scholarly journals Emerging Treatment Options for Gastroenteropancreatic Neuroendocrine Tumors

2020 ◽  
Vol 9 (11) ◽  
pp. 3655
Author(s):  
Mauro Cives ◽  
Eleonora Pelle’ ◽  
Jonathan Strosberg
Keyword(s):  
Clinical Trials ◽  
Growth Factor ◽  
Neuroendocrine Tumors ◽  
Treatment Options ◽  
Somatostatin Receptor ◽  
Growth Factor Receptor ◽  
Small Samples ◽  
Neuroendocrine Neoplasms ◽  
Two Phase ◽  
Gastroenteropancreatic Neuroendocrine Tumors

Treatment options for neuroendocrine tumors (NETs) and carcinomas (NECs) are expanding. Early-phase studies have shown preliminary evidence of the antitumor activity of alpha-emitting peptide receptor radionuclide therapy (PRRT), and novel radiopeptides incorporating somatostatin receptor antagonists (rather than agonists) have been developed. Several tyrosine kinase inhibitors (TKIs) with antiangiogenic potential have been evaluated in patients with NETs, including lenvatinib, axitinib, cabozantinib and pazopanib. Recently, two phase 3 clinical trials have demonstrated the efficacy and safety of surufatinib, an inhibitor of vascular endothelial growth factor receptor (VEGFR)-1, -2, -3, fibroblast growth factor receptor (FGFR)-1 and colony stimulating factor-1 receptor (CSF-1R), in patients with pancreatic and extra-pancreatic NETs. Multiple clinical trials of combination immunotherapy have been recently completed, but interpretation of the results is hampered by small samples sizes and discordant outcomes. This review summarizes recent data on emerging treatments for neuroendocrine neoplasms.

MC044h, a phase II trial of sorafenib in patients (pts) with metastatic neuroendocrine tumors (NET): A Phase II Consortium (P2C) study

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4504-4504 ◽  
Author(s):  
T. J. Hobday ◽  
J. Rubin ◽  
K. Holen ◽  
J. Picus ◽  
R. Donehower ◽  
...  
Keyword(s):  
Growth Factor ◽  
Neuroendocrine Tumors ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Treatment Options ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Uncontrolled Hypertension ◽  
Eligibility Criteria ◽  
Grade 3

4504 Background: Treatment options for metastatic NET, including islet cell carcinoma (ICC) and carcinoid tumor (CT), are limited. These tumors frequently express vascular endothelial growth factor receptor-2 (VEGFR-2) and platelet derived growth factor receptor receptor-β (PDGFR-β). Sorafenib, a small-molecule inhibitor of the VEGFR-2 and PDGFR-β tyrosine kinase domains, is a rational targeted therapy to evaluate in NET. Methods: Eligibility criteria included: ECOG PS = 2, = 1 prior chemotherapy, good organ function and signed informed consent. Prior interferon and prior or concurrent octreotide at a stable dose were allowed. Pts unable to take oral medications, with uncontrolled hypertension or with symptomatic coronary artery disease were excluded. Pts received sorafenib 400 mg po BID. Primary endpoint was response by RECIST in two cohorts (ie, CT and ICC) using separate 2-stage phase II designs. Results: 93 pts were enrolled: (50 CT, 43 ICC). For pts evaluable for the primary endpoint, 4 of 41 (10%) CT pts and 4 of 41 (10%) ICC pts had a PR. There were 3 minor responses (MR = 20–29% decrease in sum of target lesion diameters) in CT pts and 9 MRs in ICC pts for PR+MR rate of 17% for CT pts and 32% for ICC pts. For pts evaluable, 6-month progression-free survival was observed in 8/20 CT and 14/23 ICC pts. Grade 3–4 toxicity occurred in 43% of pts, with skin (20%), GI (7%) and fatigue (9%) most common. Translational studies from tumor tissue will be presented. Conclusions: Sorafenib at 400 mg po BID has modest activity in metastatic neuroendocrine tumors, with frequent grade = 3 toxicity. Supported by NOI CM6225. No significant financial relationships to disclose.

scholarly journals Current treatments and future potential of surufatinib in neuroendocrine tumors (NETs)

2021 ◽  
Vol 13 ◽  
pp. 175883592110426
Author(s):  
Jianming Xu
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Neuroendocrine Tumors ◽  
Safety Profile ◽  
Kinase Inhibitor ◽  
Somatostatin Analogs ◽  
Growth Factor Receptor ◽  
Phase Iii ◽  
Tumor Resistance ◽  
Two Phase

Neuroendocrine tumors (NETs) are rare, heterogeneous, often indolent tumors that predominantly originate in the lungs and gastrointestinal tract. An understanding of the biology and tumor microenvironment of NETs has led to the development of molecularly targeted treatment options including somatostatin analogs, tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors and peptide receptor radionuclide therapy. Although increases in progression-free survival have been demonstrated, most currently approved NET therapies are limited by the development of tumor resistance. Surufatinib (HMPL-012, previously known as sulfatinib) is a new, oral, small-molecule tyrosine kinase inhibitor that potently inhibits vascular endothelial growth-factor receptor 1–3, fibroblast growth-factor receptor 1, and colony-stimulating-factor-1 receptor. This unique combination of molecular activities inhibits tumor angiogenesis, regulates tumor-immune evasion, and may decrease tumor resistance. Surufatinib demonstrated statistically significant, clinically meaningful antitumor activity, including tumor shrinkage, in two phase III studies recently completed in China in advanced pancreatic NETs and advanced extrapancreatic NETs. The safety profile of surufatinib in neuroendocrine tumors studies was consistent with previous surufatinib clinical studies. In an ongoing study in United States (US) patients with NETs of pancreatic origin and NETs of extrapancreatic origin previously treated with everolimus or sunitinib, surufatinib has also demonstrated promising efficacy. Furthermore, the pharmacokinetic and safety profile of surufatinib in US patients is similar to data collected in studies done in China. These positive phase III results support the efficacy of surufatinib in patients with advanced, progressive, well-differentiated NETs regardless of tumor origin.

scholarly journals Targeted Therapies in Advanced Biliary Tract Cancer: An Evolving Paradigm

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2039 ◽  
Author(s):  
Sakti Chakrabarti ◽  
Mandana Kamgar ◽  
Amit Mahipal
Keyword(s):  
Clinical Trials ◽  
Growth Factor ◽  
Biliary Tract ◽  
Targeted Therapies ◽  
Treatment Options ◽  
Growth Factor Receptor ◽  
Braf Mutations ◽  
Curative Surgery ◽  
Her Family ◽  
Idh Mutations

Biliary tract cancers (BTCs) are a heterogeneous group of adenocarcinomas that originate from the epithelial lining of the biliary tree. BTCs are characterized by presentation with advanced disease precluding curative surgery, rising global incidence, and a poor prognosis. Chemotherapy is the mainstay of the current treatment, which results in a median overall survival of less than one year, underscoring the need for novel therapeutic agents and strategies. Next-generation sequencing-based molecular profiling has shed light on the underpinnings of the complex pathophysiology of BTC and has uncovered numerous actionable targets, leading to the discovery of new therapies tailored to the molecular targets. Therapies targeting fibroblast growth factor receptor (FGFR) fusion, isocitrate dehydrogenase (IDH) mutations, the human epidermal growth factor receptor (HER) family, DNA damage repair (DDR) pathways, and BRAF mutations have produced early encouraging results in selected patients. Current clinical trials evaluating targeted therapies, as monotherapies and in combination with other agents, are paving the way for novel treatment options. Genomic profiling of cell-free circulating tumor DNA that can assist in the identification of an actionable target is another exciting area of development. In this review, we provide a contemporaneous appraisal of the evolving targeted therapies and the ongoing clinical trials that will likely transform the therapeutic paradigm of BTC.

scholarly journals Protein Tyrosine Kinases: Their Roles and Their Targeting in Leukemia

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 184
Author(s):  
Kalpana K. Bhanumathy ◽  
Amrutha Balagopal ◽  
Frederick S. Vizeacoumar ◽  
Franco J. Vizeacoumar ◽  
Andrew Freywald ◽  
...  
Keyword(s):  
Growth Factor ◽  
Protein Kinase ◽  
Tyrosine Kinase ◽  
Protein Kinases ◽  
Tyrosine Kinases ◽  
Treatment Options ◽  
Growth Factor Receptor ◽  
Tyrosine Protein Kinase ◽  
Mesenchymal Epithelial Transition Factor ◽  
The Impact

Protein kinases constitute a large group of enzymes catalysing protein phosphorylation and controlling multiple signalling events. The human protein kinase superfamily consists of 518 members and represents a complicated system with intricate internal and external interactions. Protein kinases are classified into two main families based on the ability to phosphorylate either tyrosine or serine and threonine residues. Among the 90 tyrosine kinase genes, 58 are receptor types classified into 20 groups and 32 are of the nonreceptor types distributed into 10 groups. Tyrosine kinases execute their biological functions by controlling a variety of cellular responses, such as cell division, metabolism, migration, cell–cell and cell matrix adhesion, cell survival and apoptosis. Over the last 30 years, a major focus of research has been directed towards cancer-associated tyrosine kinases owing to their critical contributions to the development and aggressiveness of human malignancies through the pathological effects on cell behaviour. Leukaemia represents a heterogeneous group of haematological malignancies, characterised by an uncontrolled proliferation of undifferentiated hematopoietic cells or leukaemia blasts, mostly derived from bone marrow. They are usually classified as chronic or acute, depending on the rates of their progression, as well as myeloid or lymphoblastic, according to the type of blood cells involved. Overall, these malignancies are relatively common amongst both children and adults. In malignant haematopoiesis, multiple tyrosine kinases of both receptor and nonreceptor types, including AXL receptor tyrosine kinase (AXL), Discoidin domain receptor 1 (DDR1), Vascular endothelial growth factor receptor (VEGFR), Fibroblast growth factor receptor (FGFR), Mesenchymal–epithelial transition factor (MET), proto-oncogene c-Src (SRC), Spleen tyrosine kinase (SYK) and pro-oncogenic Abelson tyrosine-protein kinase 1 (ABL1) mutants, are implicated in the pathogenesis and drug resistance of practically all types of leukaemia. The role of ABL1 kinase mutants and their therapeutic inhibitors have been extensively analysed in scientific literature, and therefore, in this review, we provide insights into the impact and mechanism of action of other tyrosine kinases involved in the development and progression of human leukaemia and discuss the currently available and emerging treatment options based on targeting these molecules.

scholarly journals Assessment of γ-H2AX and 53BP1 Foci in Peripheral Blood Lymphocytes to Predict Subclinical Hematotoxicity and Response in Somatostatin Receptor-Targeted Radionuclide Therapy for Advanced Gastroenteropancreatic Neuroendocrine Tumors

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1516
Author(s):  
Thorsten Derlin ◽  
Natalia Bogdanova ◽  
Fiona Ohlendorf ◽  
Dhanya Ramachandran ◽  
Rudolf A. Werner ◽  
...  
Keyword(s):  
Treatment Response ◽  
Neuroendocrine Tumors ◽  
Peripheral Blood ◽  
Somatostatin Receptor ◽  
Therapy Response ◽  
Strand Break ◽  
Peripheral Blood Lymphocytes ◽  
Radioligand Therapy ◽  
Gastroenteropancreatic Neuroendocrine Tumors ◽  
Blood Lymphocytes

Background: We aimed to characterize γ-H2AX and 53BP1 foci formation in patients receiving somatostatin receptor-targeted radioligand therapy, and explored its role for predicting treatment-related hematotoxicity, and treatment response. Methods: A prospective analysis of double-strand break (DSB) markers was performed in 21 patients with advanced gastroenteropancreatic neuroendocrine tumors. γ-H2AX and 53BP1 foci formation were evaluated in peripheral blood lymphocytes (PBLs) at baseline, +1 h and +24 h after administration of 7.4 GBq (177Lu)Lu-DOTA-TATE. Hematotoxicity was evaluated using standard hematology. Therapy response was assessed using (68Ga)Ga-DOTA-TATE PET/CT before enrollment and after 2 cycles of PRRT according to the volumetric modification of RECIST 1.1. Results: DSB marker kinetics were heterogeneous among patients. Subclinical hematotoxicity was associated with γ-H2AX and 53BP1 foci formation (e.g., change in platelet count vs change in γ-H2AX+ cells between baseline and +1 h (r = −0.6080; p = 0.0045). Patients showing early development of new metastases had less γ-H2AX (p = 0.0125) and less 53BP1 foci per cell at +1 h (p = 0.0289), and demonstrated a distinct kinetic pattern with an absence of DSB marker decrease at +24 h (γ-H2AX: p = 0.0025; 53BP1: p = 0.0008). Conclusions: Assessment of γ-H2AX and 53BP1 foci formation in PBLs of patients receiving radioligand therapy may hold promise for predicting subclinical hematotoxicity and early treatment response.

scholarly journals Loss of Phosphatase and Tensin Homolog or Phosphoinositol-3 Kinase Activation and Response to Trastuzumab or Lapatinib in Human Epidermal Growth Factor Receptor 2–Overexpressing Locally Advanced Breast Cancers

2011 ◽  
Vol 29 (2) ◽  
pp. 166-173 ◽  
Author(s):  
Bhuvanesh Dave ◽  
Ilenia Migliaccio ◽  
M. Carolina Gutierrez ◽  
Meng-Fen Wu ◽  
Gary C. Chamness ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Single Agent ◽  
Growth Factor Receptor ◽  
Breast Cancers ◽  
Trastuzumab Resistance ◽  
Epidermal Growth

Purpose Phosphatase and tensin homolog (PTEN) loss or activating mutations of phosphoinositol-3 (PI3) kinase (PIK3CA) may be associated with trastuzumab resistance. Trastuzumab, the humanized human epidermal growth factor receptor 2 (HER2) monoclonal antibody, and lapatinib, an epidermal growth factor receptor/HER2 tyrosine kinase inhibitor, are both established treatments for HER2-overexpressing breast cancers. Understanding of the cellular response to HER2-targeted therapies is needed to tailor treatments and to identify patients less likely to benefit. Methods We evaluated the effect of trastuzumab or lapatinib in three HER2-overexpressing cell lines. We confirmed the in vitro observations in two neoadjuvant clinical trials in patients with HER2 overexpression; 35 patients received trastuzumab as a single agent for the first 3 weeks, then docetaxel every 3 weeks for 12 weeks (trastuzumab regimen), whereas 49 patients received lapatinib as a single agent for 6 weeks, followed by trastuzumab/docetaxel for 12 weeks before primary surgery (lapatinib regimen). Apoptosis, Ki67, p-MAPK, p-AKT, and PTEN were assessed by immunohistochemistry. Genomic DNA was sequenced for PIK3CA mutations. Results Under low PTEN conditions, in vitro data indicate that lapatinib alone and in combination with trastuzumab was effective in decreasing p-MAPK and p-AKT levels, whereas trastuzumab was ineffective. In the clinical trials, we confirmed that low PTEN or activating mutation in PIK3CA conferred resistance to the trastuzumab regimen (P = .015), whereas low PTEN tumors were associated with a high pathologic complete response rate (P = .007). Conclusion Activation of PI3 kinase pathway is associated with trastuzumab resistance, whereas low PTEN predicted for response to lapatinib. These observations support clinical trials with the combination of both agents.

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