**7. Conclusion**

pass through to the tumor [94]. Vascular normalization has also been shown to improve the outcome of immunotherapy, making delivery of immune cells to the tumor easier, and can even

Most of the time, resistance to chemotherapy occurs through heritable changes in the tumor genotype. However, because resistance to VEGF inhibitors does not occur through natural selection, as discussed above, it is possible that rechallenging after disease progression following an intervening interval of time during which VEGF therapy is suspended may allow for a return of efficacy in antiangiogenic VEGF inhibitors. For example, patients with metastatic renal cell carcinoma (mRCC) who experience disease progression after initial response to sunitinib can eventually respond to the drug upon rechallenge after an intervening period on alternative therapies, such as sorafenib (patients with more than 6 months off sunitinib experienced greater PFS than patients with less than 6 months off sunitinib, although in each case the second PFS was shorter than the original) [99]. Moreover, in a randomized phase III trial, patients with unresectable metastatic colorectal cancer progressing up to 3 months after discontinuing bevacizumab plus chemotherapy experienced moderate survival benefits when bevacizumab plus chemotherapy was given as a second line treatment as compared to

More research must be done to assess the efficacy of antiangiogenic agents in the adjuvant and neoadjuvant settings. In the neoadjuvant setting, VEGF inhibition may cause tumor regression, converting an unresectable tumor to a resectable one [82], with 12 of 30 patients in one single-arm phase II study who received oxaliplatin plus bevacizumab having initial nonsynchronous unresectable CLM become resectable [108]. However, antiangiogenic neoadjuvant treatment in mouse models of metastatic disease has been shown not to correlate with postsurgical survival [109]. In the adjuvant setting, it is possible that antiangiogenic therapies may prevent relapse by preventing the reestablishment of tumor vasculature. However, bevacizumab has delivered poor results in OS when used in combination with chemotherapy for

Some work is also being put into developing novel VEGF and VEGFR inhibitors. For example, ramucirumab, a monoclonal antibody that inhibits VEGFR-2, was given FDA approval in 2014 for use as a single agent in the treatment of patients with gastroesophageal carcinoma; it has since been given approval for use in combination with paclitaxel, docetaxel, and FOLFIRI [110]. Ramucirumab is the first biological treatment to show moderate survival benefits as a single agent after gatroesophageal adenocarcinoma progression following first-line chemotherapy in a phase 3 trial (ramucirumab vs. placebo, OS = 5.2 months vs. 3.8 months, respectively) [111]. The drug has also shown moderate OS benefits when used in combination with docetaxel for second-line treatment of stage IV NNSCLS compared with docetaxel alone after progression on platinum-based chemotherapy (10.5 months vs. 9.1 months, ramucirumab plus docetaxel vs. docetaxel alone, respectively) [112]. Apatinib is another novel VEGFR-2 inhibitor, a small molecule not yet given FDA approval (although it is approved for use in China in treating metastatic gastric or gastroesophageal adenocarcinoma after second-line chemotherapy) [113]. The drug thus far has shown only moderate survival benefits of 1.8

months, and several trials are ongoing to assess its efficacy in different settings [114].

decrease the intravasation of cancer cells, limiting the possibility of metastasis [94].

398 Physiologic and Pathologic Angiogenesis - Signaling Mechanisms and Targeted Therapy

chemotherapy alone [107].

adjuvant colorectal cancer, although PFS is improved [78].

Ever since its discovery, VEGF has been at the center of attention in new and developing cancer therapies. Since its early successes, however, antiangiogenic therapy has often presented only modest improvements in overall survival and progression-free survival [122]. Researchers have not given up hope that this therapeutic technique contains promise in the arsenal against cancer. Therefore, much recent research has been done in pushing the frontier of antiangiogenic therapies, trying to improve patient outcome.

Because the biology of VEGF and its receptors is well understood, current research focuses on why some tumors become resistant to antiangiogenic therapies and others are intrinsically resistant, how to circumvent this intrinsic or acquired resistance, and how to best utilize these expensive therapies by developing predictive biomarkers for treatment outcome. More research is also being done to develop novel VEGF inhibition techniques, and in characterizing the rare yet serious toxicities associated with these drugs.

As they stand now, antiangiogenic therapies face a set of limitations that severally impacts their efficacy. Tumors can acquire resistance to the drugs (if they do not already have intrinsic resistance) and demonstrate an increase in aggressiveness. Moreover, antiangiogenic therapies may cause a decrease in chemotherapy perfusion, lowering the efficacy of chemotherapies given in combination with antiangiogenic medicine [123]. These difficulties suggest that, at least when given alone, antiangiogenic therapies may face severe limitations in survival benefits. Therefore, future research should focus on more than simply inhibiting VEGF on a continuous schedule. Rather, it should focus on increasing the efficacy of chemotherapy through utilizing antiangiogenic therapy to induce vascular normalization, allowing for more efficient delivery of chemotherapeutic agents [123, 124]. Moreover, research should also find ways to decrease resistance to these therapies through inhibiting proangiogenic factors that are upregulated in response to the inhibition of VEGF and through developing predictive biomarkers for the efficacy of these expensive treatments [123, 124].

## **Author details**

Victor Gardner1 , Chikezie O. Madu1, 2 and Yi Lu<sup>2</sup> \*

\*Address all correspondence to: ylu@uthsc.edu

1 White Station High School, Memphis, TN, USA

2 Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, TN, USA

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As they stand now, antiangiogenic therapies face a set of limitations that severally impacts their efficacy. Tumors can acquire resistance to the drugs (if they do not already have intrinsic resistance) and demonstrate an increase in aggressiveness. Moreover, antiangiogenic therapies may cause a decrease in chemotherapy perfusion, lowering the efficacy of chemotherapies given in combination with antiangiogenic medicine [123]. These difficulties suggest that, at least when given alone, antiangiogenic therapies may face severe limitations in survival benefits. Therefore, future research should focus on more than simply inhibiting VEGF on a continuous schedule. Rather, it should focus on increasing the efficacy of chemotherapy through utilizing antiangiogenic therapy to induce vascular normalization, allowing for more efficient delivery of chemotherapeutic agents [123, 124]. Moreover, research should also find ways to decrease resistance to these therapies through inhibiting proangiogenic factors that are upregulated in response to the inhibition of VEGF and through developing predictive

\*

2 Department of Pathology and Laboratory Medicine, University of Tennessee Health Science

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\*Address all correspondence to: ylu@uthsc.edu

1 White Station High School, Memphis, TN, USA

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#### **Antiangiogenic Therapy for Hepatocellular Carcinoma Antiangiogenic Therapy for Hepatocellular Carcinoma**

Kosuke Kaji and Hitoshi Yoshiji Kosuke Kaji and Hitoshi Yoshiji

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/66503

#### **Abstract**

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zumab [Accessed 2016-04-14].

410 Physiologic and Pathologic Angiogenesis - Signaling Mechanisms and Targeted Therapy

ride [Accessed 2016-04-14].

cept [Accessed 2016-04-14].

Angiogenesis plays a pivotal role in many pathological processes, including hepatocellular carcinoma (HCC). This indicates that antiangiogenic agents could be promising candidates for chemoprevention against HCC. Several inhibitors targeting receptor tyrosine kinases (RTKs) for the regulation of tumoral vascularization have been developed and employed in clinical practice, including sorafenib. However, there seem to be several issues for the long-term use of this agent as some patients have experienced adverse effects while taking sorafenib. Therefore, it is desirable for patients with chronic liver diseases to be administered sorafenib as little as possible by combining other safe-to-use antiangiogenic compounds. Various factors, such as renin-angiotensin-aldosterone system (RAAS) and insulin resistance (IR), reciprocally contribute to the promotion of angiogenesis. A blockade of RAAS with an angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin-II (AT-II) receptor blocker (ARB) markedly attenuates HCC in conjunction with the suppression of angiogenesis. Moreover, the IR status has demonstrated direct acceleration in the progression of HCC via the augmentation of tumoral neovascularization. These findings suggest that a combination therapy involving a lower dose of sorafenib with other clinically used agents [e.g., RAAS blockers, insulin sensitizer agents, and branched-chain amino acids (BCAA)] may reduce the adverse effects of sorafenib without attenuating the inhibitory effect against HCC in comparison to a high-dose administration.

**Keywords:** hepatocellular carcinoma, fibrosis, renin-angiotensin system

## **1. Introduction**

Angiogenesis is the development of new vasculature from preexisting blood vessels or circulating endothelial cell (EC) stem cells. Emerging evidence indicates that angiogenesis develops inmanyorgans andundermultiplepathologic situations, aswell asduringconditions

© 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

of tissue growth and regeneration. Abnormal pathological angiogenesis is observed in patients with rheumatoid arthritis, psoriasis, diabetic retinopathy, fibrogenesis, and tumor growth [1]. Although early studies were conducted to determine the molecular processes associated with carcinogenesis and angiogenesis that were performed independently, more recent studies have revealed that both biological phenomena emerge synergistically [2].

Hepatocellular carcinoma (HCC) is the sixth most common cancer and the second leading cause of cancer-related mortality worldwide, accounting for more than 600,000 new cases annually. The greatest risk factors for developing HCC include liver cirrhosis induced by hepatitis B virus (HBV) or hepatitis C virus (HCV) infections, excessive alcohol intake, and metabolic syndrome. Regardless of the etiology, since HCC commonly develops in patients with a chronic liver disease (e.g., liver cirrhosis) only approximately one-third of the patients diagnosed with HCC are eligible for curative treatments (e.g., surgical resection) [3]. Consequently, several alternative therapies have been employed, including percutaneous radiofrequency ablation (RFA) and transarterial chemoembolization (TACE). However, no satisfactory improvement of HCC prognosis has been achieved to date. The notable characteristic of HCC that accounts for its poor prognosis is the risk of high frequency in recurrence attributed to intrahepatic metastasis or the multicentric development. The key feature of HCC progression is also hypervascularity formed by intratumoral angiogenesis as well as the frequent recurrence. Several studies have demonstrated that angiogenesis is implicated in the survival and growth of HCC. It has also been reported that angiogenesis can be induced during the early stages of tumor formation and the various carcinogenic mechanisms have been demonstrated in several different experimental models [4–7]. Therefore, several antiangiogenic agents (i.e., sorafenib) have been developed as novel treatment options for HCC.

In this chapter, mechanistic insights into angiogenesis and its contribution to hepatocarcinogenesis will initially be reviewed. In addition, newly developed antiangiogenic agents will be described in detail.
