Human Physiology & Mechanisms of Disease: Anti-angiogenesis Therapy in the Treatment for Colorectal Cancer

ABSTRACT

Angiogenesis is the process of new blood vessel formation which is an important target for therapeutic interference in many cancers, including metastatic colorectal cancer (mCRC). Different anti-angiogenic agents are available in many treatment settings for its safety and efficacy. Such agents are bevacizumab, aflibercept, ramucirumab and regorafenib. There are also other drugs with anti-angiogenic activity but with less promising results; these are sorafenib, sunitinib, vandetanib and vantalanib. Also, there are current development of new anti-angiogenics such as masitinib, VXM01, the concept of tumor vessel normalization and combination with immunotherapy. An anti-vascular endothelial growth factor agent, bevacizumab, is the most effective anti-angiogenic treatment for patients with mCRC. Aside from being in the first-line setting, bevacizumab is also effective in treatment-naïve patients, essential in maintenance therapy, can also be in the second-line setting and beyond progression. As a result, bevacizumab at present is often used as anti-angiogenic treatment appropriate to its approval for first and later treatment lines.

Keywords: metastatic colorectal cancer, angiogenesis, anti-angiogenesis, bevacizumab, aflibercept, ramucirumab, regorafenib

INTRODUCTION

 Colorectal cancer (CRC) is the third most commonly occurring cancer in men and the second most commonly occurring cancer in women. In 2018, there were over 1.8 million new cases.¹Since the increased screening and improvements in the treatment of CRC, death rates declined 52% from 1970 to 2015 among men and women. Moreover, CRC death rates among adults younger than 55 increased by 1% per year between 2006 and 2015.²An important process in tumor growth and proliferation is angiogenesis. It is also called the formation of new blood vessels.³In the hope that angiogenesis could be therapeutically inhibited, thereby slowing the growth of tumor, the action by which cancers generate new blood vessel formation has already been studied for a long time. Angiogenesis, however, is a tremendously complex variable process that is a result of the interaction of multiple pro- and anti-angiogenic factors and several convoluted and convergence signaling pathways. Vascular endothelial growth factor (VEGF) family is the key players in angiogenesis which is made up of growth factors. These growth factors are the following: VEGF-A, VEGF-B, VEGF-C, VEGF-D, placental growth factor (P1GF) and receptors such as VEGF receptor (VEGFR)-1, VEGFR-2 and VEGFR-3.⁴

 In addition to these mentioned above, platelet-derived growth factor receptor, fibroblast growth factor receptor and c-kit are other important players in tumor angiogenesis. Based on many studies within the last decade, patients with metastatic colorectal cancer also called mCRC which is treated with anti-angiogenic therapies that targets the major growth factors and receptors showed higher rates of survival. This opinion paper will discuss the effectiveness of anti-angiogenic agents in the treatment of colorectal cancer.

SEARCH STRATEGY

 The first thing I did to search for resources was to visit useful sites such as PubMed and ScienceDirect. At first, I searched using the title of my topic which is “Anti-Angiogenesis therapy in the treatment of colorectal cancer”. After that I sort out the journal articles that is only useful and will give me the appropriate information I can get. I gathered as much as possible journal articles and also searched using certain keywords to gather more journal articles. Keywords such as anti-angiogenesis, anti-angiogenics, anti-angiogenic agents, anti-angiogenic therapy, anti-angiogenic therapy treatments, VEGFR, angiogenesis and anti-angiogenic treatment for metastatic colorectal cancer. Some of the journal articles I found was restricted so I cannot access it, only the abstract is the only one that can be readable. So, in order for me to access the journal article I look for the doi of each journal article and went to Sci-hub. In sci-hub, I just pasted the doi of the journal article that I want to access and then now I can access all the details in the restricted journal articles. With that, I was able to get all the information in the journal article that I think was useful for writing this opinion paper. Even the one I found in google that was restricted, I used it in sci-hub and I already accessed it after putting the doi or even the URL and PMID where I found the journal article. Sci-hub really helped me a lot in gathering resources. Not only for journal articles but also for books, magazines and research papers. It truly removes the barriers in the way of science. Also, I used drugbank in searching for the drugs mentioned in the research articles.

DISCUSSION

Anti-angiogenic therapy plays a vital role in the management of patients with mCRC.  Bevacizumab, ziv-aflibercept, regorafenib, and ramucirumab are the anti-angiogenic agents that are approved in the treatment of patients with mCRC.⁵ The choice of agents varies based on tumor resectability and line of therapy. With the addition of bevacizumab to neoadjuvant chemotherapy, patients with the highest probability to have resectable liver metastases shows a refined pathological response. In conversion therapy, bevacizumab is used in combination with irinotecan-based chemotherapy which has a resection rates up to 61% in combination with FOLFOXIRI though at the levy of escalating toxicities. However, the addition of bevacizumab to cytotoxic chemotherapy in patients with treatment-naïve unresectable mCRC attains finer and more resistant responses with the addition to an advantage in PFS and OS when compared to chemotherapy alone. Bevacizumab plays a beneficial role when it is combined with a fluoropyrimidine in the maintenance setting and a huge benefit of continuously using bevacizumab beyond progression.⁶

Cetuximab-based chemotherapy is the option in treating patients with KRAS WT unresectable mCRC with the use of bevacizumab in the first-line setting. Ziv-aflibercept improved survival when used in the second-line setting in combination with an irinotecan-based chemotherapy in patients who have failed oxaliplatin-based therapy. Regoragenib is used to compare the placebo in the treatment of patients with refractory mCRC. Herewith, it has improved the survival of patients with mCRC. Lastly, ramucirumab improves the survival in the second-line setting when used in combination with chemotherapy.

Regardless of these advances in anti-angiogenic therapies, mCRC remains untreatable disease with a median of overall survival of roughly about over 2 years in patients exposed to all available treatments. Additional insights into tumor biology and tumor microenvironment may help ameliorate results in patients with mCRC.

FUTURE DIRECTIONS

Sorafenib, sunitinib, vandetanib and vantalanib are other drugs with anti-angiogenic activity but with less promising results. As a result, their clinical development in mCRC was stopped.¹⁵ Masitinib, VXM01, the concept of tumor vessel normalization and combination with immunotherapy are among the current development of new anti-angiogenics. Masitinib, an oral tyrosine kinase inhibitor that selectively targets c-Kit, PDGFR- α/β, Lyn tyrosine kinase, and FGFR3 (fibroblast growth factor receptor 3)¹⁶ has a promising results that led to the commencement of an ongoing phase III trial and results are expected for 2018.¹⁷ VXM01, an anti-angiogenic vaccine applied orally to a live, attenuated Salmonella bacteria carries an expression plasmid encoding VEGFR-2¹⁸ and is currently being tested in a phase I study in patients with mCRC, liver metastasis after second or third-line therapy, to examine its after treatment with VXM01 for its safety, efficacy, and immune biomarkers. Normalization of the drug-induced in the vascular network in preclinical models arise from improved access of chemotherapeutics and better therapeutic efficacy. The combination of immunotherapy and anti-angiogenic therapy yields synergistic antitumor activity for the reason that anti-angiogenic agents can enhance the ease of access of tumor tissue for host immune cells and at the same time it can decrease tumor-induced

immunosuppression. ¹⁹ With the approval of bevacizumab for the treatment of mCRC in 2004, the therapeutic concept of angiogenesis inhibition became clinical reality. Also, biosimilars for bevacizumab are already on the horizon before the patents expiration date in the USA (July 2019) and in Europe (January 2022). ²⁰

As a result, bevacizumab at present is often used as anti-angiogenic treatment appropriate to its approval for first and later treatment lines while ramucirumab and aflibercept are only approved for use in combination with FOLFIRI in the second-line setting (refer to possible treatment scenarios in fig 2). Even so, the progress of new anti-angiogenic compounds which targets angiogenic signaling without VEGFR inhibition and of combinatorial therapeutic procedure is ongoing. For the next years, the search for biomarkers predicting response to anti-angiogenic therapies is under way same as with the results from current large phase III trials with novel anti-angiogenic compounds will be expected. Moreover, a deeper understanding of the intricacy of the tumor setting same as with the molecular and cellular dynamics of tumor angiogenesis is needed to foresee the clinical responsiveness of individual cancers.

For future references, promising angiogenic biomarkers will be a crucial tool for rational treatment distribution and cost containment.  In the future, predictive angiogenic biomarkers will be indispensable tools for rational treatment allocation and cost containment.^21,22

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