scholarly journals SUN-485 Combined Treatment with Laser Ablation and Tyrosin Kinase Inhibitors. a Novel Multimodality Approach to Locally Advanced Thyroid Cancer?

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Enrico Papini ◽  
Salvatore Monti ◽  
Carmela Coccaro ◽  
Agnese Persichetti ◽  
Federica Presciuttini ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Laser Ablation ◽  
Kinase Inhibitors ◽  
Combined Treatment ◽  
Locally Advanced ◽  
Progressive Increase ◽  
Tumor Burden ◽  
Whole Body ◽  
Laser Source ◽  
Tyrosin Kinase

Abstract Background. Direct loco-regional treatments are considered for local control of cervical metastasis of thyroid cancer. In our feasibility study, laser ablation was employed for initial debulking of an unresectable radioiodine-refractory thyroid cancer in a combined treatment with tyrosin kinase inhibitors (TKI). Clinical case. On June 2016, a 69-year-old woman underwent partial resection of a papillary thyroid cancer with extensive tracheal infiltration. On August 2016, whole body scan performed after 131-I treatment (8140 MBq) demonstrated nearly absent thyroid bed uptake. Due to progressive increase of the cervical mass, the patient experienced dysphonia and dysphagia and, after multidisciplinary consultation, was treated with laser ablation (LTA). After local anesthesia, two 300 nm fiberoptics were inserted into the lesion through 21G spinal needles. Two illuminations with 4-watt output power and 3600 Joules energy delivery were peformed with a diode-laser source. LTA resulted in rapid mass volume decrease (28 x12 x16 mm, 2.8 mL, vs 52 x 29 x 29 mm, 22.7 mL) and improvement of pressure symptoms that lasted 6 months. In May 2017, due to initial regrowth of the tumor mass, the patient started therapy with Lenvatinib, at 10-24 mg/day. The cervical tumor burden remained controlled until April 2019, when occurred rapid disease progression and death of the patient. Discussion. These preliminary results suggest that locally-advanced unresectable and radioiodine-refractory thyroid tumors can be managed with preliminary LTA mass debulking, for rapid control of local disease, followed by long-term TKI treatment. References. Mauri G et al. Cardiovasc Intervent Radiol. 2016 Jul; 39(7):1023-30; Park KW et al. Ann Surg Oncol 2011; 18:2564-2568. Schlumberger M et al. NEJM 2015 12; 372(7):621-30.

Combined Treatment with Laser Ablation and Tyrosine-Kinase Inhibitor as a Novel Multimodality Approach to Locally Advanced Thyroid Cancer: a Case Report

2021 ◽  
Vol 21 ◽  
Author(s):  
Agnese Persichetti ◽  
Salvatore Monti ◽  
Carmela Coccaro ◽  
Federica Presciuttini ◽  
Maria Grazia Deiana ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Laser Ablation ◽  
Tyrosine Kinase ◽  
Combined Treatment ◽  
Locally Advanced ◽  
Tumor Burden ◽  
Whole Body ◽  
Laser Source ◽  
Thyroid Tumors ◽  
Multimodality Approach

Background: Direct locoregional treatments were recently proposed for the local control of cervical and distant metastasis of thyroid cancer, but data on their use as part of a multimodality approach for primary thyroid tumors are poor. In this feasibility study, laser ablation (LTA) was successfully used for the initial debulking of unresectable radioiodine-refractory thyroid cancer in sequential therapy with tyrosine-kinase inhibitors (TKI). Clinical case: A 69-year-old woman underwent partial resection of papillary thyroid cancer with extensive tracheal infiltration. Post-treatment whole-body scan (131I, 8140 MBq) showed the absence of cervical thyroid uptake. The patient experienced a rapid increase in her cervical mass associated with dysphonia, dyspnea, and dysphagia. Due to a concomitant severe hypertensive state and cardiac failure, the patient was treated with LTA after a multidisciplinary consultation. After local anesthesia, two 300 nm optic fibers were inserted into the lesion through 21G spinal needles. Two illuminations with 4-watt output power and 3600 Joules energy delivery were performed with a diode-laser source. LTA resulted in rapid cancer debulking, and mass volume decreased from 23.9 to 7.5 mL resulting in significant improvement of pressure symptoms. Three months later, the patient was started on lenvatinib due to the initial regrowth of the tumor mass. The cervical tumor burden was controlled by TKI for 20 months when a rapid disease progression occurred, and the patient died. Discussion: Locally advanced, unresectable, and radioiodine-refractory thyroid tumors can be managed with a novel multimodality approach. The initial debulking with LTA of the locally aggressive disease results in rapid control of the tumor burden threatening patients’ life and is effectively followed by long-term control with TKI treatment. Conclusion: Based on this experience, sequential multimodality treatment with an initial locally directed laser ablation procedure followed by TKI therapy may be considered as a salvage option in patients with unresectable and rapidly progressive RR thyroid tumors.

scholarly journals Rationale for therapeutic decision-making in locally advanced and metastatic radioactive iodine (RAI)-refractory differentiated thyroid cancer, starting from a clinical case

2021 ◽  
Vol 8 (4) ◽  
pp. 72-83
Author(s):  
Cristina Alina Silaghi ◽  
◽  
Oana Stãnoiu-Pînzariu ◽  
Horaţiu Silaghi ◽  
◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Brain Metastases ◽  
Radioactive Iodine ◽  
Kinase Inhibitors ◽  
Locally Advanced ◽  
Rare Condition ◽  
Progression Free Survival ◽  
Whole Body ◽  
Radioactive Iodine Therapy ◽  
Thyroid Cells

Iodine uptake and organification are the hallmarks of thyroid cells differentiation. The loss of these characteristics in thyroid cancer leads to radioactive iodine refractoriness, a rare condition that bears a low survival rate and poor prognosis. We present a 52-year-old patient presenting dry cough and dyspnea in the supine position. Imaging examinations revealed a thyroid nodule with a high suspicion of malignancy in the right thyroid lobe, multiple laterocervical and mediastinal lymph nodes, lung, bone, and brain metastases. Fine needle aspiration cytologic features have advocated for papillary thyroid cancer (PTC). The patient underwent total thyroidectomy and selective lymphadenectomy. Subsequently, the patient received suppressive treatment with levothyroxine and four courses of radioactive iodine therapy. In addition, to treat bone and brain metastases, the patient experienced external radiotherapy and glucocorticoid therapy. Despite this rigorous therapeutic management, the patient obtained an incomplete structural and functional response. Although the last two posttherapeutic 131I whole-body scans were negative, the patient had elevated stimulated thyroglobulin levels and loco-regional recurrence by thyroid ultrasound. This aspect would suggest that thyroid cells become unable to uptake 131I, most likely through the emergence of new genetic mutations in the cancer cells. In conclusion, our patient's case suggests a 131I-refractory PTC, requiring the initiation of novel targeted systemic agents such as tyrosine kinase inhibitors, in order to improve structural and functional outcomes of radioactive iodine therapy and to afford prolonged progression-free survival advantage.

scholarly journals Lenvatinib Administered via Nasogastric Tube in Poorly Differentiated Thyroid Cancer

2019 ◽  
Vol 2019 ◽  
pp. 1-4 ◽  
Author(s):  
Eleonora Molinaro ◽  
David Viola ◽  
Nicola Viola ◽  
Pierpaolo Falcetta ◽  
Francesca Orsolini ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Thyroid Carcinoma ◽  
Gastric Tube ◽  
Kinase Inhibitors ◽  
Locally Advanced ◽  
Differentiated Thyroid Carcinoma ◽  
Cervical Esophagus ◽  
Extrinsic Compression ◽  
Poorly Differentiated ◽  
Iodine 131

Background. The tyrosine kinase inhibitors (TKIs) are indicated for the treatment of locally advanced or metastatic progressive thyroid carcinoma (CDT), refractory to radioactive iodine. The following report describes the efficacy of lenvatinib administered through a nose-gastric tube (SNG) in a patient affected with a poorly differentiated thyroid carcinoma (PDTC) which determined a stenosis of the esophagus. Material and Methods. A patient was followed up for papillary thyroid carcinoma follicular variant (T3NxMx), subjected to total thyroidectomy and treated with iodine-131 radio metabolic therapy. Two years after surgery, following the onset of dysphonia and dysphagia, patient was submitted to a computed tomography (CT) scan of the neck that showed the presence of a lesion of 6 × 2.5 × 3.5 cm, which determined trachea deviation and cervical esophagus compression. The biopsy indicated the presence of PDTC, triggering tracheal lumen reduction and sub-stenosis of the cervical esophagus for an ab-extrinsic compression. A nose-gastric tube (SNG) was placed and lenvatinib was started at a dose of 20 mg/day, administered via this probe after opening the capsules and diluting the drug in 10 ml of saline solution. Results. One month later, CT showed a significant cervical lesion reduction. Bronchoscopy confirmed tracheal infiltration, but the residual caliber was improved from 50% to 75%. At the esophagogastroduodenoscopy (EGDS), the sub stenosis of the cervical esophagus was no longer appreciated; however, a double perforation of the esophagus was found, without fistula. Conclusion. Lenvatinib therapy is effective also when administered via SNG. Our result is of particular relevance in the management of thyroid cancer patients, especially in the presence of subjects unable to swallow. Further studies are needed to validate the administration of lenvatinib by SNG, in order to extend the indications to this alternative administration way, beside the oral one.

The dilemma of metastatic medullary thyroid carcinoma: when to start systemic treatment

2019 ◽  
Vol 105 (6) ◽  
pp. NP28-NP31
Author(s):  
Marco Siano ◽  
Salvatore Alfieri ◽  
Roberta Granata ◽  
Giuseppina Calareso ◽  
Ester Orlandi ◽  
...  
Keyword(s):  
Thyroid Carcinoma ◽  
Lymph Nodes ◽  
Medullary Thyroid Carcinoma ◽  
Systemic Therapy ◽  
Kinase Inhibitors ◽  
Locally Advanced ◽  
Tumor Burden ◽  
Bone Lesions ◽  
Progression Rate ◽  
Medullary Thyroid

Purpose: Two tyrosine kinase inhibitors (TKIs), vandetanib and cabozantinib, have been approved for recurrent/metastatic (R/M) medullary thyroid carcinoma (MTC). To date, it is still debated when and which TKI has to be started in R/M MTC patients. This is due to 1) TKI-related toxicity burden, 2) no overall survival benefit for either TKI, and 3) progression-free survival improvement in MTC subgroups ( RETM918T and RAS mutations) treated with cabozantinib. Herein, we present a case of R/M MTC with a discordant disease behavior because of spontaneous regression of some parenchymal sites along with progression of bone metastases, putting into the question the best timing for starting TKIs in R/M MTC. Methods: We report a 46-year-old man with relapse (lymph nodes in the neck and mediastinum) after curative treatment (total thyroidectomy plus central compartment and right neck dissection) for a locally advanced MTC with only somatic RETM918T mutation. Considering the low tumor burden, absence of symptoms, as well as the potential TKI-related side effects, we decided not to start systemic therapy when metastases first appeared. Results: Some lymph nodes spontaneously regressed, while new symptomatic bone lesions appeared with need for palliative radiotherapy. In total, first-line systemic therapy (cabozantinib) was started after 2 years since first distant metastases appearance. Conclusions: Radiologic progression of disease alone seems not to be adequate for MTC patients’ selection to be treated. The progression rate, the tumor burden, and the site of disease should also be taken into account for the clinical decision process.

scholarly journals Radionuclide monitoring of targeted therapy of iodine-negative differentiated thyroid cancer

2021 ◽  
Vol 29 (1) ◽  
pp. 141-155
Author(s):  
O. I. Solodiannykova ◽  
Ya. V. Kmetyuk ◽  
V. V. Danylenko ◽  
H. H. Sukach
Keyword(s):  
Thyroid Cancer ◽  
Targeted Therapy ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Differentiated Thyroid Cancer ◽  
Kinase Inhibitors ◽  
Whole Body ◽  
Pet Ct ◽  
18F Fdg ◽  
99Mtc Mibi

Background. Current management of treating iodine-negative metastases of differentiated thyroid cancer has its features. In recent years, tyrosine kinase inhibitors (sorafenib, sunitinib) have been registered and indicated to treat refractory forms of differentiated thyroid cancer in Ukraine. However, there were only few studies dealing with cytologic aspects of predicting radioiodine resistance of papillary thyroid cancer, development of radionuclide monitoring and diagnostic algorithm to detect relapses and metastases in patients with iodine-negative forms of differentiated thyroid cancer. At the same time, scientific and clinical aspects of treatment of radioiodineresistant differentiated thyroid cancer in Ukrainian oncology and radiology are barely studied. Thus, the status of treatment and post-therapeutic monitoring of patients with iodine-negative forms of differentiated thyroid cancer, still remains insufficiently studied and requires further scientific and clinical development. Purpose – develop a technique of treatment of iodine-negative metastases of differentiated thyroid cancer. Materials and methods. Thirty-eight patients with iodine-negative metastases of differentiated thyroid cancer were provided with treatment, where in 10 patients the efficiency of treatment was assessed by means of whole body scintigraphy with 99mTc-MIBI, in 10 patients – with 99mTcDMCA. In 10 patients the short-term results of treatment with tyrosine kinase inhibitors were evaluated by PET with 18F-FDG. Eight patients represented a group where the bones were affected and treatment was provided by means of radionuclide or external-beam radiotherapy. The average age of patients varied from 43 to 76, the median was 57.8 + 3.9; out of those: 24 women, 14 men. Pathohistologically, papillary cancer was diagnosed in 31, follicular – in 5, papillary-follicular – in 2. The studies were performed by means of the two-detector gamma camera manufactured by Mediso (Hungary) and the single-photon emission computed tomography (SPECT) E. CAM 180, Siemens (Germany). PET/CT were performed on the Biograph-64-TruePoint-Siemens combined tomograph (Germany), according to the guidelines of the European Association of Nuclear Physicians. Results. Prior to initiating therapy, 10 patients with differentiated thyroid cancer underwent whole body scintigraphy with 99mTc-MIBI and re-examination in three months in order to assess treatment success. After diagnostic examination, the patient was prescribed targeted therapy with Nexavar according to the treatment protocol. Regression of the focus in the lungs was achieved within 70 %. Further monitoring of antitumor treatment success was performed by means of whole body scintigraphy with 99mTc-MIBI. Ten patients, who had PET/CT with 18F-FDG made before treatment, also underwent targeted therapy by means of Nexavar. Diagnostic scanning with 18F-FDG after therapy revealed decreased functional activity of the lesion in the neck, however no decrease in the dimensions of the lesion was observed. Conclusions. Treatment of iodine-negative metastases of differentiated thyroid cancer by means of tyrosine kinase inhibitors was accompanied by a decreasing number of metastatic foci and reducing level of their functional activity. The studies have confirmed the possibility of applying techniques with non-iodine RP (99mTc-MIBI, 99mTc-DMCA) to assess the effectiveness of treatment of iodine-negative metastases of differentiated thyroid cancer . PET/CT with 18F-FDG is a highly informative technique for assessing the effect of tyrosine kinase inhibitors on the functional activity of metastatic foci according to metabolic scans in treatment of iodine-negative metastases of differentiated thyroid cancer. If there are no positive changes after 3–4 courses, external-beam radiotherapy with total radiation dose of 30–50 Gy is indicated, which is capable of reducing the volume of metastatic foci as well as their metabolic activity. The social and economic significance of the obtained findings have made it possible to improve the overall and recurrence-free survival rates in the working population of patients with differentiated thyroid cancer and reduce the cost of following-up patients with iodine-negative forms of differentiated thyroid cancer.

A pooled analysis of response to selective RET inhibitors among patients with medullary thyroid cancer with M918T versus non-M918T RET mutations.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 6078-6078
Author(s):  
Janice Kim ◽  
Diana Bradford ◽  
Somak Chatterjee ◽  
Pallavi Shruti Mishra-Kalyani ◽  
Yuan-Li Shen ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Medullary Thyroid Cancer ◽  
Kinase Inhibitors ◽  
Locally Advanced ◽  
The United States ◽  
Medullary Thyroid ◽  
Prior Therapy ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
M918t Mutation

6078 Background: Medullary thyroid cancer (MTC) accounts for 1 to 2% of thyroid cancers in the United States; RET alterations occur in >95% of hereditary and 50% of sporadic forms. Up to 80% of patients with sporadic MTC have somatic M918T RET mutations, which is associated with poor prognosis (1). The tyrosine kinase inhibitors (TKIs) cabozantinib and vandetanib are approved to treat patients with MTC regardless of RET status; however, retrospective analyses have suggested that there may be greater benefit in patients with M918T mutations (1,2). Newly approved therapies selpercatinib and pralsetinib, developed for patients with RET mutations, have demonstrated higher response rates than previous first line therapies. In this analysis, we examine the differences in overall response rate (ORR) between patients with MTC with RET M918T non- RET M918T mutations. Methods: An analysis of ORR in patients with MTC with RET M918T mutations with non-M918T mutations was conducted using the efficacy populations used to support the approvals of pralsetinib and selpercatinib using the following groups: Patients who received prior cabozantinib or vandetanib (referred to as “previously treated”). Patients with no prior cabozantinib or vandetanib (“TKI naïve”). All patients regardless of prior therapy. Results: Exploratory analysis of ORR of pooled population of Selpercatinib and Pralsetinib in patients with MTC with RET M918T mutations and non-M918T mutations. 1 Prior vandetanib or cabozantinib. 2 No prior vandetanib or cabozantinib. Two groups of patients were analyzed ( RET M918T mutation and RET non-M918T mutation), with subgroups with respect to prior treatment. Among all patients regardless of prior therapy, the ORR was similar between M918T non-M918T groups. Among previously treated patients, the ORR was lower in the M918T group vs. the non-M918T group, while in the TKI naïve group the ORR was higher in the M918T groups vs the non-M918T group although the 95% CIs overlap in both comparisons. Conclusions: There were no major differences in ORR among mutational subtypes in patients with MTC treated with RET inhibitors, regardless of prior therapy. ORR was similar between patients with M918T and non-M918T mutations. Additional experience in ongoing clinical studies may provide additional data regarding responses across specific mutation types. References: 1.Sherman SI et al “Correlative analyses of RET and RAS mutations in a phase 3 trial of cabozantinib...” Cancer. 2016;122(24):3856-3864. 2.Wells SA Jr et al “Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer...” J Clin Oncol. 2012;30(2):134-41.[Table: see text]

ECOG 8802: Phase II trial of doxorubicin (Dox) and gemcitabine (Gem) in metastatic renal cell carcinoma (RCC) with sarcomatoid features

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 5038-5038
Author(s):  
N. Haas ◽  
J. Manola ◽  
M. Pins ◽  
G. Liu ◽  
D. McDermott ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Type I Error ◽  
Locally Advanced ◽  
Mtor Inhibitors ◽  
Tumor Burden ◽  
Type I ◽  
Peristomal Infection ◽  
Efficacy Criteria ◽  
Mixed Histology ◽  
Ecog Ps

5038 Background: Patients (pts) with RCC containing sarcomatoid features have poor prognoses.Cytokine therapy is ineffective, and experience with mTor inhibitors or multi-targeted tyrosine kinase inhibitors is early. We evaluated Dox/Gem in these pts with locally advanced or metastatic disease to confirm previous activity of this regimen in a single institution trial. Methods: Pts received Dox 50mg/m2 IV push and Gem 1500mg/m2 IV over 30 minutes every 2 weeks (with G-CSF 5 mcg/kg/d days 2 or 3 to 10 or pegfilgrastim 6 mg day 2) until disease progression or unacceptable toxicity. Dose reductions occurred for low granulocytes and or platelets, mucositis, cardiac toxicity, or other grade 3 - 4 toxicities. Dox was discontinued after a cumulative dose of 450 mg/m2 unless pt had normal cardiac function. The study targeted a promising response rate (RR) of 20% vs. 5%, with 90% power and 8% Type I error. A 2-stage design was used; >4 responses were needed for efficacy. Results: From February 2004 to April 2007, 39 pts with RCC of sarcomatoid (47%) or mixed histology (53%) containing sarcomatoid features were accrued by ECOG (n = 35), NCCTG (n = 2), and CALGB (n = 2). 1 pt withdrew before treatment. Pts were mostly male (81%), with cT3/T4 (68%), node negative (61%), M1 (58%) disease at diagnosis and ECOG PS 0–1. Metastases included lung (71%) and lymph nodes (58%). Pts received a median 6.5 cycles (range, 1 - 16). Treatment was moderately tolerable: grade 4 neutropenia (3 pts, 1 with fever), grade 4 dyspnea (1 pt), grade 4 peristomal infection (1 pt). 2 of 38 pts stopped treatment due to toxicity. 1 complete and 5 partial responses (PR) were observed (16%, 90% CI 7.1–28.8%). A 7th patient had an unconfirmed PR and an eighth patient had > 50 percent decrease in tumor burden after an initial progression. 9 patients had stable disease. Two pts are alive without progression (1 with a PFS of 2.5 years), 1 is alive with progression, and 35 patients have died. Median PFS is 3.5 months (95% CI 2.8–5.2 mos). Median OS is 8.8 mos (6.1–11.1 mos). Conclusions: Dox/Gem met efficacy criteria in RCC with sarcomatoid features. A TKI/Gem regimen in ECOG is planned. No significant financial relationships to disclose.

scholarly journals EFFICACY AND SAFETY OF MULTI-TARGETED KINASE INHIBITORS IN PROGRESSIVE, RADIOIODINE-REFRACTORY DIFFERENTIATED THYROID CANCERS: A META-ANALYSIS

2016 ◽  
Vol 2 (1) ◽  
Author(s):  
Mutahir A Tunio ◽  
Mushabbab AlAsiri ◽  
Yasser Bayoumi
Keyword(s):  
Thyroid Cancer ◽  
Differentiated Thyroid Cancer ◽  
Radioactive Iodine ◽  
Kinase Inhibitors ◽  
Meta Analysis ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Cochrane Library ◽  
Differentiated Thyroid Cancers ◽  
The Impact

Purpose: A meta-analysis was conducted to evaluate the impact of oral multitargeted kinase inhibitors (MTKIs) in radioactive-iodine refractory locally advanced, recurrent/metastatic differentiated thyroid cancer (DTC) on disease control rate (DCR), progression-free survival (PFS) and overall survival (OS) rates. Materials and Methods: The PubMed/MEDLINE, CANCERLIT, EMBASE, Cochrane Library database and other search engines were searched to identify randomised controlled trials (RCTs) comparing MTKIs with placebo in locally advanced, recurrent/metastatic DTC. Pooled data were expressed as odds ratio (OR), with 95% con dence intervals (CIs, Mantel–Haenszel xed-effect model). Results: Three RCTs with a total patient population of 954 patients were identi ed. The use of MTKIs was associated with improved PFS (OR: 0.262, 95% CI: 0.19–0.35; heterogeneity (I2) = 22.4%; P < 0.0001), improved DCR (complete and partial responses + stable disease, P < 0.0001) and improved OS 0.66, 95% CI: 0.46–0.96 (I2 = 43%, P = 0.034). Lenvatinib (compliance = 87%) was associated with more grade ≥3 hypertension. However, its other adverse effects were much lower than sorafenib (compliance = 56%) and vandetanib. Conclusion: In radioactive iodine-refractory recurrent, metastatic DTC patients, lenvatinib and sorafenib were associated with improved PFS, DRC and OS rates, while the compliance was better with lenvatinib. Key words: Meta-analysis, multitargeted kinase inhibitors, progressive differentiated thyroid cancer, radioactive iodine- refractory 

scholarly journals Integrated computational and Drosophila cancer model platform captures previously unappreciated chemicals perturbing a kinase network

2018 ◽  
Author(s):  
Peter Man-Un Ung ◽  
Masahiro Sonoshita ◽  
Alex P. Scopton ◽  
Arvin C. Dar ◽  
Ross L. Cagan ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Virtual Screening ◽  
Drug Response ◽  
Medullary Thyroid Cancer ◽  
Kinase Inhibitors ◽  
Chemical Space ◽  
Quantitative Measure ◽  
Fruit Fly ◽  
Whole Body ◽  
Medullary Thyroid

AbstractDrosophila provides an inexpensive and quantitative platform for measuring whole animal drug response. A complementary approach is virtual screening, where chemical libraries can be efficiently screened against protein target(s). Here, we present a unique discovery platform integrating structure-based modeling with Drosophila biology and organic synthesis. We demonstrate this platform by developing chemicals targeting a Drosophila model of Medullary Thyroid Cancer (MTC) with disease-promoting kinase network activated by mutant dRetM955T. Structural models for kinases relevant to MTC were generated for virtually screening to identify initial hits that were dissimilar to known kinase inhibitors yet suppressed dRetM955T-induced oncogenicity. We then combined features from the hits and known inhibitors to create a ‘hybrid’ molecule with improved dRetM955T phenotypic outcome. Our platform provides a framework to efficiently explore novel chemical spaces, develop compounds outside of the current inhibitor chemical space, and ‘correct’ cancer-causing signaling networks to improve disease prognosis while minimizing whole body toxicity.AUTHOR SUMMARYEffective and safe treatment of multigenic diseases often involves drugs that modulate whole systems by interacting with multiple nodes in pathways and networks, i.e., polypharmacology. Polypharmacology is increasingly appreciated as a potential desirable property of kinase drugs; however, most known drugs that interact with multiple targets have been identified as such by chance, and most polypharmacological compounds are not chemically unique resembling to structures of known kinase inhibitors. The fruit fly Drosophila has been established as a robust screening platform that provides an inexpensive, rapid, and quantitative measure of whole animal drug response, complementing computational approaches. We present a chemical genetics approach that efficiently combines Drosophila with structural prediction and virtual screening, creating a unique discovery platform. We demonstrate the utility of our approach by developing useful small molecules targeting a kinase network in a Drosophila model of Medullary Thyroid Cancer (MTC) driven by the active mutant dRetM955T.

Sign in / Sign up

Export Citation Format

Share Document