Phase I/II trial of intraperitoneal implantation of agarose-agarose macrobeads (MB) containing mouse renal adenocarcinoma cells (RENCA) in patients (pts) with advanced colorectal cancer (CRC).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e14517-e14517
Author(s):  
Allyson J. Ocean ◽  
Tapan Parikh ◽  
Nathaniel Berman ◽  
Juliet Escalon ◽  
Manish A. Shah ◽  
...  
Keyword(s):  
Phase I ◽  
Tumor Marker ◽  
Therapeutic Option ◽  
Early Response ◽  
In Vivo Models ◽  
Significant Difference ◽  
Novel Concept ◽  
Ecog Ps

e14517 Background: RENCA tumor cells encapsulated in two concentric agarose layers which release signals to treat advanced cancers is a novel concept that has been substantiated in in vitro and in vivo models as reported in Cancer Research 71(3), 716-735, 2011.We report results of a phase I/II study in advanced CRC pts. Methods: Previously-treated advanced CRC pts (ECOG PS 0-2) were enrolled with informed consent obtained. Pts had intraperitoneal implantation up to 4 times via laparoscopy with 8 (37/40 pts- established dose) or 16 (3/40 pts) RENCA MB/kg. Serial exams, lab profiles, and imaging were done pre- and 3 months (mo.) post-implant to assess efficacy. Endpoints of safety, tumor marker decrease, response, and overall survival (OS) were evaluated. Results: 40 pts were implanted with RENCA MB (12 pts phase I; 28 pts phase II); 17M: 23F. Mean age 58.3. 14/40 pts had >1 implant (≥2: 14 pts; ≥3: 2 pts; =4: 2 pts). Response to MB is marked by a prominent initial rise in CRP, ESR, and IL-6, indicating a systemic inflammatory response (SIR) (100% of pts) and a parallel decrease in CEA and/or CA 19-9 in approximately 70%. SIR including its accompanying fatigue and anorexia lasts days to 3 wks. Overall, there was a statistically significant difference (p=0.009) in OS between the 70% of pts showing a decrease in tumor markers by at least 20% during the first 30 days post-implant (OS; 9.7 mo., C.I. 6.5-13.5) and those who did not (OS; 4.4 mo., C.I. 1.1-7.6). On PET-CT imaging, a striking feature of response, most often seen in pts with the longest OS, is tumor necrosis. MB were well-tolerated and no Grade ≥3 adverse events were treatment-related. Conclusions: For advanced, treatment-resistant CRC pts, early response to MB implantation characterized by tumor marker decrease in association with SIR correlates with a statistically significant increase in OS. RENCA MB represent a possible new therapeutic option for late-stage CRC. Clinical trial information: NCT01053013.

Physiological Functions of Peroxisome Proliferator-Activated Receptor β

2014 ◽  
Vol 94 (3) ◽  
pp. 795-858 ◽  
Author(s):  
Jaap G. Neels ◽  
Paul A. Grimaldi
Keyword(s):  
Therapeutic Option ◽  
Cell Types ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
In Vivo Models ◽  
Physiological Functions ◽  
Regulatory Pathways ◽  
Inflammatory Conditions

The peroxisome proliferator-activated receptors, PPARα, PPARβ, and PPARγ, are a family of transcription factors activated by a diversity of molecules including fatty acids and fatty acid metabolites. PPARs regulate the transcription of a large variety of genes implicated in metabolism, inflammation, proliferation, and differentiation in different cell types. These transcriptional regulations involve both direct transactivation and interaction with other transcriptional regulatory pathways. The functions of PPARα and PPARγ have been extensively documented mainly because these isoforms are activated by molecules clinically used as hypolipidemic and antidiabetic compounds. The physiological functions of PPARβ remained for a while less investigated, but the finding that specific synthetic agonists exert beneficial actions in obese subjects uplifted the studies aimed to elucidate the roles of this PPAR isoform. Intensive work based on pharmacological and genetic approaches and on the use of both in vitro and in vivo models has considerably improved our knowledge on the physiological roles of PPARβ in various cell types. This review will summarize the accumulated evidence for the implication of PPARβ in the regulation of development, metabolism, and inflammation in several tissues, including skeletal muscle, heart, skin, and intestine. Some of these findings indicate that pharmacological activation of PPARβ could be envisioned as a therapeutic option for the correction of metabolic disorders and a variety of inflammatory conditions. However, other experimental data suggesting that activation of PPARβ could result in serious adverse effects, such as carcinogenesis and psoriasis, raise concerns about the clinical use of potent PPARβ agonists.

ME-143, a novel inhibitor of tumor-specific NADH oxidase (tNOX): Results from a first-in-human phase I study.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3067-3067
Author(s):  
Carla Kurkjian ◽  
Shubham Pant ◽  
Howard A. Burris ◽  
Johanna C. Bendell ◽  
Suzanne Fields Jones ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Phase I Study ◽  
Nadh Oxidase ◽  
Testicular Atrophy ◽  
Pharmacokinetic Analysis ◽  
In Vivo Models ◽  
Human Dose

3067 Background: ME-143, a second generation isoflavone-derived compound, specifically binds tNOX, shifting the ceramide-S1P equilibrium and resulting in prompt apoptosis via pleotrophic caspase activation. A first generation compound, phenoxodiol (PXD), showed promising phase II activity with cisplatin in ovarian cancer. ME-143 is broadly active against human cancers in both in vitro and in vivo models, with IC50’s 1-2 logs lower than PXD. Toxicology studies up to 140mg/kg (human dose equivalent ~23mg/kg) showed no STD level. The only significant findings were dose dependent hypospermia and testicular atrophy in rats. We report clinical and PK results from the first-in-human phase I study. Methods: A 3+3 dose escalation design was used with 4 dose cohorts: 2.5, 5, 10, and 20mg/kg IV over 30 minutes weekly times 3, followed by a 1 week break, and then continuous weekly dosing in patients with advanced solid tumors. Dense PK sampling was performed at 0, 5, 10, 20, 30, 60, 90, 120, 180, 240, 300, 360 minutes, and 24 hours post-infusion day 1 and 15 of the first treatment cycle. Results: To date, 9 patients have been enrolled, 3 in each of the first 3 cohorts. Median time on treatment is 56 days (range 6 to 62). Five patients have discontinued protocol therapy, all due to PD. No DLT’s have been observed. Related AE’s include grade 1: myalgia (1), anorexia (1), fatigue (2), headache (1), diarrhea (1), vomiting (1) and grade 2: fatigue (1). Preliminary PK analyses in the first 2 cohorts is shown in table below. Conclusions: ME-143 appears to be well tolerated when administered IV. Preliminary PK data suggest that drug levels achieve target concentration extrapolated from pre-clinical studies (AUC0-t ~10mg*hr/mL) and exceed levels obtained with IV PXD in the phase II study (AUC0-t ~2mg*hr/mL) . Updated clinical data from all planned dose cohorts, including the final pharmacokinetic analysis and planned phase II dose, will be presented. [Table: see text]

Phase I study of TH-302, an investigational hypoxia-targeted drug, and dexamethasone in patients with relapsed/refractory multiple myeloma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8602-8602
Author(s):  
Irene M. Ghobrial ◽  
Jacob Laubach ◽  
Philippe Armand ◽  
Erica Boswell ◽  
Courtney Hanlon ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Phase I ◽  
Clinical Activity ◽  
Heavily Pretreated ◽  
Hepatorenal Function ◽  
Definition Of ◽  
Ecog Ps

8602 Background: TH-302 is an investigational 2-nitroimidazole prodrug of the DNA alkylator Br-IPM designed to be selectively activated in hypoxia. In multiple myeloma (MM) mouse models, diseased animals demonstrate a marked expansion of areas of hypoxia in the bone marrow. TH-302 exhibited anti-tumor activity against MM in vitro and in vivo and synergism was seen when combined with bortezomib (Hu et al, Blood 2010; Chesi et al, Blood 2012). Based on these findings, a phase I/II study of TH-302 plus dexamethasone (dex) was initiated for patients (pts) with relapsed/refractory MM. Methods: Eligible pts in the study (NCT01522872) had ECOG PS ≤ 2, receipt of at least two prior therapies, and acceptable hepatorenal function and hematologic status. A standard 3+3 dose escalation design was used with a fixed oral 40 mg dose of dex and 40% dose increments of TH-302. TH-302 was administered IV with dex on days 1, 4, 8, and 11 of a 21-day cycle. The objectives were to determine DLTs and the MTD; assess the safety, tolerability and preliminary clinical activity of TH-302 plus dex; and study the relationship between hypoxia within the bone marrow and response to TH-302. Results: Eleven pts have been treated: 7M/4F with a median age 61 years (range: 53 – 86) and 6 prior therapies (range: 3 – 10). All received both bortezomib and lenalidomide/thalidomide containing regimens. TH-302 was dosed at 240 (n=5), 340 (n=4), and 480 (n=2) mg/m² for a median of 5 cycles. No DLTs were reported at 240 or 340 mg/m². Two pts treated at 480 mg/m² had DLTs of grade 3 mucositis, exceeding the definition of MTD. A dose expansion is thus ongoing at 340 mg/m2. Two patients had SAEs related to TH-302 (pneumonia). Five pts continue on study after a median of 7 cycles (range: 2–11). Nine pts have had efficacy evaluations: 2 pts with partial responses, 2 pts with minimal responses, and 5 pts with stable disease, for an overall response rate (of MR or better) of 44%. Conclusions: TH-302 can be administered at 340 mg/m2 biweekly + dex, with dose limiting mucositis seen at higher doses. Initial clinical activity has been noted with an ORR of 44% in heavily pretreated MM pts who are relapsed/refractory to both bortezomib and lenalidomide. Clinical trial information: NCT01522872.

Efficacy of a novel cytotoxic polybisphosphonate for treatment of bone metastasis in castration-resistant prostate cancer (CRPC).

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 236-236
Author(s):  
Sten Nilsson ◽  
Henriette Lindberg ◽  
Camilla Thellenberg-Karlsson ◽  
Claes Nyman ◽  
Marcela Marquez ◽  
...  
Keyword(s):  
Phase I ◽  
Controlled Trial ◽  
Continuous Treatment ◽  
Castration Resistant Prostate Cancer ◽  
Short Term Treatment ◽  
Double Blind ◽  
In Vivo Models ◽  
Continuous Growth

236 Background: A cytostatic polybisphosphonate was developed for Tx of mCRPC. It has a) anti-resorptive effects, osteoclast inhib., b) tum. cell spec./tox, confirmed in in-vivo models. Tox. study shows high tolerability. Animal PK study has shown T½ < 3 hrs; principal accumulation in liver, spleen, kidneys. Methods: Clin phase I/IIa (clinicaltrials.gov NCT01595087): Prim obj: to define MTD of ODX given every 3rd week. Sec. obj: OS, bone metab. and resp. markers, PSA, QoL and PK. Explorative in vitrostudies (basis for rand. phase IIb trial in pts. with docetax-res. mCRPC). A docetax-resist. cell-line was developed from DU145 in escalating conc. of docetax, then continuous growth in docetax 500 µg/ml. Cells subj. to cytotox. exp. with ODX (iCELLigence system and fluorom microculture cytotox assay). Results: Clin Phase I/IIa first-in-man trial (clinicaltrials.gov NCT01595087): 17/28 patients rec. 4-7 doses every 3rd week. No DLTs; max dose adm.: 3.0 mg/kg: no drug-related SAEs. Tx was well tolerated. Efficacy and QoL data w. considerable variability as to be expected in this population of pts. w. mCRPC. Max blood conc. ODX: 110-160 fmol/mL; 85-90 % cleared within first 1 hr. Efficacy of ODX in docetax-res DU145TR: A dose-dependent cytotox effect seen when adding ODX in “sub-clin.” doses. All cells were apparently killed in the clin. relevant dose 6 uM. Conclusions: ODX is a novel drug cand. w. high cytotox. efficacy in vivo and in vitro, even in highly docetax-res. cells. Animal studies and Phase I trial show excellent tolerability. Studies now ongoing to elucidate whether short-term treatment is as efficacious as continuous treatment and whether some cells de facto may develop resistance also to this new treatment concept. A multicenter rand. double-blind pbo. controlled trial (EudraCT 2014-002054-39) starts Q4 2014 in mCRPC pts failing docetax and/or cabazitaxel AND abiraterone and/or enzalutamide. Clinical trial information: NCT01595087.

Trastuzumab versus MYL-1401O (a proposed trastuzumab biosimilar) in a phase I bioequivalence study: In vivo and in vitro immunomodulation.

2017 ◽  
Vol 35 (7_suppl) ◽  
pp. 10-10
Author(s):  
Régine Audran ◽  
Haithem Chtioui ◽  
Anne-Christine Thierry ◽  
Carole Mayor ◽  
Laure Vallotton ◽  
...  
Keyword(s):  
Phase I ◽  
Mononuclear Cell ◽  
Ex Vivo ◽  
Reference Drug ◽  
Gm Csf ◽  
Significant Difference ◽  
Ifn Γ ◽  
The Impact

10 Background: Trastuzumab is a humanized monoclonal antibody targeting breast cancer cells overexpressing the HER2-oncoprotein. During a Phase-I single centre, single dose, randomized, double-blind, cross-over study assessing the bioequivalence of a proposed trastuzumab biosimilar (MYL-1401O) versus the initially marketed drug (Herceptin), we investigated in addition a large panel of pharmacodynamics parameters comparing the immunomodulatory activity of both drugs. Methods: 22 healthy males were included, 19 subjects receiving randomly a single intravenous infusion of MYL-1401O and 22 of Herceptin, separated by 16 to 22 week wash-out. Blood samples drawn pre- and post- infusion were assessed for in vivo serum cytokines induction (IL-1β, IL-2, IL-6, IL-10, IL-12, TNF-α, GM-CSF and IFN-γ) whereas the impact of treatment on mononuclear cell subsets and their level of activation was tested ex vivo. Volunteers’ PBMC (peripheral blood monocnuclear cells) were stimulated in vitro with recall antigens and mitogen for cytokine production. At baseline, we performed in addition a cytokine release assay on PBMC upon stimulation with trastuzumab as a preclinical safety test. Results: Trastuzumab infusion induced a transient and weak peak of serum IL-6 at 6h, and a modulation of mononuclear cell subset profile and level of activation. Notably CD16+ cells frequency decreased at 3h and peaked at 48h. Except for CD8+ T cells, there were no significant differences between Herceptin and its proposed biosimilar ex vivo. PBMC stimulated in vitro with trastuzumab secreted IL-6, TNF-a, IL-1β, GM-CSF, IFN-γ, and IL-10, but no IL-2. There was no significant difference between the two mAbs. Conclusions: Based on these in vivo, ex vivo and in vitro experiments, there is a strong assumption that MYL-1401O is biosimilar to the reference drug Herceptin for its immunomodulation properties as already proven for its bioequivalence. Clinical trial information: 2011-001406-94.

scholarly journals CADASIL from Bench to Bedside: Disease Models and Novel Therapeutic Approaches

2021 ◽  
Author(s):  
Arianna Manini ◽  
Leonardo Pantoni
Keyword(s):  
Therapeutic Option ◽  
In Vitro Models ◽  
Monogenic Disease ◽  
Therapeutic Approaches ◽  
In Vivo Models ◽  
Human Phenotype ◽  
Knock Out ◽  
Novel Therapeutic

AbstractCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic disease caused by NOTCH3 mutations and characterized by typical clinical, neuroradiological, and pathological features. NOTCH3 belongs to a family of highly conserved transmembrane receptors rich of epidermal growth factor repeats, mostly expressed in vascular smooth muscle cells and pericytes, which perform essential developmental functions and are involved in tissues maintenance and renewal. To date, no therapeutic option for CADASIL is available except for few symptomatic treatments. Novel in vitro and in vivo models are continuously explored with the aim to investigate underlying pathogenic mechanisms and to test novel therapeutic approaches. In this scenario, knock-out, knock-in, and transgenic mice studies have generated a large amount of information on molecular and biological aspects of CADASIL, despite that they incompletely reproduce the human phenotype. Moreover, the field of in vitro models has been revolutionized in the last two decades by the introduction of induced pluripotent stem cells (iPSCs) technology. As a consequence, novel therapeutic approaches, including immunotherapy, growth factors administration, and antisense oligonucleotides, are currently under investigation. While waiting that further studies confirm the promising results obtained, the data reviewed suggest that our therapeutic approach to the disease could be transformed, generating new hope for the future.

In Vitro and In Vivo Evaluations of Three Computer-Aided Shade Matching Instruments

2012 ◽  
Vol 37 (3) ◽  
pp. 219-227 ◽  
Author(s):  
K Yuan ◽  
X Sun ◽  
F Wang ◽  
H Wang ◽  
J Chen
Keyword(s):  
In Vivo Model ◽  
In Vivo Models ◽  
B Values ◽  
Significant Difference ◽  
Computer Aided ◽  
Natural Teeth ◽  
Shade Matching ◽  
Vitro Model

SUMMARY This study evaluated the accuracy and reliability of three computer-aided shade matching instruments (Shadepilot, VITA Easyshade, and ShadeEye NCC) using both in vitro and in vivo models. The in vitro model included the measurement of five VITA Classical shade guides. The in vivo model utilized three instruments to measure the central region of the labial surface of maxillary right central incisors of 85 people. The accuracy and reliability of the three instruments in these two evaluating models were calculated. Significant differences were observed in the accuracy of instruments both in vitro and in vivo. No significant differences were found in the reliability of instruments between and within the in vitro and the in vivo groups. VITA Easyshade was significantly different in accuracy between in vitro and in vivo models, while no significant difference was found for the other two instruments. Shadepilot was the only instrument tested in the present study that showed high accuracy and reliability both in vitro and in vivo. Significant differences were observed in the L*a*b* values of the 85 natural teeth measured using three instruments in the in vivo assessment. The pair-agreement rates of shade matching among the three instruments ranged from 37.7% to 48.2%, and the incidence of identical shade results shared by all three instruments was 25.9%. As different L*a*b* values and shade matching results were reported for the same tooth, a combination of the evaluated shade matching instruments and visual shade confirmation is recommended for clinical use.

First-in-human phase-I pharmacokinetic trial of NS-9, a liposomal poly(I):poly(C), in patients with liver metastases from various primary cancers

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13016-13016
Author(s):  
R. P. Perez ◽  
L. D. Lewis ◽  
G. I. Cohen ◽  
J. Hwang ◽  
S. Malik ◽  
...  
Keyword(s):  
Phase I ◽  
Liver Metastases ◽  
Cationic Liposome ◽  
Dose Escalation Study ◽  
Phase Ii Studies ◽  
Elevated Glucose ◽  
Grade 3 ◽  
Ecog Ps

13016 Background: NS-9 is a complex of poly-inosinate [poly(I)] and poly-cytidylate [poly(C)] in a cationic liposome and is active in vitro and in vivo. Objectives: to determine the tolerability, safety, and maximal tolerated dose (MTD), and pharmacokinetics of NS-9 by 1 hr IV infusion, given daily x5 q 28 days. Methods: A phase I dose escalation study was undertaken in patients with liver metastases from solid tumors. Eligible patients were adults with ECOG PS 0–1 and no recent chemotherapy (≥ 4 wks prior). Dose cohorts studied were 0.1, 0.15, 0.2, 0.3 and 0.4mg/m2. Results: 18 patients were enrolled (13M:5F) median age 58 (range 21 to 77 yrs). Tumor types included neuroendocrine (8), and ocular melanoma (1), gastric (1), GE junction (1), esophageal (2), and colorectal (5) carcinomas. Two of three patients treated at the first dose level (0.4 mg/m2) had grade 3/4 reversible lipase elevation with or without acute pancreatitis, a dose limiting toxicity (DLT). De-escalation to doses ranging from 0.1 to 0.2 mg/m2/day was with no DLT. At 0.3 mg/m2 two of three patients treated had a DLT (neutropenia and thrombocytopenia). The MTD was determined at 0.2 mg/m2. Common toxicities included pyrexia, chills, nausea, fatigue, abdominal pain, myalgia, anorexia, sweating, neutropenia, thrombocytopenia, and elevated glucose, amylase, and LFTs. Pharmacokinetics showed rapid elimination (T1/2 ranged from 2.4 to 5.0 hours) without accumulation after multiple doses. 1 patient (esophageal Ca) had a PR in the target lesions in the liver. Conclusions: The MTD is 0.2 mg/m2/day with a hint of antitumor activity. NS-9 should be pursued in phase-II studies. No significant financial relationships to disclose.

Molecular Targets and Early Response Biomarkers for the Prediction of Developmental Toxicity In Vitro

2007 ◽  
Vol 35 (3) ◽  
pp. 335-342 ◽  
Author(s):  
Michael Stigson ◽  
Kim Kultima ◽  
Måns Jergil ◽  
Birger Scholz ◽  
Henrik Alm ◽  
...  
Keyword(s):  
High Throughput Screening ◽  
Developmental Toxicity ◽  
Molecular Targets ◽  
Toxicity Testing ◽  
Early Response ◽  
In Vitro Tests ◽  
In Vivo Models ◽  
Response Biomarkers

There is an urgent need for new in vitro methods to predict the potential developmental toxicity of candidate drugs in the early lead identification and optimisation process. This would lead to a reduction in the total number of animals required in full-scale developmental toxicology studies, and would improve the efficiency of drug development. However, suitable in vitro systems permitting robust high-throughput screening for this purpose, for the most part, remain to be designed. An understanding of the mechanisms involved in developmental toxicity may be essential for the validation of in vitro tests. Early response biomarkers — even a single one — could contribute to reducing assay time and facilitating automation. The use of toxicogenomics approaches to study in vitro and in vivo models in parallel may be a powerful tool in defining such mechanisms of action and the molecular targets of toxicity, and also for use in finding possible biomarkers of early response. Using valproic acid as a model substance, the use of DNA microarrays to identify teratogen-responsive genes in cell models is discussed. It is concluded that gene expression in P19 mouse embryocarcinoma cells represents a potentially suitable assay system, which could be readily used in a tiered testing system for developmental toxicity testing.

scholarly journals EPCO-02. MOLECULAR CHARACTERIZATION OF TWO NOVEL MPNST SUBGROUPS IDENTIFIES THERAPEUTIC OPPORTUNITIES

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii69-ii69
Author(s):  
Suganth Suppiah ◽  
Sheila Mansouri ◽  
Yasin Mamatjan ◽  
Jeff Liu ◽  
Vikas Patil ◽  
...  
Keyword(s):  
Malignant Transformation ◽  
Cellular Proliferation ◽  
Cpg Island ◽  
Therapeutic Option ◽  
In Vivo Models ◽  
Peripheral Nerve Sheath Tumors ◽  
Shh Pathway ◽  
Pathway Activation

Abstract Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive Schwann-cell derived sarcomas. These tumors are resistant to all current therapies, with exception to gross total surgical resection, and unresectable or metastatic tumors are considered incurable. Our understanding of the molecular alterations driving malignant transformation is limited, and to date, targeted therapies have proven ineffective. In this study, we leverage multi-platform genomic and epigenomic profiling of human MPNSTs and neurofibromas to identify targetable molecular pathways that lead to malignant transformation. Unsupervised consensus hierarchical clustering of the top 20K most variable methylated probes yielded seven stable and robust subgroups that are clinically relevant. The high-grade MPNSTs formed two distinct methylation-based clusters (MPNST-G1 and MPNST-G2). MPNST-G1 had worse prognosis compared to MPNST-G2 (0.6 years versus 1.4 years, p &lt; 0.05). PTCH1 loss or SMO gain was prevalent in MPNST-G1 compared to MPNST-G2 (75% vs 12.5%, p &lt; 0.05). In addition, MPNST-G1 harbored PTCH1 CpG island promoter hypermethylation in (87.5% vs 12.5%, p &lt; 0.001). Transcriptome profiling recapitulated the two distinct MPNST subgroups. We next demonstrated that that RB1 signaling pathways are aberrant in both MPNST-G1 and MPNST-G2. However, SHH pathway activation is observed in MPNST-G1, while WNT/CCND1/ ß-catenin pathway activation is observed in MPNST-G2. Network-based drug-disease proximity analysis identified SMO inhibitors as a potential FDA approved drug as a potential targeted therapy. To determine if SHH pathway activation is sufficient for malignant transformation, we knocked out PTCH1 in immortalized neurofibroma cells lines. In 3 different cell lines with PTCH1 knockout, we observed induction of a malignant phenotype, with increased cellular proliferation and invasion. Most importantly, in-vitro and in-vivo models confirm that targeting the SHH pathway, with sonidegib, was effective in inhibiting tumor growth proving SMO inhibition to be a novel therapeutic option in these lethal cancers.

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