Combination Of Anti-angiogenic Drugs Research Articles

Updated results from ALTER-S002: A single-arm multicenter trial of the combination of anlotinib with chemotherapy in patients with stage IIB classic osteosarcoma of the extremity.

11529 Background: The overexpression of multiple tyrosine kinase receptors in osteosarcoma indicated a promising therapy targeting these receptors. Anlotinib is a multi-targeted tyrosine kinase inhibitor that potentially inhibits tumor angiogenesis. The combination of anti-angiogenic drugs with chemotherapeutic agents is proposed to act synergistically to achieve favorable tumor control, especially as the neoadjuvant therapy. We had reported the neoadjuvant therapy data of anlotinib in combination with chemotherapy for treatment-naive stage IIB classical osteosarcoma of the extremity in the 2023 ESMO congress. Here we report an update on the effectiveness and safety of the follow-up. Methods: In this open-label, single-arm, multicenter phase II clinical trial. Eligible patients(pts) were aged 12-40 years with histologically confirmed primary localized extremity classic osteosarcoma, stage IIB, operable. Pts received anlotinib (10mg, po, d1-14, q3w), doxorubicin (A) (20-25mg/m2 iv, d1-3, q3w) and cisplatin (P) (70-90mg/m2, iv, d1, q3w) for the first nine weeks. Pts underwent radical surgery after the exclusion of contraindications at week 10. After surgery, pts received A+P at weeks 12-14, and anlotinib plus A+P at weeks 15-20 with the drug dose unchanged. Since week 21, anlotinib (12mg, po, d1-14, q3w) monotherapy was maintained until week 104 or the occurrence of an EFS event. The primary endpoint was 24-month EFS rate, secondary endpoints were 36-month EFS rate, local recurrence rate, lung metastasis rate, 3-year OS rate and safety. Results: From May 2020 to Apr 2022, 52 eligible pts were enrolled, while 51 pts underwent surgery after 3 cycles of neoadjuvant therapy. At the data cut-off date (Oct. 2023), the median EFS was not reached, 12 and 24-month EFS rates were 84.18% (95% CI :70.82, 91.77) and 73.43% (95% CI :57.40, 84.21), respectively. The stratified analysis of EFS showed that the length and diameter of the target lesion are independent prognostic factors. The median OS was not reached, the 24-month OS rate was 95.92% (95% CI :84.65, 98.96). Among the 51 pts who underwent surgical treatment, 12(23.53%, 95% CI: 12.79, 37.49) pts experienced recurrence or metastasis. Most treatment-related adverse events (TRAEs) were grade 1-2. Grade 3/4 TRAEs (≥20%) included neutropenia (51.92%), leukopenia (38.46%), thrombocytopenia (36.54%) and anemia (32.69%). Conclusions: The updated results suggested that anlotinib combined with doxorubicin and cisplatin in the perioperative period showed favorable efficiency and manageable adverse events in Stage IIB classic osteosarcoma of the extremity. Clinical trial information: ChiCTR 2000033298.

Progress in the treatment of soft tissue sarcoma in the 2023 annual meeting of the American Society of Clinical Oncology

Soft tissue sarcoma (STS) is a group of rare malignant tumors originating from mesenchymal tissue, with a high degree of malignancy and a wide range of pathological subtypes. The prognosis varies among different subtypes, and treatment increasingly relies on selecting appropriate treatment methods for different subtypes. Surgical treatment is still the main treatment method at present, and the development of immune and targeted therapy also brings new hope for the treatment of soft tissue sarcoma. Immune checkpoint inhibitors, oncolytic viruses and T cell therapy have shown well safety and efficacy in clinical trials. Targeted drugs such as trabectedin and lenvatinib have changed the treatment pattern of soft tissue sarcoma. Currently, chemotherapy based on doxorubicin and ifosfamide is still the first line treatment for patients with advanced soft tissue sarcoma who have distant metastasis. However, the adverse reactions of doxorubicin limit its application in elderly patients, and trofosfamide has shown good efficacy and safety as an alternative in clinical trials. The efficacy of postoperative radiotherapy has been confirmed, which can reduce the local recurrence rate after surgical resection of soft tissue sarcoma. In summary, multimodal comprehensive treatment has become the main strategy for the treatment of soft tissue sarcoma. The combination of different treatment methods can generate synergistic effects and help patients obtain more clinical benefits, such as the combination of doxorubicin and immune checkpoint inhibitors, and the combination of antiangiogenic drugs and chemotherapy drugs. At the 2023 annual meeting of the American Society of Clinical Oncology (ASCO), oncologists from all over the world reported many researches related to the treatment of soft tissue sarcoma. This article aims to review the new progress in the treatment of soft tissue sarcoma in the 2023 annual meeting of ASCO.

Efficacy and safety of radiation therapy combined with anti-angiogenic agentsand immunotherapy for MSS/pMMR metastatic colorectal cancer: A real-world study.

e15559 Background: The combination of anti-angiogenic drugs and immune checkpoint inhibitors (ICIs) can reshape tumor microenvironment, and their effectiveness has been demonstrated in pattients with microsatellite stable (MSS) or mismatch repair profificient (pMMR) metastatic colorectal cancer (mCRC). Radiotherapy (RT) can induce tumor immunogenic cell death, increase infiltration of tumor-infiltrating T lymphocytes and enhance neoantigen expression. Whether the application of RT can further improve the prognosis of pts with MSS/pMMR mCRC receiving anti-vascular drugs and immunotherapy remains to be explored. Methods: We retrospectively identified data on mCRC pts who received anti-angiogenic targeted agents and ICIs after failure of standard therapy at our institution from January 2015 to September 2022. Pts either received RT (RT+TT+IT group) or did not (TT+IT group) during the course of the disease. Baseline characteristics of the groups were compared with the Chi-squared, Fisher's exact, or the independent sample t-test as appropriate. Progression-free survival (PFS) and overall survival (OS) were examined by the Kaplan-Meier method with a log-rank test. Univariate and multivariate Cox regression analysis was conducted to identify prognostic factors for PFS and OS. Results: Of the 89 pts who received anti-angiogenic targeted therapy in combination with ICIs, 43 (48.3%) received RT and 46 (51.7%) did not. All pts were MSS/pMMR. The objective response rate (ORR) of the RT+TT+IT and TT+IT groups was 18.6% (8/43) and 10.9% (5/46) and the disease control rate (DCR) was 83.7% (36/43) and 67.4% (31/46) (both p > 0.05), respectively. The median PFS time was slightly higher in the RT+TT+IT group than in the TT+IT group (5.0 vs. 4.3 months, p = 0.065). In addition, the PFS of RT sequential/simultaneous TT+IT was superior to TT+IT sequential radiotherapy (RT→IT+TT vs. RT-IT+TT vs. IT+TT→RT: median 7.5 vs. 6.1 v.s 3.8 months, p = 0.004). The median OS of RT+TT+IT group was significantly better than that of TT+IT group (15.2 vs. 7.2 months, p = 0.026). Application of RT appeared to be most benefificial in pts aged 56 or younger, advanced stage of initial diagnosis, metastatic lesions involving ≥2 organs, primary lesion not resected, RAS mutations. Cox multivariate regression analysis showed that the number of anti-angiogenic agents plus ICIs cycles > 4 was an independent prognostic factor for OS. No treatment-related deaths were reported, and radiation pneumonia occurred in one patient in the combined radiotherapy group in a manageable manner. Conclusions: The addition of RT during the course of disease can significantly improve the survival benefit of MSS/pMMR mCRC pts treated with anti-angiogenic drugs combined with ICIs posterior line therapy.

Clinical outcomes and biomarkers of phyllodes tumors of the breast: A single-center retrospective study.

Phyllodes tumors (PTs) are rare neoplasms with a certain risk of recurrence and/or metastasis. In clinical practice, there is a lack of high-quality clinical studies and unified guidelines to guide the treatment. All malignant and recurrence/metastasis PTs were retrospectively collected, which were diagnosed from 2008 to 2022. A total of 82 patients were enrolled, including 69 malignant and 13 borderline tumors. 96.3% (79/82) received surgical treatment. During a median follow-up of 55.5months, 20 patients (20/82, 24.4%) had distant metastasis (DM), while 32 (32/82, 39.0%) had local recurrence (LR). Univariate analysis showed the survival of PTs was associated with surgical methods (p < 0.001), tumor size (p=0.026), and biological behavior (p=0.017), but not age at diagnosis. In relapsed borderline PTs, we did not find deaths due to disease progression. Patients with DM were all malignant PTs, with disease-progression occurring within 3 years in more than 80% of patients. Among salvage treatments, the combination of antiangiogenic drugs improved the prognosis to some extent, with a significant increase in mPFS (2.77 vs. 1.53 months), but no significant statistical results were obtained (p=0.168). Lactate dehydrogenase (LDH) was an independent predictor of the prognosis for malignant PTs (p=0.001, HR=1.203, 95%CI, 1.082-1.336). Borderline PTs rarely metastasize, and even if LR occurs, surgical resection can lead to long-term survival. In metastatic phyllodes tumors (MPT), systemic therapy is not effective, but antiangiogenic drugs may prolong survival. LDH is an independent prognostic factor for malignant PTs to identify high-risk tumors.

The Anti-VEGF(R) Drug Discovery Legacy: Improving Attrition Rates by Breaking the Vicious Cycle of Angiogenesis in Cancer.

Simple SummarySeveral anti-angiogenic drugs have been approved for cancer treatment, alone or in combination with other anti-tumoral agents. Angiogenesis inhibitors cause drug resistance, metastasis formation, and reduced delivery of chemotherapeutic agents, as a consequence of decrease of tumor vasculature. The endothelial cells as gatekeepers inspired a revisited interpretation of the vascular function in several malignancies.Resistance to anti-vascular endothelial growth factor (VEGF) molecules causes lack of response and disease recurrence. Acquired resistance develops as a result of genetic/epigenetic changes conferring to the cancer cells a drug resistant phenotype. In addition to tumor cells, tumor endothelial cells also undergo epigenetic modifications involved in resistance to anti-angiogenic therapies. The association of multiple anti-angiogenic molecules or a combination of anti-angiogenic drugs with other treatment regimens have been indicated as alternative therapeutic strategies to overcome resistance to anti-angiogenic therapies. Alternative mechanisms of tumor vasculature, including intussusceptive microvascular growth (IMG), vasculogenic mimicry, and vascular co-option, are involved in resistance to anti-angiogenic therapies. The crosstalk between angiogenesis and immune cells explains the efficacy of combining anti-angiogenic drugs with immune check-point inhibitors. Collectively, in order to increase clinical benefits and overcome resistance to anti-angiogenesis therapies, pan-omics profiling is key.

An exploratory clinical study of gefitinib combined with anlotinib in the first-line treatment of stage ⅢB-Ⅳ EGFR gene mutant non-small cell lung cancer patients with slow progress.

e21089 Background: Anlotinib is a new type of small molecule anti-angiogenic drug that can inhibit the activity of a variety of tyrosine kinase receptors. Based on the initial efficacy of the combination of anti-angiogenic drugs and EGFR-TKIs and a clearer definition of people who are sensitive to EGFR-TKIs treatment, this study explores the slow progress of first-line use of gefitinib in patients with non-small cell lung cancer slowly progress, the efficacy and safety of combined Anlotinib. Methods: Fifteen patients with first-line non-small cell lung cancer who received gefitinib treatment and slowly progressed after enrolled in Xuchang Central Hospital, 15 received anlotinib(12mg/d from day 1 to day 14 in a 21-day cycle) combined with gefitinib（250mg /d） treatment until the disease progressed or died or was intolerable Adverse events. The primary endpoint was the progression-free survival(PFS), and the secondary endpoints were objective response rate (ORR), disease control rate( DCR) and safety. Results: As of January 4, 2021, a total of 15 patients have been enrolled and 14 patients can be evaluated. 0CR, 5PR, 8SD, 1PD. The median progression-free survival was 13.3 months (95% Cl, 3.71-4.89), and the most common adverse reactions were Grade 1, including hypertension (42.86%) and fatigue (21.42%). No higher-grade adverse reactions. Conclusions: Gefitinib combined with Anlotinib Hydrochloride Capsules is safe, effective and well tolerated when the first-line treatment of EGFR gene mutant non-small cell lung cancer patients progresses slowly.

Angiogenesis, programmed death ligand 1 (PD-L1) and immune microenvironment association in laryngeal carcinoma.

In the specific field of laryngeal carcinoma (LSCC), evidence about the interaction between angiogenetic pathway and immune microenvironment has not yet been explored. Given the potential relevance of such an interaction for prognostic and therapeutic purposes, the main aim of this exploratory study was to investigate the existence of a correlation between angiogenesis (quantified through CD31 expression), programmed cell death ligand 1 (PD-L1) expression, and immune microenvironment. A secondary aim was to verify whether considering a combination of angiogenesis and immune microenvironment variables might improve prognostic accuracy compared to the traditional clinical-pathological prognostic tools. CD31-assessed micro-vessel density (MVD), PD-L1 in terms of combined positive score (CPS), and tumour infiltrating lymphocytes (TILs) were assessed on 45 consecutive cases of LSCC. Cox proportional hazards model revealed increasing CD31-assessed MVD values, PD-L1 CPS <1, and TILs count rate <30%, as predictive of reduced disease free survival (DFS). Multivariate analysis found that MVD (p<0.0001) and TILs (p=0.0420) retained their significant independent prognostic value. Spearman's correlation model disclosed a significant negative correlation between CD31-assessed MVD values and PD-L1 CPS (p=0.0040). PD-L1 CPS and TILs count rate were positively correlated (p<0.0001). DFS was significantly lower in the CD31-assessed MVD >7, PD-L1 CPS <1, TILs <30% group than in the MVD ≤7, PD-L1 CPS ≥1, TILs ≥30% group (p=0.0001). These data preliminarily support an integrated interpretation of the prognostic role or angiogenesis and immune microenvironment markers in LSCC. This is of potential clinical relevance suggesting a synergistic effect of the combination of anti-angiogenic drugs with programmed death-1/PD-L1 checkpoint inhibitors in advanced LSCC.

Neuropilin 1 and Neuropilin 2 gene invalidation or pharmacological inhibition reveals their relevance for the treatment of metastatic renal cell carcinoma

BackgroundDespite the improvement of relapse-free survival mediated by anti-angiogenic drugs like sunitinib (Sutent®), or by combinations of anti-angiogenic drugs with immunotherapy, metastatic clear cell Renal Cell Carcinoma (mccRCC) remain incurable. Hence, new relevant treatments are urgently needed. The VEGFs coreceptors, Neuropilins 1, 2 (NRP1, 2) are expressed on several tumor cells including ccRCC. We analyzed the role of the VEGFs/NRPs signaling in ccRCC aggressiveness and evaluated the relevance to target this pathway.MethodsWe correlated the NRP1, 2 levels to patients’ survival using online available data base. Human and mouse ccRCC cells were knocked-out for the NRP1 and NRP2 genes by a CRISPR/Cas9 method. The number of metabolically active cells was evaluated by XTT assays. Migration ability was determined by wound closure experiments and invasion ability by using Boyden chamber coated with collagen. Production of VEGFA and VEGFC was evaluated by ELISA. Experimental ccRCC were generated in immuno-competent/deficient mice. The effects of a competitive inhibitor of NRP1, 2, NRPa-308, was tested in vitro and in vivo with the above-mentioned tests and on experimental ccRCC. NRPa-308 docking was performed on both NRPs.ResultsKnock-out of the NRP1 and NRP2 genes inhibited cell metabolism and migration and stimulated the expression of VEGFA or VEGFC, respectively. NRPa-308 presented a higher affinity for NRP2 than for NRP1. It decreased cell metabolism and migration/invasion more efficiently than sunitinib and the commercially available NRP inhibitor EG00229. NRPa-308 presented a robust inhibition of experimental ccRCC growth in immunocompetent and immunodeficient mice. Such inhibition was associated with decreased expression of several pro-tumoral factors. Analysis of the TCGA database showed that the NRP2 pathway, more than the NRP1 pathway correlates with tumor aggressiveness only in metastatic patients.ConclusionsOur study strongly suggests that inhibiting NRPs is a relevant treatment for mccRCC patients in therapeutic impasses and NRPa-308 represents a relevant hit.

Immuno-Metabolism and Microenvironment in Cancer: Key Players for Immunotherapy.

Immune checkpoint inhibitors (ICIs) have changed therapeutic algorithms in several malignancies, although intrinsic and secondary resistance is still an issue. In this context, the dysregulation of immuno-metabolism plays a leading role both in the tumor microenvironment (TME) and at the host level. In this review, we summarize the most important immune-metabolic factors and how they could be exploited therapeutically. At the cellular level, an increased concentration of extracellular adenosine as well as the depletion of tryptophan and uncontrolled activation of the PI3K/AKT pathway induces an immune-tolerant TME, reducing the response to ICIs. Moreover, aberrant angiogenesis induces a hypoxic environment by recruiting VEGF, Treg cells and immune-suppressive tumor associated macrophages (TAMs). On the other hand, factors such as gender and body mass index seem to affect the response to ICIs, while the microbiome composition (and its alterations) modulates both the response and the development of immune-related adverse events. Exploiting these complex mechanisms is the next goal in immunotherapy. The most successful strategy to date has been the combination of antiangiogenic drugs and ICIs, which prolonged the survival of patients with non-small-cell lung cancer (NSCLC) and hepatocellular carcinoma (HCC), while results from tryptophan pathway inhibition studies are inconclusive. New exciting strategies include targeting the adenosine pathway, TAMs and the microbiota with fecal microbiome transplantation.

NOGGO Ov-42/MAMOC: Rucaparib maintenance after bevacizumab maintenance following carboplatin-based first line-chemotherapy in ovarian cancer patients.

TPS6102 Background: Ovarian cancer (OC) is associated with the highest mortality rates among gynecological malignancies, with most patients being diagnosed in advanced stages. The most common histological subtype is high grade serous OC, which is characterized by deficiency in homologous recombination. Debulking surgery, followed by platinum based chemotherapy and bevacizumab (bev), followed by maintenance therapy with bev, is the standard therapy for advanced BRCA wild type (BRCAwt) OC patients in Germany. BRCA mutant patients will receive maintenance with olaparib, according to SOLO1 data. The anticancer effects of PARP inhibitors (PARPi) seem to be increased by the addition of antiangiogenic drugs. Preclinical data showed increased HRD in tumors pretreated with bev, and clinical trials showed a benefit of the combination of antiangiogenic drugs and PARPi vs. PARPi alone. NOGGO Ov-42/MAMOC trial (NCT04227522) is a phase III, randomized, placebo-controlled study evaluating rucaparib maintenance following bevacizumab maintenance for the treatment of advanced primary high grade BRCAwt OC. Methods: 190 patients with histologically confirmed advanced (FIGO stage IIIA- IV of the 2014 FIGO classification) high grade serous or high grade endometrioid (based on local histopathological findings) OC, fallopian tube cancer, primary peritoneal cancer or clear cell carcinoma of the ovary will be randomized 2:1 to receive either rucaparib 600mg BID or placebo as maintenance therapy following first line chemotherapy with 6 cycles of Carboplatin/Paclitaxel and at least 12 cycles of bev, given together with chemotherapy and as maintenance. Only BRCAwt patients will be included in the trial. Randomization is stratified by surgery planned timepoint (neoadjuvant vs. adjuvant), surgical outcome (no residual tumor mass vs. residual tumor mass), response to chemotherapy followed by bev (CR/NED vs. PR/SD) and study center. Treatment will continue for 24 months or until disease progression, unacceptable toxicity, or withdrawal. Primary endpoint is PFS in BRCAwt patients per RECIST v1.1. Secondary endpoints are PFS2, quality of life (EORTC QLQ-C30/OV28, FSI, SF-12, PROC-CTCAE, every day memory questionnaire), daily activity, time to next medical intervention, time to next subsequent therapy, safety assessments and OS. Clinical trial information: NCT04227522.

A systematical comparison of anti-angiogenesis and anti-cancer efficacy of ramucirumab, apatinib, regorafenib and cabozantinib in zebrafish model

AimsGastric cancer (GC) is one of the most common malignant tumors in the world. Anti-angiogenic therapy is a useful strategy for the treatment of advanced GC. This study was aimed to systemically compare the anti-angiogenesis, anti-cancer efficacy, as well as the safety of four known anti-angiogenic drugs, namely ramucirumab, apatinib, regorafenib and cabozantinib. Main methodsAnti-angiogenic effect was evaluated for the intersegmental vessels (ISVs) and subintestinal veins (SIVs) formation in the Tg (fli-1: EGFP) zebrafish embryos. Anti-cancer efficacy was tested for the in vivo cell proliferation in cell line derived tumor xenograft (CDX) model based on Tg (fli-1: EGFP) zebrafish embryos. Key findingsAll four drugs exhibited anti-angiogenic abilities and tumor inhibition effects in fli-1: EGFP transgenic zebrafish. Using zebrafish xenografted model, we found that effectiveness of ramucirumab in anti-GC-proliferation is better than apatinib, regorafenib and cabozantinib. The combination of anti-angiogenic drugs and cisplatin showed no significant benefit in tumors. Meanwhile, toxicity assay showed that all tested anti-angiogenic drugs could cause cardiovascular-related side effects. The therapeutic index (LD50/ED50) of cabozantinib is higher than apatinib and regorafenib, suggesting a potential as an anti-GC drug. SignificanceThe comparison of GC-related anti-angiogenic drugs was first reported. It was found that cabozantinib had a potential as an anti-GC drug. Zebrafish model was an ideal animal model for the research of anti-angiogenic behaviors.

Abstract 1742: Dual inhibitor of immunokinase and pan-RAF for the treatment of KRAS-mutated cancers

Abstract Tumor-associated macrophages (TAMs) represent most of the white blood cell population in solid tumors. TAMs usually display an M2-like phenotype due to signals from the tumor microenvironment, such as IL-10, VEGFA and CSF-1/M-CSF. These anti-inflammatory and pro-tumorigenic macrophages promote tumor growth and metastasis. The presence of TAMs is usually correlated with a poor clinical outcome in cancer patients. Modulation of the immunosuppressive factors within the tumor microenvironment is a key issue in tumor immunology. TAMs subvert the anti-cancer function of tumor-infiltrating T lymphocytes. TAMs also modify the immune cell population within the tumor microenvironment to decrease anti-tumor immune cells while simultaneously increase the immunosuppressive cell population to promote tumorigenesis. As a result, targeting of TAMs may be a promising new approach to cancer treatment. CSF-1 is the crucial growth and differentiation factor for macrophage and CSF-1R is exclusively expressed by cells of the monocyte lineage, suggesting that CSF-1R is an attractive therapeutic target to enable interference with TAMs. In preclinical models, macrophage depletion by CSF-1R inhibitor increased the antitumor effects of VEGF-targeted therapies. Furthermore, failure of antiangiogenic therapy is caused by the pro-angiogenic Tie2-expressing monocytes infiltrating tumor tissues. These data provide the rationale for the combination of antiangiogenic drugs with macrophage targeting strategies to increase the therapeutic efficacy and to prevent drug resistance. Therefore, we tried to find inhibitors of immunokinase using structure-based molecular modeling and identified a selective inhibitor, SJP-1601. SJP-1601 potentially inhibited CSF-1R, Tie2, and VEGFR2 in vitro kinase assay. Interestingly, SJP-1601 also inhibited B-RAF, C-RAF and B-RAF V600E in kinase panel assay. We orally administered SJP-1601 in colorectal cancer xenografts with mutant K-RAS and observed the dose-dependent reduction of tumor volume. In addition, oral administration of SJP-1601 attenuated tumor growth correlated with enriched CD8+ T cells and decreased regulatory T cells in tumor stroma in BALB/c mice bearing 4T1 tumor cells or C57BL/6 mice bearing MC38 tumor cells. These data confirmed the preclinical merit of CSF1-CSF1R signaling blockade alone or as a part of combinatorial therapies to offer synergistic immunotherapeutic effects in treatments of human cancer. In this study, we discovered an orally active dual inhibitor of immunokinase &amp; pan-RAF. SJP-1601 not only improved the efficacy of adoptive T cell therapy through inhibition of immunosuppressive macrophage recruitment and activation in immunocompetent mice but also potentiated the response of xenograft with mutant KRAS by preventing pan-RAF. Our findings suggest that SJP-1601 could be an excellent preclinical candidate for the treatment of cancer with mutant K-RAS. Citation Format: Sungpyo Hong, Soon Kil Ahn, Ho-Seok Kwon, Yongbin Park, Min-Hyo Ki, Hee Jong Shin. Dual inhibitor of immunokinase and pan-RAF for the treatment of KRAS-mutated cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1742.

The Role of Angiogenesis in Cancer Treatment.

A number of anti-angiogenesis drugs have been FDA-approved and are being used in cancer treatment, and a number of other agents are in different stages of clinical development or in preclinical evaluation. However, pharmacologic anti-angiogenesis strategies that arrest tumor progression might not be enough to eradicate tumors. Decreased anti-angiogenesis activity in single mechanism-based anti-angiogenic strategies is due to the redundancy, multiplicity, and development of compensatory mechanism by which blood vessels are remodeled. Improving anti-angiogenesis drug efficacy will require identification of broad-spectrum anti-angiogenesis targets. These strategies may have novel features, such as increased porosity, and are the result of complex interactions among endothelial cells, extracellular matrix proteins, growth factors, pericyte, and smooth muscle cells. Thus, combinations of anti-angiogenic drugs and other anticancer strategies such as chemotherapy appear essential for optimal outcome in cancer patients. This review will focus on the role of anti-angiogenesis strategies in cancer treatment.

Angiogenesis inhibition: quo vadis

Angiogenesis Inhibitors: Quo VadisTracy Batchelor, M.D., Massachusetts General Hospital, Harvard Medical SchoolThe United States Food and Drug Administration has approved 10 anti-angiogenic drugs for over 12 types of cancer since 2001. Bevacizumab, a monoclonal antibody that binds the vascular endothelial growth factor (VEGF)-A ligand, received accelerated approval in the United States as monotherapy for recurrent glioblastoma in 2009. This approval was based on radiographic response rates in two prospective studies. However, bevacizumab did not improve overall survival in two subsequent, randomized phase III trials in patients with newly diagnosed glioblastoma. To date, no survival benefit for newly diagnosed or recurrent glioblastoma patients has been demonstrated in randomized phase III trials of 3 different anti-angiogenic agents (bevacizumab, cediranib, cilengitide). Controversy remains regarding the mechanism of action of this class of agents in glioblastoma and whether survival will ultimately be extended by these expensive and potentially toxic biologics/drugs. Combinations of anti-angiogenic drugs with other drugs may be required to improve survival, similar to other solid cancers. These trials are ongoing. A challenging aspect of anti-angiogenic drug development in glioblastoma is the lack of validated biomarkers of tumor response and tumor resistance. Moreover, defining tumor response and tumor progression in the setting of anti-VEGF therapy has highlighted the limitations of conventional imaging endpoints in this disease. Revised response criteria for anti-angiogenic agents have been developed and incorporated into prospective clinical trials. Magnetic resonance imaging (MRI) and positron emission tomography (PET) techniques that may accurately predict response and progression are under development. Angiogenesis Inhibitors: Quo Vadis Tracy Batchelor, M.D., Massachusetts General Hospital, Harvard Medical School The United States Food and Drug Administration has approved 10 anti-angiogenic drugs for over 12 types of cancer since 2001. Bevacizumab, a monoclonal antibody that binds the vascular endothelial growth factor (VEGF)-A ligand, received accelerated approval in the United States as monotherapy for recurrent glioblastoma in 2009. This approval was based on radiographic response rates in two prospective studies. However, bevacizumab did not improve overall survival in two subsequent, randomized phase III trials in patients with newly diagnosed glioblastoma. To date, no survival benefit for newly diagnosed or recurrent glioblastoma patients has been demonstrated in randomized phase III trials of 3 different anti-angiogenic agents (bevacizumab, cediranib, cilengitide). Controversy remains regarding the mechanism of action of this class of agents in glioblastoma and whether survival will ultimately be extended by these expensive and potentially toxic biologics/drugs. Combinations of anti-angiogenic drugs with other drugs may be required to improve survival, similar to other solid cancers. These trials are ongoing. A challenging aspect of anti-angiogenic drug development in glioblastoma is the lack of validated biomarkers of tumor response and tumor resistance. Moreover, defining tumor response and tumor progression in the setting of anti-VEGF therapy has highlighted the limitations of conventional imaging endpoints in this disease. Revised response criteria for anti-angiogenic agents have been developed and incorporated into prospective clinical trials. Magnetic resonance imaging (MRI) and positron emission tomography (PET) techniques that may accurately predict response and progression are under development.

Combining Antiangiogenics to Overcome Resistance: Rationale and Clinical Experience

Antiangiogenic therapies are now well established in oncology clinical practice; however, despite initial optimism, the results of late-phase trials, especially in the adjuvant setting, have largely proved disappointing. In the context of metastatic disease, resistance to antiangiogenic agents arises through a range of mechanisms, including the development of alternative angiogenic pathways. One of the proposed strategies to overcome this resistance is to combine antiangiogenic agents with different mechanisms of action. Early-phase clinical trials assessing the tolerability and efficacy of different combinations of antiangiogenic drugs, including those that target the VEGF pathway or the angiopoietins, as well as vascular disrupting agents, are increasing in number. An example of this strategy is the combination of sorafenib and bevacizumab, which has elicited major responses in different tumor types, including ovarian carcinoma and glioblastoma. However, overlapping and cumulative toxicities pose a real challenge. This review summarizes the preclinical rationale for this approach and current clinical experience in combining antiangiogenic therapies.

Circulating endothelial cells and serum caspase-cleaved CK18 to predict for response and survival in non-small cell lung cancer patients receiving endostatin and paclitaxel-carboplatin combined chemotherapy.

e18088 Background: Combinations of anti-angiogenic drugs with chemotherapeutics are widely used for cancers control. Whether can better efficacy of such a combinated modality be achieved and predicted earlier is a great challenge. Circulating endothelial cells (CECs) and cytokeratins (CKs) might have a role in tumour angiogenesis and in tumour cell death. Measurement of CECs and CKs in the blood of patients with tumors could be a simple, non-invasive approach to monitor or predict responses and survival to treatment. Methods: One hundred and seven patients with primary advanced non-small cell lung cancer (NSCLC) were enrolled, randomly assigned to either the endostatin treatment group (paclitaxel+ carboplatin+ endostatin) or the control group (paclitaxel+carboplatin). CEC count and serum CK8, caspase-cleaved CK18 (ccCK18) and uncleaved CK18 (CK18) were measured in the 107 subjects at before treatment (baseline), week 3, and week 6 of treatment, respectively. Results: Higher baseline CEC count was observed in patients with good tumor response (p=0.002 for all the 107 patents; p=0.000 in the treatment group). When compared with the baseline level, after 6 weeks therapy in the endostatin group, CECs decreased significantly (p=0.000), but the CKs levels increased. The increased levels of ccCK18 and CK18 at week 6 reached significance in the treatment group (p=0.001 and p=0.048, respectively). Tumor response showed strong correlation with the reduction extent of CECs (p=0.000) and the increase value of ccCK18 (p=0.040) after endostatin therapy. The best cut-off values of the changes of CECs and ccCK18 for prediction of survival were designed being 0.58/ul and 19.6ng/ml, respectively. Furthermore, obvious reduction of CECs and more rise of ccCK18 significantly correlated with the longer median survival (p= 0.013 and p = 0.016 for PFS, p = 0.009 and p=0.012 for OS, respectively). Conclusions: CECs and CKs would be the impressive biomarkers to explore for selecting NSCLC patients who might benefit from endostain in combination with paclitaxel plus carboplatin treatment.

Progress in tumor vascular normalization for anticancer therapy: challenges and perspectives

Antitumor angiogenic therapy has been shown promising in the treatment of several advanced cancers since the approval of the first antiangiogenic drug Avastin in 2004. Although the current antiangiogenic drugs reduce the density of tumor blood vessels and result in tumor shrinkage at the early stage of treatment, recent studies have shown that antiangiogenic therapy has transient and insufficient efficacy, resulting in tumor recurrence in patients after several months of treatment. Blockage of blood and oxygen supplies creates a hypoxic and acidic microenvironment in the tumor tissues, which fosters tumor cells to become more aggressive and metastatic. In 2001, Jain proposed tumor vascular normalization as an alternative approach to treating cancers based on the pioneering work on tumor blood vessels by several other researchers. At present, normalizing the disorganized tumor vasculature, rather than disrupting or blocking them, has emerged as a new option for anticancer therapy. Preclinical and clinical data have shown that tumor vascular normalization using monoclonal antibodies, proteins, peptides, small molecules, and pericytes resulted in decreased tumor size and reduced metastasis. However, current tumor vascular normalizing drugs display moderate anticancer efficacy. Accumulated data have shown that a variety of vasculogenic/angiogenic tumor cells and genes play important roles in tumor neovascularization, growth, and metastasis. Therefore, multiple-targeting of vasculogenic tumor cells and genes may improve the efficacy of tumor vascular normalization. To this end, the combination of antiangiogenic drugs with tumor vascular normalizing therapeutics, as well as the integration of Western medicine with traditional Chinese medicine, may provide a good opportunity for discovering novel tumor vascular normalizing drugs for an effective anticancer therapy.

Hypoxia, angiogenesis, and lung cancer

Lung cancer is responsible for more deaths than any other cancer in America. As a result, novel ways to treat it are needed to improve patient outcomes. A tumor must form new blood vessels to grow and metastasize to distant sites; this angiogenesis is mediated by factors such as vascular endothelial growth factor (VEGF). Because it increases VEGF levels, hypoxia has been thought to be a primary trigger of angiogenesis. Tumor hypoxia and higher levels of serum markers of angiogenesis have been associated with poor prognosis in non-small cell lung cancer (NSCLC). In recent years, antiangiogenic compounds have been developed and tested in various solid malignancies, including NSCLC, for which bevacizumab, a monoclonal antibody against VEGF, was recently approved. Combinations of antiangiogenic drugs and conventional cytotoxic chemotherapy are currently under development.

Targeting Angiogenesis in Head and Neck Cancer

Tumor angiogenesis is a hallmark of advanced cancers and an attractive treatment target in multiple solid tumors. In the past 5 years anti-angiogenic therapies have seen a rapid ascent into mainstream clinical practice. For head and neck cancer (HNC), definitive evidence in the form of a pivotal trial is still pending. Nevertheless, preclinical and early clinical data support a central role of angiogenesis for HNC: up to 90% of HNCs express angiogenic factors such as vascular endothelial growth factor (VEGF) and the respective receptors (VEGFR1-3), and multiple studies support the prognostic implications of angiogenic markers for this tumor. Contrary to concerns that anti-angiogenic therapies could increase hypoxia and thereby treatment resistance, anti-angiogenic therapies in preclinical models appear to overcome resistance and preclinically synergize with traditional therapies, eg, radiation. Clinical use of anti-angiogenic agents for HNC, including bevacizumab, sorafenib, sunitinib, and others, is currently limited to clinical trials, and several larger trials are still ongoing. Single-agent anti-angiogenic drugs so far have not shown activity in unselected HNC patients, with a response rate of less than 4% for the small molecule anti-angiogenics sorafenib and the investigational agent SU5416. On the other hand, combinations of anti-angiogenic drugs with other treatments (analogous to other solid tumors) appear promising; for example, the combination of bevacizumab with the EGFR inhibitor erlotinib showed a response rate of 14.6%. Studies of bevacizumab with chemotherapy (phase III Eastern Cooperative Oncology Group [ECOG] trial) and in combination with chemoradiation are currently ongoing. The side effect profile is comparable to what has been observed in other tumor types and include hypertension, proteinuria, and thrombotic and hemorrhagic events. With the intense research effort preclinically and clinically, and some encouraging early results, anti-angiogenic therapies and biomarkers appear to be poised to play an important role in the treatment of HNC in the near future.

Drug Insight: VEGF as a therapeutic target for breast cancer

Angiogenesis is implicated in the pathogenesis of malignancy and metastasis. Inhibition of angiogenesis has demonstrated clinically significant improvements in outcomes in a variety of malignancies, including breast cancer. The humanized monoclonal antibody against VEGF, bevacizumab, is the clinically most mature of the antiangiogenic agents and has recently been shown to improve outcome when combined with chemotherapy in the first-line metastatic setting of breast cancer. A variety of other antiangiogenic agents are currently under investigation, including drugs that inhibit the VEGF receptor 2, the cognate receptor for VEGF found on endothelial cells. The combination of antiangiogenic drugs with one another and with other biologic agents is also being explored in an attempt to improve efficacy and to overcome the drug resistance seen with the initial studies of antiangiogenic agents. This Review will focus on the current state of therapeutics designed to inhibit this angiogenic process in breast cancer.