83. SSTR2 expression is highly sensitive and specific for Epstein Barr Virus-positive nasopharyngeal carcinoma, likely mediated via virally induced changes in nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) pathways 85, making it a valuable biomarker for this disease 86. Concordant with the degree of SSTR2 expression amongst HNSCC, 68Ga-DOTATATE was shown to be an effective imaging modality with comparable results to traditional 18F-FDG-PET/CT 87.

SSTR2 is somewhat expressed amongst lymphoma subtypes, with immunopositivity predominantly shown in dendritic cells and follicular centers of lymph nodes. IHC analysis performed by Juntikka et al. demonstrated approximately 50% of cells staining positive for SSTR2 in diffuse large B-cell lymphoma, Hodgkin lymphoma, and follicular lymphoma 88. SSTR3 and 5 were not expressed in diffuse large B-cell and follicular subtypes but were expressed in Hodgkin lymphoma within cytoplasmic domains. Interestingly, CXCR4 was co-expressed with SSTR2, pointing to potential future targeted co-therapeutic options. Largely, studies analyzing SSTR2 in lymphomas show too little expression to make them suitable candidates for somatostatin receptor radio-imaging and therapy 89,90. An exception to this conclusion has been found in differentiating gastric versus extra-gastric MALT-type lymphomas, as somatostatin receptor scintigraphy has better uptake in extra-gastric MALT-type lymphomas 91.

Somatostatin Receptor 2 in Gastroenteropancreatic Neuroendocrine Tumors

With the heterogeneity of this spectrum of disease in GEP NETs, efforts are being made to identify biomarkers for predicting response to treatment and outcomes. 90% of GEP NETs express SSTR2 on tumor surface 92. Okuwaki et al. studied 79 pancreatic NETs and found that negative SSTR2 staining was a significant independent predictor of poor outcome 93. Wang et al. looked at SSTR2 and SSTR5 expression among 143 GEP NETs, finding that positive expression for these two receptors was associated with improved survival compared to negative expression 53. Conversely, van Adrichem et al. in a study of 73 GEP NETs, found that negative SSTR2 staining was not significantly related to OS, disease stage, or tumor grade 94. Despite an unclear relationship between SSTR2 expression and outcomes, expression of these receptors has implications in the diagnosis and treatment of GEP NETs.

Radiolabeled SSAs, including 68Ga-DOTA-SSA and 111In-pentetrotide, are used as radiopharmaceuticals in PET/CT imaging for NET diagnosis and staging 5,11. Further, radiolabeled SSAs and unlabeled SSAs are employed in peptide receptor radionuclide therapy (PRRT) which has been shown to prolong PFS in metastatic GEP NETs 56,95,96. Utilizing these mechanisms has proved beneficial in some patients, however, there is a subset, albeit small, of patients that do not express SSTR2. Few have sought to delineate differences between SSTR2 positivity and negativity in these lesions. Hu et al. examined 223 cases of non-functional pancreatic NETs, of which 23 were negative for SSTR2 and found that SSTR2 negativity was significantly associated with earlier onset, larger, more advanced lesions, peripheral aggression, metastasis to liver and lymph nodes (LN), and worse PFS 11. Refardt et al. examined 69 SSTR2 positive and 69 SSTR2 negative propensity score matched patients with well-differentiated NETs and found that those negative for the receptor had a worse prognosis despite receiving more aggressive treatment 5.

With no known mutations affecting its expression 97, it has become clear that SSTR2 loss in advanced tumors is chiefly mediated through epigenetic mechanisms 6. Simply put, epigenetics is the study of heritable gene expression alterations that do not involve changes to the underlying DNA sequence. Examples of epigenetic mechanisms include DNA methylation, histone modifications, chromatin remodeling and non-coding RNAs 98. Preclinical work from several labs, including ours, have identified broad-based epigenetic silencing mechanisms, such as DNA CpG methylation and histone deacetylation, in negatively controlling SSTR2 expression 6,99. DNA methylation involves the covalent addition of a methyl group to cytosines, just upstream of a guanine nucleotide (CpG), by a family of enzymes called, DNA methyltransferases 100. DNA CpG methylation causes compaction of chromatin, impeding transcription factor binding, resulting in gene silencing 101. CpG sites occur at increased frequencies in regions called CpG islands, which are often concentrated in gene regulatory elements, such as promoters and enhancers 102. CpG islands are routinely found to be hypermethylated in cancers, often leading to silencing of tumor suppressor genes. Importantly, the SSTR2 gene was found to have a CpG island in its promoter, upstream of the transcription start site 103. As expected, increased promoter CpG methylation has been correlated with decreased expression of SSTR2 gene transcript 99,103,104. In addition to CpG methylation, histone deacetylation also plays a major role in regulating SSTR2 expression. Enzymes termed histone acetyltransferases (HATs) attach acetyl groups to select lysine residues on histone protein N-terminal tails. Histone acetylation acts to open chromatin, leading to increased transcription factor binding and gene transcription 105. Opposite to that of HATs, histone deacetylases (HDACs) remove acetyl groups from histone protein tails, facilitating chromatin compaction, resulting in decreased gene expression 106. Performing chromatin immunoprecipitation (ChIP) experiments, it was shown that promoter histone acetylation levels correlate with SSTR2 gene expression levels 103. Unique to epigenetics is the plasticity of their marks. While direct damage to DNA and its base pairs is permanent, epigenetic changes and their marks are not. The focused clinical goal regarding SSTR2-based epigenetic studies is to ultimately turn back on its expression, resulting in improved patient responses to SSTR2-focused radioligand imaging and therapy modalities. With that in mind, numerous preclinical NET cell culture studies have demonstrated that epidrug treatment, with either DNA methyltransferase inhibitors (DNMTi) or histone deacetylase inhibitors (HDACi), increases SSTR2 expression levels 6,99,107-110. Thus, these studies, and others, have shown the utility of epigenetic targeting to increase expression of SSTR2.

Prognostic Implications & Modifications

SOMATOSTATIN ANALOGS

Current therapy for SSTR2 positive GEP NETs is based on the use of somatostatin analogs (SSAs). Natural somatostatin peptides have a half-life of a few minutes – thus, octreotide was developed with a half-life of several hours 4. Octreotide has a high affinity for both SSTR2 and SSTR5 and can be administered by subcutaneous injection or through intravenous infusion with a maximum daily dose of 3000 µg 4. Lanreotide is another SSA that can be administered by subcutaneous injection every 28 days 111. These drugs are typically well-tolerated with side effects being dose-dependent 111. SSAs are useful in the symptomatic control of functioning NETs given their antisecretory effect. Both octreotide and lanreotide can be used to address carcinoid syndrome and one meta-analysis found that they provided symptomatic improvement in 65-72% of patients 112. However, with long-term use of these medications, decreased response has been observed which may be attributable to tumor progression, tachyphylaxis or treatment resistance 111. Multiple studies have found that SSAs also exert antiproliferative effects on these tumors in addition to symptom control. The PROMID trial investigated eighty-five patients with well-differentiated metastatic neuroendocrine midgut tumors in a placebo-controlled, prospective, randomized study where patients received either octreotide or placebo with a primary endpoint of time to tumor progression. Those that received octreotide had significantly longer time to tumor progression (14.3 months) compared to those receiving the placebo (6 months) and at the 6 month mark, they also had significantly lower tumor progression rates (37% vs 66%) 56. The CLARINET trial investigated the antiproliferative effect of lanreotide in 204 patients with grade 1/2 differentiated, nonfunctioning, SSTR positive NETs of the foregut, midgut, pancreas and unknown primary with a primary endpoint of PFS 113. Those that received lanreotide had significantly prolonged PFS compared to placebo (32.8 months vs 18 months) 113. Further, the CLARINET FORTE trial investigated the safety and efficacy of increasing the frequency of dosing of lanreotide autogel (LAN) in ninety-nine patients with pancreatic or midgut NETs that had progression in the previous two years while on standard dosing of LAN with a primary endpoint of PFS. They found that the median PFS in midgut NETs was 8.3 months and 5.6 months in pancreatic NETs with increased dosing frequency of LAN and that it was well tolerated and safe 114. Thus, lack of response with standard dosing does not necessarily mean a new treatment has to be pursued. More recently, another SSA was developed, pasireotide, which has high affinity for SSTR1-3 and SSTR5 115. Though not statistically significant, a randomized double-blind phase III study compared pasireotide long-acting release with octreotide long-acting repeatable in managing symptoms of NETs of the digestive tract refractory to first-generation SSAs and found that those on pasireotide had better tumor control rate than those on octreotide 115. In a post hoc analysis of these study participants, pasireotide had a five month longer PFS than patients on octreotide which was statistically significant 115. In summary, SSAs provide both symptom control and antiproliferative benefits to patients with SSTR2 positive GEP NETs.

SOMATOSTATIN RECEPTOR-BASED IMAGING

SSTR-based imaging is a useful adjunct to standard imaging techniques that allows enhanced sensitivity for most types of NETs and is an integral part of tumor staging and preoperative imaging 116. Computed tomography (CT) and magnetic resonance imaging (MRI) are often employed to detect NETs but have a sensitivity between 50-80% 117. SSTR-based imaging offers numerous benefits – it can reveal additional metastases compared to conventional imaging, assess response to therapy, and by demonstrating sufficient SSTR expression in tumors it deems patients eligible for peptide receptor radionuclide therapy (PRRT) 116. Currently, 68Ga-DOTA-SSA and 111In-pentetrotide are the radiopharmaceuticals of choice for SSTR-based imaging. 68Ga is an isotope normally chelated to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) which is then bound to a peptide: DOTATATE, DOTATOC, or DOTANOC 118. DOTATATE is the most common and has the highest affinity to SSTR2 118. The most avid uptake of 68Ga-DOTATATE occurs in the spleen, adrenal glands, kidneys and pituitary gland which is attributed to the presence of SSTR2 118. Uptake in the liver and salivary glands is related to nonspecific clearance of the tracer 118. DOTATOC has high affinity for SSTR2 and SSTR5 while DOTANOC has the widest receptor binding profile, binding SSTR2, SSTR3, and SSTR5 119. Numerous studies have identified benefits to these imaging modalities compared to standard techniques 120-123.

SSTR-based imaging is not without pitfalls. Tumors must express SSTRs to be visualized on these modalities which is less common among poorly differentiated lesions. False negative results are often related to tumor heterogeneity 118. False positives can occur secondary to physiologic reasons, osteoblastic lesions, inflammatory processes, and incidentally. For example, the uncinate process of the pancreas can demonstrate increased activity due to higher expression of SSTR2, often presenting as ill-defined enhancement 124. Accessory spleens can be a source of false positives as well. Any process that leads to increased osteoblastic activity can create foci with increased uptake secondary to high SSTR2 expression in osteoblasts 124. Macrophages and leukocytes also express SSTR2 therefore, active inflammatory processes can contribute to false positives 124.

Treatment with SSA does not preclude clinicians from using SSTR-based imaging. Investigations into the use of long-acting octreotide and these imaging modalities have found that the use of SSAs diminished physiologic uptake in the liver, spleen and thyroid 125,126. These medications did not compromise tracer uptake in primary tumors or metastatic lesions and tended to improve tumor-to-background ratio 125,126.

Peptide Receptor Radionuclide Therapy

177Lu-dotatate therapy was approved by the United States Food and Drug Administration (FDA) in 2018 for the treatment of SSTR positive, well-differentiated, GEP NETs. The radionuclide, 177Lu, is attached to a SSA, DOTATATE, to target tumor cells that express SSTR and deliver ionizing radiation to them which induces apoptosis through single and double-stranded DNA breaks 127. Numerous studies have investigated the benefit of this therapy. In the NETTER-1 global phase 3 trial, 229 patients with SSTR positive, grade 1 or 2 midgut NETs who progressed on standard dosing of long-acting octreotide were assigned to receive either four cycles of 7.4 GBq 177Lu-DOTATATE with intramuscular long-acting octreotide 30 mg every 4 weeks or long-acting octreotide 60 mg every 4 weeks 96. Results of this study demonstrated longer PFS and higher response rate in the PRRT group than high-dose long-acting octreotide in patients with advanced midgut NET 96. Follow up from this trial showed that these patients also experienced a longer time to deterioration in the 177Lu-dotatate group and that 36% of the patients in the control group had to crossover to 177Lu-dotatate therapy 128,129. Thus, there is both a survival benefit and symptom control provided by this treatment. The NETTER-2 trial was another randomized multicenter phase 3 trial that enrolled 226 patients with newly diagnosed grade 2 or 3, SSTR positive GEP NETs to evaluate 177Lu-dotatate with 30 mg intramuscular long-acting octreotide followed by 30 mg long-acting octreotide every 4 weeks with patients receiving just high dose 60 mg long-acting octreotide every 4 weeks 130. 177Lu-dotatate therapy plus long-acting octreotide significantly extended median PFS by 14 months in patients with grade 2 or 3 advanced GEP NETs 130. Currently ongoing, is the COMPOSE trial which aims to evaluate PFS in patients receiving a different radioligand, 177Lu-DOTATOC, with chemotherapy in patients with grade 2 or 3 GEP NETs and a Ki-67% between 15-55%.

Chromogranin A (CgA) levels are often used as a biochemical marker in NETs with an elevated level correlating to hepatic tumor burden, rapid tumor progression and shorter overall survival (OS) 131. In patients who undergo PRRT, 25-52% of them exhibit a drop in CgA >50% – such a drop has been associated with prolonged PFS and OS 132. CgA can, however, be increased by both tumor progression and cell damage or lysis from PRRT and is thus unreliable 132.

PRRT is contraindicated in pregnant or breastfeeding patients, those with severe cardiac impairment or those with a life expectancy less than 3 months 133. The most common side effects include hematologic toxicity, commonly lymphopenia, nephrotoxicity secondary to renal excretion of radiolabeled SSAs, and hepatotoxicity 132.

Efforts to improve the efficacy of this treatment modality are ongoing. PRRT is known to induce double and single-stranded DNA breaks – most of these breaks are single-stranded which require poly-[ADP-ribose]-polymerase 1 (PARP-1) activity for repair 134. Without repair, these single-stranded breaks cause replication fork arrest and thus double-stranded break formation during replication 134. Olaparib is a PARP-1 inhibitor and has been found to synergistically sensitize SSTR2-expressing human tumor cells to 177Lu-DOTATATE treatment 134. Investigations have also shown that inhibition of heat shock protein 90 (Hsp90) with ganetespib can enhance the anti-tumor effect of 177Lu-DOTATATE therapy in an SSTR expressing xenograft model 135. Hsp90 expression is higher in small intestine NETs relative to tumor stroma 135. Investigations are also underway exploring alternative radionuclides to use in PRRT 132.

Epigenetic Therapeutic Implications & Future Directions

Although epidrug treatment has been shown to increase expression of SSTR2, evidence of therapeutic benefit from this re-expression is necessary to drive novel SSTR2-directed therapies to the clinic. To date, several GEP-NET cell culture studies have demonstrated increased uptake of 68Ga-radiolabeled somatostatin analogs after either DNMTi or HDACi epidrug treatment 108-110,136,137. While in vitro epidrug therapy can both increase expression of SSTR2 and radiolabeled somatostatin analog uptake, the results from limited in vivo studies have been mixed. Studies using DNMTi or HDACi treatment of mice, harboring NET cell line xenografts, have shown increased uptake of radiolabeled 68Ga somatostatin analogs 108,110,136. One in vivo study demonstrated uptake of 177Lu-DOTATATE PRRT in NET cell line tumor xenografts 138; unfortunately, no effects on tumor size or therapeutic benefit was seen. Additional in vivo studies demonstrated contradictory results, depending on the specific HDACi employed, regarding SSTR2 expression increases and 177Lu-DOTATATE uptake 139,140. Lack of functional effects or therapeutic benefit from the limited in vivo studies to date may hint at necessary changes or finetuning in epidrug selection or dosing regimen parameters. A recent publication from our group, using an SSTR2-low PNET cell line xenograft tumor model, demonstrated that HDACi treatment led to increased tumor uptake of 177Lu-DOTATATE and resulted in significant antitumor response, compared to 177Lu-DOTATATE treatment alone 99. Currently, human studies combining epidrug and radiolabeled somatostatin analogs are also limited. One study showed no tumor uptake of 68Ga-DOTATATE after dual DNMTi and HDACi treatment in advanced NET patients having low baseline levels of SSTR2 expression 141. In contrast, a study of metastatic midgut NET patients revealed increased 68Ga-DOTATOC after HDACi treatment 142. Future GEP-NET patient trials combining novel epidrug therapy and somatostatin radioligand regimens are eagerly anticipated. Currently, participants are being recruited for a Phase 1 trial in the United Kingdom investigating whether pre-treatment with ASTX727 (cedazuridine 100 mg + decitabine 35 mg) results in re-expression of SSTR2 in patients with metastatic neuroendocrine tumors 143.

Recent research endeavors from our lab have delved deeper into the finer details of SSTR2 epigenetic regulation, beyond just broad-based DNA CpG methylation and histone deacetylation events. Our unpublished work, using functional genomic and chemical screens, has identified various repressor complexes responsible for silencing of SSTR2 expression and further demonstrates the unique interconnectedness of various epigenetic mechanisms. Ultimately, our clinical research goal is to formulate the optimal epidrug treatment regimen. This epidrug regimen would have negligible patient toxicity and would increase SSTR2 cell surface expression in SSTR2 low/negative GEP-NET patients, resulting in augmented somatostatin radioligand imaging and therapeutic efficacy.

Conclusion

In summary, GEP NETs encompass a heterogeneous group of tumors often characterized by SSTR2 positivity. Though surgery is the only curative option, most patients at the time of diagnosis are not candidates and must instead rely on treatment based on the use of SSA. SSA provide both symptoms control and antiproliferative properties. PRRT is a newer therapeutic modality that takes advantage of SSTR2 positivity to target ionizing radiation. SSTR2 expression is associated with well-differentiated tumors and the loss of expression in more advanced ones is attributed to epigenetic silencing 6. Efforts are now being made to employ epidrugs to increase the expression of SSTR2 in poorly differentiated GEP NETs so that SSTR-based imaging, SSA, and PRRT can be utilized in this subset of patients.

Conflicts of Interest

The authors have no conflicts of interest to declare.

Funding

Funding provided by the National Institutes of Health ZIA BC 011899 to Dr. Samira M. Sadowski.

Author Contributions

LFR and SMS contributed to the manuscript conception. LFR, RMS, JPM, and SMS prepared the article. LFR, RMS, and SMS provided critical revisions to the article. LFR, RMS, JPM and SMS reviewed the article.

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