Introduction
It took two centuries to describe the role of angiogenesis inhibitors in tumor shrinkage
by Judah Folkman, after the term angiogenesis was initially coined by John Hunter.
Even later, the vascular endothelial growth factor (VEGF) was discovered by Napoleon
Ferrara. This concept of angiogenesis has revolutionized the field of oncology in
better understanding the mechanism of cancer progression, resulting in the development
of numerous targeted therapies for cancer treatment. Hence, in 2000, Hanahan and Weinberg
rightly enumerated the induction of angiogenesis as one of the hallmarks of cancer.
Definition
The terms vasculogenesis and angiogenesis, both meaning formation of new vessels,
are used interchangeably, but they have a clear difference. Vasculogenesis is the
process of the de novo blood vessel formation in early life (during embryogenesis),
either from circulating or tissue-resident endothelial stem cells, while angiogenesis
is the process of new blood vessel formation in later life (after birth) by the extension
from a preexisting vessel (sprouting) or by division within the vessel (splitting).[1]
Types of Angiogenesis
Sprouting
This type of angiogenesis involves the release of angiogenic growth factors, which
bind to corresponding receptors on the endothelial cell (EC). This binding leads to
production of proteases, which degrades the basement membrane. Through chemotaxis,
EC escapes and migrates to the tumor, incorporates, and proliferates in tumor stroma.
This results in solid sprouts (pericytes and smooth muscle cells), followed by formation
of lumen and branching of the new blood vessel.
Splitting/Intussusceptive
This model of angiogenesis involves the extension of the capillary wall into the lumen
and splits a single vessel into two. It has four phases.: First, two opposing capillary
walls establish a contact zone. Second, the EC junctions are reorganized, and the
two-layered vessel is perforated facilitating the entry of growth factors. In the
third step, a core consisting of pericytes and smooth muscles is formed between the
two new vessels at the contact zone. Finally, the core is separated and two new blood
vessels are formed.
Role of Angiogenesis
The physiological angiogenesis is seen in wound healing, tissue regeneration, and
in menstruation. Pathologically, angiogenesis plays an important role in tumorigenesis,
diabetic retinopathy, and in chronic Inflammation.
Angiogenic Switch
Up to the volume of 2 mm, the tumor can derive oxygen and nutrients from surrounding
vessels through diffusion and beyond this critical volume results in a hypoxic environment.
This hypoxia stimulates the production of hypoxic inducible factor-1 alpha (HIF-1α).
This HIF-1α is destroyed in normal cell with normoxemic conditions. However, in hypoxia,
this protein is not destroyed and its level is upregulated leading to turning “ON”
mode of angiogenic switch. Once angiogenesis is initiated, the grade of neovascularization
of the tumor depends on the subtle balance between proangiogenic and antiangiogenic
factors ([Fig. 1]), which in turn is dependent on tumor biology. Examples of hypervascular tumors
are renal cell carcinoma and thyroid cancer. The typical example of hypovascular tumors
is pancreatic adenocarcinoma.
Fig. 1 The pro and anti-angiogenic factors in angiogenesis.
Steps of Angiogenesis in Cancer
Steps of Angiogenesis in Cancer
Differences between Tumoral Blood Vessels and Normal Blood Vessels
Differences between Tumoral Blood Vessels and Normal Blood Vessels
Tumoral blood vessels are disorganized (tortuous and undefined) and unevenly distributed.
These are excessively dilated, and are highly permeable (leaky) due to lack of basement
membrane, pericytes intermittently, resulting in sluggish flow with leaking of blood
into the tumoral tissues. This leads to increased interstitial pressure in the tumor
resulting in decreased drug delivery to tissues.[2]
Pathways Modulating Angiogenesis
Pathways Modulating Angiogenesis
Direct-acting:
i. VEGF pathway:
Increases vascular permeability and stimulates EC migration and proliferation
VEGF receptors: 1,2,3
VEGF ligands: A, B, C
ECM proteins
Matrix metalloproteinases cause basement degradation
Integrins help in migration and organization into tubes
Angiopoietin and Tie 2
Angiopoietin 1 and Tie 2 recruit peri-ECs and pericytes
Angiopoietin 2 and Tie 2 stabilize the ECs
ii. DLL4-notch pathway
Promotes functional vessels downstream of VEGF both physiologically and pathologically
Indirect/secondary pathways:
These pathways redirect cells to the site of angiogenesis that is mediated by transforming
growth factor-α (TGF-α), TGF-β, hepatocyte growth factor, androgens, and estrogens.
Strategies for Antiangiogenic Therapies
Strategies for Antiangiogenic Therapies
Drugs that stop formation of new blood vessels by sprouting (angiogenesis inhibitors).
Drugs that attack the tumor's established blood supply (vascular disrupting drugs).
Drugs attacking both cancer cells or immune cells and blood vessels (dual/double-barreled
approach)
-
Approved antiangiogenic agents: Table 1 summarizes the various FDA approved anti- angiogenics till date.
-
Vascular disrupting agents: These drugs target the EC and its receptors are still investigational.
-
Combination therapies: Antiangiogenic therapies can be combined with radiation therapy, signal transduction
inhibitors, oncolytic virus therapy, vascular disrupting agents, chemotherapy, or
immune checkpoint inhibitors (ICI).
Table 1
Approved antiangiogenic agents
|
mAbs
|
Small molecule TKI—VEGF A, B, C, PDGFR
|
Drugs with secondary antiangiogenetic function
|
|
Abbreviations: PDGFR, Platelet derived growth factor receptor; COX, cyclo-oxygenase;
EGFR TKI, epidermal growth factor receptor-tyrosine kinase inhibitors; HDAC, histone
deacetylase; mAbs, monoclonal antibodies; mTOR, mammalian target of rapamycin; PlGF,
placental growth factor; VEGF, vascular endothelial growth factor.
|
|
Bevacizumab –VEGF A
|
Sorafenib, sunitinib, imatinib, pazopanib, lenvatinib, regorafenib, cabozantinib,
vandetanib, axitinib
|
Immunomodulatory drugs—thalidomide, lenalidomide
mTOR inhibitors—Temsirolimus, everolimus
EGFR TKI—gefitinib, erlotinib, afatinib
EGFR mAbs—cetuximab, panitumumab
COX2 inhibitors—Celecoxib
HDAC inhibitors—Belinostat, Vorinostat
|
|
Ramucirumab—VEGFR 2
|
|
Receptor fusion protein
|
|
Ziv-Aflibercept-VEGF Trap—VEGF-A, VEGF-B, PlGF
|
The Rationale for Chemotherapy and VEGF Combined Therapies
The Rationale for Chemotherapy and VEGF Combined Therapies
-
More effective intratumoral delivery of chemotherapy drugs with normalized vasculature.
-
Extended drug-free periods.
-
Stem cells become more sensitive to chemotherapy after disruption of its microenvironment.
-
Chemotherapy amplifies the antiangiogenic effect by direct action on ECs.
Clinical Implications
Few of the many indications for angiogenesis targeting therapies in combination with
chemotherapy are enumerated in [Table 2].
Table 2
FDA-approved drugs for angiogenesis and their indications
|
Drug
|
Indications
|
|
Abbreviations: EOC, epithelial ovarian cancer; FDA, U.S. Food and Drug Administration;
GBM, glioblastoma multiforme; GE, gastroesophageal; GIST, gastrointestinal stromal
tumors; HCC, hepatocellular carcinoma; KRAS, Kirsten rat sarcoma; mCRC, metastatic
colorectal carcinoma; mHNSCC, metastatic head and neck squamous cell carcinoma; mNSCLC,
metastatic nonsmall cell lung cancer; NET, neuroendocrine tumors; RCC, renal cell
carcinoma.
|
|
1.
|
Bevacizumab
|
Recurrent and/or metastatic GBM, mNSCLC, Stage III, IV and metastatic EOC, mCRC
|
|
2.
|
Ramucirumab
|
2nd line metastatic gastric/GE junction adenocarcinomas, mCRC
|
|
3.
|
Panitumumab
|
KRAS wild mCRC
|
|
4.
|
Cetuximab
|
KRAS wild mCRC, mHNSCC
|
|
5.
|
Sorafenib
|
HCC,
|
|
6.
|
Sunitinib
|
RCC, GIST, Pancreatic NET
|
|
7.
|
Lenvatinib
|
mRCC, HCC
|
|
8.
|
Regorafenib
|
3rd line mCRC
|
|
9.
|
Pazopanib
|
RCC, metastatic soft tissue sarcomas
|
|
10.
|
Vandetanib, cabozantinib
|
Medullary thyroid cancer
|
The Rationale for ICI-VEGF Combination Therapies
The Rationale for ICI-VEGF Combination Therapies
There are potential interactions of angiogenic pathways, in particular VEGF and tumor
immune response. In the priming phase of the immune response, VEGF shall inhibit the
dendritic cell maturation leading to reduced antigen presentation and also cause exhaustion
of T cells by inhibiting their activation. In the effector phase, VEGF recruits myeloid-derived
suppressor cells and regulatory T cells (Treg) and suppresses the activity of primed
T cells in the tumor niche. VEGF also results in neoangiogenesis that can alter the
quality and quantity of infiltrate of the tumor immune microenvironment adding to
immune suppression. VEGF-induced immune suppression can be reversed by using VEGF
TKIs and anti-VEGF antibodies which increases the efficacy of ICIs.[3]
Clinical Implications
In [Table 3], some of the recently approved indications for ICI-VEGF combination therapies have
been listed out.
Table 3
FDA-approved ICI-VEGF combination therapies and their indications
|
Primary diagnosis
|
ICI-VEGF
|
|
Abbreviations: FDA, U.S. Food and Drug Administration; HCC, hepatocellular carcinoma;
ICI-VEGF, immune checkpoint inhibitor vascular endothelial growth factor; mNSCLC,
metastatic nonsmall cell lung cancer; PD-L1, programmed death ligand 1; RCC, renal
cell carcinoma; TPS, tumor cell proportion score.
|
|
1.
|
mNSCLC (adenocarcinoma)
|
Pembrolizumab + bevacizumab + chemotherapy (PD-L1 by TPS 1–49%)
|
|
1.
|
RCC
|
Pembrolizumab + axitinib, nivolumab + cabozantinib
|
|
2.
|
HCC
|
Atezolizumab + bevacizumab
|
|
3.
|
Endometrial carcinoma
|
Pembrolizumab + lenvatinib
|
Biomarkers for Antiangiogenic Therapies
Biomarkers for Antiangiogenic Therapies
There are no approved biomarkers to select patients for antiangiogenic therapies and
some are under investigation.
-
Circulating biomarkers—VEGF levels in serum, plasma, urine.
-
Noninvasive imaging of blood vessels for a reduction in tumor microvessel density.
-
Dynamic contrast-enhanced magnetic resonance imaging, computed tomography scan with
flow parameters, high-frequency microultrasound, positron emission tomography-computed
tomography.
-
Elevated blood pressure (hypertension).
-
Circulating endothelial progenitor cells.
-
Tumor biopsy analysis for vessel density.
-
Genetic VEGF single nucleotide polymorphisms.
Side Effects of Antiangiogenic Therapies
Side Effects of Antiangiogenic Therapies
Most common side effects of antiangiogenic therapies are bleeding (20–50%), gastrointestinal
(GI) perforation (0.3–2.4%), arterial and venous thromboembolism (2.4%), and proteinuria
(<1%). Angiogenesis, an important process for healing of surgical sites, is counteracted
by the antiangiogenic therapies. Hence, anti-VEGF therapies are withheld 4 weeks prior
to surgery and restarted 6 to 8 weeks postsurgery.
Contraindications of Antiangiogenic Agents
Contraindications of Antiangiogenic Agents
The most common U.S. Food and Drug Administration (FDA) labeled contraindications
for antiangiogenic agents are hypersensitivity to that particular drug or its components,
GI fistulas/perforation, and recent history of hemoptysis. Other contraindications
specific to each drug include ocular or periocular infection, active intraocular inflammation
(aflibercept), pregnancy (thalidomide and lenalidomide), severe hepatic impairment
(Vorinostat), and history of asthma, urticarial, or allergic reaction to aspirin (celecoxib).
Mechanisms of Resistance to Antiangiogenic Drugs[4]
Mechanisms of Resistance to Antiangiogenic Drugs[4]
Intrinsic
Escape by different modes of vascularization
-
Vasculogenesis 2. Vascular Co-optation 3. Vascular mimicry
Acquired
Amplification of proangiogenic genes
Secretion of multiple proangiogenic factors
Recruiting proangiogenic bone marrow-derived dendritic cells
Conclusion
Despite being one of the hallmarks of cancer, targeting and treatment with single-agent
antiangiogenic therapies gave disappointing results. This is probably due to the various
resistance mechanisms as explained above. Combination therapies with chemotherapeutic
drugs and ICIs have helped to overcome this hurdle. One has to be cautious about the
bleeding and thrombotic complications of these drugs. Research is ongoing for newer
ways of targeting angiogenesis with nanotechnology and use of bispecific allelic antibodies.
