Platelet-derived growth factor (PDGF) and its receptors (PDGFR) play important roles in tumorigenesis through stimulating tumor growth and promoting angiogenesis via enhancing pericyte recruitment ...and vessel maturation. Here we produced a neutralizing antibody, 1B3, directed against mouse PDGFRβ. 1B3 binds to PDGFRβ with high affinity (9
×
10
−11
M) and blocks PDGF-BB from binding to the receptor with an IC
50 of ∼1.2
nM. The antibody also blocks ligand-stimulated activation of PDGFRβ and downstream signaling molecules, including Akt and MAPK p42/44, in tumor cells. In animal studies, 1B3 significantly enhanced the antitumor and the anti-angiogenic activities of DC101, an antibody directed against mouse vascular endothelial growth factor receptor 2, in a pancreatic (BxPC-3) and a non-small cell lung (NCI-H460) tumor xenograft models. Treatment with the combination of 1B3 and DC101 in BxPC-3 xenograft-bearing mice resulted in tumor regression in 58% of mice compared to that in 18% of mice treated with DC101 alone. Taken together, these results lend great support to use PDGFRβ antagonists in combinations with other antitumor and/or anti-angiogenic agents in the treatment of a variety of cancers.
A series of arylphthalazine derivatives were synthesized and evaluated as antagonists of VEGF receptor II (VEGFR-2). IM-094482
57, which was prepared in two steps from commercially available starting ...materials, was found to be a potent inhibitor of VEGFR-2 in enzymatic, cellular and mitogenic assays (comparable activity to ZD-6474). Additionally,
57 inhibited the related receptor, VEGF receptor I (VEGFR-1), and showed excellent exposure when dosed orally to female CD-1 mice.
Rational strategies utilizing anticancer efficacy and biological principles are needed for the prioritization of specific combination targeted therapy approaches for clinical development, from among ...the many with experimental support.
Antibodies targeting epidermal growth factor receptor (EGFR) (cetuximab), insulin-like growth factor-1 receptor (IGF-IR) (IMC-A12) or vascular endothelial growth factor receptor 2 (VEGFR2) (DC101), were dosed alone or in combination, in 11 human tumor xenograft models established in mice. Efficacy readouts included the tumor burden and incidence of metastasis, as well as tumor active hypoxia inducible factor-1 (HIF-1), human VEGF and blood vessel density.
Cetuximab and DC101 contributed potent and non-overlapping benefits to the combination approach. Moreover, DC101 prevented escape from IMC-A12 + cetuximab in a colorectal cancer model and cetuximab prevented escape from DC101 therapy in a pancreatic cancer model.
Targeting VEGFR2 + EGFR was prioritized over other treatment strategies utilizing EGFR, IGF-IR and VEGFR2 antibodies. The criteria that proved to be valuable were a non-overlapping spectrum of anticancer activity and the prevention of resistance to another therapy in the combination.
Although the addition of epidermal growth factor receptor (EGFR) antibodies to various platinum-based chemotherapy regimens for non-small cell lung cancer (NSCLC) is being actively pursued in the ...clinic, rationale for the prioritization of specific regimens is lacking.
We evaluated the antitumor effects of necitumumab, a recombinant human IgG1 antibody targeting EGFR, in combination with cisplatin plus gemcitabine, pemetrexed, or paclitaxel in a panel of 9 subcutaneous tumor models of NSCLC established in nu/nu athymic mice.
Necitumumab in combination with cisplatin/gemcitabine was particularly effective, although interestingly, the mechanisms underlying these benefits were model dependent. For example, increased tumor cell apoptosis contributed towards combination efficacy in the A549 model, in association with increased expression of hsa-miR-29b and reduced expression of antiapoptotic genes including DNA methyltransferase DNMT3B, commonly up-regulated in patients with NSCLC. Such inverse effects of combination therapy on DNMT3B and hsa-miR-29b expression were found in multiple models. Importantly, in the A549 model, hsa-miR-29b down-regulation of DMNT3b reduced promoter methylation of tumor suppressor genes such as Cell adhesion molecule 1 (CADM1), Ras associated (RalGDS/AF-6) domain family member 1 (RASSF1), and Fragile histidine triad gene (FHIT), increasing their expression.
These results offer a preclinical rationale for combining an EGFR antibody with cisplatin/gemcitabine for patients with NSCLC, and provide potential molecular biomarkers for tailoring therapy.
The development of small molecule heparanase inhibitor
7a (IC
50
=
0.27
μM) is reported.
A novel class of 1-4-(1
H-benzoimidazol-2-yl)-phenyl-3-4-(1
H-benzoimidazol-2-yl)-phenyl-ureas are described ...as potent inhibitors of heparanase. Among them are 1,3-bis-4-(1
H-benzoimidazol-2-yl)-phenyl-urea (
7a) and 1,3-bis-4-(5,6-dimethyl-1
H-benzoimidazol-2-yl)-phenyl-urea (
7d), which displayed good heparanase inhibitory activity (IC
50 0.075–0.27
μM). Compound
7a showed good efficacy in a B16 metastasis model.
Clinically relevant targets for developmental drug efficacy in animal models of cancer are critical yet understudied parameters.
Cetuximab, a chimeric antibody to epidermal growth factor receptor ...(EGFR), was administered to athymic mice bearing subcutaneous tumors established with 13 human colorectal cancer cell lines of varying biomarker status, defined by DNA sequencing and RT-PCR.
If tumor growth inhibition is taken as a target, as is commonly done, then in contrast to the clinical situation where KRAS mutation strongly predicts for a lack of clinically meaningful benefit in colorectal cancer patients, cetuximab alone and in combination with irinotecan-based chemotherapy were efficacious in a similar proportion of KRAS wild-type and mutant models. It was only when tumor regression was utilized to define relevant efficacy that cetuximab monotherapy was efficacious in KRAS wild-type, but not mutant models. Adding cytotoxic therapy to cetuximab treatment increased tumor regression frequency in both genotypes to the point that once again the response was similar for KRAS wild-type and mutant models.
Our data support shifting the threshold for claiming clinically relevant targeted therapy efficacy in subcutaneous xenograft models towards tumor regression, rather than tumor growth inhibition, focusing on the evaluation of tumor cells that are addicted to the pathways being targeted.
The cancer chemotherapeutic agent Taxol (paclitaxel) causes a dose‐related peripheral neuropathy in humans. We produced a dose‐dependent large‐fiber sensory neuropathy, without detrimental effects on ...general health, in mature rats by using two intravenous injections 3 days apart. Tests of other dosing schedules demonstrated the dependence of the severity of the neuropathy and of animal health on both the dose and the frequency of dosing. Pathologically, severe axonal degeneration and hypomyelination were observed in sections of dorsal roots, whereas ventral roots remained intact. Electrophysiologically, H‐wave amplitudes in the hindlimb and amplitudes of predominantly sensory compound nerve action potentials in the tail were reduced. These effects persisted for at least 4 months after treatment. Motor amplitudes were not affected, but both motor and sensory conduction velocities decreased. The ability of rats to remain balanced on a narrow beam was impaired, indicating proprioceptive deficits. Muscle strength, measured by hindlimb and forelimb grip strength, and heat nociception, measured by tail‐flick and hindlimb withdrawal tests, were not affected by Taxol. This model of Taxol‐induced neuropathy in mature rats, with minimal effects on general health, parallels closely the clinical syndrome observed after Taxol treatment in humans.
Targeted therapy for cancer is shifting towards an approach of inhibiting multiple pathways, justified in part by the ability of cancer cells to overcome the inhibition of a single pathway. However ...the literature is replete with preclinical data supporting the anticancer potential of numerous combinations of targeted agents, making it difficult to select the combination strategies to invest in through clinical development. One characteristic of a combination strategy that can be utilized for prioritization is synergy. Synergy indicates that the effect of the combination is greater than that predicted from the monotherapy potencies. Here we describe a detailed method for establishing synergy between two treatments in vivo. We utilized this method to establish that antibodies targeting the epidermal growth factor receptor and vascular endothelial growth factor receptor-2 are synergistic with regard to antitumor effects, in a BxPC-3 subcutaneous xenograft model for pancreatic cancer.
Experimental autoimmune encephalomyelitis (EAE) is utilized as an animal model for multiple sclerosis (MS). In both EAE and MS, activated T-lymphocytes specific for self-antigens present in myelin ...are linked to CNS inflammation and the breakdown of the blood-brain barrier (BBB) to peripheral blood leukocytes and plasma proteins, predominately in myelin rich white matter. One aspect of MS that has received relatively little attention is the finding that certain CNS regions are more likely than others to develop disease in different patient populations. Understanding the factors predisposing specific brain regions to autoimmune attack, or protecting other regions, would provide a better understanding of the disease as a process, and may also offer additional targets for therapeutic development. EAE offers a model to search for these factors and the first step in such a process is to identify the brain regions that are susceptible to EAE. Until recently the spinal cord in rodents has been considered the region most susceptible to EAE, with disease in more rostral regions occurring later and with reduced severity. However a more recent study has shown that the cerebellum of SJL/J mice, like the spinal cord, is especially susceptible to BBB breakdown in EAE. Although many factors known to be involved in BBB formation and breakdown remain to be assessed for their possible role in increasing the susceptibility of the cerebellum, one potentially important factor is the location of venules, which are the most affected vascular elements in inflamed tissue. There is a prevalence of large EAE susceptible venules traveling in the myelin rich white matter tracts in SJL/J mouse cerebellar cortex, indicating that the vascularization of this tissue may contribute to the increased susceptibility to inflammation in response to autoimmune attacks directed against CNS myelin.
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