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Targeted antiangiogenic agents in combination with cytotoxic chemotherapy in preclinical and clinical studies in sarcoma

Targeted antiangiogenic agents in combination with cytotoxic chemotherapy in preclinical and... Sarcomas are a heterogeneous group of mesenchymal malignancies. In recent years, studies have demonstrated that inhibition of angiogenic pathways or disruption of established vasculature can attenuate the growth of sarcomas. However, when used as monotherapy in the clinical setting, these targeted antiangiogenic agents have only provided modest survival benefits in some sarcoma subtypes, and have not been efficacious in others. Preclinical and early clinical data suggest that the addition of conventional chemotherapy to antiangiogenic agents may lead to more effective therapies for patients with these tumors. In the current review, the authors summarize the available evidence and possible mechanisms supporting this approach. Keywords: Sarcoma, Antiangiogenesis, Combination drug therapy, Combination chemotherapy clinical trials [6]. These agents have shown single-agent Background activity in sarcoma. Most notably, pazopanib has been Sarcomas are a heterogeneous group of malignancies, approved by the US Food and Drug Administration and including soft tissue sarcomas (STS) and tumors of bone the European Medicines Agency for advanced STS. As and cartilage. Conventional chemotherapy regimens for monotherapy, these agents have only provided survival advanced or metastatic sarcomas have low survival rates, benefits on the order of weeks to months in some sar - substantial toxicity, and frequent emergence of resist- coma subtypes, and have not been efficacious in others ance, making alternative novel treatment approaches a [7]. Therefore, combining antiangiogenic agents (AA) priority. with other systemic agents active in sarcoma may lead to Sarcomas express proangiogenic factors that may rep- more effective therapies for patients with these tumors. resent therapeutic targets, with vascular endothelial This review summarizes evidence supporting the use growth factor (VEGF) being the best characterized. In of targeted AA in combination with cytotoxic chemo- animal models of human sarcomas, inhibitors of angio- therapy in sarcomas. We performed an extensive review genesis have shown promising antitumor activity [1–3]. of the available medical literature using the US National Antiangiogenic therapies have a number of potential Library of Medicine’s PubMed search function to find rel - advantages compared to chemotherapy including over- evant primary articles based on key search terms includ- coming chemoresistance [4, 5], more favorable toxicity ing “angiogenesis”, “antiangiogenic”, “antiangiogenesis”, profile, and broad spectrum of activity. Since 2004, over and “antivascular”. These search terms were searched with ten drugs that target VEGF or its receptors have been “chemotherapy” and “sarcoma”, “bone tumor”, or “soft tis- approved as cancer therapeutics, with many more in sue cancer”. The “Related Articles” function of PubMed and reference lists from relevant articles were used to iden- *Correspondence: kieuhoa.vo@ucsf.edu tify additional articles. Additionally, in order to identify Department of Pediatrics, UCSF School of Medicine, San Francisco recent trials not yet published, we also performed a search School of Medicine, UCSF Benioff Children’s Hospital, University of California, 550 16th Street, 4th Floor, Box 0434, San Francisco, of abstracts presented at the American Society of Clinical CA 94158, USA Oncology (ASCO) annual meetings from 2013 to 2015. Full list of author information is available at the end of the article © 2016 The Author(s). This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Vo et al. Clin Sarcoma Res (2016) 6:9 Page 2 of 11 In the current review, we provide the results of this morphological changes, including decreased intersti- search beginning with the preclinical data supporting tial fluid pressure (IFP), decreased tumor hypoxia, and AA in combination with chemotherapy in this diverse improved penetration of macromolecules from these ves- group of diseases. The review concludes with an assess - sels into tumors [11–13]. ment of the completed and ongoing clinical studies that Based on this hypothesis, Liu and colleagues examined have treated patients with sarcoma using this therapeutic the vascular density and structural changes of tumors strategy. obtained from lung cancer xenograft mice treated with bevacizumab combined with gemcitabine and cisplatin Preclinical efficacy of targeted AA in combination [14]. They demonstrated significant reduction in VEGF with chemotherapy levels and microvessel density (MVD) and increased Angiogenesis is tightly regulated at the molecular level. number of normal vessels as analyzed by electron micros- Dysregulation of angiogenesis occurs in various patholo- copy in mice treated with combination therapy compared gies and is one of the hallmarks of cancer. Concentrated to those mice treated with chemotherapy alone [14]. The efforts in this area of research are leading to the discov - tumor volume of mice in the combined treatment group ery of a growing number of pro- and anti-angiogenic was significantly lower compared to the bevacizumab molecules, many of which are already in clinical trials. monotherapy and chemotherapy groups, which also cor- The complex interactions among these molecules and related with significant survival advantage [14]. how they affect vascular structure and function in dif - Improved chemotherapy delivery secondary to tumor ferent environments are now beginning to be elucidated vessel normalization was demonstrated in a study of [6, 8–10]. This integrated understanding is leading to the bevacizumab and topotecan in neuroblastoma xenograft development of a number of therapeutic approaches to models. After a single bevacizumab dose, there were treat cancer, including the use of AA in combination with decreases in tumor MVD, tumor vessel permeability, chemotherapy. and tumor IFP compared to controls [15]. Intratumoral perfusion, as assessed by contrast-enhanced ultrasonog- Biological mechanisms supporting combination approaches raphy, was also improved [15]. Moreover, intratumoral in solid tumor malignancies other than sarcoma drug delivery accompanied these changes: penetration of With the discovery of VEGF as a major driver of tumor topotecan was improved when given 1–3 days after beva- angiogenesis, efforts have focused on novel therapeutics cizumab, compared to concomitant administration or aimed at inhibiting VEGF activity. Unfortunately, clinical 7 days apart, and resulted in greater tumor growth inhi- trials of anti-VEGF monotherapy in patients with solid bition than with monotherapy or concomitant adminis- tumors have resulted in only modest responses. Intrigu- tration of the two drugs [15]. Similarly, the increase in ingly, the combination of anti-VEGF therapy with con- antitumor activity of chemotherapy during the transient ventional chemotherapy has improved survival in cancer vascular normalization period produced by bevacizumab patients compared with chemotherapy alone [6]. has also been confirmed in animal models of colorectal The proposed mechanisms of benefit from combined cancer (irinotecan) [16] and melanoma (melphalan) [17]. AA and chemotherapy include: (1) normalization of In vivo [(15)O]H2O positron emission tomogra- the tumor vasculature by altering vascular permeabil- phy (PET) imaging in a mouse model of lung cancer ity and increasing drug accessibility (Fig.  1a); (2) syner- showed that treatment with the VEGFR/platelet-derived gistic effects leading to enhanced direct cytotoxicity of growth factor receptor (PDGFR) inhibitor PTK787 cre- cancer cells and/or endothelial cells (Fig.  1b); and/or (3) ated a 7-day window of improved tumor blood flow decreased chemoresistance (Fig. 1c). when tumor vessels are transiently normalized [18]. An A paradoxical hypothesis that may explain the anti- improvement in pericyte coverage and reduced leakiness tumor effect of this combination approach relies on the from tumor vessels in xenografts accompanied this nor- theory of transient “normalization” of the abnormal malization phase [18]. Initiation of newer targeted agents tumor vasculature, which results in improved blood during this window of vessel normalization also resulted perfusion and enhanced chemotherapy accessibility and in increased drug delivery and apoptotic efficacy of erlo - antitumor activity (Fig.  1a) [6]. Several preclinical stud- tinib, an epidermal growth factor receptor (EGFR) inhibi- ies using direct and indirect AA support the normaliza- tor [18]. Together, these findings offer strong supportive tion hypothesis [11–13]. Blockade of VEGF signaling evidence that strategic administration of AA can pro- results in transient pruning and active remodeling of mote transient vessel normalization that improves drug the immature and leaky blood vessels of tumors in ani- delivery and efficacy in a range of solid tumors. mal models so that it more closely resembled the normal In contrast, a study by Van der Veldt et al. in non-small vasculature. Functional improvements accompany these cell lung cancer (NSCLC) showed that pretreatment Vo et al. Clin Sarcoma Res (2016) 6:9 Page 3 of 11 Treatment with Treatment with Chemotherapy Alone Targeted AA plus Chemotherapy Tumor Capillary Tumor Capillary Apoptotic cell Capillary Capillary Abnormal Tumor Vessels Normalized Vessels ↓ interstitial pressure ↓ tumor hypoxia ↑ chemotherapy accessibility Treatment with Treatment with Chemotherapy Alone Targeted AA plus Chemotherapy Tumor cell Tumor cell Apoptotic Apoptotic Capillary Capillary cell cell Basement membrane Endothelial Apoptotic Apoptotic cell cell cells Combination therapy: Targeted AA with Chemotherapy Tumor cells ↑ Wnt/β-catenin ↓ Wnt/β-catenin signaling signaling Chemoresistance, Re-sensitization cell proliferation to chemotherapy, cell death Fig. 1 Proposed biological mechanisms supporting combination antiangiogenesis approaches in sarcoma. a Transient “normalization” of the abnormal tumor vasculature by AA results in improved blood perfusion and enhanced chemotherapy accessibility and antitumor activity. b The synergistic interaction of combination therapy leads to enhanced direct cytotoxicity of tumor cells and/or endothelial cells. c Combination therapy leads to up- or down-regulation signaling pathways involved in chemoresistance. For example, down-regulation of the Wnt/β-catenin pathway by the combination of masitinib and gemcitabine contribute to the re-sensitization of gemcitabine-resistant pancreatic tumor cells leading to apop- totic death [27]. AA antiangiogenic agents Vo et al. Clin Sarcoma Res (2016) 6:9 Page 4 of 11 with bevacizumab reduced both perfusion and net influx down-regulation and loss of Mcl-1 expression [24]. rate of radiolabeled docetaxel as measured by PET with These results suggest that sorafenib enhanced sensitiv - effects persisting after 4 days [19]. This study highlighted ity to chemotherapy by altering signaling in the mitogen- the importance of drug scheduling and advocated further activated protein kinase (MAPK) and the mitochondrial studies to optimize scheduling of antiangiogenic drugs apoptotic pathways. These in vitro findings highlight the combined with cytotoxic chemotherapy. potential for AA to have effects independent of classical Other preclinical studies reporting the impact of AA antiangiogenic mechanisms. upon delivery of cytotoxic therapies include sunitinib, an The timing and sequence of AA with chemotherapy inhibitor of VEGFR and PDGFR, combined with temo- can also be critical in determination of synergy or zolomide in orthotopic glioma models [20, 21]. Sunitinib antagonism. Troiani et al. demonstrated the sequence- significantly increased temozolomide tumor distribu - dependent interactions of ZD6474 (VEGR, EGFR, tion [21]. A “vascular normalization index” incorporating and RET inhibitor) with oxaliplatin in colon cancer MVD and protein expression of α-SMA and collagen IV cell lines in  vitro using three combination schedules was proposed as an indication of the number of tumor [25]. Treatment with oxaliplatin followed by ZD6474 vessels with relatively good quality, and significantly cor - was highly synergistic, whereas the reverse sequence related with the unbound temozolomide AUC in tumor or concurrent exposure was clearly antagonistic [25]. interstitial fluid [21]. Oxaliplatin induced a G2-M arrest, which was antag- Interestingly, when used as monotherapy, several pre- onized if the cells were previously or concurrently clinical studies have shown that the normalization of treated with ZD6474. ZD6474 enhanced oxaliplatin- blood vessels by AA may result in paradoxical increased induced apoptosis, but only when added after oxalipl- invasion of local vessels by the tumor and resulting atin [25]. metastases. A recent study of the effects of combination Alternatively, Naumova and colleagues demonstrated therapy in breast cancer model suggest that the addi- that paclitaxel and SU6668, a VEGFR2/PDGFR inhibitor, tion of chemotherapy to AA can help prevent local inva- synergistically inhibited the proliferation and increased sion of vessels promoted by the AA and result in lower apoptosis of endothelial cells [26]. These findings, metastatic rate. Antiangiogenic therapy with DC101 together with the in  vivo inhibition of angiogenesis in (VEGFR2 inhibitor), while blunting tumor volume Matrigel plugs and the reduction of MVD of paclitaxel- growth, was found to increase local invasion in multiple resistant ovarian carcinoma xenograft models, support primary tumor models, including a patient-derived xeno- the hypothesis that the enhanced effect exerted by the graft [22]. This effect was blocked by concurrent chemo - combination of paclitaxel and SU6668 on tumor growth therapy with paclitaxel [22]. Similarly, the combination is mediated by an effect on the vasculature [26]. of paclitaxel with DC101 caused a marked reduction of Another mechanism of combination therapy involves micro- or macrometastatic disease in contrast to DC101 overcoming chemoresistance (Fig.  1c). Acquired drug monotherapy, which was associated with small increases resistance is a major problem in the treatment of cancer. in metastatic disease. Boehm et al. reported that chronic, intermittent therapy Synergistic effects of combination therapy of AA with of three different mouse tumors with endostatin, an angi - chemotherapy have been seen in several preclinical mod- ogenic inhibitor, did not show any evidence of acquired els of solid cancers (Fig. 1b). For example, in vitro studies drug resistance [5]. In contrast, standard chemotherapy, of bladder cancer demonstrated the efficacy of pazopanib using maximum doses of cyclophosphamide, resulted in with docetaxel, even in docetaxel-resistant bladder can- drug resistance in lung carcinoma xenografts [5]. These cer cell lines [23]. While the mechanism(s) of these syn- results provided initial evidence that a specific angio - ergistic effects have not been fully elucidated, and may be genic inhibitor does not induce drug resistance in three dependent on the specific combination regimen used and different tumor xenografts. Perhaps the most significant tissue type treated, we have highlighted several examples finding of this study was that repeated cycles of endosta - of mechanisms related to enhanced direct cytotoxicity of tin therapy induced tumor dormancy that persisted after cancer cells and/or endothelial cells. therapy. While the mechanism(s) is not yet clear, recent Sorafenib increased apoptosis in melanoma-derived studies may help to elucidate these findings. cell lines treated with melphalan or temozolomide For example, a series of in  vitro and in  vivo stud- [24]. The molecular mechanisms underlying sorafenib ies using preclinical models of human pancreatic can- enhancement were investigated by analyzing the changes cer characterized the synergistic effects of combination in signaling events in melanoma cell lines in response to therapy with gemcitabine with masitinib, a selective sorafenib treatment alone. Response to sorafenib cor- inhibitor of PDGFR [27]. The masitinib and gemcitabine related with extracellular signal-regulated kinase (ERK) combination synergistically inhibited proliferation of Vo et al. Clin Sarcoma Res (2016) 6:9 Page 5 of 11 gemcitabine-refractory cell lines [27]. Analysis of gene tube-like formation in vitro. Furthermore, the combina- expression profiling of gemcitabine-resistant pancreatic tion enhanced apoptosis of endothelial cells [28]. cells revealed differences in gene expression unique to To elucidate the role of recombinant human VEGF the masitinib plus gemcitabine combination. The most in STS growth, metastasis, and chemoresistance, Zhang significantly altered pathway involved genes associ - and colleagues generated stably VEGF -transfected ated with Wnt/β-catenin signaling [27]. This pathway is STS cell lines to study the effect of VEGF overexpres - involved in pancreatic development and re-activation sion in vitro and in vivo. VEGF -transfected xenografts has been implicated in pancreatic carcinoma, suggesting formed highly vascular tumors with shorter latency, a mechanism of augmented cell death with combination accelerated growth, enhanced chemoresistance, and therapy in gemcitabine-resistant cells as compared to increased incidence of pulmonary metastases [29]. Com- gemcitabine monotherapy [27]. bined therapy with DC101 and low-dose doxorubicin in vivo suppressed the growth of VEGF -overexpressing Preclinical studies of combination approaches in sarcoma xenografts, inhibited angiogenesis, increased the vessel Targeted AA and cytotoxic chemotherapy have been maturation index, and suppressed tumor cell prolifera- combined in several laboratory models of sarcoma, tion compared to monotherapy-treated mice. The addi - mainly STS, as summarized in Table  1. Most notably, tion of DC101 induced endothelial cell sensitivity to studies have shown that VEGFR2 blockade by DC101 doxorubicin and suppressed the activity of matrix met- combined with chemotherapy inhibits tumor growth, alloproteinases secreted by endothelial cells [29]. These metastases, and angiogenesis in STS xenografts [28, results suggested that the antitumor effects of combined 29]. Combined DC101 and continuous low-dose doxo- therapy with DC101 and doxorubicin were secondary to rubicin resulted in more effective growth inhibition of tumor-associated endothelial cell growth modulation and STS xenografts compared to either agent alone [28]. chemosensitization [29]. DC101 plus doxorubicin also enhanced the inhibition Likewise, the enhanced antitumor effects of combina - of tumor angiogenesis and endothelial cell activity, as tion therapy using low-dose topotecan and pazopanib in demonstrated by significantly reduced MVD and inhibi - mouse models of osteosarcoma and rhabdomyosarcoma tion of neovascularization [28]. Additionally, this com- are thought to be related to augmented antiangiogen- bination regimen directly exerted enhanced inhibitory esis [30]. The metronomic administration of pazopanib effects on endothelial cell migration, proliferation, and and topotecan in  vitro showed reduction in circulating Table 1 Preclinical studies of combination approaches in sarcoma Drug combination Sarcoma tumor models Results compared to models treated with chemotherapy alone Reference Pazopanib + topotecan OS KHOS and RMS RH30 cell lines ↑ Antitumor and antiangiogenic effects, [30] and xenografts ↑ Survival, ↓ Circulating endothelial cells and/or endothelial progenitor cells, ↓ MVD VDA (OXi4503/CA1P) + EWS xenografts ↑ Antitumor effects [59] doxorubicin ↑ Necrosis ↓ Perfused vasculature Bevacizumab + topotecan ASPS xenografts ↑ Antitumor effects compared to bevacizumab monotherapy, but [60] not topotecan alone Vandetanib + doxorubicin Multiple STS cell lines and xenografts ↑ Antitumor and antiangiogenic effects [31] ↓ Local growth leiomyosarcoma ↓ Lung metastases in fibrosarcoma DC101 + doxorubicin Multiple STS cell lines and xenografts ↑ Antitumor and antiangiogenic effects [29] transfected with VEGF ↓ Tumor growth and pulmonary metastases ↓ MVD ↑ Percentage of mature vessels ↓ Matrix metalloproteinases secreted by endothelial cells DC101 + doxorubicin Leiomyosarcoma SKLMS-1 and RMS ↑ Antitumor and antiangiogenic effects [28] RD cell lines and xenografts ↓ MVD and neovascularization ↑ Apoptosis of endothelial cells ↓ Endothelial cell migration, proliferation, tube-like formation TNP-470 + etoposide Angiosarcoma ISOS-1 cell line and ↑ Antitumor effects [61] xenograft ↑ Growth inhibition ASPS alveolar soft part sarcoma, ES Ewing sarcoma, MVD microvessel density, OS osteosarcoma, RMS rhabdomyosarcoma, STS soft tissue sarcoma, VDA vascular- disrupting agent, VEGF(R) vascular endothelial growth factor (receptor) Vo et al. Clin Sarcoma Res (2016) 6:9 Page 6 of 11 endothelial cells, circulating endothelial progenitor cells, when AA are added to chemotherapy in patients with and tumor MVD which correlated with antitumor activ- cancer and support clinical investigation in sarcoma. ity and enhancement in survival compared with mono- therapy agents in all preclinical models [30]. Clinical studies of combination approaches in sarcoma Concomitant use of a dual VEGFR2/EGFR inhibi- Targeted AA and chemotherapy have been combined tor (vandetanib) with doxorubicin resulted in additional in numerous early phase clinical trials in children and cytotoxicity and endothelial cell growth inhibition with adults with advanced solid tumors. Phase 1 studies lowered doxorubicin doses compared to vandetanib that included patients with sarcoma are summarized in monotherapy in leiomyosarcoma, fibrosarcoma, and Table  2. The backbone chemotherapy regimens used in uterine sarcoma models [31]. In addition, vandetanib in these trials included taxane- and platinum-based thera- combination with low-dose doxorubicin resulted in sig- pies, camptothecins, and gemcitabine. Although not nificant inhibition of human fibrosarcoma xenograft lung powered to evaluate the antitumor activity of AA com- metastases compared to control and doxorubicin-only bined with chemotherapy, the results of these phase 1 groups [31]. Collectively, these studies suggest that AA studies suggest that these regimens are generally well tol- plus chemotherapy regimens may also help to reduce erated with promising clinical activity in sarcomas. In a the dose and therefore cumulative toxicities of cytotoxic phase 1b study of the combination of bevacizumab added chemotherapy. to gemcitabine and docetaxel in patients with advanced STS, the overall response rate observed was 31  %, with Clinical efficacy of targeted AA in combination 5 complete and 6 partial responses, and 18 patients with with chemotherapy stable disease lasting for a median of 6 months [41]. Sev- Clinical studies of combination approaches in solid tumors eral pediatric phase 1 clinical trials have demonstrated Outside the field of sarcoma, AA have been combined the safety of combining AA, specifically bevacizumab, with chemotherapy with varying outcomes. A retrospec- with cytotoxic chemotherapy in patients with advanced tive study of patients with advanced solid malignancies solid tumors, with tumor responses in patients with treated on phase 1 protocols between 2004 and 2013 Ewing sarcoma [42]. In addition to those listed in Table 2, showed that chemotherapy concomitant with VEGF(R) combination antiangiogenic approaches combining AA inhibitors was associated with significantly higher odds and conventional chemotherapy, such as ifosfamide and ratio for clinical benefit compared with chemotherapy doxorubicin, studied in other malignancies, may warrant without VEGF(R) inhibitors [32]. further study in sarcoma [43, 44]. For example, in lung, breast, and colorectal carci- There have been four reported phase 2 studies evalu - noma, AA have shown increased activity when combined ating the combination of AA with chemotherapy in with standard chemotherapy, as highlighted below. In sarcoma. The combination of bevacizumab with doxo - advanced non-small cell lung cancer, a randomized phase rubicin was evaluated in 17 patients with metastatic STS 2 trial showed a trend towards increased response rate [45]. While two partial responses (12  %) were observed, and time to progression when bevacizumab was com- this response rate was not greater than that observed bined with paclitaxel and carboplatin [33]. Several large for single-agent doxorubicin [45]. However, 11 patients randomized trials in patients with metastatic breast (65  %) had stable disease lasting four cycles or longer, cancer showed significantly higher response rates and suggesting that further consideration of this treatment increased progression-free survival (PFS) when treated regimen may be warranted in STS [45]. In general, the with bevacizumab combined with chemotherapy com- toxicity of bevacizumab and doxorubicin was similar pared to those treated with chemotherapy alone [34–38]. to that reported for single-agent doxorubicin with one Perhaps the disease in which bevacizumab has had the notable exception: the reported 35  % rate of grade 2 or greatest impact in combination with chemotherapy is higher cardiotoxicity with this combination regimen metastatic colorectal cancer. After a randomized phase was greater than expected (compared to historical con- 2 study showed encouraging results when bevacizumab trols) [45]. Despite close monitoring and standard use was combined with fluorouracil and leucovorin [39], a of dexrazoxane, the observed cardiac toxicity warrants a randomized phase 3 trial of irinotecan, fluorouracil, and change in the dose and/or schedule in future studies of leucovorin with bevacizumab or placebo showed that this combination. bevacizumab increased response rate, time to progres- The Children’s Oncology Group (COG) evaluated bev - sion, and overall survival [40]. Given these findings, beva - acizumab or temsirolimus in combination with vinorel- cizumab is now included in the first-line management of bine (V) and cyclophosphamide (C) in a randomized patients with metastatic colorectal cancer. These clinical phase 2 study in patients with advanced rhabdomyosar- findings provided proof of principle of additive activity coma. Both treatment regimens were well tolerated and Vo et al. Clin Sarcoma Res (2016) 6:9 Page 7 of 11 Table 2 Completed phase 1 (or pilot) trials of combination approaches that enrolled patients with sarcoma Drug combination Sarcoma tumor type (number enrolled) Responses Reference Trials with bevacizumab Bevacizumab + pegylated SN-38 (EZN-2208) STS (5) SD (2) [62] Bevacizumab + bendamustine Angiosarcoma (1) None [63] Bevacizumab + irinotecan RMS (1) None [64] Bevacizumab + vincristine/irinotecan/temozolomide STS (3); OS (2); ES (1) SD (2) [65] Bevacizumab + vincristine/irinotecan/temozolomide ES (2); RMS (1); Clear cell sarcoma (1) CR (1); PR (1) [42] Bevacizumab + sorafenib + cyclophosphamide OS (2); RMS (2); Other STS (4) PR (1); SD (3) [66] Bevacizumab + gemcitabine/doxetaxel STS (36) CR (5); PR (6); SD (18) [41] Bevacizumab + ifosphamide/etoposide/carboplatin STS (7); OS (3); Chondrosarcoma (2); Undifferentiated (1) PR (4); SD (5) [67] Trials with VEGFR and PDGFR inhibitors Pazopanib + cisplatin Sarcoma (5) CR (1); SD (2) [68] Pazopanib + topotecan STS (6); OS (2) Unknown [69] Pazopanib + ifosfamide Sarcoma (19) PR (3) [70] Pazopanib + paclitaxel/carboplatin OS (1); Giant cell tumor (1); Other sarcoma (1) None [71] PDGFR inhibitor (CP-868,596) + docetaxel ± axitinib ES (3); Other sarcoma (5) SD (3) [72] Semaxanib + cisplatin/irinotecan GIST (2); STS (1) None [73] Sorafenib + irinotecan OS (4); Synovial sarcoma (1); DSRCT (1); MPNST (1) Unknown [74] Sunitinib + pemetrexed/carboplatin Synovial sarcoma (1) None [75] Sunitinib + gemcitabine OS (1); STS (1) SD (1) [76] Sunitinib + ifosfamide ES (2); STS (6); Other sarcoma (7) PR (2); SD (3) [77] Sunitinib + irinotecan OS (1); STS (1) None [78] Sunitinib + docetaxel OS and STS (unknown) None [79] Trials with other antiangiogenic agents Ombrabulin (AVE8062) + docetaxel Muscle/bone tumors (5) None [80] Thrombospondin-1 mimetic (ABT-510) + gemcitabine/ Sarcoma (1) None [81] cisplatin Thrombospondin-1 mimetic (ABT-510) + 5-FU/leucovorin Synovial sarcoma (1) None [82] TNP-470 + paclitaxel/carboplatin Sarcoma (2) None [83] Only includes SD, PR, and CR responses among patients with sarcoma. CR complete response; DRSCT desmoplastic small round cell tumor; ES Ewing sarcoma; GIST gastrointestinal stromal tumor; MPNST malignant peripheral nerve sheath tumor; OS osteosarcoma; PDGFR platelet-derived growth factor receptor; PR partial response; RMS rhabdomyosarcoma; STS soft tissue sarcoma; SD stable disease; VEGF(R) vascular endothelial growth factor (receptor) without unexpected toxicities. In a preliminary report, that may activate the proangiogenic pathway indepen- patients randomized to VC plus temsirolimus had a dently of the classic ligand-receptor activation shown in superior event-free survival compared to VC plus beva- recent studies. These findings suggest that the extracel - cizumab (65 vs. 50  %, respectively) [46]. As a VC alone lular blockade of VEGF by a monoclonal antibody, such arm was not included in the trial, it is not known if as bevacizumab, would not interfere with angiosarcoma bevacizumab improved outcomes compared to the VC proliferation [47]. Given these findings, the authors did backbone. not recommend the addition of bevacizumab to pacli- Ray-Coquard and colleagues examined the addition taxel for the treatment of advanced angiosarcoma. of bevacizumab added to paclitaxel in a randomized Recently, the Spanish Group for Research on Sarcomas phase 2 study of patients with angiosarcoma. While the presented their findings of a phase 2 study of sorafenib combination antiangiogenic regimen was shown to be and ifosfamide in 35 patients with advanced STS [48]. active in patients with angiosarcoma, the PFS and over- This combination antiangiogenic regimen had accept - all survival was similar in both arms [47]. Nevertheless, able toxicity in patients previously treated with anthracy- there was increased toxicity in the bevacizumab arm, clines. The study met its primary endpoint requiring at which included one fatal drug-related toxicity (intestinal least 19/35 patients to be free of progression at 3 months. obstruction) [47]. The lack of benefit from bevacizumab The combination was shown to be active in patients with may be due in part to key mutations in angiosarcoma advanced STS. Six (17  %) patients had partial responses Vo et al. Clin Sarcoma Res (2016) 6:9 Page 8 of 11 to this regimen. The 3-month PFS was found to be 66 % docetaxel, which resulted in temporary tumor regression (23/35) in patients treated with sorafenib plus ifosfamide, with progression free survival of 12  months [49]. Dra- which may exceed the 3-month PFS in patients treated matic improvement was also seen in another patient with with ifosfamide alone, thus warranting further investiga- inoperable face and neck angiosarcoma who was treated tion [48]. with bevacizumab and paclitaxel [50]. In three pediat- Additional clinical trials evaluating combination ric patients with Ewing sarcoma or undifferentiated sar - therapy with targeted AA and cytotoxic chemotherapy coma who were treated with bevacizumab, gemcitabine, in patients with sarcoma are ongoing (Table  3). With and docetaxel, two patients had a partial response and early promising results, the latest phase 2 trials have the third patient had stable disease for >6  months [51]. been largely directed towards pediatric sarcoma. These Lastly, in a retrospective analysis of 14 patients with include bevacizumab, cyclophosphamide, and topote- hemangiopericytomas and malignant solitary fibrous can in patients with relapsed/refractory Ewing sar- tumors who were treated with bevacizmuab and temo- coma (NCT01492673); and maintenance bevacizumab zolomide, 11 patients (79 %) achieved a partial response, therapy in high-risk Ewing sarcoma and desmoplastic with a median time to response of 2.5 months [52]. small round cell tumor (NCT01946529). Furthermore, Extensively reviewed elsewhere [53, 54], metronomic the COG is actively enrolling patients on a randomized chemotherapy is an alternative antiangiogenic strategy, phase 2/3 trial of preoperative chemoradiation or preop- involving the application of daily, low-dose chemother- erative radiation plus or minus pazopanib in STS histolo- apy. With this low-dose approach, apoptosis is induced in gies other than rhabdomyosarcoma (NCT02180867). the less frequently dividing endothelial cells rather than In adults, phase 2 studies are evaluating pazo- in the tumor cells [53]. This approach has been used in panib and topotecan in patients with high-risk sar- sarcoma with promising results [55–58]. In a feasibility comas (NCT02357810); pazopanib plus gemcitabine study of metronomic cyclophosphamide plus predniso- in advanced STS (NCT02203760, NCT01593748 and lone in 26 elderly patients with inoperable or metastatic NCT01532687); pazopanib and paclitaxel in advanced STS, the response rate was 27  % and the disease control angiosarcoma (NCT02212015); sorafenib, epirubicin, rate (responses and stable disease >12  weeks) was 69  % ifosfamide, and radiotherapy followed by surgery in [56]. Currently, there are three open phase 1 studies high-risk STS (NCT02050919). Lastly, there is one open examining the combination of bevacizumab or pazopanib randomized phase 3 trial evaluating bevacizumab ver- added to metronomic chemotherapy that may include sus placebo combined with docetaxel and gemicitabine eligible sarcoma patients (Table 3). in the treatment of advanced uterine leiomyosarcoma (NCT01012297). Conclusions Outside of the context of formal clinical trials, several Advances in the biology of sarcomas have established the retrospective case studies/series have also highlighted critical role of tumor angiogenesis and multiple signaling the potential efficacy of these combination regimens. A pathways involved in tumor development, growth, and child with transformed malignant angiosarcoma was suc- therapy resistance. Numerous preclinical studies have cessfully treated with bevacizumab, gemcitabine, and demonstrated that targeting proangiogenic mechanisms Table 3 Ongoing phase 1 (or pilot) clinical trials of combination approaches in sarcoma Targeted antiangiogenic agent Chemotherapy regimen Tumor type NCT Bevacizumab Doxorubicin/temsirolimus Advanced solid tumors, including sarcoma 00761644 Bevacizumab Doxorubicin Advanced Kaposi sarcoma 00923936 Bevacizumab Gemcitabine/docetaxel/valproic acid Advanced sarcoma 01106872 Bevacizumab Gemcitabine/paclitaxel Advanced solid tumors, including sarcoma 01113476 Bevacizumab Irinotecan/temozolomide + standard alkylator- Newly diagnosed DSRCT 01189643 based chemotherapy Bevacizumab Metronomic doxorubicin + radiation Resectable STS 01746238 Bevacizumab Metronomic cyclophosphamide/valproic acid/ Advanced solid tumors, including sarcoma 02446431 temsirolimus Pazopanib Gemcitabine Advanced leiomyosarcoma 01442662 Pazopanib Docetaxel/gemcitabine Operable STS 01719302 Pazopanib Metronomic topotecan Advanced solid tumors, including sarcoma 02303028 DSRCT desmoplastic small round cell tumor; NCT ClinicalTrials.gov Identifier/Number; STS soft tissue sarcoma Vo et al. 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Proc Natl Acad Sci USA. authors; data analysis and interpretation: all authors; manuscript writing: all 1996;93(25):14765–70. authors; final approval of manuscript: all authors; accountability for all aspects 14. Liu Y, Xia X, Zhou M, Liu X. Avastin(R) in combination with gemcitabine of the work: all authors. All authors read and approved the final manuscript. and cisplatin significantly inhibits tumor angiogenesis and increases the survival rate of human A549 tumor-bearing mice. Exp Ther Med. Author details 2015;9(6):2180–4. Department of Pediatrics, UCSF School of Medicine, San Francisco School 15. Dickson PV, Hamner JB, Sims TL, Fraga CH, Ng CY, Rajasekeran S, Hage- of Medicine, UCSF Benioff Children’s Hospital, University of California, 550 16th dorn NL, McCarville MB, Stewart CF, Davidoff AM. Bevacizumab-induced Street, 4th Floor, Box 0434, San Francisco, CA 94158, USA. Dana-Farber/Bos- transient remodeling of the vasculature in neuroblastoma xenografts ton Children’s Cancer and Blood Disorders Center, 450 Brookline Avenue, Dana results in improved delivery and efficacy of systemically administered 3, Boston, MA 02215, USA. chemotherapy. Clin Cancer Res. 2007;13(13):3942–50. 16. Vangestel C, Van de Wiele C, Van Damme N, Staelens S, Pauwels P, Acknowledgements Reutelingsperger CP, Peeters M. (99)mTc-(CO)(3) His-annexin A5 micro- The authors acknowledge the assistance of Diana Lim with graphic design. SPECT demonstrates increased cell death by irinotecan during the vascular normalization window caused by bevacizumab. J Nucl Med. Competing interests 2011;52(11):1786–94. The authors declare that they have no competing interests. 17. Turley RS, Fontanella AN, Padussis JC, Toshimitsu H, Tokuhisa Y, Cho EH, Hanna G, Beasley GM, Augustine CK, Dewhirst MW, et al. 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Targeted antiangiogenic agents in combination with cytotoxic chemotherapy in preclinical and clinical studies in sarcoma

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Springer Journals
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Copyright © 2016 by The Author(s).
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Biomedicine; Cancer Research; Oncology; Surgical Oncology
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2045-3329
DOI
10.1186/s13569-016-0049-z
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27274393
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Abstract

Sarcomas are a heterogeneous group of mesenchymal malignancies. In recent years, studies have demonstrated that inhibition of angiogenic pathways or disruption of established vasculature can attenuate the growth of sarcomas. However, when used as monotherapy in the clinical setting, these targeted antiangiogenic agents have only provided modest survival benefits in some sarcoma subtypes, and have not been efficacious in others. Preclinical and early clinical data suggest that the addition of conventional chemotherapy to antiangiogenic agents may lead to more effective therapies for patients with these tumors. In the current review, the authors summarize the available evidence and possible mechanisms supporting this approach. Keywords: Sarcoma, Antiangiogenesis, Combination drug therapy, Combination chemotherapy clinical trials [6]. These agents have shown single-agent Background activity in sarcoma. Most notably, pazopanib has been Sarcomas are a heterogeneous group of malignancies, approved by the US Food and Drug Administration and including soft tissue sarcomas (STS) and tumors of bone the European Medicines Agency for advanced STS. As and cartilage. Conventional chemotherapy regimens for monotherapy, these agents have only provided survival advanced or metastatic sarcomas have low survival rates, benefits on the order of weeks to months in some sar - substantial toxicity, and frequent emergence of resist- coma subtypes, and have not been efficacious in others ance, making alternative novel treatment approaches a [7]. Therefore, combining antiangiogenic agents (AA) priority. with other systemic agents active in sarcoma may lead to Sarcomas express proangiogenic factors that may rep- more effective therapies for patients with these tumors. resent therapeutic targets, with vascular endothelial This review summarizes evidence supporting the use growth factor (VEGF) being the best characterized. In of targeted AA in combination with cytotoxic chemo- animal models of human sarcomas, inhibitors of angio- therapy in sarcomas. We performed an extensive review genesis have shown promising antitumor activity [1–3]. of the available medical literature using the US National Antiangiogenic therapies have a number of potential Library of Medicine’s PubMed search function to find rel - advantages compared to chemotherapy including over- evant primary articles based on key search terms includ- coming chemoresistance [4, 5], more favorable toxicity ing “angiogenesis”, “antiangiogenic”, “antiangiogenesis”, profile, and broad spectrum of activity. Since 2004, over and “antivascular”. These search terms were searched with ten drugs that target VEGF or its receptors have been “chemotherapy” and “sarcoma”, “bone tumor”, or “soft tis- approved as cancer therapeutics, with many more in sue cancer”. The “Related Articles” function of PubMed and reference lists from relevant articles were used to iden- *Correspondence: kieuhoa.vo@ucsf.edu tify additional articles. Additionally, in order to identify Department of Pediatrics, UCSF School of Medicine, San Francisco recent trials not yet published, we also performed a search School of Medicine, UCSF Benioff Children’s Hospital, University of California, 550 16th Street, 4th Floor, Box 0434, San Francisco, of abstracts presented at the American Society of Clinical CA 94158, USA Oncology (ASCO) annual meetings from 2013 to 2015. Full list of author information is available at the end of the article © 2016 The Author(s). This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Vo et al. Clin Sarcoma Res (2016) 6:9 Page 2 of 11 In the current review, we provide the results of this morphological changes, including decreased intersti- search beginning with the preclinical data supporting tial fluid pressure (IFP), decreased tumor hypoxia, and AA in combination with chemotherapy in this diverse improved penetration of macromolecules from these ves- group of diseases. The review concludes with an assess - sels into tumors [11–13]. ment of the completed and ongoing clinical studies that Based on this hypothesis, Liu and colleagues examined have treated patients with sarcoma using this therapeutic the vascular density and structural changes of tumors strategy. obtained from lung cancer xenograft mice treated with bevacizumab combined with gemcitabine and cisplatin Preclinical efficacy of targeted AA in combination [14]. They demonstrated significant reduction in VEGF with chemotherapy levels and microvessel density (MVD) and increased Angiogenesis is tightly regulated at the molecular level. number of normal vessels as analyzed by electron micros- Dysregulation of angiogenesis occurs in various patholo- copy in mice treated with combination therapy compared gies and is one of the hallmarks of cancer. Concentrated to those mice treated with chemotherapy alone [14]. The efforts in this area of research are leading to the discov - tumor volume of mice in the combined treatment group ery of a growing number of pro- and anti-angiogenic was significantly lower compared to the bevacizumab molecules, many of which are already in clinical trials. monotherapy and chemotherapy groups, which also cor- The complex interactions among these molecules and related with significant survival advantage [14]. how they affect vascular structure and function in dif - Improved chemotherapy delivery secondary to tumor ferent environments are now beginning to be elucidated vessel normalization was demonstrated in a study of [6, 8–10]. This integrated understanding is leading to the bevacizumab and topotecan in neuroblastoma xenograft development of a number of therapeutic approaches to models. After a single bevacizumab dose, there were treat cancer, including the use of AA in combination with decreases in tumor MVD, tumor vessel permeability, chemotherapy. and tumor IFP compared to controls [15]. Intratumoral perfusion, as assessed by contrast-enhanced ultrasonog- Biological mechanisms supporting combination approaches raphy, was also improved [15]. Moreover, intratumoral in solid tumor malignancies other than sarcoma drug delivery accompanied these changes: penetration of With the discovery of VEGF as a major driver of tumor topotecan was improved when given 1–3 days after beva- angiogenesis, efforts have focused on novel therapeutics cizumab, compared to concomitant administration or aimed at inhibiting VEGF activity. Unfortunately, clinical 7 days apart, and resulted in greater tumor growth inhi- trials of anti-VEGF monotherapy in patients with solid bition than with monotherapy or concomitant adminis- tumors have resulted in only modest responses. Intrigu- tration of the two drugs [15]. Similarly, the increase in ingly, the combination of anti-VEGF therapy with con- antitumor activity of chemotherapy during the transient ventional chemotherapy has improved survival in cancer vascular normalization period produced by bevacizumab patients compared with chemotherapy alone [6]. has also been confirmed in animal models of colorectal The proposed mechanisms of benefit from combined cancer (irinotecan) [16] and melanoma (melphalan) [17]. AA and chemotherapy include: (1) normalization of In vivo [(15)O]H2O positron emission tomogra- the tumor vasculature by altering vascular permeabil- phy (PET) imaging in a mouse model of lung cancer ity and increasing drug accessibility (Fig.  1a); (2) syner- showed that treatment with the VEGFR/platelet-derived gistic effects leading to enhanced direct cytotoxicity of growth factor receptor (PDGFR) inhibitor PTK787 cre- cancer cells and/or endothelial cells (Fig.  1b); and/or (3) ated a 7-day window of improved tumor blood flow decreased chemoresistance (Fig. 1c). when tumor vessels are transiently normalized [18]. An A paradoxical hypothesis that may explain the anti- improvement in pericyte coverage and reduced leakiness tumor effect of this combination approach relies on the from tumor vessels in xenografts accompanied this nor- theory of transient “normalization” of the abnormal malization phase [18]. Initiation of newer targeted agents tumor vasculature, which results in improved blood during this window of vessel normalization also resulted perfusion and enhanced chemotherapy accessibility and in increased drug delivery and apoptotic efficacy of erlo - antitumor activity (Fig.  1a) [6]. Several preclinical stud- tinib, an epidermal growth factor receptor (EGFR) inhibi- ies using direct and indirect AA support the normaliza- tor [18]. Together, these findings offer strong supportive tion hypothesis [11–13]. Blockade of VEGF signaling evidence that strategic administration of AA can pro- results in transient pruning and active remodeling of mote transient vessel normalization that improves drug the immature and leaky blood vessels of tumors in ani- delivery and efficacy in a range of solid tumors. mal models so that it more closely resembled the normal In contrast, a study by Van der Veldt et al. in non-small vasculature. Functional improvements accompany these cell lung cancer (NSCLC) showed that pretreatment Vo et al. Clin Sarcoma Res (2016) 6:9 Page 3 of 11 Treatment with Treatment with Chemotherapy Alone Targeted AA plus Chemotherapy Tumor Capillary Tumor Capillary Apoptotic cell Capillary Capillary Abnormal Tumor Vessels Normalized Vessels ↓ interstitial pressure ↓ tumor hypoxia ↑ chemotherapy accessibility Treatment with Treatment with Chemotherapy Alone Targeted AA plus Chemotherapy Tumor cell Tumor cell Apoptotic Apoptotic Capillary Capillary cell cell Basement membrane Endothelial Apoptotic Apoptotic cell cell cells Combination therapy: Targeted AA with Chemotherapy Tumor cells ↑ Wnt/β-catenin ↓ Wnt/β-catenin signaling signaling Chemoresistance, Re-sensitization cell proliferation to chemotherapy, cell death Fig. 1 Proposed biological mechanisms supporting combination antiangiogenesis approaches in sarcoma. a Transient “normalization” of the abnormal tumor vasculature by AA results in improved blood perfusion and enhanced chemotherapy accessibility and antitumor activity. b The synergistic interaction of combination therapy leads to enhanced direct cytotoxicity of tumor cells and/or endothelial cells. c Combination therapy leads to up- or down-regulation signaling pathways involved in chemoresistance. For example, down-regulation of the Wnt/β-catenin pathway by the combination of masitinib and gemcitabine contribute to the re-sensitization of gemcitabine-resistant pancreatic tumor cells leading to apop- totic death [27]. AA antiangiogenic agents Vo et al. Clin Sarcoma Res (2016) 6:9 Page 4 of 11 with bevacizumab reduced both perfusion and net influx down-regulation and loss of Mcl-1 expression [24]. rate of radiolabeled docetaxel as measured by PET with These results suggest that sorafenib enhanced sensitiv - effects persisting after 4 days [19]. This study highlighted ity to chemotherapy by altering signaling in the mitogen- the importance of drug scheduling and advocated further activated protein kinase (MAPK) and the mitochondrial studies to optimize scheduling of antiangiogenic drugs apoptotic pathways. These in vitro findings highlight the combined with cytotoxic chemotherapy. potential for AA to have effects independent of classical Other preclinical studies reporting the impact of AA antiangiogenic mechanisms. upon delivery of cytotoxic therapies include sunitinib, an The timing and sequence of AA with chemotherapy inhibitor of VEGFR and PDGFR, combined with temo- can also be critical in determination of synergy or zolomide in orthotopic glioma models [20, 21]. Sunitinib antagonism. Troiani et al. demonstrated the sequence- significantly increased temozolomide tumor distribu - dependent interactions of ZD6474 (VEGR, EGFR, tion [21]. A “vascular normalization index” incorporating and RET inhibitor) with oxaliplatin in colon cancer MVD and protein expression of α-SMA and collagen IV cell lines in  vitro using three combination schedules was proposed as an indication of the number of tumor [25]. Treatment with oxaliplatin followed by ZD6474 vessels with relatively good quality, and significantly cor - was highly synergistic, whereas the reverse sequence related with the unbound temozolomide AUC in tumor or concurrent exposure was clearly antagonistic [25]. interstitial fluid [21]. Oxaliplatin induced a G2-M arrest, which was antag- Interestingly, when used as monotherapy, several pre- onized if the cells were previously or concurrently clinical studies have shown that the normalization of treated with ZD6474. ZD6474 enhanced oxaliplatin- blood vessels by AA may result in paradoxical increased induced apoptosis, but only when added after oxalipl- invasion of local vessels by the tumor and resulting atin [25]. metastases. A recent study of the effects of combination Alternatively, Naumova and colleagues demonstrated therapy in breast cancer model suggest that the addi- that paclitaxel and SU6668, a VEGFR2/PDGFR inhibitor, tion of chemotherapy to AA can help prevent local inva- synergistically inhibited the proliferation and increased sion of vessels promoted by the AA and result in lower apoptosis of endothelial cells [26]. These findings, metastatic rate. Antiangiogenic therapy with DC101 together with the in  vivo inhibition of angiogenesis in (VEGFR2 inhibitor), while blunting tumor volume Matrigel plugs and the reduction of MVD of paclitaxel- growth, was found to increase local invasion in multiple resistant ovarian carcinoma xenograft models, support primary tumor models, including a patient-derived xeno- the hypothesis that the enhanced effect exerted by the graft [22]. This effect was blocked by concurrent chemo - combination of paclitaxel and SU6668 on tumor growth therapy with paclitaxel [22]. Similarly, the combination is mediated by an effect on the vasculature [26]. of paclitaxel with DC101 caused a marked reduction of Another mechanism of combination therapy involves micro- or macrometastatic disease in contrast to DC101 overcoming chemoresistance (Fig.  1c). Acquired drug monotherapy, which was associated with small increases resistance is a major problem in the treatment of cancer. in metastatic disease. Boehm et al. reported that chronic, intermittent therapy Synergistic effects of combination therapy of AA with of three different mouse tumors with endostatin, an angi - chemotherapy have been seen in several preclinical mod- ogenic inhibitor, did not show any evidence of acquired els of solid cancers (Fig. 1b). For example, in vitro studies drug resistance [5]. In contrast, standard chemotherapy, of bladder cancer demonstrated the efficacy of pazopanib using maximum doses of cyclophosphamide, resulted in with docetaxel, even in docetaxel-resistant bladder can- drug resistance in lung carcinoma xenografts [5]. These cer cell lines [23]. While the mechanism(s) of these syn- results provided initial evidence that a specific angio - ergistic effects have not been fully elucidated, and may be genic inhibitor does not induce drug resistance in three dependent on the specific combination regimen used and different tumor xenografts. Perhaps the most significant tissue type treated, we have highlighted several examples finding of this study was that repeated cycles of endosta - of mechanisms related to enhanced direct cytotoxicity of tin therapy induced tumor dormancy that persisted after cancer cells and/or endothelial cells. therapy. While the mechanism(s) is not yet clear, recent Sorafenib increased apoptosis in melanoma-derived studies may help to elucidate these findings. cell lines treated with melphalan or temozolomide For example, a series of in  vitro and in  vivo stud- [24]. The molecular mechanisms underlying sorafenib ies using preclinical models of human pancreatic can- enhancement were investigated by analyzing the changes cer characterized the synergistic effects of combination in signaling events in melanoma cell lines in response to therapy with gemcitabine with masitinib, a selective sorafenib treatment alone. Response to sorafenib cor- inhibitor of PDGFR [27]. The masitinib and gemcitabine related with extracellular signal-regulated kinase (ERK) combination synergistically inhibited proliferation of Vo et al. Clin Sarcoma Res (2016) 6:9 Page 5 of 11 gemcitabine-refractory cell lines [27]. Analysis of gene tube-like formation in vitro. Furthermore, the combina- expression profiling of gemcitabine-resistant pancreatic tion enhanced apoptosis of endothelial cells [28]. cells revealed differences in gene expression unique to To elucidate the role of recombinant human VEGF the masitinib plus gemcitabine combination. The most in STS growth, metastasis, and chemoresistance, Zhang significantly altered pathway involved genes associ - and colleagues generated stably VEGF -transfected ated with Wnt/β-catenin signaling [27]. This pathway is STS cell lines to study the effect of VEGF overexpres - involved in pancreatic development and re-activation sion in vitro and in vivo. VEGF -transfected xenografts has been implicated in pancreatic carcinoma, suggesting formed highly vascular tumors with shorter latency, a mechanism of augmented cell death with combination accelerated growth, enhanced chemoresistance, and therapy in gemcitabine-resistant cells as compared to increased incidence of pulmonary metastases [29]. Com- gemcitabine monotherapy [27]. bined therapy with DC101 and low-dose doxorubicin in vivo suppressed the growth of VEGF -overexpressing Preclinical studies of combination approaches in sarcoma xenografts, inhibited angiogenesis, increased the vessel Targeted AA and cytotoxic chemotherapy have been maturation index, and suppressed tumor cell prolifera- combined in several laboratory models of sarcoma, tion compared to monotherapy-treated mice. The addi - mainly STS, as summarized in Table  1. Most notably, tion of DC101 induced endothelial cell sensitivity to studies have shown that VEGFR2 blockade by DC101 doxorubicin and suppressed the activity of matrix met- combined with chemotherapy inhibits tumor growth, alloproteinases secreted by endothelial cells [29]. These metastases, and angiogenesis in STS xenografts [28, results suggested that the antitumor effects of combined 29]. Combined DC101 and continuous low-dose doxo- therapy with DC101 and doxorubicin were secondary to rubicin resulted in more effective growth inhibition of tumor-associated endothelial cell growth modulation and STS xenografts compared to either agent alone [28]. chemosensitization [29]. DC101 plus doxorubicin also enhanced the inhibition Likewise, the enhanced antitumor effects of combina - of tumor angiogenesis and endothelial cell activity, as tion therapy using low-dose topotecan and pazopanib in demonstrated by significantly reduced MVD and inhibi - mouse models of osteosarcoma and rhabdomyosarcoma tion of neovascularization [28]. Additionally, this com- are thought to be related to augmented antiangiogen- bination regimen directly exerted enhanced inhibitory esis [30]. The metronomic administration of pazopanib effects on endothelial cell migration, proliferation, and and topotecan in  vitro showed reduction in circulating Table 1 Preclinical studies of combination approaches in sarcoma Drug combination Sarcoma tumor models Results compared to models treated with chemotherapy alone Reference Pazopanib + topotecan OS KHOS and RMS RH30 cell lines ↑ Antitumor and antiangiogenic effects, [30] and xenografts ↑ Survival, ↓ Circulating endothelial cells and/or endothelial progenitor cells, ↓ MVD VDA (OXi4503/CA1P) + EWS xenografts ↑ Antitumor effects [59] doxorubicin ↑ Necrosis ↓ Perfused vasculature Bevacizumab + topotecan ASPS xenografts ↑ Antitumor effects compared to bevacizumab monotherapy, but [60] not topotecan alone Vandetanib + doxorubicin Multiple STS cell lines and xenografts ↑ Antitumor and antiangiogenic effects [31] ↓ Local growth leiomyosarcoma ↓ Lung metastases in fibrosarcoma DC101 + doxorubicin Multiple STS cell lines and xenografts ↑ Antitumor and antiangiogenic effects [29] transfected with VEGF ↓ Tumor growth and pulmonary metastases ↓ MVD ↑ Percentage of mature vessels ↓ Matrix metalloproteinases secreted by endothelial cells DC101 + doxorubicin Leiomyosarcoma SKLMS-1 and RMS ↑ Antitumor and antiangiogenic effects [28] RD cell lines and xenografts ↓ MVD and neovascularization ↑ Apoptosis of endothelial cells ↓ Endothelial cell migration, proliferation, tube-like formation TNP-470 + etoposide Angiosarcoma ISOS-1 cell line and ↑ Antitumor effects [61] xenograft ↑ Growth inhibition ASPS alveolar soft part sarcoma, ES Ewing sarcoma, MVD microvessel density, OS osteosarcoma, RMS rhabdomyosarcoma, STS soft tissue sarcoma, VDA vascular- disrupting agent, VEGF(R) vascular endothelial growth factor (receptor) Vo et al. Clin Sarcoma Res (2016) 6:9 Page 6 of 11 endothelial cells, circulating endothelial progenitor cells, when AA are added to chemotherapy in patients with and tumor MVD which correlated with antitumor activ- cancer and support clinical investigation in sarcoma. ity and enhancement in survival compared with mono- therapy agents in all preclinical models [30]. Clinical studies of combination approaches in sarcoma Concomitant use of a dual VEGFR2/EGFR inhibi- Targeted AA and chemotherapy have been combined tor (vandetanib) with doxorubicin resulted in additional in numerous early phase clinical trials in children and cytotoxicity and endothelial cell growth inhibition with adults with advanced solid tumors. Phase 1 studies lowered doxorubicin doses compared to vandetanib that included patients with sarcoma are summarized in monotherapy in leiomyosarcoma, fibrosarcoma, and Table  2. The backbone chemotherapy regimens used in uterine sarcoma models [31]. In addition, vandetanib in these trials included taxane- and platinum-based thera- combination with low-dose doxorubicin resulted in sig- pies, camptothecins, and gemcitabine. Although not nificant inhibition of human fibrosarcoma xenograft lung powered to evaluate the antitumor activity of AA com- metastases compared to control and doxorubicin-only bined with chemotherapy, the results of these phase 1 groups [31]. Collectively, these studies suggest that AA studies suggest that these regimens are generally well tol- plus chemotherapy regimens may also help to reduce erated with promising clinical activity in sarcomas. In a the dose and therefore cumulative toxicities of cytotoxic phase 1b study of the combination of bevacizumab added chemotherapy. to gemcitabine and docetaxel in patients with advanced STS, the overall response rate observed was 31  %, with Clinical efficacy of targeted AA in combination 5 complete and 6 partial responses, and 18 patients with with chemotherapy stable disease lasting for a median of 6 months [41]. Sev- Clinical studies of combination approaches in solid tumors eral pediatric phase 1 clinical trials have demonstrated Outside the field of sarcoma, AA have been combined the safety of combining AA, specifically bevacizumab, with chemotherapy with varying outcomes. A retrospec- with cytotoxic chemotherapy in patients with advanced tive study of patients with advanced solid malignancies solid tumors, with tumor responses in patients with treated on phase 1 protocols between 2004 and 2013 Ewing sarcoma [42]. In addition to those listed in Table 2, showed that chemotherapy concomitant with VEGF(R) combination antiangiogenic approaches combining AA inhibitors was associated with significantly higher odds and conventional chemotherapy, such as ifosfamide and ratio for clinical benefit compared with chemotherapy doxorubicin, studied in other malignancies, may warrant without VEGF(R) inhibitors [32]. further study in sarcoma [43, 44]. For example, in lung, breast, and colorectal carci- There have been four reported phase 2 studies evalu - noma, AA have shown increased activity when combined ating the combination of AA with chemotherapy in with standard chemotherapy, as highlighted below. In sarcoma. The combination of bevacizumab with doxo - advanced non-small cell lung cancer, a randomized phase rubicin was evaluated in 17 patients with metastatic STS 2 trial showed a trend towards increased response rate [45]. While two partial responses (12  %) were observed, and time to progression when bevacizumab was com- this response rate was not greater than that observed bined with paclitaxel and carboplatin [33]. Several large for single-agent doxorubicin [45]. However, 11 patients randomized trials in patients with metastatic breast (65  %) had stable disease lasting four cycles or longer, cancer showed significantly higher response rates and suggesting that further consideration of this treatment increased progression-free survival (PFS) when treated regimen may be warranted in STS [45]. In general, the with bevacizumab combined with chemotherapy com- toxicity of bevacizumab and doxorubicin was similar pared to those treated with chemotherapy alone [34–38]. to that reported for single-agent doxorubicin with one Perhaps the disease in which bevacizumab has had the notable exception: the reported 35  % rate of grade 2 or greatest impact in combination with chemotherapy is higher cardiotoxicity with this combination regimen metastatic colorectal cancer. After a randomized phase was greater than expected (compared to historical con- 2 study showed encouraging results when bevacizumab trols) [45]. Despite close monitoring and standard use was combined with fluorouracil and leucovorin [39], a of dexrazoxane, the observed cardiac toxicity warrants a randomized phase 3 trial of irinotecan, fluorouracil, and change in the dose and/or schedule in future studies of leucovorin with bevacizumab or placebo showed that this combination. bevacizumab increased response rate, time to progres- The Children’s Oncology Group (COG) evaluated bev - sion, and overall survival [40]. Given these findings, beva - acizumab or temsirolimus in combination with vinorel- cizumab is now included in the first-line management of bine (V) and cyclophosphamide (C) in a randomized patients with metastatic colorectal cancer. These clinical phase 2 study in patients with advanced rhabdomyosar- findings provided proof of principle of additive activity coma. Both treatment regimens were well tolerated and Vo et al. Clin Sarcoma Res (2016) 6:9 Page 7 of 11 Table 2 Completed phase 1 (or pilot) trials of combination approaches that enrolled patients with sarcoma Drug combination Sarcoma tumor type (number enrolled) Responses Reference Trials with bevacizumab Bevacizumab + pegylated SN-38 (EZN-2208) STS (5) SD (2) [62] Bevacizumab + bendamustine Angiosarcoma (1) None [63] Bevacizumab + irinotecan RMS (1) None [64] Bevacizumab + vincristine/irinotecan/temozolomide STS (3); OS (2); ES (1) SD (2) [65] Bevacizumab + vincristine/irinotecan/temozolomide ES (2); RMS (1); Clear cell sarcoma (1) CR (1); PR (1) [42] Bevacizumab + sorafenib + cyclophosphamide OS (2); RMS (2); Other STS (4) PR (1); SD (3) [66] Bevacizumab + gemcitabine/doxetaxel STS (36) CR (5); PR (6); SD (18) [41] Bevacizumab + ifosphamide/etoposide/carboplatin STS (7); OS (3); Chondrosarcoma (2); Undifferentiated (1) PR (4); SD (5) [67] Trials with VEGFR and PDGFR inhibitors Pazopanib + cisplatin Sarcoma (5) CR (1); SD (2) [68] Pazopanib + topotecan STS (6); OS (2) Unknown [69] Pazopanib + ifosfamide Sarcoma (19) PR (3) [70] Pazopanib + paclitaxel/carboplatin OS (1); Giant cell tumor (1); Other sarcoma (1) None [71] PDGFR inhibitor (CP-868,596) + docetaxel ± axitinib ES (3); Other sarcoma (5) SD (3) [72] Semaxanib + cisplatin/irinotecan GIST (2); STS (1) None [73] Sorafenib + irinotecan OS (4); Synovial sarcoma (1); DSRCT (1); MPNST (1) Unknown [74] Sunitinib + pemetrexed/carboplatin Synovial sarcoma (1) None [75] Sunitinib + gemcitabine OS (1); STS (1) SD (1) [76] Sunitinib + ifosfamide ES (2); STS (6); Other sarcoma (7) PR (2); SD (3) [77] Sunitinib + irinotecan OS (1); STS (1) None [78] Sunitinib + docetaxel OS and STS (unknown) None [79] Trials with other antiangiogenic agents Ombrabulin (AVE8062) + docetaxel Muscle/bone tumors (5) None [80] Thrombospondin-1 mimetic (ABT-510) + gemcitabine/ Sarcoma (1) None [81] cisplatin Thrombospondin-1 mimetic (ABT-510) + 5-FU/leucovorin Synovial sarcoma (1) None [82] TNP-470 + paclitaxel/carboplatin Sarcoma (2) None [83] Only includes SD, PR, and CR responses among patients with sarcoma. CR complete response; DRSCT desmoplastic small round cell tumor; ES Ewing sarcoma; GIST gastrointestinal stromal tumor; MPNST malignant peripheral nerve sheath tumor; OS osteosarcoma; PDGFR platelet-derived growth factor receptor; PR partial response; RMS rhabdomyosarcoma; STS soft tissue sarcoma; SD stable disease; VEGF(R) vascular endothelial growth factor (receptor) without unexpected toxicities. In a preliminary report, that may activate the proangiogenic pathway indepen- patients randomized to VC plus temsirolimus had a dently of the classic ligand-receptor activation shown in superior event-free survival compared to VC plus beva- recent studies. These findings suggest that the extracel - cizumab (65 vs. 50  %, respectively) [46]. As a VC alone lular blockade of VEGF by a monoclonal antibody, such arm was not included in the trial, it is not known if as bevacizumab, would not interfere with angiosarcoma bevacizumab improved outcomes compared to the VC proliferation [47]. Given these findings, the authors did backbone. not recommend the addition of bevacizumab to pacli- Ray-Coquard and colleagues examined the addition taxel for the treatment of advanced angiosarcoma. of bevacizumab added to paclitaxel in a randomized Recently, the Spanish Group for Research on Sarcomas phase 2 study of patients with angiosarcoma. While the presented their findings of a phase 2 study of sorafenib combination antiangiogenic regimen was shown to be and ifosfamide in 35 patients with advanced STS [48]. active in patients with angiosarcoma, the PFS and over- This combination antiangiogenic regimen had accept - all survival was similar in both arms [47]. Nevertheless, able toxicity in patients previously treated with anthracy- there was increased toxicity in the bevacizumab arm, clines. The study met its primary endpoint requiring at which included one fatal drug-related toxicity (intestinal least 19/35 patients to be free of progression at 3 months. obstruction) [47]. The lack of benefit from bevacizumab The combination was shown to be active in patients with may be due in part to key mutations in angiosarcoma advanced STS. Six (17  %) patients had partial responses Vo et al. Clin Sarcoma Res (2016) 6:9 Page 8 of 11 to this regimen. The 3-month PFS was found to be 66 % docetaxel, which resulted in temporary tumor regression (23/35) in patients treated with sorafenib plus ifosfamide, with progression free survival of 12  months [49]. Dra- which may exceed the 3-month PFS in patients treated matic improvement was also seen in another patient with with ifosfamide alone, thus warranting further investiga- inoperable face and neck angiosarcoma who was treated tion [48]. with bevacizumab and paclitaxel [50]. In three pediat- Additional clinical trials evaluating combination ric patients with Ewing sarcoma or undifferentiated sar - therapy with targeted AA and cytotoxic chemotherapy coma who were treated with bevacizumab, gemcitabine, in patients with sarcoma are ongoing (Table  3). With and docetaxel, two patients had a partial response and early promising results, the latest phase 2 trials have the third patient had stable disease for >6  months [51]. been largely directed towards pediatric sarcoma. These Lastly, in a retrospective analysis of 14 patients with include bevacizumab, cyclophosphamide, and topote- hemangiopericytomas and malignant solitary fibrous can in patients with relapsed/refractory Ewing sar- tumors who were treated with bevacizmuab and temo- coma (NCT01492673); and maintenance bevacizumab zolomide, 11 patients (79 %) achieved a partial response, therapy in high-risk Ewing sarcoma and desmoplastic with a median time to response of 2.5 months [52]. small round cell tumor (NCT01946529). Furthermore, Extensively reviewed elsewhere [53, 54], metronomic the COG is actively enrolling patients on a randomized chemotherapy is an alternative antiangiogenic strategy, phase 2/3 trial of preoperative chemoradiation or preop- involving the application of daily, low-dose chemother- erative radiation plus or minus pazopanib in STS histolo- apy. With this low-dose approach, apoptosis is induced in gies other than rhabdomyosarcoma (NCT02180867). the less frequently dividing endothelial cells rather than In adults, phase 2 studies are evaluating pazo- in the tumor cells [53]. This approach has been used in panib and topotecan in patients with high-risk sar- sarcoma with promising results [55–58]. In a feasibility comas (NCT02357810); pazopanib plus gemcitabine study of metronomic cyclophosphamide plus predniso- in advanced STS (NCT02203760, NCT01593748 and lone in 26 elderly patients with inoperable or metastatic NCT01532687); pazopanib and paclitaxel in advanced STS, the response rate was 27  % and the disease control angiosarcoma (NCT02212015); sorafenib, epirubicin, rate (responses and stable disease >12  weeks) was 69  % ifosfamide, and radiotherapy followed by surgery in [56]. Currently, there are three open phase 1 studies high-risk STS (NCT02050919). Lastly, there is one open examining the combination of bevacizumab or pazopanib randomized phase 3 trial evaluating bevacizumab ver- added to metronomic chemotherapy that may include sus placebo combined with docetaxel and gemicitabine eligible sarcoma patients (Table 3). in the treatment of advanced uterine leiomyosarcoma (NCT01012297). Conclusions Outside of the context of formal clinical trials, several Advances in the biology of sarcomas have established the retrospective case studies/series have also highlighted critical role of tumor angiogenesis and multiple signaling the potential efficacy of these combination regimens. A pathways involved in tumor development, growth, and child with transformed malignant angiosarcoma was suc- therapy resistance. Numerous preclinical studies have cessfully treated with bevacizumab, gemcitabine, and demonstrated that targeting proangiogenic mechanisms Table 3 Ongoing phase 1 (or pilot) clinical trials of combination approaches in sarcoma Targeted antiangiogenic agent Chemotherapy regimen Tumor type NCT Bevacizumab Doxorubicin/temsirolimus Advanced solid tumors, including sarcoma 00761644 Bevacizumab Doxorubicin Advanced Kaposi sarcoma 00923936 Bevacizumab Gemcitabine/docetaxel/valproic acid Advanced sarcoma 01106872 Bevacizumab Gemcitabine/paclitaxel Advanced solid tumors, including sarcoma 01113476 Bevacizumab Irinotecan/temozolomide + standard alkylator- Newly diagnosed DSRCT 01189643 based chemotherapy Bevacizumab Metronomic doxorubicin + radiation Resectable STS 01746238 Bevacizumab Metronomic cyclophosphamide/valproic acid/ Advanced solid tumors, including sarcoma 02446431 temsirolimus Pazopanib Gemcitabine Advanced leiomyosarcoma 01442662 Pazopanib Docetaxel/gemcitabine Operable STS 01719302 Pazopanib Metronomic topotecan Advanced solid tumors, including sarcoma 02303028 DSRCT desmoplastic small round cell tumor; NCT ClinicalTrials.gov Identifier/Number; STS soft tissue sarcoma Vo et al. 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Proc Natl Acad Sci USA. authors; data analysis and interpretation: all authors; manuscript writing: all 1996;93(25):14765–70. authors; final approval of manuscript: all authors; accountability for all aspects 14. Liu Y, Xia X, Zhou M, Liu X. Avastin(R) in combination with gemcitabine of the work: all authors. All authors read and approved the final manuscript. and cisplatin significantly inhibits tumor angiogenesis and increases the survival rate of human A549 tumor-bearing mice. Exp Ther Med. Author details 2015;9(6):2180–4. Department of Pediatrics, UCSF School of Medicine, San Francisco School 15. Dickson PV, Hamner JB, Sims TL, Fraga CH, Ng CY, Rajasekeran S, Hage- of Medicine, UCSF Benioff Children’s Hospital, University of California, 550 16th dorn NL, McCarville MB, Stewart CF, Davidoff AM. Bevacizumab-induced Street, 4th Floor, Box 0434, San Francisco, CA 94158, USA. Dana-Farber/Bos- transient remodeling of the vasculature in neuroblastoma xenografts ton Children’s Cancer and Blood Disorders Center, 450 Brookline Avenue, Dana results in improved delivery and efficacy of systemically administered 3, Boston, MA 02215, USA. chemotherapy. Clin Cancer Res. 2007;13(13):3942–50. 16. Vangestel C, Van de Wiele C, Van Damme N, Staelens S, Pauwels P, Acknowledgements Reutelingsperger CP, Peeters M. (99)mTc-(CO)(3) His-annexin A5 micro- The authors acknowledge the assistance of Diana Lim with graphic design. SPECT demonstrates increased cell death by irinotecan during the vascular normalization window caused by bevacizumab. J Nucl Med. Competing interests 2011;52(11):1786–94. The authors declare that they have no competing interests. 17. Turley RS, Fontanella AN, Padussis JC, Toshimitsu H, Tokuhisa Y, Cho EH, Hanna G, Beasley GM, Augustine CK, Dewhirst MW, et al. Bevacizumab- Funding induced alterations in vascular permeability and drug delivery: a novel This work was supported in part by the Alex’s Lemonade Stand Foundation approach to augment regional chemotherapy for in-transit melanoma. (KTV, KKM, SGD), the Campini Foundation (KTV, KKM, SGD), and the Mildred V. Clin Cancer Res. 2012;18(12):3328–39. Strouss Chair (KKM). The contents are solely the responsibility of the authors 18. Chatterjee S, Wieczorek C, Schottle J, Siobal M, Hinze Y, Franz T, Florin A, and do not necessarily represent the official views of the funding agencies. Adamczak J, Heukamp LC, Neumaier B, et al. Transient antiangiogenic treatment improves delivery of cytotoxic compounds and therapeutic Received: 22 March 2016 Accepted: 11 May 2016 outcome in lung cancer. Cancer Res. 2014;74(10):2816–24. 19. Van der Veldt AA, Lubberink M, Bahce I, Walraven M, de Boer MP, Greuter HN, Hendrikse NH, Eriksson J, Windhorst AD, Postmus PE, et al. 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