Phase I/IIa Study of Cilengitide and Temozolomide With Concomitant Radiotherapy Followed by Cilengitide and Temozolomide Maintenance Therapy in Patients With Newly Diagnosed Glioblastoma
ABSTRACT Invasion and migration are key processes of glioblastoma and are tightly linked to tumor recurrence. Integrin inhibition using cilengitide has shown synergy with chemotherapy and radiotherapy in vitro and promising activity in recurrent glioblastoma. This multicenter, phase I/IIa study investigated the efficacy and safety of cilengitide in combination with standard chemoradiotherapy in newly diagnosed glioblastoma.
Patients (age > or = 18 to < or = 70 years) were treated with cilengitide (500 mg) administered twice weekly intravenously in addition to standard radiotherapy with concomitant and adjuvant temozolomide. Treatment was continued until disease progression or for up to 35 weeks. The primary end point was progression-free survival (PFS) at 6 months.
Fifty-two patients (median age, 57 years; 62% male) were included. Six- and 12-month PFS rates were 69% (95% CI, 54% to 80%) and 33% (95% CI, 21% to 46%). Median PFS was 8 months (95% CI, 6.0 to 10.7 months). Twelve- and 24-month overall survival (OS) rates were 68% (95% CI, 53% to 79%) and 35% (95% CI, 22% to 48%). Median OS was 16.1 months (95% CI, 13.1 to 23.2 months). PFS and OS were longer in patients with tumors with O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation (13.4 and 23.2 months) versus those without MGMT promoter methylation (3.4 and 13.1 months). The combination of cilengitide with temozolomide and radiotherapy was well tolerated, with no additional toxicity. No pharmacokinetic interactions between temozolomide and cilengitide were identified.
Compared with historical controls, the addition of concomitant and adjuvant cilengitide to standard chemoradiotherapy demonstrated promising activity in patients with glioblastoma with MGMT promoter methylation.
- SourceAvailable from: Liu Rongbin
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- "e l s e v i e r . c o m / l o c a t e / j c o n r e l tumors, and certain of them have already been used at different stages of clinical trials    . This study aimed to identify breast cancer-targeting peptides for molecular imaging by phage display. "
ABSTRACT: Breast cancer is the most common malignant cancer and is the leading cause of cancer death among females. Molecular imaging is a promising approach for the early detection and staging of breast cancer as well as for assessing therapeutic responses. Tumor-targeting peptides are effective targeting vehicles for molecular imaging. Here, we identified a breast cancer-targeting peptide CLKADKAKC (CK3) contains a cryptic C-end rule motif that may mediate its binding to neuropilin-1 (NRP-1), an attractive therapeutic target which expression was associated with poor outcome of the patients with breast cancer. Phage CK3 bound to NRP-1-positive breast cancer cells, which could be inhibited by peptide CK3 in a dose-dependent manner or by knock-down NRP-1 expression. Consistently, NRP-1 overexpression in cells increased the binding of phage CK3. Furthermore, peptide CK3 co-localized with NRP-1. Importantly, unlike previously reported NRP-1-targeting peptides with exposed C-end rule motifs, peptide CK3 did not penetrate into lungs and heart in vivo, which could make it more clinically applicable. Single-photon emission CT (SPECT) and near-infrared fluorescence (NIRF) imaging showed enrichment of peptide CK3 to the xenograft tumors in nude mice. In conclusion, as a novel NRP-1-targeting peptide, peptide CK3 could be used for breast cancer molecular imaging, which may represent a new avenue for breast cancer diagnostics, staging and assessments of therapeutic response.Journal of Controlled Release 07/2014; 192. DOI:10.1016/j.jconrel.2014.07.039 · 7.26 Impact Factor
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- "Thus, the inhibition of integrin signaling has a therapeutic potential, particularly in some complicated cases such as glioblastoma multiforme cancers. Indeed, clinical trials with the synthetic drug cilengitide, which is based on a cyclo (–RGDfV–) peptide, a specific inhibitor of av-containing integrins, have reached phase III (Desgrosellier and Cheresh, 2010; Reardon et al., 2008; Stupp et al., 2010). "
ABSTRACT: Extracellular matrix (ECM) molecules, their receptors at the cell surface, and cell adhesion molecules (CAMs) involved in cell-cell or cell-ECM interactions are implicated in processes related to major diseases of the central nervous system including Alzheimer's disease (AD), epilepsy, schizophrenia, addiction, multiple sclerosis, Parkinson's disease, and cancer. There are multiple strategies for targeting the ECM molecules and their metabolizing enzymes and receptors with antibodies, peptides, glycosaminoglycans, and other natural and synthetic compounds. ECM-targeting treatments include chondroitinase ABC, heparin/heparan sulfate-mimicking oligosaccharides, ECM cross-linking antibodies, and drugs stimulating expression of ECM molecules. The amount or activity of ECM-degrading enzymes like matrix metalloproteinases can be modulated indirectly via the regulation of endogenous inhibitors like TIMPs and RECK or at the transcriptional and translational levels using, e.g., histone deacetylase inhibitors, synthetic inhibitors like Periostat, microRNA-interfering drugs like AC1MMYR2, and natural compounds like flavonoids, epigallocatechin-3-gallate, anacardic acid, and erythropoietin. Among drugs targeting the major ECM receptors, integrins, are the anticancer peptide cilengitide and anti-integrin antibodies, which have a potential for treatment of stroke, multiple sclerosis, and AD. The latter can be also potentially treated with modulators of CAMs, such as peptide mimetics derived from L1-CAM and NCAM1.Progress in brain research 01/2014; 214:353-88. DOI:10.1016/B978-0-444-63486-3.00015-3 · 5.10 Impact Factor
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- "Indeed, later phase I/II trials showed an enhanced median overall survival for patients with newly diagnosed GBM after combined treatment with radiotherapy, TMZ and CGT (Table 1)  . Thereby, prolonged overall survival seemed to correlate with a methylated MGMT promoter . However, Merck KGaA recently stated that patients with newly diagnosed glioblastoma and methylated MGMT gene promoter status did not live significantly longer when treated with CGT plus radiochemotherapy in the follow-up CENTRIC phase III trial (www.merckgroup.com). "
ABSTRACT: The survival of cancer patients suffering from glioblastoma multiforme is limited to just a few month even after treatment with the most advanced techniques. The indefinable borders of glioblastoma cell infiltration into the surrounding healthy tissue prevent complete surgical removal. In addition, genetic mutations, epigenetic modifications and microenvironmental heterogeneity cause resistance to radio- and chemotherapy altogether resulting in a hardly to overcome therapeutic scenario. Therefore, the development of efficient therapeutic strategies to combat these tumors requires a better knowledge of genetic and proteomic alterations as well as the infiltrative behavior of glioblastoma cells and how this can be targeted. Among many cell surface receptors, members of the integrin family are known to regulate glioblastoma cell invasion in concert with extracellular matrix degrading proteases. While preclinical and early clinical trials suggested specific integrin targeting as promising therapeutic approach, clinical trials failed to deliver improved cure rates up to now. Little is known about glioblastoma cell motility, but switches in invasion modes and adaption to specific microenvironmental cues as a consequence of treatment may maintain tumor cell resistance to therapy. Thus, understanding the molecular basis of integrin and protease function for glioblastoma cell invasion in the context of radiochemotherapy is a pressing issue and may be beneficial for the design of efficient therapeutic approaches. This review article summarizes the latest findings on integrins and extracellular matrix in glioblastoma and adds some perspective thoughts on how this knowledge might be exploited for optimized multimodal therapy approaches.Biochimica et Biophysica Acta 07/2013; DOI:10.1016/j.bbcan.2013.07.001 · 4.66 Impact Factor