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• W2335877573 abstract "•Translating theoretical concepts to clinical application is a complex process•The original concept of anti-angiogenesis should be modified to reflect reality•Lessons learned from anti-angiogenesis may benefit other drug-development efforts Formation of new blood vessels in tumors, a process termed tumor angiogenesis, is a crucial step during oncogenic progression. Blocking tumor angiogenesis is therefore expected to have a profound impact on tumor growth. It took several decades of collective efforts to translate this intriguing idea into tangible clinical benefit. Today, anti-angiogenesis agents represent standard-of-care therapies for multiple types of cancers, and the clinical experience has taught us many lessons about the concept and application of anti-angiogenesis. This Perspective is an attempt to summarize these lessons and how they can be leveraged to improve anti-angiogenesis therapy. Formation of new blood vessels in tumors, a process termed tumor angiogenesis, is a crucial step during oncogenic progression. Blocking tumor angiogenesis is therefore expected to have a profound impact on tumor growth. It took several decades of collective efforts to translate this intriguing idea into tangible clinical benefit. Today, anti-angiogenesis agents represent standard-of-care therapies for multiple types of cancers, and the clinical experience has taught us many lessons about the concept and application of anti-angiogenesis. This Perspective is an attempt to summarize these lessons and how they can be leveraged to improve anti-angiogenesis therapy. The expansion of tissues, be it normal or malignant, relies on adequate supply of oxygen and nutrients as well as efficient removal of metabolic wastes. Therefore, generation of new blood vessels becomes an indispensable step in the process of tissue growth. Based on this fundamental premise, Folkman articulated the concepts of tumor angiogenesis and anti-angiogenesis in the 1970s, proposing that no tumors could grow beyond 2 mm3 unless they are vascularized. Hence, by blocking new vessel formation, it may be possible to restrict tumors to tiny sizes and at a dormant state, thereby turning cancer from a killer into a chronic asymptomatic disease (Folkman, 1971Folkman J. Tumor angiogenesis: therapeutic implications.N. Engl. J. Med. 1971; 285: 1182-1186Crossref PubMed Google Scholar). The promise of this compelling hypothesis has been subjected to rigorous evaluation in the past 10 years since the US Food and Drug Administration (FDA) granted approval to the first anti-angiogenesis drug, bevacizumab, a monoclonal antibody that blocks the function of vascular endothelial growth factor (VEGF, or VEGFA). Since then a number of other anti-angiogenic drugs, including other forms of VEGFA inhibitors or small molecules that block the VEGFA receptors' functions, have been approved and have become widely used in the clinic to treat various cancers (Tarallo and De Falco, 2015Tarallo V. De Falco S. The vascular endothelial growth factors and receptors family: up to now the only target for anti-angiogenesis therapy.Int. J. Biochem. Cell Biol. 2015; 64: 185-189Crossref Scopus (3) Google Scholar). The benefits of these anti-angiogenesis agents have proved to be modest, as they provide moderate improvement of overall survival in some indications and delay disease progression without prolonging overall survival in other cancers. The disparity between the theoretical potentials of anti-angiogenesis therapy and medical reality has prompted scrutiny of the validity of preclinical studies. To better understand how preclinical studies can be translated, we must revisit the roots of the angiogenesis concept and apply this perspective to a careful evaluation of the preclinical and clinical outcomes of anti-angiogenesis studies. More than two centuries ago, the Scottish surgeon Dr. John Hunter recognized that tissue expansion in adult animals required new blood vessel formation, and invented the term “angiogenesis” (from the Greek words angeion [vessel] and genesis [creation]) to describe the growth of new blood vessels into growing tissues (Hunter, 1787Hunter J. The Works of John Hunter. Cambridge University Press, 1787Google Scholar). In 1907, Professor E. Goldmann from Freiburg pointed out that extensive formation of new blood vessels also occurred during tumor growth, and speculated that “the impetus which gives rise to the proliferation of blood vessels emanates from the invading cells” (Goldmann, 1907Goldmann E. The growth of malignant disease in man and the lower animals.Lancet. 1907; ii: 1236-1240Abstract Google Scholar). The existence of such impetus—tumor-derived angiogenesis activity—was experimentally demonstrated by Dr. Judah Folkman and colleagues in 1971 (Folkman et al., 1971Folkman J. Merler E. Abernathy C. Williams G. Isolation of a tumor factor responsible for angiogenesis.J. Exp. Med. 1971; 133: 275-288Crossref PubMed Google Scholar). In the same year, Folkman proposed a seminal hypothesis: “prevention of new vessel sprouts from penetrating into an early tumor” will keep the “tiny tumor” in “a dormant” state. He postulated that non-vascularized tumors may have diminished metastatic potential and will be more sensitive to chemo- and immunotherapies. He named this hypothesis “anti-angiogenesis” therapy for solid tumors, and suggested “one approach to the initiation of ‘anti-angiogenesis’ would be the production of an antibody against tumor angiogenesis factor” (Folkman, 1971Folkman J. Tumor angiogenesis: therapeutic implications.N. Engl. J. Med. 1971; 285: 1182-1186Crossref PubMed Google Scholar). The “anti-angiogenesis” theory moved one step closer to reality in the 1980s when two angiogenic growth factors were isolated: basic fibroblast growth factor (bFGF) was isolated by Shing and Klagsbrun (Shing et al., 1984Shing Y. Folkman J. Sullivan R. Butterfield C. Murray J. Klagsbrun M. Heparin affinity: purification of a tumor-derived capillary endothelial cell growth factor.Science. 1984; 223: 1296-1299Crossref PubMed Scopus (473) Google Scholar) and VEGFA (also called vascular permeability factor or VPF) was isolated by Ferrara’s group (Leung et al., 1989Leung D.W. Cachianes G. Kuang W.J. Goeddel D.V. Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen.Science. 1989; 246: 1306-1309Crossref PubMed Google Scholar), Plouet and colleagues (Plouet et al., 1989Plouet J. Schilling J. Gospodarowicz D. Isolation and characterization of a newly identified endothelial cell mitogen produced by AtT-20 cells.Embo J. 1989; 8: 3801-3806PubMed Google Scholar), and Dvorak’s group (Senger et al., 1983Senger D.R. Galli S.J. Dvorak A.M. Perruzzi C.A. Harvey V.S. Dvorak H.F. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid.Science. 1983; 219: 983-985Crossref PubMed Google Scholar). It was soon recognized that VEGFA plays a dominant role in angiogenesis as developmental studies revealed that loss of a single allele of vegf in mice led to a complete absence of blood vessels and lethality in embryos (Carmeliet et al., 1996Carmeliet P. Ferreira V. Breier G. Pollefeyt S. Kieckens L. Gertsenstein M. Fahrig M. Vandenhoeck A. Harpal K. Eberhardt C. et al.Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele.Nature. 1996; 380: 435-439Crossref PubMed Scopus (2834) Google Scholar, Ferrara et al., 1996Ferrara N. Carver-Moore K. Chen H. Dowd M. Lu L. O'Shea K.S. Powell-Braxton L. Hillan K.J. Moore M.W. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene.Nature. 1996; 380: 439-442Crossref PubMed Scopus (2559) Google Scholar). VEGFA quickly became the preferred target for the development of anti-angiogenesis drugs. In 1993, Ferrara and colleagues demonstrated that a VEGFA blocking antibody reduced tumor growth and vascular density in animal models (Kim et al., 1993Kim K.J. Li B. Winer J. Armanini M. Gillett N. Phillips H.S. Ferrara N. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo.Nature. 1993; 362: 841-844Crossref PubMed Google Scholar). This work laid the foundation for developing a VEGFA antibody as a cancer therapeutic (Ferrara et al., 2004Ferrara N. Hillan K.J. Gerber H.P. Novotny W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer.Nat. Rev. Drug Discov. 2004; 3: 391-400Crossref PubMed Google Scholar). At the turn of the twenty-first century, anti-angiogenesis therapy in cancer became a medical reality. In 2003, the anti-VEGFA monoclonal antibody bevacizumab was shown to prolong overall survival of patients with metastatic colon cancer when combined with conventional chemotherapeutic agents (Hurwitz et al., 2004Hurwitz H. Fehrenbacher L. Novotny W. Cartwright T. Hainsworth J. Heim W. Berlin J. Baron A. Griffing S. Holmgren E. et al.Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer.N. Engl. J. Med. 2004; 350: 2335-2342Crossref PubMed Scopus (6892) Google Scholar). Subsequently, bevacizumab in combination with chemotherapy was also shown to extend overall survival in additional populations, including patients with metastatic non-small cell lung cancer (Sandler et al., 2006Sandler A. Gray R. Perry M.C. Brahmer J. Schiller J.H. Dowlati A. Lilenbaum R. Johnson D.H. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer.N. Engl. J. Med. 2006; 355: 2542-2550Crossref PubMed Scopus (3597) Google Scholar) and advanced cervical cancer (Tewari et al., 2014Tewari K.S. Sill M.W. Long 3rd, H.J. Penson R.T. Huang H. Ramondetta L.M. Landrum L.M. Oaknin A. Reid T.J. Leitao M.M. et al.Improved survival with bevacizumab in advanced cervical cancer.N. Engl. J. Med. 2014; 370: 734-743Crossref PubMed Scopus (163) Google Scholar). The clinical success of bevacizumab motivated many pharmaceutical companies to develop other VEGFA pathway inhibitors, including a monoclonal antibody against VEGF receptor 2 (VEGFR2) that blocks ligand binding, a recombinant chimeric receptor that sequesters multiple ligands in the VEGF family, and many small-molecule tyrosine kinase inhibitors that block the activity of all VEGF receptors (Figure 1). A number of these inhibitors have also demonstrated clinical benefits in patients with various cancers (Bellou et al., 2013Bellou S. Pentheroudakis G. Murphy C. Fotsis T. Anti-angiogenesis in cancer therapy: Hercules and Hydra.Cancer Lett. 2013; 338: 219-228Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar, Ivy et al., 2009Ivy S.P. Wick J.Y. Kaufman B.M. An overview of small-molecule inhibitors of VEGFR signaling.Nat. Rev. Clin. Oncol. 2009; 6: 569-579Crossref PubMed Scopus (173) Google Scholar, Tarallo and De Falco, 2015Tarallo V. De Falco S. The vascular endothelial growth factors and receptors family: up to now the only target for anti-angiogenesis therapy.Int. J. Biochem. Cell Biol. 2015; 64: 185-189Crossref Scopus (3) Google Scholar), and have become FDA-approved and/or European Medicines Agency (EMA)-approved cancer drugs (Table 1).Table 1Summary of VEGFA Pathway Inhibitor Drugs Approved by the US Food and Drug Administration and/or European Medicines AgencyDrug NameAnti-angiogenesis TargetsExamples of Other TargetsDisease IndicationsDrug CombinationBrand NameBevacizumabVEGFAmetastatic colorectal cancerchemotherapyAvastin®metastatic non-squamous non-small cell lung cancerchemotherapyrecurrent glioblastoma (FDA only)metastatic renal cell carcinomainterferon-αmetastatic Her2-negative breast cancer (EMA only)chemotherapyplatinum-resistant recurrent ovarian cancerchemotherapypersistent, recurrent, or metastatic cervical cancerchemotherapyRamucirumabVEGFR2metastatic colorectal cancerchemotherapyCyramza®platinum-resistant metastatic non-small cell lung cancerchemotherapyadvanced gastric or gastroesophageal junction adenocarcinomachemotherapygastric or gastroesophageal junction adenocarcinomaZiv-afliberceptVEGFA, VEGFB, PlGFsecond-line metastatic colorectal cancerchemotherapyZaltrap®Axitiniball VEGFRsPDGFRs, cKITsecond-line advanced renal cell carcinomaInlyta®Pazopanib hydrochlorideall VEGFRscKIT, FMS, FGFR2, FLT3, MLK1, PDGFRsecond-line advanced soft tissue sarcomaVotrient®advanced renal cell carcinomaRegorafeniball VEGFRsPDGFRs, FGFRs, Tie2, DDR2, Trk2A, Eph2A, RAF-1, STK5advanced gastrointestinal stromal tumorsStivarga®second-line metastatic colorectal cancerSorafenib tosylateall VEGFRscKIT, DDR2, FGFRs, FLT3, FMS, MUSK, cRAF, PDGFRs, Ret, TAO2second-line metastatic or recurrent thyroid carcinomaNexavar®advanced renal cell carcinomaunresectable hepatocellular carcinomaSunitinib malateall VEGFRsARK5, CaMKIIs, CHK2, cKIT, cRAF, FGFR1, Flt3, FMS, Mer, PDGFR, Ret, TrkAunresectable, locally advanced, or metastatic pancreatic neuroendocrine tumorsSutent®advanced renal cell carcinomagastrointestinal stromal tumorsVandetaniball VEGFRsEGFRs, Retunresectable, locally advanced, or metastatic medullary thyroid cancerCaprelsa®Cabozantinib-S-malateall VEGFRscMET, Ret, cKIT, Axlprogressive metastatic medullary thyroid cancerCometriq™Lenvatiniball VEGFRsPDGFRβ, FGFR1, PDGFRαradioactive iodine-refractory thyroid cancerLenvima®EMA, European Medicines Agency; FDA, US Food and Drug Administration; FGFR, fibroblast growth factor receptor; PDGFR, platelet-derived growth factor receptor; PlGF, placental growth factor.Source: http://www.cancer.gov/about-cancer/treatment/drugs Open table in a new tab EMA, European Medicines Agency; FDA, US Food and Drug Administration; FGFR, fibroblast growth factor receptor; PDGFR, platelet-derived growth factor receptor; PlGF, placental growth factor. Source: http://www.cancer.gov/about-cancer/treatment/drugs While the efficacy of these anti-angiogenesis drugs is clinically significant, none of them fulfill the original goal of chronically keeping tumors in a dormant state. What accounts for the disparity between theory and reality? One important reason is the stages of cancers being treated. All the aforementioned successful clinical experiments were conducted on patients with metastatic disease, who generally have large and vascularized tumors in multiple organs, rather than those with tiny dormant tumors. Clearly, the classic anti-angiogenesis concept does not adequately describe how VEGFA inhibitors function in vascularized tumors. In this context, it is worth noting that VEGFA is a multifunctional factor that promotes vascular endothelial cell (EC) proliferation, migration, and survival, and regulates vascular permeability (Dvorak et al., 1995Dvorak H.F. Brown L.F. Detmar M. Dvorak A.M. Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis.Am. J. Pathol. 1995; 146: 1029-1039PubMed Google Scholar, Ferrara et al., 2003Ferrara N. Gerber H.P. LeCouter J. The biology of VEGF and its receptors.Nat. Med. 2003; 9: 669-676Crossref PubMed Scopus (5108) Google Scholar, Shibuya, 2013Shibuya M. Vascular endothelial growth factor and its receptor system: physiological functions in angiogenesis and pathological roles in various diseases.J. Biochem. 2013; 153: 13-19Crossref PubMed Scopus (127) Google Scholar). The most prominent effect of inhibiting VEGFA activity is the pruning of tumor microvessels in animal models and the rapid decline of tumor perfusion in human tumors (O'Connor et al., 2009O'Connor J.P. Carano R.A. Clamp A.R. Ross J. Ho C.C. Jackson A. Parker G.J. Rose C.J. Peale F.V. Friesenhahn M. et al.Quantifying antivascular effects of monoclonal antibodies to vascular endothelial growth factor: insights from imaging.Clin. Cancer Res. 2009; 15: 6674-6682Crossref PubMed Scopus (83) Google Scholar). This anti-vascular activity is believed to be the main driver of efficacy, and is likely due to the pro-survival function of VEGFA. To fully understand the anti-vascular mechanism in cancer, one needs to also understand how VEGFA inhibition selectively eliminates microvessels in tumors while sparing microvessels in normal tissues. In most species, as the organism develops into adulthood its blood vessels also undergo maturation. Vessel maturation is a complex process that involves multiple cellular and molecular changes, including the deposition of a proper basement membrane, formation of tissue-specific EC-EC junctions, and recruitment of mural cells (Chung and Ferrara, 2011Chung A.S. Ferrara N. Developmental and pathological angiogenesis.Annu. Rev. Cell Dev. Biol. 2011; 27: 563-584Crossref PubMed Scopus (167) Google Scholar, Jain, 2003Jain R.K. Molecular regulation of vessel maturation.Nat. Med. 2003; 9: 685-693Crossref PubMed Scopus (1418) Google Scholar). It has been shown that the maturation status of a vessel determines its sensitivity to VEGFA blockade, and the majority of blood vessels in adult animals can resist VEGFA deprivation (Baffert et al., 2004Baffert F. Thurston G. Rochon-Duck M. Le T. Brekken R. McDonald D.M. Age-related changes in vascular endothelial growth factor dependency and angiopoietin-1-induced plasticity of adult blood vessels.Circ. Res. 2004; 94: 984-992Crossref PubMed Scopus (81) Google Scholar, Gerber et al., 1999Gerber H.P. Hillan K.J. Ryan A.M. Kowalski J. Keller G.A. Rangell L. Wright B.D. Radtke F. Aguet M. Ferrara N. VEGF is required for growth and survival in neonatal mice.Development. 1999; 126: 1149-1159Crossref PubMed Google Scholar, Kamba et al., 2006Kamba T. Tam B.Y. Hashizume H. Haskell A. Sennino B. Mancuso M.R. Norberg S.M. O'Brien S.M. Davis R.B. Gowen L.C. et al.VEGF-dependent plasticity of fenestrated capillaries in the normal adult microvasculature.Am. J. Physiol. Heart Circ. Physiol. 2006; 290: H560-H576Crossref PubMed Scopus (448) Google Scholar). In tumors, many microvessels are defective in one or more aspects in the maturation process. For instance, some tumor microvessels form loose contact with mural cells and lack an intact basement membrane (Baluk et al., 2005Baluk P. Hashizume H. McDonald D.M. Cellular abnormalities of blood vessels as targets in cancer.Curr. Opin. Genet. Dev. 2005; 15: 102-111Crossref PubMed Scopus (369) Google Scholar). These defects render them more dependent on survival factors such as VEGFA, and hence they are selectively eliminated upon VEGFA blockade (Benjamin et al., 1999Benjamin L.E. Golijanin D. Itin A. Pode D. Keshet E. Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal.J. Clin. Invest. 1999; 103: 159-165Crossref PubMed Google Scholar). The aforementioned mechanism should guide us in comparing efficacies between preclinical and clinical studies. The outcome of VEGFA inhibition in numerous preclinical tumor models is the reduction of tumor growth rates but not tumor shrinkage (Bagri et al., 2010Bagri A. Berry L. Gunter B. Singh M. Kasman I. Damico L.A. Xiang H. Schmidt M. Fuh G. Hollister B. et al.Effects of anti-VEGF treatment duration on tumor growth, tumor regrowth, and treatment efficacy.Clin. Cancer Res. 2010; 16: 3887-3900Crossref PubMed Scopus (68) Google Scholar, Singh et al., 2010Singh M. Lima A. Molina R. Hamilton P. Clermont A.C. Devasthali V. Thompson J.D. Cheng J.H. Bou Reslan H. Ho C.C. et al.Assessing therapeutic responses in Kras mutant cancers using genetically engineered mouse models.Nat. Biotechnol. 2010; 28: 585-593Crossref PubMed Scopus (135) Google Scholar), presumably due to the fact that not all tumor vessels were eliminated (O'Connor et al., 2009O'Connor J.P. Carano R.A. Clamp A.R. Ross J. Ho C.C. Jackson A. Parker G.J. Rose C.J. Peale F.V. Friesenhahn M. et al.Quantifying antivascular effects of monoclonal antibodies to vascular endothelial growth factor: insights from imaging.Clin. Cancer Res. 2009; 15: 6674-6682Crossref PubMed Scopus (83) Google Scholar). How do these preclinical studies relate to human data? Since tumor cell proliferation rates are much higher in preclinical xenograft tumor models than in human cancer, it is more difficult to induce tumor regression in these models. However, a steep (greater than 60%) tumor growth inhibition (TGI) could predict tumor regression in patients (Gould et al., 2015Gould S.E. Junttila M.R. de Sauvage F.J. Translational value of mouse models in oncology drug development.Nat. Med. 2015; 21: 431-439Crossref PubMed Scopus (11) Google Scholar). As only ∼20% of the preclinical models showed a greater than 60% TGI, it is not surprising that single-agent bevacizumab did not cause tumor shrinkage in most patients. For example, high-dose bevacizumab caused tumor regression in 10% of patients while promoting stable disease in 64% of patients with renal cell carcinoma, a tumor type that expresses highest levels of VEGFA and appears to be the most sensitive to VEGFA blockade (Yang et al., 2003Yang J.C. Haworth L. Sherry R.M. Hwu P. Schwartzentruber D.J. Topalian S.L. Steinberg S.M. Chen H.X. Rosenberg S.A. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer.N. Engl. J. Med. 2003; 349: 427-434Crossref PubMed Scopus (2142) Google Scholar). In this context, the outcomes of the majority of preclinical studies and the clinical performance of the VEGFA inhibitors correlated well. Under both conditions, VEGFA inhibition primarily drives tumor stasis or slower growth instead of tumor shrinkage. Despite the good correlation, it is important to recognize a few limitations of the preclinical models: first, the time scales in animal studies and human studies are quite different, so the longer time scale in human studies could reveal complex tumor evolution that is not captured in animal studies; second, implantation-based preclinical tumor models usually measure one tumor per individual animal, whereas each human patient with metastatic disease typically has multiple lesions; third, there are many factors such as drug side effects, mortality, and patient compliance that influence the clinical outcome, which are difficult to capture in preclinical studies (Figure 2). A confounding factor in translating the original concept of anti-angiogenesis therapy is that it only considered such therapy as a stand-alone treatment, whereas in most approved indications in the clinic VEGFA antagonists are used in combination with chemotherapy. Such a clinical reality calls for an evaluation of how anti-angiogenesis agents function when combined with chemotherapy. It is often claimed that bevacizumab is inactive unless combined with chemotherapy. Is this substantiated by the clinical evidence? First we must examine how the clinical efficacy of a therapy is measured. Although prolonged survival is the gold standard for clinical benefit, surrogate end points such as tumor shrinkage are more readily assessed. In clinical trials, the response to anti-cancer therapy is evaluated according to radiographic criteria such as the Response Evaluation Criteria in Solid Tumors guidelines (RECIST1.1) (Eisenhauer et al., 2009Eisenhauer E.A. Therasse P. Bogaerts J. Schwartz L.H. Sargent D. Ford R. Dancey J. Arbuck S. Gwyther S. Mooney M. et al.New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).Eur. J. Cancer. 2009; 45: 228-247Abstract Full Text Full Text PDF PubMed Scopus (4435) Google Scholar). In each patient, the tumor burden at any point in time is expressed as a sum of the diameters (as typically measured using computed tomography) of up to five measurable “target lesions.” The patient is deemed to have experienced an “objective response” if tumor shrinkage resulting in a ≥30% reduction in the sum of diameters is observed. If at any point a ≥20% increase in the sum of diameters with respect to the nadir value is observed, the patient is determined to have disease progression. The time between the initiation of treatment and the time when the patient experiences disease progression is defined as progression-free survival (PFS) (for a graphic description of these clinical parameters, see Figure 2). Although single-agent bevacizumab is active in reducing tumor growth rate constants, as determined by mathematical modeling (Stein et al., 2008Stein W.D. Yang J. Bates S.E. Fojo T. Bevacizumab reduces the growth rate constants of renal carcinomas: a novel algorithm suggests early discontinuation of bevacizumab resulted in a lack of survival advantage.Oncologist. 2008; 13: 1055-1062Crossref PubMed Scopus (36) Google Scholar), it alone does not induce tumor regression. On the other hand, most chemotherapy agents are cytotoxic and can significantly increase tumor shrinkage rates (Blagoev et al., 2014Blagoev K.B. Wilkerson J. Stein W.D. Yang J. Bates S.E. Fojo T. Therapies with diverse mechanisms of action kill cells by a similar exponential process in advanced cancers.Cancer Res. 2014; 74: 4653-4662Crossref Google Scholar, Malhotra and Perry, 2003Malhotra V. Perry M.C. Classical chemotherapy: mechanisms, toxicities and the therapeutic window.Cancer Biol. Ther. 2003; 2: S2-S4Crossref PubMed Google Scholar). Therefore, mathematical principle dictates that the combination of the reduced tumor growth rate constants associated with bevacizumab and the increased tumor shrinkage rates associated with chemotherapy will lead to prolongation of PFS over chemotherapy alone. In addition to this basic mechanism, other intriguing hypotheses are proposed to explain the combination activities of chemotherapy plus VEGFA inhibitors. The most prominent hypothesis is the vascular normalization effect, which suggests that by eliminating immature/abnormal vessels, the resulting vascular network is more efficient, leading to improved circulation and decreased tumor interstitial pressure. This structural change increases the effect of radiation therapy and delivery of chemotherapeutics within a short time window (Carmeliet and Jain, 2011Carmeliet P. Jain R.K. Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases.Nat. Rev. Drug Discov. 2011; 10: 417-427Crossref PubMed Scopus (387) Google Scholar, Winkler et al., 2004Winkler F. Kozin S.V. Tong R.T. Chae S.S. Booth M.F. Garkavtsev I. Xu L. Hicklin D.J. Fukumura D. di Tomaso E. et al.Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases.Cancer Cell. 2004; 6: 553-563Abstract Full Text Full Text PDF PubMed Scopus (733) Google Scholar). This hypothesis provides an attractive explanation for the observation that the addition of bevacizumab increases the response rate to chemotherapies for many types of cancers (Hurwitz et al., 2004Hurwitz H. Fehrenbacher L. Novotny W. Cartwright T. Hainsworth J. Heim W. Berlin J. Baron A. Griffing S. Holmgren E. et al.Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer.N. Engl. J. Med. 2004; 350: 2335-2342Crossref PubMed Scopus (6892) Google Scholar, Miller et al., 2005Miller K.D. 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Med. 2006; 355: 2542-2550Crossref PubMed Scopus (3597) Google Scholar, Tewari et al., 2014Tewari K.S. Sill M.W. Long 3rd, H.J. Penson R.T. Huang H. Ramondetta L.M. Landrum L.M. Oaknin A. Reid T.J. Leitao M.M. et al.Improved survival with bevacizumab in advanced cervical cancer.N. Engl. J. Med. 2014; 370: 734-743Crossref PubMed Scopus (163) Google Scholar). However, direct evidence demonstrating increased chemotherapy delivery in cancer patients has yet to be obtained; in fact, contrary evidence has been reported instead (Van der Veldt et al., 2012Van der Veldt A.A. Lubberink M. Bahce I. Walraven M. de Boer M.P. Greuter H.N. Hendrikse N.H. Eriksson J. Windhorst A.D. Postmus P.E. et al.Rapid decrease in delivery of chemotherapy to tumors after anti-VEGF therapy: implications for scheduling of anti-angiogenic drugs.Cancer Cell. 2012; 21: 82-91Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar). Hitherto we have been discussing the vascular pruning effect of VEGFA inhibitors. Does the classic anti-angiogenesis concept have a place in the current landscape? It is conceivable that after maximal pruning of existing tumor vessels by the initial treatment, continuation of VEGFA inhibition would prevent new vessel formation (i.e., applying the true anti-angiogenesis mechanism) and sustain the treatment effect. In preclinical models, continuous treatment maintained low tumor vessel densities and tumor growth rates, whereas stopping treatment restored vessel densities and growth rates to levels comparable with those of untreated tumors (Bagri et al., 2010Bagri A. Berry L. Gunter B. Singh M. Kasman I. Damico L.A. Xiang H. Schmidt M. Fuh G. Hollister B. et al.Effects of anti-VEGF treatment duration on tumor growth, tumor regrowth, and treatment efficacy.Clin. Cancer Res. 2010; 16: 3887-3900Crossref PubMed Scopus (68) Google Scholar, Mabuchi" @default.
• W2335877573 created "2016-06-24" @default.
• W2335877573 creator A5023480345 @default.
• W2335877573 date "2016-04-01" @default.
• W2335877573 modified "2023-10-04" @default.
• W2335877573 title "The Complexity of Translating Anti-angiogenesis Therapy from Basic Science to the Clinic" @default.
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