Somatostatin Receptor Agonists Research Articles

Disulfiram mediated anti-tumour effect in pituitary neuroendocrine tumours by inducing cuproptosis

ContextMedical treatment plays a critical role in pituitary neuroendocrine tumour (PitNET) treatment. Dopamine agonists and somatostatin receptor agonists are the only known drugs for effectively treating PitNET. Thus, the identification of potential therapeutic targets and drugs is urgently needed. ObjectiveTo discover potential drugs that can suppress PitNET growth and to further investigate the underlying mechanism involved. MethodsHigh-throughput drug screening of primary cultures of 17 patient-derived PitNETs was performed to identify potential therapeutic compounds. Cell viability assays, Western blot analysis and flow cytometry were used to investigate pituitary neuroendocrine tumour cell lines and patient-derived PitNET cultures in vitro. In vivo drug efficacy was examined in a mouse xenograft model. ResultsSeventeen primary PitNET samples were collected for high-throughput drug screening, and a class of copper ionophores that can effectively inhibit cell growth, such as zinc pyrithione, elesclomol, and disulfiram (DSF), was identified. Subsequent experiments initially validated the dose-dependent cell growth-suppressing effect of these copper ionophores on AtT20, GH3, and MMQ cells and several primary PitNET cell lines. Moreover, we confirmed that the cytotoxic effect of DSF depends on the presence of copper. Additionally, we determined that cell death occurs via cuproptosis, with events such as Fe-S cluster protein loss, dihydrolipoyl transacetylase oligomerization and heat shock protein 70 upregulation. Finally, we verified the cytotoxic effects of DSF in vivo. ConclusionThe present study revealed copper ionophores as a potential class of drugs for PitNET treatment. DSF induced PitNET cell death via cuproptosis and might be a promising option for PitNET therapy.

DOTATOC PET/CT imaging of a typical carcinoid tumor in a human ex-vivo perfused lung lobe.

The use of Isolated lung perfusion (ILP), combined with medical imaging modalities such as positron emission tomography-computed tomography (PET/CT), provides real-time visualization of tumors in ventilated and perfused vital lung tissue. This experiment intends to show the feasibility and benefits of using ILP combined with PET/CT imaging. Following lung surgery on a 49-year-old male, his left lower lobectomy specimen, which held a typical carcinoid tumor, was preserved on normothermic ILP. Gallium-68-Edotreotide ([68Ga]-DOTATOC) was administered into the ILP circuit, and dynamic emission data from PET/CT was acquired. ILP was carried out for 120 minutes. Near physiologic gas exchange and glucose metabolism were preserved throughout the experiment. The time activity curves (TAC) of 5 different volumes of interest (VOI) showed notable differences in tracer uptake over time. The peripheral area of the carcinoid exhibited delayed but high somatostatin receptor agonist uptake compared to the surrounding parenchyma and the intrapulmonary artery. However, the central area of the carcinoid showed very low [68Ga]-DOTATOC uptake. This experiment demonstrates the potential of ILP combined with PET/CT for kinetic modeling in experimental nuclear medicine imaging. By providing visualization of tracer uptake in perfused lung tissue, this model could potentially improve our understanding of tumor physiology and molecular imaging.

Identification of a Novel SSTR3 Full Agonist for the Treatment of Nonfunctioning Pituitary Adenomas.

Somatostatin receptor (SSTR) agonists have been extensively used for treating neuroendocrine tumors. Synthetic therapeutic agonists showing selectivity for SSTR2 (Octreotide) or for SSTR2 and SSTR5 (Pasireotide) have been approved for the treatment of patients with acromegaly and Cushing's syndrome, as their pituitary tumors highly express SSTR2 or SSTR2/SSTR5, respectively. Nonfunctioning pituitary adenomas (NFPAs), which express high levels of SSTR3 and show only modest response to currently available SSTR agonists, are often invasive and cannot be completely resected, and therefore easily recur. The aim of the present study was the evaluation of ITF2984, a somatostatin analog and full SSTR3 agonist, as a new potential treatment for NFPAs. ITF2984 shows a 10-fold improved affinity for SSTR3 compared to Octreotide or Pasireotide. Molecular modeling and NMR studies indicated that the higher affinity for SSTR3 correlates with a higher stability of a distorted β-I turn in the cyclic peptide backbone. ITF2984 induces receptor internalization and phosphorylation, and triggers G-protein signaling at pharmacologically relevant concentrations. Furthermore, ITF2984 displays antitumor activity that is dependent on SSTR3 expression levels in the MENX (homozygous mutant) NFPA rat model, which closely recapitulates human disease. Therefore, ITF2984 may represent a novel therapeutic option for patients affected by NFPA.

177Lu-DOTATATE in neuroendocrine tumors: Real-world evidence of efficacy and safety in a community setting.

e16249 Background: Neuroendocrine tumors (NET) have an incidence of around 6.98/100k per year. Long-acting somatostatin receptor agonists (SSA) are first-line therapy for non-resectable disease. In January 2018, the United States FDA approved 177Lu-DOTATATE (PRRT) for second-line therapy in patients with somatostatin receptor-positive GEP-NETs based on the results from NETTER-1 randomized controlled trials. Those trials did not explore frequency of SSA dosing in relation to 177Lu-DOTATATE and its effects on mPFS. Methods: This is a retrospective observational analysis of the safety and efficacy of 177Lu-DOTATATE in treating NETs which progressed on SSA or other second-line therapy, as well as effects on PFS of differential dosing of SSA between PRRT treatments. Organizational IRB approval was obtained. All patients who received 177Lu-DOTATATE at Scripps MD Anderson Cancer Center from 1/2018 to 12/2022 were identified and relevant data were abstracted from the EHR. Patients received 200 mCi of PRRT followed by SSA every 8 weeks for 4 doses. Disease progression was defined as development of new metastases or growth in diameter of existing disease on imaging. Some patients chose to receive SSA between doses of PRRT for symptomatic control every 4 weeks, and these patients were stratified in analysis. For both groups, the mPFS was calculated and plotted on a Kaplan-Meier survival curve and p-values were calculated using the log-rank method. Results: Demographics: 34 patients completed the 4 PRRT doses at our institution. Demographically, our population was similar to NETTER-1 with regards to age (67 ± 12 years) and time since diagnosis (3 years). We included 5 patients with >5% Ki67 staining on pathology. The most common primary site was pancreas in our study compared to ileum in the RCT. Efficacy: The calculated mPFS in our population was 25.4 months (95% CI 11.6 – 43.4), versus in NETTER-1 mPFS had not been reached for the treatment group at 20 months. In our study there was no statistically significant difference in mPFS in patients who had received SSA every 4 weeks versus every 8 weeks (p=0.47). Safety: Symptom-focused side-effects of 177Lu-DOTATATE were not recorded at our center. Only 2 patients were incompletely treated due to measurable toxicities, including a grade 2 thrombocytopenia, and one patient with a grade 2 leukopenia with grade 3 neutropenia. Conclusions: Our population differed from NETTER-1 not only in size but by including patients with >5% Ki67 staining index which may indicate more aggressive disease. No difference was found in mPFS when dosing patients with SSA every 4 weeks compared to every 8, suggesting that interval SSA treatment for symptomatic control may not interfere with 177Lu-DOTATATE efficacy. Our analysis suggests that 177Lu-DOTATATE can be used safely as second-line therapy of NETs at a community-based institution with improved mPFS when compared to the control group studied in the larger NETTER-1 RCT.

Genetically engineered human pituitary corticotroph tumor organoids exhibit divergent responses to glucocorticoid receptor modulators

Cushing's disease (CD) is a serious endocrine disorder attributed to an adrenocorticotropic hormone (ACTH)-secreting pituitary neuroendocrine tumor (PitNET) that that subsequently leads to chronic hypercortisolemia. PitNET regression has been reported following treatment with the investigational selective glucocorticoid receptor (GR) modulator relacorilant, but the mechanisms behind that effect remain unknown. Human PitNET organoid models were generated from induced human pluripotent stem cells (iPSCs) or fresh tissue obtained from CD patient PitNETs (hPITOs). Genetically engineered iPSC derived organoids were used to model the development of corticotroph PitNETs expressing USP48 (iPSCUSP48) or USP8 (iPSCUSP8) somatic mutations. Organoids were treated with the GR antagonist mifepristone or the GR modulator relacorilant with or without somatostatin receptor (SSTR) agonists pasireotide or octreotide. In iPSCUSP48 and iPSCUSP8 cultures, mifepristone induced a predominant expression of SSTR2 with a concomitant increase in ACTH secretion and tumor cell proliferation. Relacorilant predominantly induced SSTR5 expression and tumor cell apoptosis with minimal ACTH induction. Hedgehog signaling mediated the induction of SSTR2 and SSTR5 in response to mifepristone and relacorilant. Relacorilant sensitized PitNET organoid responsiveness to pasireotide. Therefore, our study identified the potential therapeutic use of relacorilant in combination with somatostatin analogs and demonstrated the advantages of relacorilant over mifepristone, supporting its further development for use in the treatment of Cushing's disease patients.

Alpha-peptide receptor radionuclide therapy using actinium-225 labeled somatostatin receptor agonists and antagonists.

Peptide receptor radionuclide therapy (PRRT) has over the last two decades emerged as a very promising approach to treat neuroendocrine tumors (NETs) with rapidly expanding clinical applications. By chelating a radiometal to a somatostatin receptor (SSTR) ligand, radiation can be delivered to cancer cells with high precision. Unlike conventional external beam radiotherapy, PRRT utilizes primarily β or α radiation derived from nuclear decay, which causes damage to cancer cells in the immediate proximity by irreversible direct or indirect ionization of the cells' DNA, which induces apoptosis. In addition, to avoid damage to surrounding normal cells, PRRT privileges the use of radionuclides that have little penetrating and more energetic (and thus more ionizing) radiations. To date, the most frequently radioisotopes are β- emitters, particularly Yttrium-90 (90Y) and Lutetium-177 (177Lu), labeled SSTR agonists. Current development of SSTR-targeting is triggering the shift from using SSTR agonists to antagonists for PRRT. Furthermore, targeted α-particle therapy (TAT), has attracted special attention for the treatment of tumors and offers an improved therapeutic option for patients resistant to conventional treatments or even beta-irradiation treatment. Due to its short range and high linear energy transfer (LET), α-particles significantly damage the targeted cancer cells while causing minimal cytotoxicity toward surrounding normal tissue. Actinium-225 (225Ac) has been developed into potent targeting drug constructs including somatostatin-receptor-based radiopharmaceuticals and is in early clinical use against multiple neuroendocrine tumor types. In this article, we give a review of preclinical and clinical applications of 225Ac-PRRT in NETs, discuss the strengths and challenges of 225Ac complexes being used in PRRT; and envision the prospect of 225Ac-PRRT as a future alternative in the treatment of NETs.

ODP334 Must we Wait for the Development of Metastasis to be Able to Distinguish Dopamine Resistant Aggressive Prolactinoma from Prolactin Producing Pituitary Carcinomas? Case Report and Literature Review

Abstract Background Prolactinomas, the most prevalent type of neuroendocrine disease, account for approximately 40% of all pituitary adenomas. In the vast majority of cases, these are benign tumors with excellent clinical response to medical therapy with dopamine agonist agents such as bromocriptine and cabergoline. Rarely medical treatment fails to normalize prolactin levels and/or decrease the size of the tumor, posing a challenge to the clinician. Case presentation 40-year-old man who underwent resection of a 7.4 cm pituitary prolactinoma via frontal craniotomy followed by radiotherapy. He developed panhypopituitarism and was placed on chronic hormonal replacement therapy plus high dose cabergoline. Two years later he presented with recurrence of his disease and was diagnosed with an unresectable 4.9 cm pituitary adenoma showing cortical breakthrough of the sellar floor, invasion into the optic chiasm, erosion of the posterior sphenoid walls, extension into the sphenoid sinuses and posteriorly into the pons, midbrain and third ventricle, as well as complete encasement of the distal, superior cerebellar and posterior cerebral arteries. The patient underwent endoscopic trans sphenoidal partial tumor resection and CSF leak repair. Pathology revealed a pituitary prolactinoma with Ki-67 of up to 8% and positive p53 immunostaining. His cabergoline dose was adjusted to 0.5 mg PO daily and he was also started on Sandostatin 20 mg IM monthly as well as appropriate hormonal replacement of the other deficient pituitary hormonal axes. Follow up imaging revealed stability of the lesion. The patient continues to do clinically well and actively follows with endocrinology and neurosurgery with serial brain MRIs and laboratory workup. Discussion The histological and biochemical characteristics of aggressive prolactin secreting tumors has been reported to be of minimal utility in distinguishing benign from malignant lesions. Tumors can only be diagnosed as carcinomas after they have metastasized and they can only be classified as aggressive after treatment failure or unusual growth, which creates a disadvantage for the prognosis and management of these patients. Clinicians are in need of better guidelines that can help them identify the rare cases that might warrant more aggressive clinical interventions beyond dopamine agonists such as surgery, radiation, temozolomide, somatostatin receptor agonists and others, with the hope of delaying or preventing the development of metastasis. Case reports of atypical presentations of aggressive prolactinomas such as the one here presented, can help broaden our understanding of the predictable signs of poor prognosis. Presentation: No date and time listed

P-69 - New bicyclic somatostatin receptor agonists for imaging and therapy of neuroendocrine neoplasia

P-69 - New bicyclic somatostatin receptor agonists for imaging and therapy of neuroendocrine neoplasia

Impact of SSTR PET on Inter-Observer Variability of Target Delineation of Meningioma and the Possibility of Using Threshold-Based Segmentations in Radiation Oncology.

Simple SummaryDifferences in tumor segmentations between radiation oncologists is one of the largest sources of uncertainty in radiation therapy planning. This study investigated the influence of additional functional information from somatostatin receptor PET imaging on the inter observer variability in the delineation of meningioma. Further, this study assessed the usability of a simple thresholding approach for lesion delineation. It could be shown, that additional PET information was able to significantly reduce the inter observer variability. The threshold based delineation approach required a relatively low threshold value and showed only moderate agreement with the radiation oncologists.Aim: The aim of this study was to assess the effects of including somatostatin receptor agonist (SSTR) PET imaging in meningioma radiotherapy planning by means of changes in inter-observer variability (IOV). Further, the possibility of using threshold-based delineation approaches for semiautomatic tumor volume definition was assessed. Patients and Methods: Sixteen patients with meningioma undergoing fractionated radiotherapy were delineated by five radiation oncologists. IOV was calculated by comparing each delineation to a consensus delineation, based on the simultaneous truth and performance level estimation (STAPLE) algorithm. The consensus delineation was used to adapt a threshold-based delineation, based on a maximization of the mean Dice coefficient. To test the threshold-based approach, seven patients with SSTR-positive meningioma were additionally evaluated as a validation group. Results: The average Dice coefficients for delineations based on MRI alone was 0.84 ± 0.12. For delineation based on MRI + PET, a significantly higher dice coefficient of 0.87 ± 0.08 was found (p < 0.001). The Hausdorff distance decreased from 10.96 ± 11.98 mm to 8.83 ± 12.21 mm (p < 0.001) when adding PET for the lesion delineation. The best threshold value for a threshold-based delineation was found to be 14.0% of the SUVmax, with an average Dice coefficient of 0.50 ± 0.19 compared to the consensus delineation. In the validation cohort, a Dice coefficient of 0.56 ± 0.29 and a Hausdorff coefficient of 27.15 ± 21.54 mm were found for the threshold-based approach. Conclusions: SSTR-PET added to standard imaging with CT and MRI reduces the IOV in radiotherapy planning for patients with meningioma. When using a threshold-based approach for PET-based delineation of meningioma, a relatively low threshold of 14.0% of the SUVmax was found to provide the best agreement with a consensus delineation.

Preoperative medical treatments and surgical approaches for acromegaly: A systematic review.

Acromegaly is a condition characterized by an overproduction of growth hormone which infers high morbidity and mortality if left untreated. The objective of this review is to analyse and appraise the current evidence for the generalized use of preoperative medications and the various surgical approaches as described in the literature. A thorough search from MEDLINE via PubMed, EMBASE, and Cochrane Library has been performed which identified a total of 37 papers. The preoperative use of somatostatin receptor agonists (SAs) in acromegaly is a controversial topic with current guidelines suggesting against their generalized routine use. Most authors noticed an insignificant long-term remission of acromegaly when given SAs compared with nil preoperative therapy, except for invasive macroadenomas as SAs have been found to reduce the tumour volume and aid towards the total resection of the adenoma. Furthermore, according to the evidence available, endoscopic transsphenoidal surgery is the optimum method for hypophysectomy in terms of its remission and safety profile.

Radiolabeled Somatostatin Analogues for Diagnosis and Treatment of Neuroendocrine Tumors.

Simple SummaryNeuroendocrine neoplasms (NENs) are rare and heterogeneous tumors, presenting in often challenging clinical scenarios, and require multidisciplinary discussion for optimal care. The theranostic approach (DOTA peptides labelled with 68Ga for imaging well-differentiated neuroendocrine tumors NETs, and labelled with 90Y or 177Lu for therapy) plays a crucial role in the management of NENs to assess disease extension and criteria for peptide receptor radionuclide therapy (PRRT) eligibility of based on somatostatin receptor (SSTR) expression. The present paper is an overview of currently employed radiolabeled SSTR analogues used for both diagnosis and therapy of NENs. Further emerging radiopharmaceuticals targeting SSTRs (e.g., fluorinated SSTR agonists, radiolabeled SSTR antagonists) as well as strategies to improve PRRT efficacy (by means of implementation of personalized treatment schemes, dosimetry, amelioration of response assessment strategies, and optimization of treatment sequencing) are also discussed. Finally, although very preliminary, some studies employing radiomic features in various kinds of NET are reported.Neuroendocrine neoplasms (NENs) are rare and heterogeneous tumors that require multidisciplinary discussion for optimal care. The theranostic approach (DOTA peptides labelled with 68Ga for diagnosis and with 90Y or 177Lu for therapy) plays a crucial role in the management of NENs to assess disease extension and as a criteria for peptide receptor radionuclide therapy (PRRT) eligibility based on somatostatin receptor (SSTR) expression. On the diagnostic side, [68Ga]Ga-DOTA peptides PET/CT (SSTR PET/CT) is the gold standard for imaging well-differentiated SSTR-expressing neuroendocrine tumors (NETs). [18F]FDG PET/CT is useful in higher grade NENs (NET G2 with Ki-67 > 10% and NET G3; NEC) for more accurate disease characterization and prognostication. Promising emerging radiopharmaceuticals include somatostatin analogues labelled with 18F (to overcome the limits imposed by 68Ga), and SSTR antagonists (for both diagnosis and therapy). On the therapeutic side, the evidence gathered over the past two decades indicates that PRRT is to be considered as an effective and safe treatment option for SSTR-expressing NETs, and is currently included in the therapeutic algorithms of the main scientific societies. The positioning of PRRT in the treatment sequence, as well as treatment personalization (e.g., tailored dosimetry, re-treatment, selection criteria, and combination with other alternative treatment options), is warranted in order to improve its efficacy while reducing toxicity. Although very preliminary (being mostly hampered by lack of methodological standardization, especially regarding feature selection/extraction) and often including small patient cohorts, radiomic studies in NETs are also presented. To date, the implementation of radiomics in clinical practice is still unclear. The purpose of this review is to offer an overview of radiolabeled SSTR analogues for theranostic use in NENs.

Clinical Applications of Somatostatin Receptor (Agonist) PET Tracers beyond Neuroendocrine Tumors.

Somatostatin receptor (SSTR) agonist tracers used in nuclear medicine scans are classically used for neuroendocrine tumor diagnosis and staging. SSTR are however, expressed more widely in a variety of cells as seen in the distribution of physiological tracer uptake during whole body scans. This provides opportunities for using these tracers for applications other than NETs and meningiomas. In this qualitative systematic review, novel diagnostics in SSTR-PET imaging are reviewed. A total of 70 studies comprised of 543 patients were qualitatively reviewed. Sarcoidosis, atherosclerosis and phosphaturic mesenchymal tumors represent the most studied applications currently with promising results. Other applications remain in progress where there are many case reports but a relative dearth of cohort studies. [18F]FDG PET provides the main comparative method in many cases but represents a well-established general PET technique that may be difficult to replace, without prospective clinical studies.

Combination of terbium-161 with somatostatin receptor antagonists\u2014a potential paradigm shift for the treatment of neuroendocrine neoplasms

PurposeThe β¯-emitting terbium-161 also emits conversion and Auger electrons, which are believed to be effective in killing single cancer cells. Terbium-161 was applied with somatostatin receptor (SSTR) agonists that localize in the cytoplasm (DOTATOC) and cellular nucleus (DOTATOC-NLS) or with a SSTR antagonist that localizes at the cell membrane (DOTA-LM3). The aim was to identify the most favorable peptide/terbium-161 combination for the treatment of neuroendocrine neoplasms (NENs).MethodsThe capability of the 161Tb- and 177Lu-labeled somatostatin (SST) analogues to reduce viability and survival of SSTR-positive AR42J tumor cells was investigated in vitro. The radiopeptides’ tissue distribution profiles were assessed in tumor-bearing mice. The efficacy of terbium-161 compared to lutetium-177 was investigated in therapy studies in mice using DOTATOC or DOTA-LM3, respectively.ResultsIn vitro, [161Tb]Tb-DOTA-LM3 was 102-fold more potent than [177Lu]Lu-DOTA-LM3; however, 161Tb-labeled DOTATOC and DOTATOC-NLS were only 4- to fivefold more effective inhibiting tumor cell viability than their 177Lu-labeled counterparts. This result was confirmed in vivo and demonstrated that [161Tb]Tb-DOTA-LM3 was significantly more effective in delaying tumor growth than [177Lu]Lu-DOTA-LM3, thereby, prolonging survival of the mice. A therapeutic advantage of terbium-161 over lutetium-177 was also manifest when applied with DOTATOC. Since the nuclear localizing sequence (NLS) compromised the in vivo tissue distribution of DOTATOC-NLS, it was not used for therapy.ConclusionThe use of membrane-localizing DOTA-LM3 was beneficial and profited from the short-ranged electrons emitted by terbium-161. Based on these preclinical data, [161Tb]Tb-DOTA-LM3 may outperform the clinically employed [177Lu]Lu-DOTATOC for the treatment of patients with NENs.

Selective Somatostatin 5 (SST5) and Somatostatin 2 (SST2) Nonpeptide Agonists Potently Suppress Glucose- and Tolbutamide-Stimulated Dynamic Insulin Secretion From Isolated Human Islets

Congenital hyperinsulinism (HI) is the most common cause of persistent hypoglycemia in newborns and infants and arises from dysregulated insulin secretion. Rapid recognition and treatment are vital to prevent seizures, permanent developmental delays, coma, or even death. Very few medical options exist to treat congenital HI patients: the KATP channel activator diazoxide, the injectable somatostatin receptor peptide agonists octreotide and lanreotide, or chronic glucose infusions. However, side effects and/or limited efficacy render these therapies inadequate for many patients.Somatostatin is a 14-amino acid peptide hormone with a broad spectrum of biological actions, which are regulated through five somatostatin receptor subtypes (SST1-SST5). Somatostatin’s common physiological role is to down-regulate secretion of other hormones in various tissues. Its role in the maintenance of euglycemia is to regulate insulin and glucagon secretion from pancreatic β- and α-cells, respectively. Somatostatin regulates insulin secretion by decreasing the intracellular levels of cAMP, inhibition of voltage-gated calcium channels (VGCC), activation of the G protein-activated inward rectifier K+ channel (GIRK), and direct inhibition of insulin exocytosis.Several studies have evaluated the effect of somatostatin, somatostatin peptide analogs, and a limited number of nonpeptide somatostatin receptor agonists on insulin secretion in static assays using isolated human islets. However, the lack of highly selective agonists has made the interpretation of the contribution of SST receptor sub-types difficult to discern. Our programs for the treatment of hyperinsulinism, acromegaly, and other indications have led to the development of selective nonpeptide SST2, SST3, SST4, and SST5 agonists, possessing EC50s < 1 nM in cell-based assays of receptor activation and selectivity > 130 times over the other members of the family. The ability of these selective nonpeptide agonists to regulate glucose- and tolbutamide-stimulated dynamic insulin secretion from human islets was evaluated using a perifusion system (Biorep, FL).We found that selective SST2 and SST5 agonists potently suppressed dynamic insulin secretion in contrast to SST3 or SST4 selective agonists. Importantly, SST5 agonists were shown to have a greater effect than selective SST2 agonists or diazoxide, demonstrating their potential utility in human conditions such as congenital HI. In addition, SST5 activation is also known to have a smaller effect on glucagon secretion and is also less prone to agonist-driven desensitization than SST2 activation. Taken together, these studies support our program to identify, characterize, and develop potent, nonpeptide, orally-bioavailable, selective SST5 agonists with appropriate pharmaceutical and safety characteristics for the treatment of congenital HI.

Cluster headache pathophysiology - insights from current and emerging treatments.

Cluster headache is a debilitating primary headache disorder that affects approximately 0.1% of the population worldwide. Cluster headache attacks involve severe unilateral pain in the trigeminal distribution together with ipsilateral cranial autonomic features and a sense of agitation. Acute treatments are available and are effective in just over half of the patients. Until recently, preventive medications were borrowed from non-headache indications, so management of cluster headache is challenging. However, as our understanding of cluster headache pathophysiology has evolved on the basis of key bench and neuroimaging studies, crucial neuropeptides and brain structures have been identified as emerging treatment targets. In this Review, we provide an overview of what is known about the pathophysiology of cluster headache and discuss the existing treatment options and their mechanisms of action. Existing acute treatments include triptans and high-flow oxygen, interim treatment options include corticosteroids in oral form or for greater occipital nerve block, and preventive treatments include verapamil, lithium, melatonin and topiramate. We also consider emerging treatment options, including calcitonin gene-related peptide antibodies, non-invasive vagus nerve stimulation, sphenopalatine ganglion stimulation and somatostatin receptor agonists, discuss how evidence from trials of these emerging treatments provides insights into the pathophysiology of cluster headache and highlight areas for future research.

SPECT Imaging of SST2-Expressing Tumors with 99mTc-Based Somatostatin Receptor Antagonists: The Role of Tetraamine, HYNIC, and Spacers.

[99mTc]Tc-HYNIC-TOC is the most widely used 99mTc-labeled somatostatin receptor (SST) agonist for the SPECT imaging of SST-expressing tumors, such as neuroendocrine tumors. Recently, radiolabeled SST antagonists have shown improved diagnostic efficacy over agonists. 99mTc-labeled SST antagonists are lacking in clinical practice. Surprisingly, when [99mTc]Tc-HYNIC was conjugated to the SST2 antagonist SS01, SST2 imaging was not feasible. This was not the case when [99mTc]Tc-N4 was conjugated to SS01. Here, we assessed the introduction of different spacers (X: β-Ala, Ahx, Aun and PEG4) among HYNIC and SS01 with the aim of restoring the affinity of HYNIC conjugates. In addition, we used the alternative antagonist JR11 for determining the suitability of HYNIC with 99mTc-labeled SST2 antagonists. We performed a head-to-head comparison of the N4 conjugates of SS01 and JR11. [99mTc]Tc-HYNIC-TOC was used as a reference, and HEK-SST2 cells were used for in vitro and in vivo evaluation. EDDA was used as a co-ligand for all [99mTc]Tc-HYNIC conjugates. The introduction of Ahx restored, to a great extent, the SST2-mediated cellular uptake of the [99mTc]Tc-HYNIC-X conjugates (X: spacer), albeit lower than the corresponding [99mTc]Tc-N4-conjugates. SPECT/CT images showed that all 99mTc-labeled conjugates accumulated in the tumor and kidneys with [99mTc]Tc-HYNIC-PEG4-SS01, [99mTc]Tc-N4-SS01 and [99mTc]Tc-N4-JR11 having notably higher kidney uptake. Biodistribution studies showed similar or better tumor-to-non-tumor ratios for the [99mTc]Tc-HYNIC-Ahx conjugates, compared to the [99mTc]Tc-N4 counterparts. The [99mTc]Tc-HYNIC-Ahx conjugates of SS01 and JR11 were comparable to [99mTc]Tc-HYNIC-TOC as imaging agents. HYNIC is a suitable chelator for the development of 99mTc-labeled SST2 antagonists when a spacer of appropriate length, such as Ahx, is used.

Multimodal Non-Surgical Treatments of Aggressive Pituitary Tumors.

Up to 35% of aggressive pituitary tumors recur and significantly affect mortality and quality of life. Management can be challenging and often requires multimodal treatment. Current treatment options, including surgery, conventional medical therapies such as dopamine agonists, somatostatin receptor agonists and radiotherapy, often fail to inhibit pituitary tumor growth. Recently, anti-tumor effects of chemotherapeutic drugs such as Temozolomide, Capecitabine, and Everolimus, as well as peptide receptor radionuclide therapy on aggressive pituitary tumors have been increasingly investigated and yield mixed, although sometimes promising, outcomes. The purpose of this review is to provide thorough information on non-surgical medical therapies and their efficacies and used protocols for aggressive pituitary adenomas from pre-clinical level to clinical use.

First-in-Humans Study of the SSTR Antagonist 177Lu-DOTA-LM3 for Peptide Receptor Radionuclide Therapy in Patients with Metastatic Neuroendocrine Neoplasms: Dosimetry, Safety, and Efficacy.

The objective of this study was to assess the safety, dosimetry, and efficacy of the 177Lu-labeled somatostatin receptor (SSTR) antagonist DOTA-p-Cl-Phe-cyclo(d-Cys-Tyr-d-4-amino-Phe(carbamoyl)-Lys-Thr-Cys)d-Tyr-NH2 (177Lu-DOTA-LM3) in patients with metastatic neuroendocrine neoplasms (NENs). Methods: Fifty-one patients (aged 27-76 y; mean, 51.6 ± 13.9 y) with metastatic NENs underwent peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTA-LM3 between August 2017 and December 2019. The median administered activity per cycle was 6.1 ± 0.88 GBq (range, 2.8-7.4 GBq). 68Ga-NODAGA-LM3 PET/CT was used for patient selection and follow-up after 177Lu-DOTA-LM3 PRRT. Morphologic and molecular responses were evaluated in accordance with RECIST 1.1 and the criteria of the European Organisation for Research and Treatment of Cancer (EORTC). Treatment-related adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. Dosimetry was performed on 11 patients and compared with the SSTR agonist 177Lu-DOTATOC in 247 patients undergoing PRRT on the same dosimetry protocol. Results: Higher uptake and a longer effective half-life were found for 177Lu-DOTA-LM3 than for the agonist 177Lu-DOTATOC in the whole body and in the kidneys, spleen, and metastases, resulting in higher mean absorbed organ and tumor doses. All patients tolerated therapy without any serious acute adverse effects. Mild nausea without vomiting was observed in 5 (9.8%) patients; no other symptoms were reported. The most severe delayed adverse event was Common Terminology Criteria (CTC)-3 thrombocytopenia in 3 (5.9%) patients. Neither CTC-4 thrombocytopenia nor CTC-3-4 anemia or leukopenia was observed after treatment. No significant decline in renal function was observed, nor was hepatotoxicity. According to RECIST 1.1, disease control could be reached in 40 patients (disease control rate, 85.1%) of the 47 patients monitored after 177Lu-DOTA-LM3 PRRT, with a partial response in 17 (36.2%) and stable disease in 23 (48.9%), whereas 7 patients (14.9%) had progressive disease, and by EORTC criteria, there was complete remission in 2 patients (4.3%), partial remission in 21 (44.7%), stable disease in 18 (38.3%), and progressive disease in 6 (12.8%). Conclusion: The antagonist PRRT with 177Lu-DOTA-LM3 could be administered without severe adverse effects and was well tolerated by most patients, with thrombocytopenia occurring in only a few. No other severe adverse effects were observed; in particular, there was no nephrotoxicity. The SSTR antagonist 177Lu-DOTA-LM3 appears to be promising for PRRT, provides a favorable biodistribution and higher tumor radiation doses than SSTR agonists, and was effective in treating advanced metastatic NENs, especially in patients with low or no SSTR agonist binding, even achieving complete remission in some patients.

Somatostatin receptor radionuclide therapy in neuroendocrine tumors.

Peptide receptor radionuclide therapy (PRRT) using 177Lu-DOTATATE has been approved for the treatment of gastroenteropancreatic NETs. An understanding of benefits and risks is important for the appropriate implementation of this therapy. This review summarizes study data supporting the use of radiolabeled somatostatin analogs for the treatment of advanced NETs and highlights risks, including potential toxicities in specific populations. Key ongoing clinical trials, including randomized studies, are designed to better define the position of PRRT within the broader therapeutic landscape. Preclinical and early-phase human studies are focused on the development of novel somatostatin-receptor agonists and antagonists, new radionuclides, and radiosensitizing combination therapies.

Multimodal Imaging of 2-Cycle PRRT with 177Lu-DOTA-JR11 and 177Lu-DOTATOC in an Orthotopic Neuroendocrine Xenograft Tumor Mouse Model.

Peptide receptor radionuclide therapy (PRRT) using radiolabeled somatostatin receptor (SSTR) analogs is a common approach in advanced neuroendocrine neoplasms. Recently, SSTR antagonists have shown promising results for imaging and therapy due to a higher number of binding sites than in commonly used agonists. We evaluated PRRT with SSTR agonist 177Lu-DOTATOC and antagonist 177Lu-DOTA-JR11 longitudinally in an orthotopic murine pancreatic neuroendocrine neoplasm model expressing human SSTR2. Morphologic and metabolic changes during treatment were assessed using multimodal imaging, including hybrid PET/MRI and SPECT/CT. Methods: In vitro radioligand binding and internalization assays and cell-cycle analysis were performed. SSTR2-transfected BON cells (BON-SSTR2) were used for in vivo experiments. Tumor-bearing mice received 2 intravenous injections of 100 μL of saline, 30 MBq of 177Lu-DOTATOC, or 20 MBq of 177Lu-DOTA-JR11 with an interval of 3 wk. Weekly T2-weighted MRI was performed for tumor monitoring. Viability of the tumor tissue was assessed by 18F-FDG PET/MRI once after PRRT. Tumor and kidney uptake of the respective radiopharmaceuticals was measured 24 h after injection by SPECT/CT. Results: Compared with 177Lu-DOTATOC, 177Lu-DOTA-JR11 treatment resulted in an increased accumulation of cells in G2/M phase. Animals treated with the SSTR antagonist showed a significant reduction in tumor size (P < 0.001) and an increased median survival (207 d; interquartile range [IQR], 132-228) compared with 177Lu-DOTATOC (126 d; IQR, 118-129). SPECT/CT revealed a 4-fold higher median tumor uptake for the antagonist and a 3-fold higher tumor-to-kidney ratio in the first treatment cycle. During the second therapy cycle, tumor uptake of 177Lu-DOTATOC was significantly lower (P = 0.01) whereas 177Lu-DOTA-JR11 uptake remained stable. Imaging of tumor morphology indicated comparatively larger necrotic fractions for 177Lu-DOTA-JR11 despite further tumor growth. These results were confirmed by 18F-FDG PET, revealing the least amount of viable tumor tissue in 177Lu-DOTA-JR11-treated animals, at 6.2% (IQR, 2%-23%). Conclusion:177Lu-DOTA-JR11 showed a higher tumor-to-kidney ratio and a more pronounced cytotoxic effect than did 177Lu-DOTATOC. Additionally, tumor uptake was more stable over the course of 2 treatment cycles.