1. A REVIEW AND UPDATE ON THE ANTI-ANGIOGENIC AGENT, ABT-510
Shah S1
1Faculty of Health and Life Sciences, University of Liverpool, Liverpool
INTRODUCTION
RESULTS
Angiogenesis is an obligatory phase and prerequisite leading to tumour invasion and metastasis1,2. Thrombospondin-1 (TSP-1) is a pivotal endogenous anti-angiogenic regulator with actions including antagonism of vascular endothelial growth factor (VEGF) and CD36 induced cell apoptosis3. It has been modified and enhanced synthetically in the form of ABT-510, a potent and novel anti-angiogenic therapeutic agent, in the hope of finding an effective chemotherapeutic agent which can prevent the progression of advanced solid organ tumours4.
The main outcome measure for most studies was 6 month progression-free survival (PFS). ABT-510 performed poorly in studies investigating different solid tumours but showed encouraging results in patients with glioblastoma (74%) and metastatic melanoma (86%).
The mean 6 month PFS across all studies was only 31.2%. Mean OST and TTP were 491 days and 155 days respectively. There was no discernable association between tumour type, OST and TTP making comparison of results across several studies increasingly difficult.
The median overall survival time (OST) and time to progression (TTP) were not disclosed for studies investigating multiple tumours. However, ABT-510 performed well in combination with temozolamide and radiation in the treatment of glioblastoma (TTP 450 days) and as a monotherapy in the treatment of renal cell carcinoma (OST 794 days).
The functions of ABT-510 are best served to prevent tumour invasion and metastases rather than to induce tumour regression. Whilst it would be impractical to study the effects of ABT-510 in patients with low-risk tumours, the results suggest major potential for using ABT-510 in adjuvant therapy, especially after curative surgery.
AIMS AND OBJECTIVES
Table 1 – Summary of ABT-510 Clinical Trials
Nabors et al
(2010)
Gordon et al
(2008)
Baker et al
Ebbinghaus et al
(2007)
Uronis et al
(2013)
Design
RCT Phase I
RCT Phase II
Participants 23 50 88
103 34
Intervention Type
Combination
Monotherapy
Interventions
ABT-510
Temozolomide
Radiation
Bevacizumab
Outcomes:
Median OST (d)
450 -
357
794
Median TTP (d)
321 94
6 Month PFS (%) 74 6 27 35 32
Median Age (y) 55 54 59 56
Age Range
20-73
23-79
20-80
19-74
M:F Ratio
14:9
16:9
1:1
67:36
13:21
Tumour Type
Glioblastoma
Various Solid
Soft Tissue Sarcoma
Renal Cell Carcinoma
Markovic et al
Gietema et al
(2006)
Hoekstra et al
(2005)
Total (Mean) 21 13 12 39
383 (43)
Gemcitabine
Cisplatin
5-fluorouracil
Leucovarin
361
(491)
(155) 86 8 15
(31) 57
(55)
31-77
35-72
47-78
19-83
(27-77)
2:1
6:7
3:1
10:3
(3:2)
Metastatic Melanoma
The aim of this review was to systematically determine and explore the chemotherapeutic potential of TSP-1 mimetics, in particular ABT-510, and analyse whether there is a future role in prevention and therapeutic intervention of such drugs.
METHODS
Literature regarding TSP-1 and ABT-510 was collated with only pertinent articles used for review. A comprehensive database search using a keyword search strategy was also conducted to find studies evaluating ABT-510. Relevant inclusion and exclusion criteria were applied to limit search results. All human clinical trials involving ABT-510 were included for analysis.
RESULTS
There are 9 clinical trials which have studied ABT-510 as intervention for cancer. Data from these studies has been summarised in table 1.
All of the studies included showed ABT-510 to have a clinically safe toxicity profile, whether as a monotherapy or in combination. The majority of adverse events witnessed were non-severe with the most common complaint being injection-site reactions. There were limited reports of grade 3 or 4 adverse events with no evidence of any dose-limiting events. The chemotherapeutic potential of ABT-510 has been limited in phase I trials. Furthermore, trials with ABT-510 monotherapy have shown disappointing results with limited clinical benefit despite promising results in biological marker levels.
REFERENCES
CONCLUSION
Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med. 1995;1(1):27-30.
Kim KJ, Li B, Winer J, Armanini M, Gillett N, Phillips HS, et al. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature. 1993;362(6423):841-4.
Lawler J. The functions of thrombospondin-1 and -2. Current Opinion in Cell Biology. 2000;12:
Haviv F, Bradley MF, Kalvin DM, Schneider AJ et al. Thrombospondin-1 Mimetic Peptide Inhibitors of Angiogenesis and Tumor Growth: Design, Synthesis, and Optimization of Pharmacokinetics and Biological Activities. J Med Chem. 2005;48:
To date, first-generation TSP-1 mimetics have entered stage II clinical trials. ABT-510 has had limited success as a monotherapy, however it has proven to be more successful in combination therapies with other agents. More research covering ABT-510 in combination therapy must be carried out; however, future generations of TSP-1 mimetics may be where the future of angiogenesis inhibition lies.