scholarly journals The future of somatostatin receptor ligands in acromegaly

2021 ◽  
Author(s):  
Monica R Gadelha ◽  
Luiz Eduardo Wildemberg ◽  
Leandro Kasuki
Keyword(s):  
Precision Medicine ◽  
First Generation ◽  
Somatostatin Receptor ◽  
New Drugs ◽  
Response To Treatment ◽  
Tumor Shrinkage ◽  
Receptor Ligands ◽  
Biochemical Control ◽  
Somatostatin Receptor Ligands ◽  
The Future

Abstract Currently, first-generation somatostatin receptor ligands (fg-SRLs), octreotide LAR and lanreotide autogel, are the mainstays of acromegaly treatment and achieve biochemical control in approximately 40% of patients and tumor shrinkage in over 60% of patients. Pasireotide, a second-generation SRL, shows higher efficacy with respect to both biochemical control and tumor shrinkage but has a worse safety profile. In this review, we discuss the future perspectives of currently available SRLs, focusing on the use of biomarkers of response and precision medicine, new formulations of these SRLs and new drugs, which are under development. Precision medicine, which is based on biomarkers of response to treatment, will help guide the decision-making process by allowing physicians to choose the appropriate drug for each patient and improving response rates. New formulations of available SRLs, such as oral, subcutaneous depot and nasal octreotide, may improve patients’ adherence to treatment and quality of life since there will be more options available that better suit each patient. Finally, new drugs, such as paltusotine, somatropin, ONO-5788 and ONO-ST-468, may improve treatment adherence and present higher efficacy than currently available drugs.

scholarly journals gsp Mutation Is Not a Molecular Biomarker of Long-Term Response to First-Generation Somatostatin Receptor Ligands in Acromegaly

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 4857
Author(s):  
Luiz Eduardo Wildemberg ◽  
Daniel Henriques ◽  
Paula C. L. Elias ◽  
Carlos Henrique de A. Lima ◽  
Nina R. de Castro Musolino ◽  
...  
Keyword(s):  
First Generation ◽  
Somatostatin Receptor ◽  
Receptor Ligands ◽  
Biochemical Control ◽  
Molecular Biomarker ◽  
Α Subunit ◽  
Cavernous Sinus Invasion ◽  
Somatostatin Receptor Ligands ◽  
Term Response

Background: It is still controversial if activating mutations in the stimulatory G-protein α subunit (gsp mutation) are a biomarker of response to first generation somatostatin receptor ligands (fg-SRL) treatment in acromegaly. Thus, we aimed to evaluate whether gsp mutation predicts long-term response to fg-SRL treatment and to characterize the phenotype of patients harboring gsp mutations. Methods: GNAS1 sequencing was performed by Sanger. SST2 and SST5 were analyzed by immunohistochemistry (IHC) and real-time RT-PCR. The cytokeratin granulation pattern was evaluated by IHC. Biochemical control was defined as GH < 1.0 ng/mL and normal age-adjusted IGF-I levels. Results: gsp mutation was found in 54 out of 136 patients evaluated. Biochemical control with fg-SRL treatment was similar in gsp+ and gsp- patients (37% vs. 25%, p = 0.219). Tumors harboring gsp mutation were smaller (p = 0.035) and had a lower chance of invading cavernous sinuses (p = 0.001). SST5 protein (p = 0.047) and mRNA (p = 0.013) expression levels were higher in wild-type tumors. Conclusions: In this largest series available in the literature, we concluded that gsp is not a molecular biomarker of response to fg-SRL treatment in acromegaly. However, the importance of its negative association with cavernous sinus invasion and SST5 expression needs to be further investigated.

MRI follow‐up of patients with acromegaly treated after surgery with first‐generation somatostatin receptor ligands

2021 ◽  
Author(s):  
Naia Grandgeorge ◽  
Giovanni Barchetti ◽  
Solange Grunenwald ◽  
Fabrice Bonneville ◽  
Philippe Caron
Keyword(s):  
First Generation ◽  
Somatostatin Receptor ◽  
Receptor Ligands ◽  
Somatostatin Receptor Ligands

scholarly journals Maintenance of Acromegaly Control in Patients Switching From Injectable Somatostatin Receptor Ligands to Oral Octreotide

2020 ◽  
Vol 105 (10) ◽  
pp. e3785-e3797 ◽  
Author(s):  
Susan L Samson ◽  
Lisa B Nachtigall ◽  
Maria Fleseriu ◽  
Murray B Gordon ◽  
Marek Bolanowski ◽  
...  
Keyword(s):  
Somatostatin Receptor ◽  
Control Measures ◽  
Double Blind Study ◽  
Efficacy And Safety ◽  
Receptor Ligands ◽  
Biochemical Control ◽  
Phase 3 ◽  
Double Blind ◽  
Somatostatin Receptor Ligands ◽  
End Of Treatment

Abstract Purpose The phase 3 CHIASMA OPTIMAL trial (NCT03252353) evaluated efficacy and safety of oral octreotide capsules (OOCs) in patients with acromegaly who previously demonstrated biochemical control while receiving injectable somatostatin receptor ligands (SRLs). Methods In this double-blind study, patients (N = 56) stratified by prior SRL dose were randomly assigned 1:1 to OOC or placebo for 36 weeks. The primary end point was maintenance of biochemical control at the end of treatment (mean insulin-like growth factor 1 [IGF-1] ≤ 1.0 × upper limit of normal [ULN]; weeks 34 and 36). Time to loss of IGF-1 response and proportion requiring reversion to injectable SRLs were assessed as broader control measures. Results Mean IGF-1 measurements were 0.80 and 0.97 × ULN for OOC and 0.84 and 1.69 × ULN for placebo, at baseline and end of treatment, respectively. Mean growth hormone (GH) changed from 0.66 to 0.60 ng/mL for OOCs and 0.90 to 2.57 ng/mL for placebo. Normalization of IGF-1 levels (≤ 1.0 × ULN) was maintained in 58.2% for OOCs vs 19.4% for placebo (P = .008); GH levels were maintained (&lt; 2.5 ng/mL) in 77.7% for OOC vs 30.4% for placebo (P = .0007). Median time to loss of response (IGF-1 &gt; 1.0 or ≥ 1.3 × ULN definitions) for patients receiving placebo was 16 weeks; for patients receiving OOCs, it was not reached for both definitions during the 36-week trial (P &lt; .0001). Of the patients in the OOC group, 75% completed the trial on oral therapy. The OOC safety profile was consistent with previous SRL experience. Conclusions OOCs may be an effective therapy for patients with acromegaly who previously were treated with injectable SRLs.

Machine Learning-based Prediction Model for Treatment of Acromegaly With First-generation Somatostatin Receptor Ligands

2021 ◽  
Author(s):  
Luiz Eduardo Wildemberg ◽  
Aline Helen da Silva Camacho ◽  
Renan Lyra Miranda ◽  
Paula C L Elias ◽  
Nina R de Castro Musolino ◽  
...  
Keyword(s):  
Machine Learning ◽  
Support Vector Machine ◽  
Prediction Model ◽  
Predictive Value ◽  
First Generation ◽  
Somatostatin Receptor ◽  
Support Vector ◽  
Receptor Ligands ◽  
Somatostatin Receptor Ligands ◽  
Igf I

Abstract Context Artificial intelligence (AI), in particular machine learning (ML), may be used to deeply analyze biomarkers of response to first-generation somatostatin receptor ligands (fg-SRLs) in the treatment of acromegaly. Objective To develop a prediction model of therapeutic response of acromegaly to fg-SRL. Methods Patients with acromegaly not cured by primary surgical treatment and who had adjuvant therapy with fg-SRL for at least 6 months after surgery were included. Patients were considered controlled if they presented growth hormone (GH) &lt;1.0 ng/mL and normal age-adjusted insulin-like growth factor (IGF)-I levels. Six AI models were evaluated: logistic regression, k-nearest neighbor classifier, support vector machine, gradient-boosted classifier, random forest, and multilayer perceptron. The features included in the analysis were age at diagnosis, sex, GH, and IGF-I levels at diagnosis and at pretreatment, somatostatin receptor subtype 2 and 5 (SST2 and SST5) protein expression and cytokeratin granulation pattern (GP). Results A total of 153 patients were analyzed. Controlled patients were older (P = .002), had lower GH at diagnosis (P = .01), had lower pretreatment GH and IGF-I (P &lt; .001), and more frequently harbored tumors that were densely granulated (P = .014) or highly expressed SST2 (P &lt; .001). The model that performed best was the support vector machine with the features SST2, SST5, GP, sex, age, and pretreatment GH and IGF-I levels. It had an accuracy of 86.3%, positive predictive value of 83.3% and negative predictive value of 87.5%. Conclusion We developed a ML-based prediction model with high accuracy that has the potential to improve medical management of acromegaly, optimize biochemical control, decrease long-term morbidities and mortality, and reduce health services costs.

scholarly journals Pasireotide in the Personalized Treatment of Acromegaly

2021 ◽  
Vol 12 ◽  
Author(s):  
Manel Puig-Domingo ◽  
Ignacio Bernabéu ◽  
Antonio Picó ◽  
Betina Biagetti ◽  
Joan Gil ◽  
...  
Keyword(s):  
First Generation ◽  
Somatostatin Receptor ◽  
Receptor Ligands ◽  
First Line ◽  
First Line Therapy ◽  
Somatostatin Receptor Ligands ◽  
Therapeutic Algorithm ◽  
Surgical Failure ◽  
Positive Effect ◽  
T2 Mri

The delay in controlling the disease in patients who do not respond to first-line treatment with first generation somatostatin receptor ligands (first-generation SRLs) can be quantified in years, as every modification in the medical therapy requires some months to be fully evaluated. Considering this, acromegaly treatment should benefit from personalized medicine therapeutic approach by using biomarkers identifying drug response. Pasireotide has been positioned mostly as a compound to be used in first-generation SRLs resistant patients and after surgical failure, but sufficient data are now available to indicate it is a first line therapy for patients with certain characteristics. Pasireotide has been proved to be useful in patients in which hyperintensity T2 MRI signal is shown and in those depicting low SST2 and high expression of SST5, low or mutated AIP condition and sparsely granulated immunohistochemical pattern. This combination of clinical and pathological characteristics is unique for certain patients and seems to cluster in the same cases, strongly suggesting an etiopathogenic link. Thus, in this paper we propose to include this clinico-pathologic phenotype in the therapeutic algorithm, which would allow us to use as first line medical treatment those compounds with the highest potential for achieving the fastest control of GH hypersecretion as well as a positive effect upon tumor shrinkage, therefore accelerating the implementation of precision medicine for acromegaly. Moreover, we suggest the development, validation and clinical use of a pasireotide acute test, able to identify patients responsive to pasireotide LAR as the acute octreotide test is able to do for SRLs.

scholarly journals MON-LB55 Biochemical Control of Most Patients Reverting to Injectable Long-Acting Somatostatin Receptor Ligands Is Achieved After One Dose: Results From the Phase 3, Randomized, Double Blind, Placebo-Controlled Optimal Study

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Maria Fleseriu ◽  
Susan Leanne Samson ◽  
Lisa B Nachtigall ◽  
Artak Labadzhyan ◽  
Atanaska Elenkova ◽  
...  
Keyword(s):  
Rescue Therapy ◽  
Somatostatin Receptor ◽  
Clinical Signs ◽  
Placebo Treatment ◽  
Receptor Ligands ◽  
Biochemical Control ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Somatostatin Receptor Ligands ◽  
Igf I

Abstract Background: Injectable somatostatin receptor ligands (SRLs) are currently the most widely used medical therapy for acromegaly worldwide. Oral octreotide capsules (OOC) have been formulated as a potential therapy for this disorder and the safety and efficacy were evaluated in the CHIASMA OPTIMAL pivotal study (Samson et al. ENDO 2020). As reported, mean IGF-I levels of the OOC treatment group were maintained within normal range at the end of treatment in all patients. However, some patients may not respond to OOC treatment (25% of OOC group and 68% of placebo groups required rescue, P=0.003). This analysis describes the degree and rapidity with which patients achieve biochemical control (IGF-I ≤1.0 x ULN) when reverted to their prior injectable SRL treatment. Methods: Patients with confirmed acromegaly and receiving a stable dose of injectable SRL (≥3 months) were randomized to OOC (40mg/day; N=28) or placebo (N=28) for 36 weeks. Patients were dose titrated to 60 or 80mg of OOC (or placebo) through week 24 at investigator discretion based on increased IGF-I levels and/or worsening acromegaly signs/symptoms. Patients could be rescued via reversion to prior injectable SRL therapy if they met the predefined withdrawal criteria (i.e., IGF-I ≥1.3 x upper limit of normal [ULN] for 2 consecutive visits on the highest dose, and exacerbation of clinical signs/symptoms) or discontinued treatment early for any other reason. In the study, 7 patients in the OOC group and 19 in the placebo group required rescue. The change in IGF-I from Baseline was compared to the end of the Double-blind Placebo Controlled period. Results: In patients rescued up to week 32 and in whom there were at least 4 weeks of follow up, baseline IGF-I levels (mean of Screening Visit 2 and Baseline) were 0.80 and 0.87 x ULN in the OOC and placebo groups, respectively. In patients receiving rescue therapy, the end of study IGF-I levels (mean of week 34 and 36) were 0.80 and 0.89 x ULN in the OOC and placebo groups, respectively, virtually unchanged. The median time to return to normal baseline IGF-I values following loss of response was 4.0 weeks after discontinuing OOC and 4.0 weeks after discontinuing placebo treatment. Therefore, most patients who required rescue following a short trial of therapy with OOC returned to their baseline values following a single SRL injection. Conclusion: Most treatment failures in the CHIASMA OPTIMAL trial (on either OOC or placebo) rescued with injectable SRL re-established their baseline response levels after a single injectable SRL administration (at pre-study dose). Based on this data, patients may potentially be treated with OOC and for those not responding, either not biochemically controlled or who have adverse effects, they may be able to return to injectable SRLs with immediate IGF-I control after one SRL injection.

scholarly journals MANAGEMENT OF ENDOCRINE DISEASE: Personalized medicine in the treatment of acromegaly

2018 ◽  
Vol 178 (3) ◽  
pp. R89-R100 ◽  
Author(s):  
Leandro Kasuki ◽  
Luiz Eduardo Wildemberg ◽  
Mônica R Gadelha
Keyword(s):  
Personalized Medicine ◽  
First Generation ◽  
Somatostatin Receptor ◽  
Current Status ◽  
High Morbidity ◽  
Trial And Error ◽  
Receptor Ligands ◽  
Endocrine Disease ◽  
Somatostatin Receptor Ligands ◽  
Personalized Approach

Acromegaly is associated with high morbidity and elevated mortality when not adequately treated. Surgery is the first-line treatment for most patients as it is the only one that can lead to immediate cure. In patients who are not cured by surgery, treatment is currently based on a trial-and-error approach. First-generation somatostatin receptor ligands (fg-SRL) are initiated for most patients, although approximately 25% of patients present resistance to this drug class. Some biomarkers of treatment outcome are described in the literature, with the aim of categorizing patients into different groups to individualize their treatments using a personalized approach. In this review, we will discuss the current status of precision medicine for the treatment of acromegaly and future perspectives on the use of personalized medicine for this purpose.

Sign in / Sign up

Export Citation Format

Share Document