Table 4.

Effects of Tie2 activators in preclinical cancer studies.

Agent	Effects on Host	Effects on Primary Tumors	Effects on Metastases
COMP‐Ang1	[+] ↓ Host organ damage from ionizing radiation: by reducing intestinal EC apoptosis[P] a ; protecting ECs and hematopoietic cells in bone marrow to ↓ myelosuppression[ a ]	[○] Monotherapy does not ↑ tumor growth in s.c. LLC model [ a ] c [+] In combination, ↑ anti‐tumor activity of chemotherapy on s.c. LLC tumors by “normalizing” tumor blood vessels & ↑drug delivery [ c ] c [−/+] Slight trends of ↑growth but ↓invasiveness of orthotopic LM2‐4 tumors[P] d	[−] Treatment of primary s.c. LNM35 tumors ↑ metastatic dissemination to the lungs—via blood vessel enlargement and increased tumor cell intravasation and extravasation[ d ] e [○] Concurrent perioperative use does not improve adjuvant sunitinib therapy in resected orthotopic LM2‐4 model[P] d
Bow‐Ang1	Not examined.	[○/−] Monotherapy did not promote tumor growth, but concurrent use reversed inhibitory effects of Ang2 blocker on tumor growth/angiogenesis in s.c. Colo205/A431 models f [−] Long‐term use reduced tumor responsiveness to VEGF blockade by stabilizing tumor blood vessels in orthotopic SK‐NEP‐1 model g (Huang et al, 2009 ) [−/+] Slight trends of ↑growth but ↓invasiveness of LM2‐4 tumors d	[+] Perioperative short‐term use, +/−aflibercept, ↑OS of adjuvant paclitaxel chemotherapy in resected orthotopic LM2‐4 model d
AKB‐9778	[○] ↓Permeability & ↑diameter of blood vessels in skin i [○] No change in systemic blood pressure i	[○] Monotherapy does not accelerate primary tumor growth in orthotopic 4T1, E0771, P0008, MMTV‐PyVT breast cancer models i [+] Stabilized blood vessels, ↑perfusion, ↓hypoxia, and ↑radiation response in established orthotopic 4T1 primary tumors (Goel et al, 2013 )	[+] Adjuvant monotherapy ↓ lung metastases in resected orthotopic 4T1 model by inhibiting tumor cell extravasation i [+] Addition to adjuvant doxorubicin chemotherapy showed trend of ↑OS in resected orthotopic 4T1 model (Goel et al, 2013 )
ABTAA	[○] No vascular changes in kidneys, cornea, tracheal mucosa, and ear skin of normal mice j	[+] ABTAA normalized tumor vessels, ↓tumor hypoxia, favorably altered TAMs and Treg’s, ↑ chemotherapy delivery, and ↑OS in orthotopic GL261 glioma model and s.c. LLC model j	[+] ABTAA ↓ lung and lymph node metastases in s.c. LLC model j [+] ABTAA ↓ lung metastases in spontaneous MMTV‐PyMT breast cancer model j
AB‐Tie1‐39	No obvious effects on immune cell infiltration k	[+] AB‐Tie1‐39 had modest effects on primary orthotopic mouse 4T1 breast cancer k	[+] Reduced lung metastasis when used in neoadjuvant treatment settings. k

[+], Therapeutic benefit; [○], no therapeutic benefit; [−], worsened disease; s.c., subcutaneous; OS, overall survival; LLC, Lewis lung carcinoma; LM2‐4, a highly metastatic derivative of MDA‐MB‐231 human breast cancer cell line (Munoz et al, 2006; Man et al, 2007); LNM35, a highly metastatic derivative of NCI‐H460 human lung cancer cell line; SN12, SK‐NEP‐1, human renal cancer cell lines; A321, human epidermoid cancer cell line; Colo205, HT29, human colorectal cancer cell lines; TAMs, tumor‐associated macrophages; T_reg’s, tumor‐infiltrating regulatory T cell; ^{[ k ]} and ^[P], COMP‐Ang1 delivered by intravenously injected adenoviral vector versus protein.

^aCho et al (2004b).

^bLee et al (2008).

^cHwang et al (2009).

^dWu et al (2016b).

^eHolopainen et al (2009).

^fDaly et al (2013).

^gHuang et al (2009).

^hWu et al (2015).

ⁱGoel et al (2013).

^jPark et al (2017).

^kSinghal et al (2020).