Last update 01 Nov 2024

DR5 x FAP

Last update 01 Nov 2024

Basic Info

Related Targets

DR5FAP

Drugs associated with DR5 x FAP

FAP-DR5

Target

DR5 x FAP

Mechanism

DR5 agonists [+1]

Active Org.-

Originator Org.

Millennium Pharmaceuticals, Inc.

Active Indication-

Inactive Indication

Neoplasms [+1]

Drug Highest PhaseDiscontinued

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with DR5 x FAP

NCT02558140 / CompletedPhase 1

An Open-Label, Multicenter, Dose-Escalation Phase I Study of RO6874813, Administered Intravenously in Patients With Locally Advanced or Metastatic Solid Tumors

This first-in-human study consists of three parts. The primary purpose of Part 1 is to characterize the safety and tolerability of RO6874813 in participants with locally advanced and/or metastatic solid tumors whose disease has progressed despite standard therapy or for whom no standard therapy exists. In addition, the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) will be determined. In Part 2 the safety and tolerability of RO6874813 will continue to be characterized in participants with locally advanced and/or metastatic solid tumors known to be fibroblast activation protein-alpha positive (FAP+). In addition, treatment-induced efficacy of RO6874813 will be assessed by functional imaging and paired tumor biopsies. The primary purpose of Part 3 is to demonstrate anti-tumor activity of RO6874813 in participants with recurrent or metastatic FAP+ sarcomas.

Start Date11 Oct 2015

Sponsor / Collaborator

Hoffmann-La Roche, Inc.

100 Clinical Results associated with DR5 x FAP

100 Translational Medicine associated with DR5 x FAP

0 Patents (Medical) associated with DR5 x FAP

Literatures (Medical) associated with DR5 x FAP

01 May 2016·Molecular Cancer TherapeuticsQ2 · MEDICINE

RG7386, a Novel Tetravalent FAP-DR5 Antibody, Effectively Triggers FAP-Dependent, Avidity-Driven DR5 Hyperclustering and Tumor Cell Apoptosis

Q2 · MEDICINE

Article

Author: Liu, Bin ; Weber, Thomas G. ; Majety, Meher ; Klein, Christian ; Shao, Cuiying ; Mössner, Ekkehard ; Runza, Valeria ; Wang, Peng ; Umaña, Pablo ; Scheuer, Werner ; Friess, Thomas ; Vega-Harring, Suzana ; Xu, Gary ; Brünker, Peter ; Niu, Huifeng ; Wartha, Katharina ; Weiser, Barbara ; Herting, Frank ; Daouti, Sherif ; Grau-Richards, Sandra ; Bosslet, Klaus ; Hosse, Ralf J. ; Feng, Ningping ; Koller, Claudia Ferrara ; Sade, Hadassah ; Packman, Kathryn ; Waldhauer, Inja

AbstractDysregulated cellular apoptosis and resistance to cell death are hallmarks of neoplastic initiation and disease progression. Therefore, the development of agents that overcome apoptosis dysregulation in tumor cells is an attractive therapeutic approach. Activation of the extrinsic apoptotic pathway is strongly dependent on death receptor (DR) hyperclustering on the cell surface. However, strategies to activate DR5 or DR4 through agonistic antibodies have had only limited clinical success. To pursue an alternative approach for tumor-targeted induction of apoptosis, we engineered a bispecific antibody (BsAb), which simultaneously targets fibroblast-activation protein (FAP) on cancer-associated fibroblasts in tumor stroma and DR5 on tumor cells. We hypothesized that bivalent binding to both FAP and DR5 leads to avidity-driven hyperclustering of DR5 and subsequently strong induction of apoptosis in tumor cells but not in normal cells. Here, we show that RG7386, an optimized FAP-DR5 BsAb, triggers potent tumor cell apoptosis in vitro and in vivo in preclinical tumor models with FAP-positive stroma. RG7386 antitumor efficacy was strictly FAP dependent, was independent of FcR cross-linking, and was superior to conventional DR5 antibodies. In combination with irinotecan or doxorubicin, FAP-DR5 treatment resulted in substantial tumor regression in patient-derived xenograft models. FAP-DR5 also demonstrated single-agent activity against FAP-expressing malignant cells, due to cross-binding of FAP and DR5 across tumor cells. Taken together, these data demonstrate that RG7386, a novel and potent antitumor agent in both mono- and combination therapies, overcomes limitations of previous DR5 antibodies and represents a promising approach to conquer tumor-associated resistance to apoptosis. Mol Cancer Ther; 15(5); 946–57. ©2016 AACR.

01 Jul 2005·Cancer Epidemiology, Biomarkers & PreventionQ2 · MEDICINE

Sulindac Inhibits β-Catenin Expression in Normal-Appearing Colon of Hereditary Nonpolyposis Colorectal Cancer and Familial Adenomatous Polyposis Patients

Q2 · MEDICINE

Article

Author: Hollema, Harry ; van der Sluis, Tineke ; Offerhaus, Johan A. ; Giardiello, Francis M. ; Kleibeuker, Jan H. ; Zwart, Nynke ; Keller, Josbert J. ; Oldenhuis, Corina N.A.M. ; Rijcken, Fleur E.M. ; Koornstra, Jan J. ; deVries, Elisabeth G.E.

AbstractSulindac reduces colorectal cancer risk in genetically susceptible humans and animals. The molecular mechanisms underlying these effects are incompletely understood. Many studies suggest an important role for induction of apoptosis involving the mitochondrial pathway and the death receptor pathway. Alternatively, mechanisms involving the APC-β-catenin-Wnt pathway have been suggested, possibly mediated by p21. We determined the effects of sulindac on apoptosis and expression of death receptor (DR)-4 and DR5, β-catenin, and p21 in normal-appearing colorectal epithelium. Biopsies were obtained before and after sulindac treatment during two chemoprevention studies. Patients (n = 18) with hereditary nonpolyposis colorectal cancer (HNPCC) received 150 mg sulindac bd for 4 weeks in a placebo-controlled crossover design. Patients (n = 6) with familial adenomatous polyposis (FAP) received 150 mg sulindac bd for 6 months. Apoptosis was assessed by M30 staining and expression patterns of DR4, DR5, β-catenin, and p21 were studied immunohistochemically. In HNPCC patients, apoptotic indices were similar following placebo and sulindac. Also in FAP patients, apoptotic indices were not different after sulindac compared with pretreatment values. Expression of DR4 and DR5 was observed in all samples with no consistent differences between placebo/baseline and sulindac. Intensity of membranous β-catenin staining was lower in HNPCC samples following sulindac compared with placebo (P < 0.001). Similar results were obtained in FAP samples (P < 0.01). p21 expressions before and after sulindac treatment were similar in both patient groups. In conclusion, sulindac inhibits β-catenin expression in normal colorectal epithelium from HNPCC and FAP patients without affecting apoptotic indices and DR4, DR5, and p21 expression.

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