A UNIQUE, POTENT, & SELECTIVE PDGFR INHIBITOR

PLATELET DERIVED GROWTH FACTOR RECEPTOR α (PDGFRα) AMPLIFICATION & OVEREXPRESSION IN NON-SMALL CELLl LUNG CANCER (NSCLC)

PDGFRα Background1

PDGFRα activation has been reported in up to 13% of NSCLC tumors, with squamous cell carcinoma (SCC) being the most common.

  • PDGFR CN amplification > 10:            8.7% of SCC
  • PDGFR CN amplification > 4-10:        1.9% of SCC
  • Total PDGFR amplification in SCC:    10.6%

Amplification of PDGFR in Squamous Cell Carcinoma1

Survival by PDGFRα overexpression in NSCLC patients2

 

CRENOLANIB POTENTLY INHIBITS LUNG CANCER CELLS DRIVEN BY PDGFRα SIGNALING

  • In H1703, an adenosquamous NSCLC cell line overexpressing PDGFRα, crenolanib reduced cell viability with an IC50 of 44 nM3
  • In A549, a human adenocarcinoma cell line with PDGFRA amplification:4
    • Crenolanib reduced cell viability with an IC50 of about 100 nM in vitro
    • 20 mg/kg crenolanib effectively stopped tumor growth without affecting body weight in a mouse model

 

CRENOLANIB + BEVACIZUMAB: PDGFR AND VEGF DUAL INHIBITION

PDGFR is an Escape and Resistance Pathway in Response to VEGFR Inhibition

VEGF inhibitors can select for cells that overexpress PDGFRβ. By combining crenolanib, a selective PDGFRβ inhibitor, with bevacizumab, an anti-VEGF-A antibody, it may be possible to circumvent this common cause of resistance.5

 

CRENOLANIB AND BEVACIZUMAB TARGET DIFFERENT ANGIOGENIC PROCESSES

VEGF mediates the growth of blood vessels, while PDGFRββ mediates the growth of pericytes. By inhibiting both simultaneously, it should be possible to stop nearly all angiogenesis.6


1Ramos et al, Cancer Biol Ther. 2009; 8(21):2042-2050
2Donnem et al, J Thorac Oncol. 2008; 3(9):963-970
3Peyton, et al, AACR Poster 2011
4Wang et al, Oncol Targets Ther. 2014; 7:1761-1768
5Michael et al, Br J Cancer 2010; 103(10):1554-1561
6Preclinical data, not published