A Phase 1B Study of Dulanermin in Combination With Modified FOLFOX6 Plus Bevacizumab in Patients With Metastatic Colorectal Cancer

Wainberg, Zev A.; Messersmith, Wells A.; Peddi, Parvin F.; Kapp, Amy V.; Ashkenazi, Avi; Royer-Joo, Stephanie; Portera, Chia C.; Kozloff, Mark

doi:10.1016/j.clcc.2013.06.002

Cited by 52 publications

(36 citation statements)

References 15 publications

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“…Recombinant hTRAIL (Dulanermin, Genentech Inc, CA, USA) was well tolerated as a monotherapy or in combination with other chemicals 10. However, in contrast to the superior cytotoxicity of hTRAIL observed in the in vitro analysis 9, hTRAIL-induced antitumor responses were only observed in a small number of patients 11, 12. On one hand, a short half-life might contribute to the poor clinical efficacy of hTRAIL.…”

Section: Introductionmentioning

confidence: 99%

Targeted Delivery to Tumor-associated Pericytes via an Affibody with High Affinity for PDGFRβ Enhances the in vivo Antitumor Effects of Human TRAIL

Tao¹,

Yang²,

Shi³

et al. 2017

Theranostics

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Human tumor necrosis factor-related apoptosis-inducing ligand (hTRAIL) has exhibited superior in vitro cytotoxicity in a variety of tumor cells. However, hTRAIL showed a disappointing anticancer effect in clinical trials, although hTRAIL-based regimens were well tolerated. One important reason might be that hTRAIL was largely trapped by its decoy receptors, which are ubiquitously expressed on normal cells. Tumor-targeted delivery might improve the tumor uptake and thus enhance the antitumor effect of hTRAIL. Platelet-derived growth factor receptor β (PDGFRβ)-expressing pericytes are enriched in tumor tissues derived both from patients with colon cancer and from mice bearing colorectal tumor xenografts. A ZPDGFRβ affibody showed high affinity (nM) for PDGFRβ and was predominantly distributed on tumor-associated PDGFRβ-positive pericytes. Co-administration with the ZPDGFRβ affibody did not significantly enhance the antitumor effect of hTRAIL in mice bearing tumor xenografts. Fusion to the ZPDGFRβ affibody endows hTRAIL with PDGFRβ-binding ability but does not interfere with its death receptor binding and activation. The fused ZPDGFRβ affibody mediated PDGFRβ-dependent binding of hTRAIL to pericytes. In addition, hTRAIL bound on pericytes could kill tumor cells through juxtatropic activity or exhibit cytotoxicity in tumor cells after being released from pericytes. Intravenously injected hTRAIL fused to ZPDGFRβ affibody initially accumulated on tumor-associated pericytes and then diffused to the tumor parenchyma over time. Fusion to the ZPDGFRβ affibody increased the tumor uptake of hTRAIL, thus enhancing the antitumor effect of hTRAIL in mice bearing tumor xenografts. These results demonstrate that pericyte-targeted delivery mediated by a ZPDGFRβ affibody is an alternative strategy for tumor-targeted delivery of anticancer agents.

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Section: Introductionmentioning

confidence: 99%

Targeted Delivery to Tumor-associated Pericytes via an Affibody with High Affinity for PDGFRβ Enhances the in vivo Antitumor Effects of Human TRAIL

Tao¹,

Yang²,

Shi³

et al. 2017

Theranostics

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“…An antitumor response was again observed for both groups. At the end of the observation period (d109), 4/12 tumors stayed in complete macroscopic remission and 3 other tumors were in a stable, not actively growing state with volumes below 100 mm 3 . Serum concentrations of Db10-Glyco-scTRAIL-FAVSGAA were determined by ELISA 0.05 h, 4 h, and 24 h after the first injection, as well as 4 h and 24 after the last injection of the first cycle, showing that similar serum concentrations were reached after the first and last injection (Fig.…”

Section: Epidermal Growth Factor Receptor-targeted Db-sctrail Proteinmentioning

confidence: 99%

“…In contrast to other cell death-triggering tumor necrosis factor (TNF) superfamily members, e.g., TNF or CD95L (FasL), soluble, homotrimeric TRAIL is well tolerated upon systemic application in humans. [1][2][3] TRAIL activates the extrinsic apoptotic pathway via binding to death receptors (DR) 4 and 5, which leads to apoptosis of tumor cells. Nevertheless, in several clinical trials, conventional TRAIL such as dulanermin 4,5 and a circularly permuted TRAIL (CPT) 6,7 proved to be largely ineffective.…”

Section: Introductionmentioning

confidence: 99%

An optimized antibody-single-chain TRAIL fusion protein for cancer therapy

Siegemund

Seifert

Zarani³

et al. 2016

mAbs

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Fusion proteins combining oligomeric assemblies of a genetically obtained single-chain (sc) variant of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) with antibodies directed against tumorassociated antigens represent a promising strategy to overcome the limited therapeutic activity of conventional soluble TRAIL. To further improve the scTRAIL module in order to obtain a robust, thermostable molecule of high activity, we performed a comprehensive analysis of the minimal TNF homology domain (THD) and optimized linkers between the 3 TRAIL subunits constituting a scTRAIL. Through a stepwise mutagenesis of the N-and C-terminal region and the joining linker sequences, we generated bioactive scTRAIL molecules comprising a covalent linkage of the C-terminal Val280 and the Nterminal position 122 by only 2 amino acid residues in combination with conservative exchanges at positions 122 and 279. The increased thermal stability and solubility of such optimized scTRAIL molecules translated into increased bioactivity in the diabody-scTRAIL (Db-scTRAIL) format, exemplified here for an epidermal growth factor receptor-specific Db-scTRAIL. Additional modifications within the diabody linkers resulted in a fusion protein exerting high, target-dependent apoptosis induction in tumor cell lines in vitro and potent antitumor activity in vivo. Our results illustrate that protein engineering of scTRAIL and associated peptide linkers provides a promising strategy to develop antibody-scTRAIL fusion proteins as effective antitumor therapeutics.

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“…Indeed, TRAIL genes are prognostic for response to chemotherapy and overall survival in patients with CRC, and moreover are prognostic for outcome in patients with other cancers, including glioblastoma multiforme and breast cancer (19)(20)(21)(22)(23)(24). Differences in TRAIL expression in cancers compared with normal cells have led to clinical trials targeting TRAIL-induced apoptosis in CRC, but the genetic profiles of patients were not used as part of the selection criteria (25)(26)(27)(28)(29).…”

Section: Introductionmentioning

confidence: 99%

TNFRSF10C copy number variation is associated with metastatic colorectal cancer

Tanenbaum

Hall

Colbert

et al. 2016

J. Gastrointest. Oncol.

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Background: Genetic markers for distant metastatic disease in patients with colorectal cancer (CRC) are not well defined. Identification of genetic alterations associated with metastatic CRC could help to guide systemic and local treatment strategies. We evaluated the association of tumor necrosis factor receptor superfamily member 10C (TNFRSF10C) copy number variation (CNV) with distant metastatic disease in patients with CRC using The Cancer Genome Atlas (TCGA).Methods: Genetic sequencing data and clinical characteristics were obtained from TCGA for all available patients with CRC. There were 515 CRC patient samples with CNV and clinical outcome data, including a subset of 144 rectal adenocarcinoma patient samples. Using the TCGA CRC dataset, CNV of TNFRSF10C was evaluated for association with distant metastatic disease (M1 vs. M0). Multivariate logistic regression analysis with odds ratio (OR) using a 95% confidence interval (CI) was performed adjusting for age, T stage, N stage, adjuvant chemotherapy, gender, microsatellite instability (MSI), location, and surgical margin status.Results: TNFRSF10C CNV in patients with CRC was associated with distant metastatic disease [OR 4.81 (95% CI, 2.13-10.85) P<0.001] and positive lymph nodes [OR 18.83 (95% CI,.09)]; P<0.001) but not MSI (OR P=0.799). On multivariate analysis, after adjusting for pathologic T stage, N stage, adjuvant chemotherapy, gender, and MSI, TNFRSF10C CNV remained significantly associated with distant metastatic disease (OR P=0.018). Subset analysis revealed that TNFRSF10C CNV was also significantly associated with distant metastatic disease in patients with rectal adenocarcinoma (OR P=0.016).Conclusions: TNFRSF10C CNV in patients with CRC is associated with distant metastatic disease.With further validation, such genetic profiles could be used clinically to support optimal systemic treatment strategies versus more aggressive local therapies in patients with CRC, including radiation therapy for rectal adenocarcinoma.

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A Phase 1B Study of Dulanermin in Combination With Modified FOLFOX6 Plus Bevacizumab in Patients With Metastatic Colorectal Cancer

Cited by 52 publications

References 15 publications

Targeted Delivery to Tumor-associated Pericytes via an Affibody with High Affinity for PDGFRβ Enhances the in vivo Antitumor Effects of Human TRAIL

Targeted Delivery to Tumor-associated Pericytes via an Affibody with High Affinity for PDGFRβ Enhances the in vivo Antitumor Effects of Human TRAIL

An optimized antibody-single-chain TRAIL fusion protein for cancer therapy

TNFRSF10C copy number variation is associated with metastatic colorectal cancer

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