Addition Of Antiangiogenic Agents Research Articles

Endocrine-based targeted combination versus endocrine therapy alone as first-line treatment in elderly patients with hormone receptor-positive advanced breast cancer: Meta-analysis of phase II and III randomized clinical trials.

1046 Background: Combined endocrine approaches have been widely investigated as first-line treatment in hormone receptors positive metastatic breast cancer. In particular, multiple randomized trials showed that the addiction of CDK (cyclin-dependent kinase) 4/6 inhibitors to endocrine therapy (ET) increase progression free survival (PFS). Elderly patients (aged ≥65 years) are under represented in most of the clinical studies. Moreover, due to the multi-morbidity and the major toxicity associated with the targeted agents, the combination strategy in that subgroup is widely discussed. The present meta-analysis aimed to understand the role of the new endocrine approaches in women aged ≥65 years. Methods: This meta-analysis included first line phase II/III randomized published trials comparing (ET) to the experimental strategy. Trials with no data about hazard ratios (HR) for PFS in the subgroup of patients aged ≥65 years were excluded. The heterogeneity of the data was evaluated by Chi-square Q test and I2 statistic. Results: 8 studies were included in the analysis. 4 trials (Paloma1/TRIO-18, Paloma2, Monaleesa2, Monarch3) investigated the role of CDK 4/6 inhibitors, 2 trials (SWOG and FACT) analysed the combination of Fulvestrant plus Aromatase Inhibitors, while other two trials explored the association of ET with Bevacizumab (LEA) and Temsirolimus (HORIZON), respectively. Overall, the meta-analysis showed a PFS advantage for the experimental arms [HR 0.77, p 0.016] with a significant high/moderate heterogeneity [I2 65.46%, p 0.005]. The 4 studies adding CDK4/6 inhibitors to ET showed a significant improvement in PFS compared to ET alone. No significant advantages for the addition of anti-angiogenic agents or Fulvestrant to ET have been found in elderly population subgroup. Conclusions: The novel experimental combo-strategies in the first line setting showed an improvement in PFS in the subgroup of elderly patients. Adding CDK4/6 inhibitors to ET significantly prolongs PFS as compared to ET alone. The magnitude of PFS benefit due to addition of CDK4/6 inhibitors to ET is age-independent.

Epithelial ovarian cancer: Evolution of management in the era of precision medicine.

Ovarian cancer is the second most common cause of gynecologic cancer death in women around the world. The outcomes are complicated, because the disease is often diagnosed late and composed of several subtypes with distinct biological and molecular properties (even within the same histological subtype), and there is inconsistency in availability of and access to treatment. Upfront treatment largely relies on debulking surgery to no residual disease and platinum-based chemotherapy, with the addition of antiangiogenic agents in patients who have suboptimally debulked and stage IV disease. Major improvement in maintenance therapy has been seen by incorporating inhibitors against poly (ADP-ribose) polymerase (PARP) molecules involved in the DNA damage-repair process, which have been approved in a recurrent setting and recently in a first-line setting among women with BRCA1/BRCA2 mutations. In recognizing the challenges facing the treatment of ovarian cancer, current investigations are enlaced with deep molecular and cellular profiling. To improve survival in this aggressive disease, access to appropriate evidence-based care is requisite. In concert, realizing individualized precision medicine will require prioritizing clinical trials of innovative treatments and refining predictive biomarkers that will enable selection of patients who would benefit from chemotherapy, targeted agents, or immunotherapy. Together, a coordinated and structured approach will accelerate significant clinical and academic advancements in ovarian cancer and meaningfully change the paradigm of care.

Angiogenic regeneration defines loco-regional recurrence following pre-operative radio-chemotherapy for rectal cancer: a pilot study.

Previous studies from our group have brought forward the concept of angiogenic regeneration during radiotherapy (RT), as a major cause of RT failure. This process was examined herein in rectal cancer patients undergoing preoperative chemo-radiotherapy. Out of 25 patients with stage II/III rectal adenocarcinoma, 15 had incomplete response (pIR) after preoperative chemo-radiotherapy. The MIB1 proliferation index, the vascular density (VD) assessed with the anti-CD31 antibody and the Hypoxia Inducible Factor HIF1α was assessed. High VD before RT was related with poor local relapse free survival LRFS (p = 0.04), in cases with pIR. Pre-RT values of MIB1 and of HIF1α were not related with LRFS. High MIB1 index and intensification of VD beyond pre-treatment levels in post-RT samples, features indicative of angiogenic regeneration, defined poor LRFS (p = 0.04 and p = 0.0008, respectively). Angiogenic regeneration is strongly related to failure of RT and surgery to control loco-regional disease in rectal cancer patients. Addition of anti-angiogenic agents in the preoperative chemo-radiotherapy regimens may prove beneficial in subgroups of patients.

A Phase I/II Study Targeting Angiogenesis Using Bevacizumab Combined with Chemotherapy and a Histone Deacetylase Inhibitor (Valproic Acid) in Advanced Sarcomas.

Epigenetic events and genetic alterations under the control of the tumor microenvironment potentially mediate tumor induced angiogenesis involved in soft tissue sarcoma (STS) metastasis. Addition of antiangiogenic agent, such as bevacizumab, to standard chemotherapy in treatment of sarcoma has been studied in clinical trials, but most of the findings have not supported its use. We hypothesized the existence of an epigenetically mediated “angiogenic switch”, and the tumor microenvironment, prevents bevacizumab from truly blocking angiogenesis. The addition of valproic acid (VPA), a weak histone deacetylase inhibitor, and bevacizumab, a monoclonal antibody against vascular endothelial growth factor, together with the cytotoxic effects of gemcitabine and docetaxel, may enhance responses and alter chemoresistance. This was designed as a phase I/II trial with primary endpoints including safety of the treatment combination and tumor response. Unresectable or metastatic sarcoma patients >18 years of age, irrespective of number of prior treatments, received VPA 40 mg/kg orally for 5 days prior to day 1, bevacizumab at 15 mg/kg IV on day 1, gemcitabine 900 mg/m2 (day 1, day 8), and docetaxel 75 mg/m2 (day 8). Cycles were of 28 day duration. Bevacizumab and VPA were continued as maintenance after 6 cycles, until disease progression. A standard 3 + 3 phase I dose de-escalation design was utilized to evaluate safety. Gain of function p53 gene mutation testing was performed on available archival tissue specimens. A total of 46 patients (30 female, 16 male) with median age of 60 (range 24–81) years were enrolled; 34 (73.9%) patients received prior chemotherapy, 14 (30%) of which received prior gemcitabine and docetaxel. Patients received a median of 5.5 cycles (range 0–24 of treatment (min 0, one patient died prior to completing the first cycle; max: 24, one patient received 6 cycles and 18 maintenance cycles before progressing). Seventeen patients underwent dose reduction, of which VPA was reduced in 6 patients. Forty-one patients were evaluable for response. There was a confirmed complete response in 1 (epithelioid sarcoma), and a partial response (PR) in 6 (1 carcinosarcoma, 2 extrauterine leiomyosarcoma (LMS), 2 undifferentiated pleomorphic sarcoma, and 1 uterine LMS) patients. Stable disease (SD) was seen in 21 patients for at least 2 months. One subject with prior gemcitabine and docetaxel had PR, and 7 had SD. Median progression-free survival (PFS) was 5.7 months (95% CI: 2.1–8.0), and overall survival (OS) was 12.9 months (95% CI: 8.3–14.5). Three patients died due to tumor progression while on the study. The combination of VPA, bevacizumab, gemcitabine, and docetaxel appears to be moderately safe and well tolerated. Given that there are very limited options for patients with relapsed refractory STS, this drug combination may be an important therapy to consider. This combination treatment deserves further investigation in epithelioid and carcinosarcoma subtypes.

Increasing Bioavailability of Cytotoxic Agents through Prolonged Therapy and Addition of Polymechanistic Antiangiogenic Agents Enhances Antitumor Response in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) has a very poor prognosis. Meaningful therapeutic options for unresectable PDAC remain limited and therefore more efficient therapeutic strategies are urgently required. We explored the approach of manipulating dose intensity of cytotoxic agents through prolonged therapy and by combination with antiangiogenic agents in experimental PDAC. Median animal survival over controls (19 days) was increased after prolonged therapy (up to 6 weeks) with gemcitabine to 29 days (a 53% increase, p = 0.008). Addition of two antiangiogenic agents, bevacizumab and EMAP, further extended median survival to 46 days (a 142% increase, p = 0.0001). Corresponding survival extension after therapy with similar agents limited to 2 weeks was 37% for gemcitabine and 127% after gemcitabine plus antiangiogenic agents. Pharmacokinetic analysis revealed that the addition of antiangiogenic agents caused a 4.4-fold increase in gemcitabine plasma concentration and 8-fold increase in tumor concentration compared with gemcitabine monotherapy group. Prolonged therapy of docetaxel also increased animal survival (38 days, a 100% increase, p = 0.0004) that was further extended by the addition of the antiangiogenic combination (49 days, a 158% increase, p = 0.0001). In vitro evaluation of exposure time effects on cell proliferation revealed that in PDAC cells (AsPC-1) longer exposure (120 h) of gemcitabine or docetaxel caused greater relative inhibition in cell proliferation compared with 72 h exposure. At 1i­M concentration, inhibition in cell proliferation after 72 h and 120 h was 27% and 55% (gemcitabine); 64% and 84% (docetaxel). Only in endothelial cells and fibroblasts but not in PDAC cells did the combination with antiangiogenic agents create additive effects over each cytotoxic agent alone. These findings demonstrate that increasing bioavailability of cytotoxic agents, both via increased exposure through prolonged therapy or greater intratumoral dose intensity by combination with antiangiogenic agents could enhance in vivo antitumor efficacy and thus warrants further investigation.

Abstract 1178: Gene and protein expression profiling identifies molecular signature of resistance to anti-VEGF therapy in ovarian cancer

Abstract Purpose: Angiogenesis plays an important role in ovarian cancer progression, and the addition of anti-angiogenic agents targeting the vascular endothelial growth factor (VEGF) signaling pathways to conventional chemotherapy improves progression-free survival in relapsed, platinum-resistant ovarian cancer when bevacizumab is given as concurrent or maintenance therapy. Unfortunately, the long-term clinical benefits of anti-VEGF therapy have been consistently limited by the rapid development of tumor resistance. Understanding of tumor's functional adaptations to anti-VEGF therapy and identifying early indicators of resistance are crucial for better exploiting anti-angiogenic therapies. The objective of this study was to perform gene and protein expression profiling of ovarian cancer to identify tumor and stroma signature of anti-VEGF treatment-resistance using preclinical resistance models. Methods: We developed phenotypic resistance xenograft models of anti-VEGF therapy that mimic the clinical feature of resistance. SKOV3 xenografted mice were treated with sorafenib or bevacizumab over two months until there were phenotypic differences between tumors that remained responsive to the treatment and that regained growth after initial response. We conducted Illumina next generation sequencing to compare the gene expression in resistant and sensitive tumors. Sequencing analysis was performed using Perkin Elmer's Genesifter software and alignment to the H. sapiens and M. musculus reference genomes. Further, Reverse phase protein array (RPPA) analysis was done to identify differentially expressed proteins between resistant and sensitive tumors. Results: Our sequencing analysis revealed significant differences in expression of various genes between sensitive and resistant tumors. Based on their role in angiogenesis and angiogenesis resistance, we chose a set of genes for follow-up studies. In sorafenib treatment group amphiregulin and heparanase expression was ≥4 fold higher (P ≤ 0.05) in resistant group compared to sensitive group. In bevacizumab resistant group prostaglandin E receptor 1 and keratin 24 ≥3 fold higher expression ((P ≤ 0.05) was observed. RPPA analysis indicated that proteins such as ER alpha, VEGFR-2, elF4G, E-cadherin, mTOR and beta-catenin expressed ≥ 2.8 fold (P ≤ 0.0001) higher in sorafenib resistant tumors compared to sensitive tumors. Neurofibromin 2 (NF2) protein is expressed 2 fold (P ≤ 0.0001) higher in bevacizumab resistant tumors compared to sensitive tumors. Conclusion: Using gene and protein profiling, we identified important tumor and stroma biomarkers of resistance to anti-VEGF therapy in ovarian cancer that may provide insight into ovarian tumor's adaption principles to VEGF inhibition. Citation Format: Bharat Kumar Devapatla, Pharavee Jaiprasart, Sukyung Woo. Gene and protein expression profiling identifies molecular signature of resistance to anti-VEGF therapy in ovarian cancer. [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 1178. doi:10.1158/1538-7445.AM2014-1178

Update on randomized trials on recurrent disease

Approximately 75% of patients with advanced ovarian cancer will have a recurrence of their disease within the first 3 years after upfront surgery and paclitaxel–carboplatin-based chemotherapy. An optimal choice of treatment of patients with a recurrence is an important issue, and several factors should be taken into account in this decision-making, including disease, patients, and treatment. Fortunately, we have several strategies that can be of help not only with respect to palliation, but also in terms of survival benefit. Apart from surgery, which will be reviewed in another article of this series, different single cytotoxic agents and combinations and, more recently, the addition of antiangiogenic agents have shown that they can have impact on progression-free survival and, for some strategies, on the overall survival in such patients. In this review, we present an update of the clinical trials that have led to these achievements.

Abstract 2071: Addition of antiangiogenic agents enhances nab-paclitaxel antitumor activity in experimental pancreatic cancer.

Abstract Pancreatic ductal adenocarcinoma (PDAC) is characterized by early tissue invasion and metastasis, complex desmoplastic stromal response, and high resistance to systemic therapies. Nanoparticle albumin-bound (nab) paclitaxel (NPT) has the potential for pharmacodynamic advantages over conventional taxanes and has shown efficacy as mono- and combination therapeutic agent in several malignancies including pancreatic, lung and ovarian cancer. We evaluated the combination treatment benefits of nab-paclitaxel with the antiangiogenic agents bevacizumab (Bev) and sunitinib (Su) in experimental pancreatic cancer. In vitro cell proliferation and protein expression were measured by WST-1 assay and immunoblotting. Tumor growth and animal survival studies were performed in murine xenografts. Intratumoral proliferation and apoptosis were evaluated via Ki67 and TUNEL staining. Nab-paclitaxel displayed higher in vitro antiproliferative activity as a single agent in pancreatic cancer compared with gemcitabine or the polysorbate-based taxane docetaxel. In AsPC-1 PDAC cells, nab-paclitaxel IC50 was reduced more than 6-fold by an IC25 dose of sunitinib (500 nM) but not by bevacizumab (10 μg/ml). In endothelial cells HUVEC, nab-paclitaxel IC50 (82 nM) was decreased to 41 nM by bevacizumab (10 μg/ml) and to 63 nM by sunitinib (100 nM). In fibroblast WI-38 cells, nab-paclitaxel IC50 (7.2 μM) was decreased to 7.8 nM by the IC25 dose of sunitinib (2.5 μM), but no significant decrease was observed by bevacizumab (50 μg/ml) addition. Nab-paclitaxel increased stathmin phosphorylation and decreased tubulin expression in vitro. In a subcutaneous murine xenograft model, net tumor growth inhibition in NPT, Bev, Su, Bev+Su, NPT+Bev, NPT+Su and NPT+Bev+Su was 72, 44, 61, 89, 67, 93 and 86 percent. Effects of therapy on intratumoral proliferation and apoptosis corresponded with tumor growth inhibition data. In tumor tissue lysates, nab-paclitaxel caused an increase in stathmin phosphorylation but no change in tubulin expression. In an intraperitoneal murine xenograft model, compared to controls (median survival: 19 days), animal survival increased after nab-paclitaxel (32 days, p=0.0008) but not after antiangiogenic therapy with Bev (21 days), Su (24 days) or Bev+Su (22 days; for all: p=NS). Animal survival was further increased by the combination treatment of nab-paclitaxel with bevacizumab and sunitinib, with a median survival of 38, 37 and 49 days in NPT+Bev (p=0.03 vs. NPT), NPT+Su (p=0.174 vs. NPT) and NPT+Bev+Su (p=0.001 vs. NPT) groups, respectively. Nab-paclitaxel has strong antitumor activity as a single agent in this model of experimental pancreatic cancer. Nab-paclitaxel effects were further enhanced by addition of the antiangiogenic agents bevacizumab and sunitinib. These findings strongly support the potential of nab-paclitaxel based combination strategies for clinical PDAC therapy. Citation Format: Niranjan Awasthi, Changhua Zhang, Stefan Hinz, Margaret A. Schwarz, Roderich E. Schwarz. Addition of antiangiogenic agents enhances nab-paclitaxel antitumor activity in experimental pancreatic cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2071. doi:10.1158/1538-7445.AM2013-2071

Toxicities of Antiangiogenic Therapy in Non–Small-Cell Lung Cancer

The addition of antiangiogenic agents has improved overall survival in a wide variety of tumor types, including non–small-cell lung cancer (NSCLC). Antibodies to the vascular endothelial growth factor (VEGF) were the first targeted agent to yield a significant improvement in overall survival when combined with first-line chemotherapy for metastatic NSCLC. Anti-VEGF antibodies and tyrosine kinase inhibitors blocking VEGF receptor (VEGFR) activity are also being investigated in pretreated NSCLC. Initial experience with anti-VEGF antibodies suggested a mild adverse event profile. However, it has become clear with additional experience that antiangiogenic agents are associated with a distinct array of toxicities, such as hemorrhage, hypertension, thromboembolic events, and proteinuria. Furthermore, an increase in chemotherapy-associated toxicities such as neutropenia has been observed with the addition of anti-VEGF antibodies. Multitargeted small-molecule inhibitors that block activity of the VEGFR tyrosine kinase are associated with fatigue and other toxicities in addition to the aforementioned class-effect toxicities, possibly because of their inhibition of multiple signaling pathways. Currently, only patients without predominant squamous cell histology are eligible to receive bevacizumab. Trials are ongoing to address the feasibility of bevacizumab in patients who were excluded from the phase III pivotal trial. Additionally, further investigation is necessary to determine risk factors for hemorrhage with antiangiogenic agents.