IGF-1R peptide vaccines/mimics inhibit the growth of BxPC3 and JIMT-1 cancer cells and exhibit synergistic antitumor effects with HER-1 and HER-2 peptides.

The insulin-like growth factor-1 receptor (IGF-1R) plays a crucial role in cellular growth, proliferation, transformation, and inhibition of apoptosis. A myriad of human cancer types have been shown to overexpress IGF-1R, including breast and pancreatic adenocarcinoma. IGF-1R signaling interferes with numerous receptor pathways, rendering tumor cells resistant to chemotherapy, anti-hormonal therapy, and epidermal growth factor receptor (EGFR, also known as HER-1) and v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2, (ERBB2, best known as HER-2) -targeted therapies. Targeting the IGF:IGF-1R axis with innovative peptide inhibitors and vaccine antibodies thus represents a promising therapeutic strategy to overcome drug resistance and to provide new avenues for individualized and combinatorial treatment strategies. In this study, we designed, synthesized, and characterized several B-cell epitopes from the IGF-1:IGF-1R axis. The chimeric peptide epitopes were highly immunogenic in outbred rabbits, eliciting high levels of peptide vaccine antibodies. The IGF-1R peptide antibodies and peptide mimics inhibited cell proliferation and receptor phosphorylation, induced apoptosis and antibody-dependent cellular cytotoxicity (ADCC), and significantly inhibited tumor growth in the transplantable BxPC-3 pancreatic and JIMT-1 breast cancer models. Our results showed that the peptides and antibodies targeting residues 56-81 and 233-251 are potential therapeutic and vaccine candidates for the treatment of IGF-1R-expressing cancers, including those that are resistant to the HER-2-targeted antibody, trastuzumab. Additionally, we found additive antitumor effects for the combination treatment of the IGF-1R 56-81 epitope with HER-1-418 and HER-2-597 epitopes. Treatment with the IGF-1R/HER-1 or IGF-1R/HER-2 combination inhibited proliferation, invasion, and receptor phosphorylation, and induced apoptosis and ADCC, to a greater degree than single agents.

Peptide vaccines and peptidomimetics of EGFR (HER-1) ligand binding domain inhibit cancer cell growth in vitro and in vivo.

Epidermal growth factor receptor (EGFR) is a validated target for several cancers including lung, colorectal, and certain subtypes of breast cancer. Cetuximab targets ligand binding of EGFR, but major problems like high cost, short t1/2, toxicity, and emergence of resistance are associated with the drug. Immunization with EGFR B cell epitopes will train the immune system to produce specific Abs that can kill cancer cells. Also, therapy with stable, less-expensive, and nontoxic EGFR peptide mimics will block EGFR signaling and inhibit cancer growth. We designed three peptides based on the contact sites between EGF and EGFR. The B cell epitopes were synthesized alone and also linked with the measles virus T cell epitope to produce a chimeric peptide vaccine. The peptide vaccines were immunogenic in both mice and rabbits and Abs raised against the vaccine specifically bound EGFR-expressing cells and recombinant human EGFR protein. The peptide mimics and the anti-peptide Abs were able to inhibit EGFR signaling pathways. Immunization with the peptide vaccine or treatment with the B cell epitopes significantly reduced tumor growth in both transplantable breast and lung cancer models. Immunohistochemical analysis also showed significant reductions in microvascular density and actively dividing cells in the tumor sections after treatment in the FVB/n breast cancer model. The 418-435 B cell epitope was the best candidate both as a vaccine or peptide mimic because it caused significant inhibition in the two mouse models. Our results show that this novel EGFR B cell epitope has great potential to be used as a vaccine or treatment option for EGFR-expressing cancers.

Correction to: Foy KC, Miller MJ, Moldovan N, Carson III WE, Kaumaya PTP. Combined vaccination with HER-2 peptide followed by therapy with VEGF peptide mimics exerts effective anti-tumor and anti-angiogenic effects in vitro and in vivo. OncoImmunology 2012; 1:1048-1060.

[This corrects the article on p. 1048 in vol. 1.].

Immunotherapy with HER-2 and VEGF peptide mimics plus metronomic paclitaxel causes superior antineoplastic effects in transplantable and transgenic mouse models of human breast cancer.

HER-2 and the vascular endothelial factor receptor (VEGF) represent validated targets for the therapy of multiple tumor types and inhibitors of these receptors have gained increasing importance in the clinic. In this context, novel bioactive agents associated with better therapeutic outcomes and improved safety profile are urgently required. Specifically engineered HER-2- and VEGF-derived peptides in combination with low-dose chemotherapy might provide a substantial impact on tumor metastasis and cancer progression. We tested the antitumor effects of HER-2 and VEGF peptide mimics in combination with metronomic paclitaxel in both PyMT and Balb/c murine model challenged with TUBO cells. The combination of low-dose paclitaxel and HER-2 or VEGF peptide mimics had greater inhibitory effects than either agent alone. Peptide treatment caused virtually no cardiotoxic effects, while paclitaxel and the anti-HER-2 antibody trastuzumab (Herceptin), exerted consistent cardiotoxicity. The combination regimen also promoted significant reductions in tumor burden and prolonged survival rates in both transgenic and transplantable tumor models. Tumor weights were significantly reduced in mice treated with HER-2 peptides alone, and even more in animals that received HER-2 peptide with low-dose paclitaxel, which alone had no significant effects on tumor growth in the transgenic model. Specifically engineered native peptide sequences from HER-2 and VEGF used in combination with metronomic paclitaxel demonstrate enhanced anticancer efficacy and an encouraging safety profile. This novel approach to targeted therapy may offer new avenues for the treatment of breast cancer and other solid tumors that overexpress HER-2 and VEGF.

Combined vaccination with HER-2 peptide followed by therapy with VEGF peptide mimics exerts effective anti-tumor and anti-angiogenic effects in vitro and in vivo.

Overexpression of HER-2 and VEGF plays a key role in the development and metastasis of several human cancers. Many FDA-approved therapies targeting both HER-2 (Trastuzumab, Herceptin) and VEGF (Bevacizumab, Avastin) are expensive, have unacceptable toxicities and are often associated with the development of resistance. Here, we evaluate the dual antitumor effects of combining designed particular HER-2 peptide vaccine with VEGF peptide mimics. In vitro, HER-2 phosphorylation and antibody-dependent cellular toxicity were used to validate whether combining HER-2- and VEGF-targeting therapies would be effective. Moreover, a two-pronged approach was tested in vivo: (1) active immunotherapy with conformational HER-2 B-cell epitope vaccines and (2) anti-angiogenic therapy with a peptide structured to mimic VEGF. A transplantable BALB/c mouse model challenged with TUBO cells was used to test the effects of the HER-2 peptide vaccine combined with VEGF peptide mimics. Tumor sections after treatment were stained for blood vessel density and actively dividing cells. Our results show that immunization with an HER-2 peptide epitope elicits high affinity HER-2 native antibodies that are effective in inhibiting tumor growth in vivo, an effect that is enhanced by VEGF peptide mimics. We demonstrate that the combination of HER-2 and VEGF peptides induces potent anti-tumor and anti-angiogenic responses.

Psychological profiles and quality of life differ between patients with dyssynergia and those with slow transit constipation.

BACKGROUND: Pathophysiological characteristics differ between slow transit constipation (STC) and dyssynergic defecation, but whether psychological profiles and quality of life (QOL) are altered and whether they differ among these constipation subtypes are unknown. METHODS: We prospectively evaluated psychological profiles and QOL in 76 patients with dyssynergia, 38 patients with STC, and 44 control subjects using the Revised 90-item Symptom Checklist and 36-item Short-Form Health Survey. In addition, we examined the correlations of psychological and QOL domains with constipation symptoms and pathophysiological subtypes. RESULTS: Symptom scores for hostility and paranoid ideation were higher (P<.001) in patients with dyssynergic defecation than in patients with STC and control subjects. Scores for other psychological domains were higher (P<.0001) in patients with dyssynergic defecation and those with STC than in control subjects. Most QOL subscores were impaired (P<.05) in patients with dyssynergic defecation and some were impaired in patients with STC as compared with control subjects, but the two patient groups did not differ on these. The QOL subscores were strongly correlated (r(c) approximately .9) with the psychological subscores in patients with dyssynergic defecation and those with STC, although more QOL subscores among patients with dyssynergic defecation and more psychological subscores among patients with STC primarily contributed to the canonical correlations. A set of six commonly reported constipation symptoms showed significant correlations with QOL and psychological subscores, more so among patients with STC than among patients with dyssynergic defecation. CONCLUSIONS: Patients with dyssynergic defecation had greater psychological distress and impaired health-related QOL as compared with patients with STC and control subjects. Both patient groups were also more affected as compared with the control group. There was a strong correlation between psychological dysfunction and impaired QOL, and both also correlated with constipation symptoms.

Rectoanal sensorimotor response in humans during rectal distension.

PURPOSE: Rectal perception facilitates maintenance of continence and defecation. Whether perception is associated with motor changes in anorectum is unclear. We examined sensory and motor responses of the anorectum during rectal distention. METHODS: Stepwise graded rectal balloon distensions were performed in 23 healthy subjects by placing a six-sensor probe in the anorectum. Manometric changes, rectoanal reflexes, and sensory thresholds were assessed. Studies were repeated in six subjects. RESULTS: All subjects showed rectoanal inhibitory and contractile reflexes, but rectal perception was associated with an anal contractile response (sensorimotor response). In 4 subjects (17 percent) the sensorimotor response first occurred synchronously with a sensation of fullness (Group 1) and in 19 (83 percent) with a desire to defecate (Group 2). Mean balloon volume for inducing the sensorimotor response in Groups 1 and 2 were 80 +/- 14 ml and 96 +/- 26 ml (P > 0.05). The onset, amplitude, duration, and area under curve of the response were similar in both groups. At higher volumes of balloon distention, all subjects (n = 23) reported a desire and an urge to defecate. The sensorimotor response associated with an urge to defecate had higher amplitude (P = 0.01) and higher area under curve (P = 0.001) compared with that associated with a desire to defecate. Repeat studies showed good reproducibility (intraclass correlation coefficient = 0.9; P < 0.05). CONCLUSIONS: A desire to defecate is associated with a unique, consistent, and reproducible anal contractile response: the sensorimotor response. This response could play an integral role in regulating anorectal sensation and function.