Anti-angiogenic vaccines as a treatment modality for cancer

Targeting angiogenesis to inhibit tumor development is now considered a valid approach to disease modulation. Recently, a number of laboratories have focused their research on the development of cancer vaccines that target modulators of angiogenesis. In this review we describe a number of novel vaccines that target mediators of angiogenesis and inhibit tumor progression in preclinical models.     

Anti-angiogenic cancer therapy based on integrin alphavbeta3 antagonism

Angiogenesis, the formation of new blood vessels from pre-existing vasculature, is a fundamental process during cancer progression. Anti-angiogenic strategies have been pursued for cancer treatment and prevention of cancer recurrence and metastasis. Integrins are a family of cell adhesion molecules consisting of two non-covalently bound transmembrane subunits (alpha and beta). Much research has demonstrated that integrin signaling plays a key role in tumor angiogenesis and metastasis. Integrin alphavbeta3 is highly expressed on activated endothelial cells and tumor cells but is not present in resting endothelial cells and most normal organ systems, which makes it a suitable target for anti-angiogenic cancer therapy. In this review we will focus on cancer therapy targeting integrin alphavbeta3 while other integrins (such as alpha5beta1, alphaIIbbeta3, alphavbeta5, alpha6beta4) will only be briefly mentioned when relevant. MEDI-522 (a humanized anti-human integrin alphavbeta3 monoclonal antibody) and Cilengitide (cyclic peptidic integrin alphavbeta3/alphavbeta5 antagonist) are currently in clinical trials for anti-angiogenic cancer therapy. Small interfering RNA (siRNA) that specifically silences integrin alphav and/or beta3 was reported to cause tumor shrinkage in preclinical xenograft models. Combination of anti-integrin alphavbeta3 therapy and other therapeutic approaches (such as chemotherapy, radiotherapy and gene therapy) has also been applied for cancer treatment. Mounting evidence suggests that there is potentially synergistic effect of combined therapeutic approaches over single modality alone. Lastly, integrin targeted delivery (drugs, genes, and radioisotopes) and imaging (optical, MRI, ultrasound, SPECT, and PET) is discussed in detail.     

Anti-angiogenic agents in pancreatic cancer: a review

Pancreatic cancer is the fourth leading cause of cancer related death in the United States, with a 5-year survival of less than five percent. Since the majority of patients have locally advanced or metastatic disease at the time of diagnosis, there has been little progress made to extend survival. For over ten years, chemotherapy with gemcitabine has been standard treatment for those patients with advanced pancreatic cancer, prolonging survival by only 5-6 months. To improve upon this modest benefit, several investigations have explored other strategies aimed at curbing pancreatic cancer growth. Because pancreatic cancer has been found to have a profoundly hypoxic environment with high vascular in-growth, several agents have been developed to target the angiogenesis process. Major emphasis has been placed on anti- vascular endothelial growth factor (VEGF) models and the epidermal growth factor receptor (EGFR) signaling pathway. Over the past several years, a number of phase II and phase III trials have combined gemcitabine with these novel treatments, with the hope of prolonging survival in patients with pancreatic cancer. This review will discuss these therapies and their potential application in a clinical setting.     

Anti-angiogenic therapy of proliferative diabetic retinopathy

Proliferative diabetic retinopathy (PDR) remains one of the major causes of acquired blindness in developed nations. This is true despite the development of laser treatment, which can prevent blindness in the majority of those who develop this complication. The hallmark of PDR is neovascularisation (NV), abnormal angiogenesis that may ultimately cause severe vitreous cavity bleeding and/or retinal detachment. Pharmacologic therapy aimed at preventing NV, as an adjunct to laser treatment, or as an alternative to laser treatment, would be a welcome addition to the armamentarium. PDR could be prevented by improved metabolic control or by pharmacologically blunting the biochemical consequences of hyperglycaemia (e.g., with aldose reductase inhibitors, inhibitors of non-enzymatic glycation or by protein kinase C (PKC) inhibition). The angiogenesis in PDR could be treated via growth factor (e.g., vascular endothelial growth factor (VEGF), insulin like growth factor-1) blockade, integrin (e.g., α-v β-3) blockade or extracellular matrix alteration (e.g., with steroid compounds), or interference with intracellular signal transduction pathways (e.g., PKC and mitogen activated protein kinase pathway proteins). Numerous potentially useful anti-angiogenic compounds are in development, but two drugs are presently in clinical trials for the treatment of the preproliferative stage of PDR.     

Anti-angiogenic peptides for cancer therapeutics

Peptides have emerged as important therapeutics that are being rigorously tested in angiogenesis-dependent diseases due to their low toxicity and high specificity. Since the discovery of endogenous proteins and protein fragments that inhibit microvessel formation (thrombospondin, endostatin) several peptides have shown promise in pre-clinical and clinical studies for cancer. Peptides have been derived from thrombospondin, collagens, chemokines, coagulation cascade proteins, growth factors, and other classes of proteins and target different receptors. Here we survey recent developments for anti-angiogenic peptides with length not exceeding 50 amino acid residues that have shown activity in pre-clinical models of cancer or have been tested in clinical trials; some of the peptides have been modified and optimized, e.g., through L-to-D and non-natural amino acid substitutions. We highlight technological advances in peptide discovery and optimization including computational and bioinformatics tools and novel experimental techniques.     

Aromatase inhibitors: a new paradigm in breast cancer treatment

Microsomal cytochrome P450 (CYP 450) enzyme aromatase belongs to CYP 19 super family. It is involved in the conversion of androgens to estrogens. In postmenopausal women the main sites of aromatisation are skin, adipose tissue and breast. Aromatase localized in breast tumor produces sufficient estrogen for its proliferation. Hence it is an important target for the treatment of hormone dependent breast cancer in postmenopausal women. There are mainly two types of aromatase inhibitors, one is steroidal another is nonsteroidal type. The first and second generation aromatase inhibitors encounter the undesirable drug- drug interactions besides being not very specific and plagued with pharmacokinetic problems. Third generation aromatase inhibitors developed recently are more potent and specific with a greater capacity to annihilate circulating estrogen levels. These agents have satisfactory pharmacokinetic profiles and are devoid of major drug-drug interactions. Third generation aromatase inhibitors became drugs of choice for both first and second line treatment of advanced breast cancer. Aromatase inhibitors can also be used for neoadjuvant therapy of breast cancer in which they have achieved better therapeutic efficacy than tamoxifen. Early results of ATAC (Armidex Tamoxifen Alone or Combination) trial suggest that anastrozole is superior to tamoxifen in adjuvant setting for disease free survival, particularly in receptor positive patients, and in reducing the incidence of contralateral breast cancer. Therapeutic potential of aromatase inhibitors stretches beyond the postmenopausal breast cancer treatment as they also play a role in the treatment of estrogen dependent benign and malignant conditions such as gynaecomastia, prostate cancer, fibroadenomata and the induction of ovulation. By virtue of their ability to reduce estrogen levels they pose problems like demineralization of bone, hot flushes and anti-implantation effects.     

Anti-angiogenic therapy of proliferative diabetic retinopathy

Proliferative diabetic retinopathy (PDR) remains one of the major causes of acquired blindness in developed nations. This is true despite the development of laser treatment, which can prevent blindness in the majority of those who develop this complication. The hallmark of PDR is neovascularisation (NV), abnormal angiogenesis that may ultimately cause severe vitreous cavity bleeding and/or retinal detachment. Pharmacologic therapy aimed at preventing NV, as an adjunct to laser treatment, or as an alternative to laser treatment, would be a welcome addition to the armamentarium. PDR could be prevented by improved metabolic control or by pharmacologically blunting the biochemical consequences of hyperglycaemia (e.g., with aldose reductase inhibitors, inhibitors of non-enzymatic glycation or by protein kinase C (PKC) inhibition). The angiogenesis in PDR could be treated via growth factor (e.g., vascular endothelial growth factor (VEGF), insulin like growth factor-1) blockade, integrin (e.g., alpha-v beta-3) blockade or extracellular matrix alteration (e.g., with steroid compounds), or interference with intracellular signal transduction pathways (e.g., PKC and mitogen activated protein kinase pathway proteins). Numerous potentially useful anti-angiogenic compounds are in development, but two drugs are presently in clinical trials for the treatment of the preproliferative stage of PDR.     

Anti-angiogenic drugs currently in Phase II clinical trials for gynecological cancer treatment

Introduction: Numerous female patients suffer from gynecological cancers every year. When it comes to recurrent or chemoresistant cancers, there are limited treatment options. For decades, much enthusiasm has been shown for novel therapeutic strategies for cancers, and anti-angiogenesis agents appear to be a potential option. Since several promising angiogenesis inhibitors for certain cancers have been approved by Food and Drug Administration, more and more anti-angiogenic drugs are put into clinical trials.

Areas covered: In this review, the anti-angiogenic agents in Phase II clinical trials for gynecological cancer treatment are highlighted. This review mainly focuses on 5-year reports on angiogenesis inhibitors concerning ovarian cancer, cervical cancer, uterine leiomysarcoma and endometrial cancer. Inhibitors reviewed in this paper include bevacizumab, volociximab, aflibercept, temsirolimus, enzastaurin, trebananib, sunitinib, imatinib, pazopanib, sorafenib and nintedanib.

Expert opinion: These anti-angiogenic drugs while used either alone or in combination with chemotherapy, presented mixed results in treating gynecological cancers. The real challenge is how to take best advantage of the anti-angiogenesis hypothesis for therapeutic benefit. Much remains to be done before these molecules work efficaciously in treating gynecological cancer.     

Anti-angiogenic therapies in cancer clinical trials

Strategies involving vasculature have widely been acknowledged to have therapeutic potential in the management of cancer and other diseases. Based on a large body of evidence from preclinical studies and early clinical trials there is considerable optimism that anti-angiogenesis and vascular targeting will be a major clinical therapy. This review considers some 30 anti-angiogenic and vascular targeting agents that are currently in cancer clinical trials and highlights specific problems relating to the assessment of the activity of these agents in patients, trial design, potential toxicities and resistance mechanisms.     

Anti-angiogenic therapies in cancer clinical trials

Strategies involving vasculature have widely been acknowledged to have therapeutic potential in the management of cancer and other diseases. Based on a large body of evidence from preclinical studies and early clinical trials there is considerable optimism that anti-angiogenesis and vascular targeting will be a major clinical therapy. This review considers some 30 anti-angiogenic and vascular targeting agents that are currently in cancer clinical trials and highlights specific problems relating to the assessment of the activity of these agents in patients, trial design, potential toxicities and resistance mechanisms.     

Anti-angiogenic therapy via cationic liposome-mediated systemic siRNA delivery

siRNA has been touted as a therapeutic molecule against genetic diseases, which include cancers. But several challenging issues remain in order to achieve efficient systemic siRNA delivery and a sufficient therapeutic effect for siRNA in vivo. Cationic liposome shows promise as a carrier for nucleic acids, as it can selectively bind to angiogenic tumor blood vessels. In this way, anti-angiogenic therapy via cationic liposome-mediated systemic siRNA delivery could be achieved in cancer therapy. In the present study, we proved our assumption by preparing various kinds of polyethylene glycol (PEG)-coated siRNA/cationic liposome complexes (siRNA-lipoplexes) and screening the avidity of these siRNA-lipoplexes upon angiogenic tumor blood vessels by means of a murine dorsal air sac (DAS) model. The lipoplex, having a lipid composition of DC-6-14/POPC/CHOL/DOPE/mPEG(2000)-DSPE=20/30/30/20/5 (molar ratio) and a charge ratio of cationic liposome and siRNA=3.81 (+/-), showed a higher binding index to newly formed blood vessels. Systemic injection with the lipoplex containing siRNA for the Argonaute2 gene (apoptosis-inducible siRNA) resulted in significant anti-tumor effect without severe side effects in mice with Lewis lung carcinoma. Our results indicate that the PEGylated cationic liposome-mediated systemic delivery of cytotoxic siRNA achieves anti-angiogenesis, resulting in the suppression of tumor growth.     

BRAF as a target for cancer therapy

Tumors with mutations in the gene encoding the serine-threonine protein kinase BRAF are dependent on the MAPK signaling pathway for their growth, what offers an opportunity to test oncogene-targeted therapy. Mutations at the position V600 of BRAF were described in approximately 8% of all solid tumors, including 50% of melanomas, 30 to 70% of papillary thyroid carcinomas and 5 to 8% of colorectal adenocarcinomas. Specific BRAF kinase inhibitors are undergoing rapid clinical development and promising data on efficacy have been demonstrated in activated mutant BRAF V600 melanomas. This review article will address: (a) preclinical data on the antitumor activity of BRAF inhibitors in cell lines/ in vivo models and their opposing functions as inhibitors or activators of the MAPK pathway, depending on the cellular context; (b) drug development from non-selective RAF inhibitors to selective BRAF inhibitors, such as PLX4032 and GSK2118436, with emphasis in the clinical efficacy and toxicity of these agents; and (c) possible mechanisms of resistance to BRAF inhibitors and strategies to overcome its development in BRAF mutant tumors.     

Telomerase as a target for cancer therapy

Normal human somatic cells undergo telomeric attrition and replicative senescence because of inadequate levels of telomerase; however, most immortal cancer cells cope with this by deregulating telomerase. Inhibiting telomerase causes renewed telomeric attrition and eventually highly specific death in cancer cells that express the enzyme. However, most cancer cells undergo many cell divisions before they die, opening the way for acquired drug resistance. Recent attempts to solve this problem include the development of drugs that are more potent catalytic inhibitors, that deny telomerase access to the telomere in situ, or affect telomere structure. Combinations of these approaches may ultimately produce the best clinical results.     

siRNA技术在哮喘治疗中的应用

RNA干扰是由双链RNA引发的序列特异的基因沉默现象,其中长度为21～23nt的小RNA分子（small inter-fering RNA,siRNA）是引起RNA干扰现象的直接原因。利用siRNA使基因沉寂从而调节目的蛋白的表达,在疾病的基因治疗中有巨大的应用价值。哮喘是一种常见的多发病,在治疗上仍面临极大的挑战。利用siRNA技术治疗哮喘是当今最新的一种治疗手段,虽然应用才刚刚起步,但其革命性的治疗理念,无疑给哮喘患者带来了新的希望。     

A new paradigm for stem cell therapy: Substance-P as a stem cell-stimulating agent

Bone marrow is a reservoir for hematopoietic stem cells, endothelial precursor cells, and bone marrow stromal cells (also generally called mesenchymal stem cells), whose positive role in tissue repair is highly anticipated. In this report, we introduce a novel function of substance-P (SP), an 11-amino-acid peptide, as an injury-inducible messenger to mobilize bone marrow stem cells to the blood and finally to engage in tissue repair. This new drug may substitute for ex vivo cell culture of therapeutic cells by stimulating cell proliferation in the bone marrow in vivo and mobilizing those therapeutic cells to the patient’s own blood stream. Again, the additional role of SP in mitigating inflammation-mediated tissue damage can further rationalize the clinical development of SPpeptide as a stem cell stimulant.     

Targeting androgen receptor and trail:a novel treatment paradigm for breast cancer

OBJECTIVE TNF-related apoptosis-inducing ligand(TRAIL)is a promising cancer therapeutic agent due to its minimal toxicity to normal tissues and remarkable apoptotic activity in tumors.However,most breast cancer cells are resistant to TRAIL-induced apoptosis.Our objectives are to investigate the underlying molecular mechanisms and to develop strategies to overcome such resistance.METHODS To identify modulators of TRAIL-induced apoptosis,we carried out a genome wide si RNA screen.To validate the screening result,we either silenced or overexpressed the identified genes in various breast cancer cells and changes in growth and TRAIL-induced cell apoptosis were determined in vitro and in an orthotopic xenograft mouse model.Finally,we investigated whether small molecules targeting the identified genes improve the effectiveness of TRAIL-therapy.RESULTS We unexpectedly identified androgen receptor(AR)to be responsible for TRAIL resistance.While AR is classically viewed as the key factor in prostate cancer progression,we found that AR expression levels were markedly elevated in human invasive breast cancer specimens including triple-negative breast cancers(TNBC)that are highly aggressive with poor prognosis.Importantly,breast cancer cell lines express different levels of AR that correlated with their TRAIL resistance.AR overexpression in MDA-MB-231 and MDA-MB-436 cells suppressed the TRAIL sensitivity whereas knockdown of AR rendered MCF-7 and MDA-MB-453 cells sensitive to TRAIL-induced apoptosis.AR overexpression also induced TRAIL resistance in breast tumors in vivo.Further,we observed an upregulation of the TRAIL receptor,death receptor 5(DR5)in breast cancer cells,following the removal or inhibition of AR by its antagonists Casodex and MDV3100.Treatment with AR antagonists also enhanced TRAIL-induced breast cancer cell apoptosis.CONCLUSION AR signaling suppresses TRAIL-induced breast cancer cell apoptosis,in part,by suppressing DR5 expression,and a combination of AR antagonists together with TRAIL may be a novel and effective therapy for TNBC.     

Anti-angiogenic potential of CoenzymeQ10, riboflavin and niacin in breast cancer patients undergoing tamoxifen therapy

Tumour angiogenesis is a complex mechanism consisting of multi-step events including secretion or activation of angiogenic factors by tumour cells, activation of proteolytic enzymes, proliferation, migration and differentiation of endothelial cells. Both primary and metastatic tumours in the breast are dependent on angiogenesis. In the present study, 84 breast cancer patients were randomized to receive a daily supplement of CoQ(10) 100 mg, riboflavin 10 mg and niacin 50 mg (CoRN), one dosage per day along with tamoxifen (TAM) 10 mg twice a day. Serum pro-angiogenic levels were elevated in untreated breast cancer patients (Group II) and their levels were found to be reduced in breast cancer patients undergoing TAM therapy for more than 1 year (Group III). When these group III breast cancer patients were supplemented with CoRN for 45 days (Group IV) and 90 days (Group V) along with TAM, a further significant reduction in pro-angiogenic marker levels were observed. Supplementing CoRN to breast cancer patients has found to decrease the levels of pro-angiogenic factors and increase the levels of anti-angiogenic factors. A reduction in pro-angiogenic marker levels attributes to reduction in tumour burden and may suggest good prognosis and efficacy of the treatment, and might even offer protection from cancer metastases and recurrence.     

Copper chelation in cancer therapy using tetrathiomolybdate: an evolving paradigm

Background: Tetrathiomolybdate (TM) is a novel anticancer and anti-angiogenic agent, which acts through copper chelation and NF-κB inhibition. Objective: This review summarizes the scientific rationale for the use of TM as an anticancer agent in human studies. Methods: A systematic review of the literature was conducted for the use of TM in cancer including preclinical, animal and human studies. The results of this search are summarized in this review. Results/conclusions: Copper chelation using TM has demonstrated efficacy in preclinical and animal models as an alternative and novel anti-angiogenic agent. Phase I and II clinical trials conducted in solid tumors using TM have demonstrated efficacy with favorable toxicity profile. The use of copper lowering as an anti-angiogenic strategy in the cancer chemopreventative setting remains to be investigated.