SSTR Expression

This comprehensive review delves into the current practice, discussing the use of the various Food and Drug Administration-approved SSTR-agonist positron emission tomography tracers and the predictive imaging biomarkers, and elaborating on 177Lu-DOTATATE peptide receptor radionuclide therapy including the evolving areas of posttherapy imaging practices and peptide receptor radionuclide therapy retreatment. SSTR-targeted imaging and therapy can also be used in patients with PPGL; however, this patient population has demonstrated the best outcomes from norepinephrine transporter-targeted therapy with 131I-metaiodobenzylguanidine. Metaiodobenzylguanidine theranostics for PPGL will be discussed, noting that in 2024 it became commercially unavailable in the United States. Therefore, the use and reported success of SSTR theranostics for PPGL will also be explored.

The fixed relative threshold method was found to be the most effective and easily applicable method to measure SRETV on pretreatment 68Ga-DOTATATE PET/CT to predict prognosis in GEPNET patients. WB-SRETV45% (cutoff value of 11.8 cm3) and WB-SRETV60% (cutoff value of 6.3 cm3) were found to be the strongest predictors of prognosis in GEPNET patients.

SSTR PET is mandated to determine eligibility for peptide receptor radionuclide therapy. Here, the role of imaging to aid management of NEN is reviewed.

P1, N=10, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Recruiting --> Active, not recruiting

Radiomics features GLSZM-ZSNU and IB-TLSRE appear to reflect HNPGLs SDHx status and tumor behavior (metastatic vs. non-metastatic). If validated, especially IB-TLSRE might represent a simple and time-efficient radiomic index for SDHx variants early screening and prediction of tumor behavior in HNPGL cases.

Knowledge and consideration of these factors in adjusting [177Lu]Lu-oxodotreotide treatment regimen could help prevent or reduce the severity of these toxicities. Further studies are still warranted to refine these results and improve treatment management.

P1, N=10, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Sep 2024 --> Sep 2025 | Trial primary completion date: Sep 2024 --> Sep 2025

The mean absorbed dose by the kidneys was not correlated with nephrotoxicity during the studied period. In patients treated with [177Lu]Lu-DOTATATE for GEP-NETs, tumor and healthy organ dosimetry can predict survival and toxicities, thus influencing clinical management.

We treated cells derived from 23 NF-PitNETs with ITF2984, and a subset of them with octreotide, pasireotide (SRLs with high affinity for SSTR2 or 5, respectively), or cabergoline (DRD2 agonist) and we measured cell proliferation and apoptosis. In our model, SSTR3 expression levels did not correlate with ITF2984 antiproliferative nor proapoptotic effects. In conclusion, our data support a possible use of ITF2984 in the pharmacological treatment of NF-PitNET.

After pursuing other alternative treatments, including chemotherapy (ie, carboplatin, etoposide, capecitabine, temozolomide, and paclitaxel), everolimus, and atezolizumab, she returned with significant progression, including innumerable subcutaneous nodules, left pleura metastasis, multiple bone metastases, and brain metastases. To date, she has maintained sustained benefit for at least 1 year from initiation of entrectinib. Here, we present the first case of a female patient with metastatic AC harboring the ETV6-NTRK2 fusion, and successfully treated with entrectinib, providing evidence for the application of entrectinib in patients with NTRK-positive AC, and underscoring the critical role of molecular profiling for such cases.

PRRT holds a favorable toxicity profile, and it is associated with a prolonged time to progression, reduction of symptoms, and improved patients' quality of life. In light of further optimization, different new strategies have been investigated, along with the development of new radiopharmaceuticals.

In contrast to the more commonly used external beam radiation, we explored the feasibility of combining chimeric antigen receptor (CAR) T cell therapy with targeted radionuclide therapy (TRT), which is achieved by delivering β-emitting 177Lu-DOTATATE to tumor via tumor-infiltrating CAR T cells that express somatostatin receptor 2 (SSTR2)...However, this higher dose led to cell death in both the tumor and CAR T cells. Our study suggests that there may exist an optimum range of TRT dosage that can enhance T cell activity and sensitize tumor cells to T cell killing, which may result in more durable tumor control compared to a higher radiation dose.

P2, N=20, Recruiting, Jules Bordet Institute | Trial completion date: Sep 2023 --> Jun 2024 | Trial primary completion date: Sep 2023 --> Jun 2024

Overall, hybrid imaging offers valuable insights in the diagnosis, staging, and treatment planning of NENs. Further research is needed to refine response assessment criteria and standardize reporting guidelines.

This denies many patients with adequate somatostatin receptor expression and biochemical profiles from the beneficial effects of PRRT on the quality of life, daily function, and overall survival. The 2 cases highlight the favorable response of PRRT in patients with metastatic neuroendocrine tumor having a very poor performance status initially.

This initial study suggests that 225Ac-DOTATATE is a potentially promising option for treating NENs with elevated SSTR expression, with an acceptable toxicity profile and well-tolerated adverse effects.

P1, N=9, Recruiting, Molecular Targeting Technologies, Inc. | Trial completion date: Mar 2024 --> Mar 2025 | Trial primary completion date: Dec 2023 --> Dec 2024

P3, N=300, Active, not recruiting, Lund University Hospital | Not yet recruiting --> Active, not recruiting

P1, N=29, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting

P1, N=29, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jan 2024 --> Jun 2024 | Trial primary completion date: Jan 2024 --> Jun 2024

Raising awareness of OHSS due to functioning gonadotroph tumors is crucial to prevent unnecessary ovarian surgery. Comprehensive histological analysis may provide useful information to better understand the characteristics of functioning gonadotroph tumors.

Furthermore, SSTR2 expression can be used as prognostic factors. When metastatic disease occurs, SSTR2 expression can be used a possible target for somatostatin analogues.

We focused on assessing whether pretreating cells with inhibitors for phosphatidylinositol 3-kinase (PI3K) and mammalian target for rapamycin (mTOR) could enhance the antiproliferative effects of lanreotide...Additionally, combination treatment consisting of BYL719 and everolimus plus lanreotide tested in NCI-H720 and NCI-H727 led to diminished cell proliferation in a dose-dependent manner...Interestingly, SSTR expression reinduction could be exploited in therapeutic and diagnostic applications. The overall results of this study support the evaluation of combination-based therapies using lanreotide in preclinical studies to further increase its antiproliferative effect and ultimately facilitate its use in high-grade tumors.

Although 18F-FDG PET/CT has been shown to present with increased metabolic activity in PMEC, literature does not report increased somatostatin receptor expression in these tumors. We present the case of a 15-year-old boy where PMEC mimicked a typical carcinoid of the lung on DOTANOC PET/CT by showing significant uptake on 68Ga-DOTANOC.

SSTR2A negativity was correlated with extra-adrenal tumor location and PVs in cluster 1B and cluster 2 genes such as VHL, FGFR1 and HRAS. Immunohistochemistry of SSTR2A should be taken into consideration in the personalized management of PGLs.

In conclusion, in consecutive patients with well-differentiated NETs, the detection rate of NLM is higher with pMR than with DT-PET. However, when excluding patients whose tumors do not overexpress somatostatin receptors (13% of the cohort), high concordance in the detection of NLM is observed between DT PET and pMR.

P1, N=6, Active, not recruiting, Providence Health & Services | Recruiting --> Active, not recruiting | N=90 --> 6 | Trial completion date: Dec 2031 --> Dec 2026 | Trial primary completion date: Dec 2027 --> Dec 2024

Additionally, somatostatin and analogues' role in hormone secretion regulation, tumor growth, and survival is emphasized, presenting relevant therapeutic examples. In conclusion, this review advances the knowledge of receptor-ligand interactions and signaling pathways in somatostatin receptors, with potential for improved neuroendocrine tumor treatments.

In a large cohort of patients with advanced CUP-NETs treated with PRRT in a real-world scenario and followed up to 14 years after the commencement, PRRT has demonstrated favorable and clinically significant efficacy and survival with minimal and acceptable side effects. Our results indicate that PRRT is a well-tolerated and effective treatment option for patients with metastatic CUP-NETs expressing somatostatin receptors.

Minimal tumor-absorbed dose at C1 is predictive of outcome in patients with GEP-NETs treated with PRRT, providing a basis for personalized dosimetry-guided treatment strategies. An SSTR TV decrease after C1 could be used for early therapy response assessment as a predictor of PRRT outcome.

P2, N=11, Active, not recruiting, Advanced Accelerator Applications | Recruiting --> Active, not recruiting

P1, N=29, Recruiting, National Cancer Institute (NCI) | Phase classification: P1b --> P1

Moreover, in most studies gender was not a predictor of response to treatment. Studies specifically designed to address this issue are needed to develop gender-specific therapeutic algorithms, improving patients' prognosis and quality of life.

Most metastatic lung NETs lack uniform SSTR expression and are thus suboptimal candidates for SSTR-targeted therapy. SSTR imaging in lung NETs should be evaluated carefully for uniformity of expression.

The mechanistic target of rapamycin complex 1 (mTORC1) inhibitor everolimus is one of the few approved therapies for locally advanced and metastatic neuroendocrine tumours (NETs). Of all groups, the everolimus-resistant combination-treated group survived longest (69 d). Combination treatment with everolimus and alpelisib seems promising to overcome everolimus resistance in neuroendocrine neoplasms, and should be further examined in a clinical trial.

P2, N=32, Active, not recruiting, Nicholas Fidelman, MD | Trial completion date: Dec 2025 --> May 2026 | Trial primary completion date: Sep 2023 --> May 2024

Baseline TBR as well as changes in TBR were significantly associated with PFS and OS and may improve patient selection and morphological response assessment. Future trials need to assess the role of TBR for therapy monitoring also during PRRT and prospectively explore TBR as a predictive marker for patient selection.

The presented data displays no relevant correlations between increased SSTR expression and cellularity in patients with meningioma of the skull base. SSTR-PET and DWI thus may offer complementary information on tumor characteristics of meningioma.

We present a rare case, where posttherapeutic scintigraphy revealed vigorous uptake of 177Lu-DOTATATE even in the 68Ga-DOTATATE PET-negative liver metastases. Follow-up PET/CT showed a partial response to therapy.

SSTR subtypes 2A, 2B, and 5 correlated significantly with SUV in meningioma patients. The developed radiomic model based on ADC maps effectively reproduces SUV using [68Ga]Ga-DOTATOC PET.

Our results identify SSTR2 as a promising target for COAD immunotherapy. Our findings provide new insights into the biological functions of the SSTR family and their implications for the prognosis of COAD.