The purpose of this study is to evaluate increasing dose levels of VS-4718 administered in combination with gemcitabine and nab-paclitaxel in subjects with advanced cancer and to determine a recommended Phase 2 dose (RP2D) for further development of this combination in subjects with untreated advanced pancreatic cancer.

Start Date01 Sep 2015

Sponsor / Collaborator

Verastem, Inc.

NCT01849744 / TerminatedPhase 1

A Phase I Study of VS-4718, a Focal Adhesion Kinase Inhibitor, in Subjects With Metastatic Non-Hematologic Malignancies

This is a Phase I, open-label, multicenter, dose-escalation trial of VS-4718, a focal adhesion kinase inhibitor, in subjects with metastatic non-hematologic malignancies. This clinical study is comprised of 2 parts: Part 1 (Dose Escalation) and Part 2 (Expansion). The purpose of this study is to evaluate the safety (including the recommended Phase II dose), pharmacokinetics (the amount of VS-4718 in your blood) and the anti-cancer activity of VS-4718. The pharmacodynamic effects (genes or proteins that may predict or show how your body may respond to VS-4718) will also be examined in tumor biopsies and blood samples.

Start Date01 Jun 2013

Sponsor / Collaborator

Verastem, Inc.

NCT02215629 / WithdrawnPhase 1

A Phase I Dose Escalation Study of VS-4718, A Focal Adhesion Kinase Inhibitor, In Subjects With Relapsed or Refractory Acute Myeloid Leukemia or B-Cell Acute Lymphoblastic Leukemia

The main purpose of this study is to test the safety and efficacy of VS-4718 in two types of leukemia patients and to find the right dose of VS-4718 for future clinical trials.
Other purposes of this study include:
Testing for study drug VS-4718 levels in blood over time and what happens to the study drug in patients.
To find out if there are certain biomarkers in leukemia patients that predict if and how 4718 study drug may or may not work.

Start Date-

Sponsor / Collaborator

Verastem, Inc.

100 Clinical Results associated with VS-4718

100 Translational Medicine associated with VS-4718

100 Patents (Medical) associated with VS-4718

Literatures (Medical) associated with VS-4718

01 Dec 2023·MedComm

Co‐targeting FAK and Gli1 inhibits the tumor‐associated macrophages‐released CCL22‐mediated esophageal squamous cell carcinoma malignancy

Article

Author: Wang, Yan ; Zhang, Lingyuan ; Zhao, Di ; Chen, Jie ; Zhan, Qimin ; Xiao, Yuanfan ; Wu, Qingnan ; Zhu, Yanmeng ; Zhang, Jing

Abstract:

Esophageal squamous cell carcinoma (ESCC) is a frequently seen esophageal tumor type in China. Activation of signaling proteins and relevant molecular mechanisms in ESCC are partially explored, impairing the antitumor efficiency of targeted therapy in ESCC treatment. Tumor‐associated macrophages (TAMs)‐released C‐C motif chemokine 22 (CCL22) can activate intratumoral focal adhesion kinase (FAK), thus promoting the progression of ESCC. Here, we demonstrated that highly secreted CCL22 by TAMs (CCL22‐positive TAMs) induced ESCC cell stemness and invasion through facilitating transcriptional activity of intratumoral glioma‐associated oncogene 1 (Gli1), a downstream effector for Hedgehog (HH) pathway. Mechanistically, FAK‐activated protein kinase B (AKT) mediated Gli1 phosphorylation at its Ser112/Thr115/Ser116 sites and released Gli1 from suppressor of fused homolog, the endogenous inhibitor of Gli1 to activate downstream stemness‐associated factors, such as SRY‐box transcription factor 2 (SOX2), Nanog homeobox (Nanog), or POU class 5 homeobox (OCT4). Furthermore, inhibition of FAK activity by VS‐4718, the FAK inhibitor, enhanced antitumor effect of GDC‐0449, the HH inhibitor, both in xenografted models and in vitro assays. Clinically, CCL22/Gli1 axis is used to evaluate ESCC prognosis. Overall, our study establishes the communication of FAK with HH pathway and offers the novel mechanism related to Gli1 activation independent of Smoothened as well as the rationale for the anti‐ESCC combination treatment.

01 Oct 2023·Vascular pharmacology

Type I collagen proteolysis by matrix metalloproteinase-2 contributes to focal adhesion kinase activation and vascular smooth muscle cell proliferation in the aorta in early hypertension.

Article

Author: Castro, Michele M ; Parente, Juliana M ; Tostes, Rita C ; Arantes, Eliane Candiani ; Rodrigues, Daniel ; de Oliveira Neves, Viviano Gomes ; Pernomian, Laena ; de Oliveira, Isadora Sousa ; Blascke de Mello, Marcela M

INTRODUCTION:

Increased matrix metalloproteinase (MMP)-2 activity contributes to increase vascular smooth muscle cell (VSMC) proliferation in the aorta in early hypertension by cleaving many proteins of the extracellular matrix. Cleaved products from type I collagen may activate focal adhesion kinases (FAK) that trigger migration and proliferation signals in VSMC. We therefore hypothesized that increased activity of MMP-2 proteolyzes type I collagen in aortas of hypertensive rats, and thereby, induces FAK activation, thus leading to increased VSMC proliferation and hypertrophic remodeling in early hypertension.

METHODS:

Male Sprague-Dawley rats were submitted to renovascular hypertension by the two kidney-one clip (2K1C) model and treated with doxycycline (30 mg/kg/day) by gavage from the third to seventh-day post-surgery. Controls were submitted to sham surgery. Systolic blood pressure (SBP) was measured daily by tail-cuff plethysmography and the aortas were processed for zymography and Western blot for MMP-2, pFAK/FAK, integrins and type I collagen. Mass spectrometry, morphological analysis and Ki67 immunofluorescence were also done to identify collagen changes and VSMC proliferation. A7r5 cells were stimulated with collagen and treated with the MMP inhibitors (doxycycline or ARP-100), and with the FAK inhibitor PND1186 for 24 h. Cells were lysed and evaluated by Western blot for pFAK/FAK.

RESULTS:

2K1C rats developed elevated SBP in the first week as well as increased expression and activity of MMP-2 in the aorta (p < 0.05 vs. Sham). Treatment with doxycycline reduced both MMP activity and type I collagen proteolysis in aortas of 2K1C rats (p < 0.05). Increased pFAK/FAK and increased VSMC proliferation (p < 0.05 vs. Sham groups) were also seen in the aortas of 2K1C and doxycycline decreased both parameters (p < 0.05). Higher proliferation of VSMC contributed to hypertrophic remodeling as seen by increased media/lumen ratio and cross sectional area (p < 0.05 vs Sham groups). In cell culture, MMP-2 cleaves collagen, an effect reversed by MMP inhibitors (p < 0.05). Increased levels of pFAK/FAK were observed when collagen was added in the culture medium (p < 0.05 vs control) and MMP and FAK inhibitors reduced this effect.

CONCLUSIONS:

Increase in MMP-2 activity proteolyzes type I collagen in the aortas of 2K1C rats and contributes to activate FAK and induces VSMC proliferation during the initial phase of hypertension.

01 Jul 2023·International immunopharmacology

Focal adhesion kinase induces cardiac remodeling through NF-κB-mediated inflammatory responses in diabetic cardiomyopathy

Article

Author: Wang, Yi ; Li, Jie ; Huang, Fang ; Jin, Bo ; Zhang, Mengpei ; Chen, Yi ; Hong, Bo ; Wang, Jiong ; Zuo, Wei

BACKGROUND:

Hyperglycemia-induced chronic inflammation is a crucial risk factor that causes undesirable cardiac alternations in diabetic cardiomyopathy (DCM). Focal adhesion kinase (FAK) is a non-receptor protein tyrosine kinase that primarily regulates cell adhesion and migration. Based on recent studies, FAK is involved in inflammatory signaling pathway activation in cardiovascular diseases. Here, we evaluated the possibility of FAK as a therapeutic target for DCM.

METHODS:

A small molecular selective FAKinhibitor, PND-1186 (PND), was used to evaluate the effect of FAK on DCM in both high glucose-stimulated cardiomyocytes and streptozotocin (STZ)-induced type 1 diabetes mellitus (T1DM) mice.

RESULTS:

Increased FAK phosphorylation was found in the hearts of STZ-induced T1DM mice. PND treatment significantly decreased the expression of inflammatory cytokines and fibrogenic markers in cardiac specimens of diabetic mice. Notably, these reductions were correlated with improved cardiac systolic function. Furthermore, PND suppressed transforming growth factor-β-activated kinase 1 (TAK1) phosphorylation and NF-κB activation in the hearts of diabetic mice. Cardiomyocytes were identified as the main contributor to FAK-mediated cardiac inflammation and the involvement of FAK in cultured primary mouse cardiomyocytes and H9c2 cells was identified. Both FAK inhibition or FAK deficiency prevented hyperglycemia-induced inflammatory and fibrotic responses in cardiomyocytes owing to the inhibition of NF-κB. Herein, FAK activation was revealed to FAK directly binding to TAK1, leading to activation of TAK1 and downstream NF-κB signaling pathway.

CONCLUSIONS:

FAK is a key regulator of diabetes-associated myocardial inflammatory injury by directly targeting to TAK1.

100 Deals associated with VS-4718

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Advanced cancer	Phase 1	US	Verastem, Inc.	01 Sep 2015
Pancreatic Cancer	Phase 1	US	Verastem, Inc.	01 Sep 2015
Burkitt Lymphoma	Phase 1	-	Verastem, Inc.	13 Aug 2014
CD19-positive B-cell acute lymphoblastic leukemia	Phase 1	-	Verastem, Inc.	13 Aug 2014
Refractory acute myeloid leukemia	Phase 1	-	Verastem, Inc.	13 Aug 2014
Refractory B Acute Lymphoblastic Leukemia	Phase 1	-	Verastem, Inc.	13 Aug 2014
Relapsing acute myeloid leukemia	Phase 1	-	Verastem, Inc.	13 Aug 2014
Advanced Malignant Solid Neoplasm	Phase 1	US	Verastem, Inc.	01 Jun 2013

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