Combination Of Antiangiogenic Agents Research Articles

Abstract LB-196: Preventing breast cancer metastases with an anti-angiogenic and anticancer RGD-bearing nanomedicine

Abstract Overcoming drug resistance, emerging either on recurring cancer or metastasis, is a major challenge of cancer treatments. The combination of anti-angiogenic agents with chemotherapeutic ones offers a promising therapeutic approach. Such combination can be achieved exploiting the multivalency of polymer therapeutics. We have recently showed that polymer conjugation of paclitaxel (PTX), a potent cytotoxic and anti-angiogenic drug, improved its pharmacokinetic profile. We hypothesized that actively targeting PTX to αvβ3-integrin, presents an attractive therapeutic strategy for breast cancer. Interestingly, overexpression of αvβ3-integrin, occurring on tumor endothelial and some epithelial cells during tumor growth, invasion, and metastasis, was found to correlate with PTX-resistance of breast cancer cells. We designed and synthesized a novel polyglutamic acid (PGA)-PTX-E-[c(RGDfK)2] nano-sized conjugate. Polymer conjugation converted PTX to a water-soluble macromolecule, which passively targeted the tumor tissue exploiting the enhanced permeability and retention (EPR) effect. The E-[c(RGDfK)2] was utilized as an additional active targeting moiety to αvβ3 integrin. PGA is enzymatically-degradable by cathepsin B, leading to PTX release. PGA-PTX-E-[c(RGDfK)2] displayed a potent anti-angiogenic activity, determined by several well-established in vitro assays. Preferential tumor accumulation of the RGD-bearing conjugate in orthotopic mammary tumors inoculated in mice, lead to enhanced antitumor efficacy and a marked decrease in toxicity compared with free PTX. We found that metastasis establishment was dependent on αvβ3-integrin expression as determined in vitro and ex vivo. PGA-PTX-E-[c(RGDfK)2] conjugate inhibited metastatic growth in an experimental breast cancer metastases model in mice. Taken together, inclusion of an active targeting moiety to integrin expressing-cells has the potential to decrease breast cancer metastases establishment by displaying an anti-angiogenic and anticancer activity. Citation Format: Anat Eldar-Boock, Dikla Ben-Shushan, Joaquin Sanchis, Ruth Lupu, Maria J. Vicent, Ronit Satchi-Fainaro. Preventing breast cancer metastases with an anti-angiogenic and anticancer RGD-bearing nanomedicine. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-196. doi:10.1158/1538-7445.AM2014-LB-196

Abstract 2984: Normalization of tumor vasculature by anti-angiogenesis therapy in metastatic tumor: A clinical study to determine the timing and effect

Abstract Background: Clinically, combination of anti-angiogenic agents with chemotherapeutic agents demonstrated better antitumor efficacy. Instead of merely effect on vasculature regression, careful use of anti-angiogenic therapy may cause the grossly abnormal structure and function of tumor blood vessels to return to a more normal state. Treatment with anti-angiogenic agents can primarily improve chemotherapy efficacy by normalizing tumor vasculature, decrease the intra-tumor interstitial pressure, thereby leading to a more effective drug delivery. We planned to investigate the timing and effect of tumor vascular normalization in human after the administration of anti-angiogenic agent. It may help determine the appropriate timing of administration of chemotherapeutic agents after anti-angiogenic treatment. Materials and methods: This study enrolled the last 8 consecutive patients who participated in a phase II trial for treatment of refractory brain metastases from breast cancer (Eur J Can 49:2s, 2013 suppl; abstr 1878). The protocol treatment consists of bevacizumab 15mg/kg on day 1, chemotherapy of etoposide and cisplatin on day 2 (24 hours after administration of bevacizumab), in 21-day cycles. These 8 patients specifically received four dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) examinations. DCE-MRI was performed before treatment, 1 hour after the end of bevacizumab infusion (i.e., 2.5 hours after starting bevacizumab infusion), 24 hours and 21 days after bevacizumab infusion. This study was registered with ClinicalTrials.gov, identifier NCT01281696, and was approved by the ethical review board. Results: Clinically, all the 8 patients achieved partial remission at central nervous system. All of the 4 DCE-MRI parameters decreased after bevacizumab infusion. Compared to baseline values, the mean reductions at 1 hour and 24 hours were -12.8% and -24.7% for Peak, -46.6% and -65.8% for Slope, -27.9% and -55.5% for iAUC60, -46.6% and -63.9% for Ktrans, respectively (all P values <0.05). The differences between 1 hour and 24 hours reached statistical significance (all P values <0.05) for all the parameters. However, the differences in the mean percentage change between 24 hours and 21 days did not reach significance in any of the four parameters Conclusion: Normalization of tumor vasculature induced by bevacizumab was clearly demonstrated in brain metastases in human at 1 hour after completion of bevacizumab infusion, but significantly became more obvious at 24 hours after bevacizumab administration. Citation Format: Yen-Shen Lu, Bang-Bin Chen, Ching-Hung Lin, Wei-Wu Chen, Pei-Fang Wu, Ann-Lii Cheng, Tiffany Ting-Fang Shih. Normalization of tumor vasculature by anti-angiogenesis therapy in metastatic tumor: A clinical study to determine the timing and effect. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2984. doi:10.1158/1538-7445.AM2014-2984

Profile of pazopanib and its potential in the treatment of epithelial ovarian cancer.

Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer. Recently, clinical trials have focused on novel antiangiogenic agents in combination with chemotherapy or alone in women with primary and recurrent ovarian cancer. Antiangiogenic agents include monoclonal antibodies, tyrosine-kinase inhibitors, and peptibodies. Many of these agents, including bevacizumab, pazopanib, nintedanib, cediranib, and trebananib, have been evaluated in randomized Phase III clinical trials, and all have demonstrated a progression-free survival (PFS) benefit. Specifically, maintenance pazopanib was shown to improve PFS in women with newly diagnosed EOC. Pazopanib, an oral TKI, inhibits several kinase receptors, including those for vascular endothelial growth factor (-1,-2,-3), platelet-derived growth factor (-α and -β), and fibroblast growth factor. It also targets stem cell-factor receptor (c-kit), interleukin 2-inducible T-cell kinase, lymphocyte-specific protein tyrosine kinase, and colony-stimulating factor 1 receptor. Pazopanib has been investigated in several Phase II and III clinical trials, with results indicating a potential role in the management of EOC. This article provides an overview of pazopanib in the treatment of EOC.

Managing Toxicities Associated With Antiangiogenic Biologic Agents in Combination With Chemotherapy for Metastatic Colorectal Cancer

Toxicities commonly associated with antiangiogenic agents include hypertension, proteinuria, wound-healing complications, bleeding or hemorrhage, thromboembolic events, hypersensitivity reactions, and gastrointestinal perforation; however, toxicities most often attributed to chemotherapy include nausea, vomiting, diarrhea, constipation, fatigue, neuropathy, mucositis, hand-foot syndrome, hypersensitivity reactions, and myelosuppression. Patients with metastatic colorectal cancer (mCRC) who receive an antiangiogenic agent in combination with chemotherapy may experience toxicities related to both chemotherapy and the antiangiogenic agent. If possible, evidence-based interventions should be used for the management of toxicities. Patient education about expected toxicities and optimal toxicity management can promote the optimal use of therapy to improve survival and quality of life. Oncology nurses are well positioned to educate patients and their families on anticipated treatment and management of side effects. This article summarizes the incidence of toxicities associated with the antiangiogenic biologic agents aflibercept and bevacizumab, in combination with chemotherapy for patients with mCRC, and provides strategies for managing these toxicities based on clinical practice guidelines.

Evaluation of Poly-Mechanistic Antiangiogenic Combinations to Enhance Cytotoxic Therapy Response in Pancreatic Cancer

Gemcitabine (Gem) has limited clinical benefits in pancreatic ductal adenocarcinoma (PDAC). The present study investigated combinations of gemcitabine with antiangiogenic agents of various mechanisms for PDAC, including bevacizumab (Bev), sunitinib (Su) and EMAP II. Cell proliferation and protein expression were analyzed by WST-1 assay and Western blotting. In vivo experiments were performed via murine xenografts. Inhibition of in vitro proliferation of AsPC-1 PDAC cells by gemcitabine (10 µM), bevacizumab (1 mg/ml), sunitinib (10 µM) and EMAP (10 µM) was 35, 22, 81 and 6 percent; combination of gemcitabine with bevacizumab, sunitinib or EMAP had no additive effects. In endothelial HUVECs, gemcitabine, bevacizumab, sunitinib and EMAP caused 70, 41, 86 and 67 percent inhibition, while combination of gemcitabine with bevacizumab, sunitinib or EMAP had additive effects. In WI-38 fibroblasts, gemcitabine, bevacizumab, sunitinib and EMAP caused 79, 58, 80 and 29 percent inhibition, with additive effects in combination as well. Net in vivo tumor growth inhibition in gemcitabine, bevacizumab, sunitinib and EMAP monotherapy was 43, 38, 94 and 46 percent; dual combinations of Gem+Bev, Gem+Su and Gem+EMAP led to 69, 99 and 64 percent inhibition. Combinations of more than one antiangiogenic agent with gemcitabine were generally more effective but not superior to Gem+Su. Intratumoral proliferation, apoptosis and microvessel density findings correlated with tumor growth inhibition data. Median animal survival was increased by gemcitabine (26 days) but not by bevacizumab, sunitinib or EMAP monotherapy compared to controls (19 days). Gemcitabine combinations with bevacizumab, sunitinib or EMAP improved survival to similar extent (36 or 37 days). Combinations of gemcitabine with Bev+EMAP (43 days) or with Bev+Su+EMAP (46 days) led to the maximum survival benefit observed. Combination of antiangiogenic agents improves gemcitabine response, with sunitinib inducing the strongest effect. These findings demonstrate advantages of combining multi-targeting agents with standard gemcitabine therapy for PDAC.

Antiangiogenic Agents in Combination With Chemotherapy for the Treatment of Epithelial Ovarian Cancer

The purpose of this review was to provide an overview of angiogenesis, including the rationale for targeting angiogenesis as a treatment strategy for epithelial ovarian cancer (EOC) and to discuss available clinical trial data with antiangiogenic agents in EOC, with a focus on combinations with chemotherapy. This was a literature review of clinical studies evaluating select antiangiogenic agents in combination with traditional cytotoxic chemotherapy for the treatment of EOC. Several therapies that target angiogenesis-specific pathways are undergoing clinical development for EOC. Although some of these agents have demonstrated single-agent activity for EOC, there is considerable interest in combining this treatment strategy with chemotherapy in an effort to potentially improve treatment benefits in this patient population. Bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody, is the most studied antiangiogenic agent in EOC and has shown efficacy as monotherapy and combined with chemotherapy in both the relapsed/recurrent and first-line settings. However, results from recent phase 3 trials raise questions regarding patient selection and optimal dose, schedule, and duration of bevacizumab therapy. Other agents in various phases of testing include aflibercept (VEGF Trap), a fusion protein that binds all isoforms of VEGF; multitargeted antiangiogenic tyrosine kinase inhibitors (eg, BIBF 1120, cediranib, pazopanib, sorafenib); and AMG 386, a selective angiopoietin inhibitor. Toxicities associated with VEGF inhibition are also a concern with antiangiogenic therapy, including hypertension, proteinuria, thromboses, and gastrointestinal perforation. Results from recently completed and ongoing clinical trials combining antiangiogenic agents with chemotherapy are awaited in hopes of expanding therapeutic options for patients with EOC.

Reply to J.W. Locasale et al

We appreciate the thoughtful comments by Locasale et al1 regarding the tumor biomarker analysis from our recent phase II clinical trial of aflibercept for recurrent glioblastoma (NABTC 06-01).2 Our analysis demonstrated that elevated tumor levels of hypoxia-inducible factor 1α and carbonic anhydrase 9 (CA9), both markers of hypoxia, were strongly correlated with patient response to aflibercept, whereas patients with elevated CXCR4 were more likely to be resistant. Because hypoxia is known to induce CXCR4 expression, Locasale et al suggest that there may be a positive feedback loop whereby hypoxia-inducible factor 1α induces CXCR4 expression in resistant tumors, which in turn activates signal transducer and activator of transcription 3 (STAT3). We strongly agree with the authors' conclusions that both CXCR4 and STAT3 represent potential mediators of resistance to antiangiogenic therapy. There is a complex interaction between the tumor and its microenvironment, where both CXCR4 and STAT3 may be expressed in either or both compartments. Antiangiogenic therapy targets the tumor microenvironment, and not surprisingly, the tumor microenvironment plays a central role in mediating resistance to anti–vascular endothelial growth factor therapy. CXCL12 (formerly known as SDF-1α) elaborated from tumor or the microenvironment can activate CXCR4 on tumor cells in an autocrine or paracrine fashion, leading to downstream activation of the phosphoinositide 3 kinase/AKT, STAT3, and MAPK pathways to promote tumor survival, angiogenesis, metastasis, and invasion.3 STAT3 is a central signaling node in both tumor and infiltrating immune cells.4 Preclinical studies have recently demonstrated the central role of STAT3 in regulating glioma proliferation, angiogenesis, and immune evasion and in prosurvival effects on glioma stem cells.5–7 Although CXCR4 and STAT3 are expressed in glioblastoma cells, they are also expressed on multiple myeloid cell types including monocytes/macropahges, granulocytes, dendritic cells, and myeloid-derived suppressor cells, which may mediate resistance to antianigogenic therapy.8,9 Hypoxia exacerbated by prolonged or high-dose antiangiogenic therapy may increase CXCL12 expression and the attraction of CXCR4+ myeloid cells,10 which are responsible for mediating vascular endothelial growth factor–independent angiogenesis. Interestingly, recent studies have demonstrated that hypoxia also attracts and induces regulatory T-cells, which promote immune tolerance and angiogenesis.11,12 Consistent with this idea, our analysis showed that tumors expressing markers of lymphocyte proliferation such as CXCR4, CD84, ZAP70, and CD27 were resistant to aflibercept. Characterization of a positive feedback loop will ultimately require additional studies, because this level of complexity cannot be gleaned from undissected tumor tissue analysis; rather, it will require analysis of gene expression after microdissection and preclinical studies. Antiangiogenic therapy has limited efficacy in glioblastoma, because tumors rapidly develop resistance. Careful analysis of tumor tissue and blood biomarker data is critical to develop a full understanding of the potential mechanisms of response and resistance. The data from our trial will inform the next generation of trials using combinations of antiangiogenic agents and targeting resistance pathways, including inhibitors of CXCR4 and STAT3.

CON: Patients With Recurrent Ovarian Carcinoma Should Not be Treated With Antiangiogenic Agents in Combination With Chemotherapy

Elevated body mass index (BMI) is a major risk factor for morbidity and mortality, and associated with autonomic nervous system (ANS) dysregulation, principally due to sympathetic over-activity. ANS is commonly evaluated using heart rate variability assay, which remains impractical for most clinical settings.To examine whether pupillometry indices reflective of dysautonomia correlates with high BMI levels in otherwise healthy individuals.In this cross-sectional study, 101 healthy participants were tested using an automated infrared pupilometer. Pupillary light reflex (PLR) parameters were acquired and averaged. Statistical analysis included a hierarchical linear regression, controlling for possible covariates.BMI values ranging 18.2–47.1 (mean 25.3 ± 4.4 kg/m2) were positively correlated with average pupil dilatation velocity (ADV; r = 0.20, p = 0.05). After controlling for possible covariates, the results remained significant (β = 0.21, t = 2.13, p = 0.04). Separate analysis of participants with normal and increased BMI showed that ADV was significantly abnormal in the overweight group (p = 0.04).In seemingly healthy adults, BMI had a significant positive correlation with sympathetic over-activity manifested by pupillometry ADV values. ANS dysregulation is present even in individuals with moderate overweight. Further research is needed to establish standardized guidelines for PLR use as a marker for ANS dysfunction in individuals with cardiovascular risk factors.

PRO: Patients With Recurrent Ovarian Cancer Should be Treated With Antiangiogenic Agents in Combination With Chemotherapy

PRO: Patients With Recurrent Ovarian Cancer Should be Treated With Antiangiogenic Agents in Combination With Chemotherapy

Abstract 3294: Augmentation of antiangiogenic therapies to enhance Gemcitabine response in pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in the United States. Gemcitabine (Gem) is currently a standard treatment for PDAC with limited clinical benefits. Angiogenesis has been shown to play an important role in the progression of primary and metastatic solid tumors including PDAC. Sunitinib (Su) is a multitarget RTK inhibitor with antiangiogenic and antitumor activities. Bevacizumab (Bev) is a recombinant anti-VEGF monoclonal antibody. Endothelial monocyte activating polypeptide II (EMAP, E) is an antiendothelial and antiangiogenic agent that enhances antitumor effects of Gem and Bev in PDAC. In experimental PDAC, we investigated combination treatment benefits of Gem with the antiangiogenic agents Su, Bev and EMAP. The human PDAC cell line AsPC-1, the endothelial cell line HUVECs and fetal fibroblast WI-38 cells were maintained in vitro. Cell proliferation and protein expression were analyzed by WST-1 assay and Western blotting. Tumor growth and survival experiments were performed in murine xenografts. Intratumoral proliferative activity was measured using Ki67 nuclear antigen staining. Inhibition of proliferation in AsPC-1 cells by Gem (10 μM), Bev (1 mg/ml) Su (10 μM) and EMAP (20 μM) was 45, 24, 92 and 2 percent; combination of Su with Gem, Bev or EMAP had small additive effects. In HUVECs, Gem, Bev, Su and EMAP caused 95, 23, 88 and 59 percent inhibition in cell proliferation, and combining Su with Gem, Bev and EMAP had significant additive effects. In WI-38 cells, Gem, Bev, Su and EMAP caused 95, 17, 87 and 23 percent inhibition in cell proliferation and combination of Su with Gem, Bev or EMAP had no additive effects. Sunitinib treatment either alone or in combination with Gem, Bev or EMAP induced apoptosis as observed by PARP-1 cleavage. In vivo, the inhibitory effect on tumor growth after Gem (as reference, 100) was enhanced in combination with Bev, E, Su, Bev+E, Bev+Su, E+Su and Bev+E+Su by 32, 16, 56, 38, 48, 47 and 64 percent respectively; combining antiangiogenic agents without Gem did not enhance local tumor growth inhibition. Inhibition of intra-tumoral proliferative index based on Ki67 positive cells was comparable to tumor growth inhibition data. Median animal survival in controls or Gem, Bev+Gem, E+Gem, Su+Gem, Bev+E+Gem, Su+E+Gem, Bev+Su+Gem and Bev+E+Su+Gem groups was 19, 26, 36, 36, 37, 43, 36, 27 and 46 days, respectively. Combination of antiangiogenic agents with gemcitabine improves in vivo results, despite the differential inhibitory effects on various cell types in vitro. Sunitinib alone has benefits, and its effects are not limited to endothelial cells. Addition of Su to anti-VEGF and anti-integrin agents adds little benefit in the absence of Gem. However, the results strongly corroborate the benefits of combining multitargeting antiangiogenic agents with standard Gemcitabine therapy for PDAC treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3294. doi:10.1158/1538-7445.AM2011-3294

Antiangiogenic Agents in Combination with Chemotherapy in Patients with Advanced Non-Small Cell Lung Cancer

Most patients with non-small cell lung cancer (NSCLC) present with advanced disease requiring systemic chemotherapy. Treatment with the antiangiogenic agent bevacizumab in combination with standard platinum-based doublet chemotherapy has been shown to improve outcomes in patients with advanced NSCLC. Several multitargeted antiangiogenic tyrosine kinase inhibitors (e.g., sorafenib, sunitinib, cediranib, vandetanib, BIBF 1120, pazopanib, and axitinib) are also being evaluated in combination with standard chemotherapy. Here we review current clinical data with combination therapy involving antiangiogenic agents and cytotoxic chemotherapy in patients with advanced NSCLC.

Biology of vascular endothelial growth factor and its receptors in head and neck cancer: Beyond angiogenesis

Angiogenesis is a necessary process for tumor progression and is driven through molecular interactions between cancer cells and neighboring vascular endothelial cells. The primary mediators of angiogenesis are the vascular endothelial growth factors and their respective receptors on endothelial cells. There are several U.S. Food and Drug Administration-approved anti-angiogenic agents in clinical use. In head and neck cancer there are clinical trials assessing the efficacy of anti-angiogenic agents in combination with chemoradiation therapy. Although the aforementioned growth factors and receptors have been traditionally viewed as anti-angiogenic targets, there are concomitant efforts to understand the role these molecules play within the tumor cells. In this review, we first discuss the biology of angiogenic proteins and the targeting of angiogenic molecules for cancer treatment. We summarize the current clinical trials of anti-angiogenic therapies in head and neck squamous cell carcinoma. Finally, the additional role these molecules play in tumor progression independent of angiogenesis is discussed.

Targeted Agents in Ovarian Cancer

Despite recent advances in the treatment of ovarian cancer, a large majority of women with this diagnosis will die from recurrence of their disease. Targeted therapies, in the form of monoclonal antibodies and small molecule tyrosine kinase inhibitors have significantly altered the management of many solid tumors and hematologic malignancies. No such agents have been approved by the US FDA for use in ovarian cancer, although Phase II data suggests excellent single-agent activity of some of these drugs. Antiangiogenic agents in combination with chemotherapy are being evaluated in Phase III clinical trials, both in the adjuvant setting and in recurrent platinum-sensitive disease. Poly-ADP-ribose polymerase inhibitors are promising agents in BRCA1/2-mutated breast and ovarian cancers. Ongoing clinical trials are exploring the anti-tumor effect of poly-ADP-ribose polymerase inhibitors administered as single agents and in combination with chemotherapy. Many other new drugs are in earlier grades of development. In this article, we review the state of the art in targeted therapies for ovarian cancer and identify future directions for their development in the management of this often devastating disease.

Targeting multiple angiogenic pathways for the treatment of neuroblastoma

Purpose Resistance to angiogenesis inhibition can occur through the upregulation of alternative mediators of neovascularization. We used a combination of angiogenesis inhibitors with different mechanisms of action, interferon- β (IFN- β) and rapamycin, to target multiple angiogenic pathways to treat neuroblastoma xenografts. Methods Subcutaneous and retroperitoneal neuroblastoma xenografts (NB-1691 and SK-N-AS) were used. Continuous delivery of IFN- β was achieved with adeno-associated virus vector-mediated, liver-targeted gene transfer. Rapamycin was delivered intraperitoneally (5 mg/kg per day). After 2 weeks of treatment, tumor size was measured, and tumor vasculature was evaluated with intravital microscopy and immunohistochemistry. Results Rapamycin and IFN- β, alone and in combination, had little effect on tumor cell viability in vitro. In vivo, combination therapy led to fewer intratumoral vessels (69% of control), and the remaining vessels had an altered phenotype, being covered with significantly more pericytes (13× control). Final tumor size was significantly less than controls in all tumor models, with combination therapy having a greater antitumor effect than either monotherapy. Conclusion The combination of IFN- β and rapamycin altered the vasculature of neuroblastoma xenografts and resulted in significant tumor inhibition. The use of combinations of antiangiogenic agents should be further evaluated for the treatment of neuroblastoma and other solid tumors.

Single Agents with Designed Combination Chemotherapy Potential: Synthesis and Evaluation of Substituted Pyrimido[4,5-b]indoles as Receptor Tyrosine Kinase and Thymidylate Synthase Inhibitors and as Antitumor Agents

Combinations of antiangiogenic agents (AAs) with cytotoxic agents have shown significant promise in cancer treatment, and several such clinical trials are currently underway. We have designed, synthesized, and evaluated two compounds that each inhibit vascular endothelial growth factor receptor-2 (VEGFR-2) and platelet-derived growth factor receptor-beta (PDGFR-beta) for antiangiogenic effects and also inhibit human thymidylate synthase (hTS) for cytotoxic effects in single agents. The synthesis of these compounds involved the nucleophilic displacement of the common intermediate 5-chloro-9H-pyrimido[4,5-b]indole-2,4-diamine with appropriate benzenethiols. The inhibitory potency of both these single agents against VEGFR-2, PDGFR-beta, and hTS is better than or close to standards. In a COLO-205 xenograft mouse model, one of the analogs significantly decreased tumor growth (tumor growth inhibition (TGI) = 76% at 35 mg/kg), liver metastases, and tumor blood vessels compared with a standard drug and with control and thus demonstrated potent tumor growth inhibition, inhibition of metastasis, and antiangiogenic effects in vivo. These compounds afford combination chemotherapeutic potential in single agents.

Periodic Control in Antiangiogenic and Combined Anticancer Therapies

This paper is devoted to a problem of periodic scheduling of dosages of drugs in cancer treatment including modern anticancer modalities. Following considerations are focused on antiangiogenic therapy and combined antiangiogenic and chemotherapy. Combinations of antiangiogenic agents together with other types of therapies, such as chemotherapy, have shown promising results and became one of the most inspiring possibilities for cancer cure accomplishment. Conditions for asymptotic tumour eradication by periodic therapy protocols are shown from mathematical models describing the dynamics of both carcinogenesis and angiogenesis. Results of more realistic periodic control protocols are demonstrated using simulations. Keywords: Periodic control, biomedical applications, nonlinear models, anticancer therapies, asymptotic analysis.

CON: Patients with Recurrent Ovarian Carcinoma Should Not Be Treated with Antiangiogenic Agents in Combination with Chemotherapy

a O a c t t t p d b w t t Introduction The following discussion argues against the assertion that patients with recurrent ovarian cancer should routinely receive anti-angiogenic agents in combination with chemotherapy. In order to support the premise that antiangiogenic agents should not yet be routinely used in all patients, we will consider the following items: (1) standard approaches for patients with recurrent disease; (2) the activity and toxicity of bevacizumab as the predominant representative agent in recurrent ovarian cancer; (3) ongoing phase III clinical trials; and (4) critical questions that remain to be answered.

PRO: Patients with Recurrent Ovarian Cancer Should Be Treated with Antiangiogenic Agents in Combination with Chemotherapy

Irradiation after breast-conserving surgery (BCS) decreases the incidence of ipsilateral breast tumor recurrence (IBTR) and breast cancer-related death. However, daily radiation treatments are burdensome to elderly patients, whose risk of IBTR is relatively low. Since 2001, we have offered BCS without radiation to patients meeting our selection criteria. This study assessed the prognosis of the patients who chose this option.Between 2001 and 2014, 203 patients met the selection criteria: aged ≥60 years; pathologically node-negative, hormone-positive breast cancer; a negative surgical margin; and no lymphovascular invasion. Among these patients, 84 and 119 underwent BCS with or without radiation, respectively. IBTR, overall survival (OS), and breast cancer-specific survival (BCSS) were evaluated.The median follow-up duration was 6.2 years. There were no significant differences in tumor size or the number of patients with adjuvant therapy between the groups. The 5-year IBTR rates were 0.9% and 1.6% in the non-irradiated and irradiated groups, respectively (p = 0.308). The 5-year OS rates were 94.1% and 98.7% (p = 0.391). Similarly, the 5-year BCSS rates were 97.2% and 98.7% (p = 0.812).It is suggested that the omission of irradiation could be an option for elderly breast cancer patients who satisfy our criteria.

Colon perforation during antiangiogenic therapy for malignant glioma

Antiangiogenic drugs have emerged as effective treatment options for patients with recurrent malignant gliomas (MGs). Though this class of drugs is generally well tolerated, rare life-threatening complications, including thromboembolism, hemorrhage, and gastrointestinal (GI) perforation, are reported. We describe six cases of GI perforation among 244 glioma patients (2.5%) during treatment with antiangiogenic agents in combination with chemotherapy and corticosteroids. Two patients succumbed to this complication, and the others recovered. Because GI perforation is a life-threatening yet treatable complication, neurooncologists must have a low threshold to consider it in patients on antiangiogenic drug therapy who present with abdominal pain and other GI complaints.

Synergistic Antitumor Activity of Ixabepilone (BMS-247550) Plus Bevacizumab in Multiple In vivo Tumor Models

Angiogenesis is a critical step in the establishment, growth, and metastasis of solid tumors, and combination of antiangiogenic agents with chemotherapy is an attractive therapeutic option. We investigated the potential of ixabepilone, the first in a new class of antineoplastic agents known as epothilones, to synergize with antiangiogenic agents to inhibit tumor growth. In vitro and in vivo cytotoxicity of ixabepilone as single agent and in combination with two targeted antiangiogenic agents, bevacizumab or sunitinib, were examined in preclinical tumor models. Direct effects of the agents against endothelial cells was also examined and compared with the effects of paclitaxel as single agent and in combination with bevacizumab. Ixabepilone showed robust synergistic antitumor activity in combination with bevacizumab and sunitinib in preclinical in vivo models derived from breast, colon, lung, and kidney cancers. The synergistic antitumor effect was greater with ixabepilone compared with paclitaxel. Furthermore, ixabepilone was more effective than paclitaxel at killing endothelial cells expressing P-glycoprotein in vitro and inhibiting endothelial cell proliferation and tumor angiogenesis in vivo. Ixabepilone may enhance the antitumor effects of antiangiogenic therapy by direct cytotoxicity and also indirectly via the killing of tumor-associated endothelial cells. Given that ixabepilone has reduced susceptibility to drug efflux pumps compared with taxanes, these data may explain the increased antiangiogenic and antitumor activity of ixabepilone in combination with antiangiogenic agents. Phase II studies to assess the efficacy and safety of ixabepilone plus bevacizumab in locally recurrent or metastatic breast cancer are planned.