Tumor Microenvironment & Antistromal Activity


The tumor microenvironment plays a critical role for tumor growth. Stroma which makes up the most mass of the tumor, is important in growth. Within the stroma, cancer-associated fibroblasts (CAFs) play a central role and can secrete growth factors and cytokines to assist in cell proliferation and excrete extracellular matrix for tumor growth. CAFs display high levels of α-smooth muscle actin (α-SMA) which allows CAFs to contract. This ultimately causes decreased blood perfusion and increased interstitial fluid pressure which adversely affects drug delivery to tumors.

Anti-stromal Antitumor Activity of Cellax-DTX via CAF-targeting

Cellax-DTX has been shown to selectively target CAFs in tumor models resulting in decreased α-SMA and CAFs compared to free DTX and Nab-PTX. This ultimately leads to increased tumor perfusion and increased antimetastatic activity compared to free DTX and Nab-PTX in orthotopic breast tumor models. (Yang et al., 2017: https://www.ncbi.nlm.nih.gov/pubmed/27873118)

Fig 1. Treatment with Cellax  (170mg DTX/kg) decreased stroma cells (represented by α-SMA) and blood vessels (represented by CD31) greater than nab-PTX (170mg PTX/kg), free DTX (40mg DTX/kg) and saline in breast tumor models. Image from Murakami et al. Cancer Res. 2013;73(15):4862-71.





Fig 2. In the same study, they found decreased lung metastases in mice with orthotopic breast tumors with Cellax compared to nab-PTX, free DTX and control (see above for doses). Image from Murakami et al. Cancer Res. 2013;73(15):4862-71.






Cellax-DTX has also displayed efficacy in pancreatic tumor models due to its ability to target and deplete the stroma associated with tumors. (Yang et al., 2017: https://www.ncbi.nlm.nih.gov/pubmed/27873118)

Fig 3. Cellax treatment groups displayed lower levels of α-SMA compared to Nab-PTX and free DTX in PAN02 pancreatic tumor model. Cellax treatment groups also showed reduced tumor weight and increased percent survival compared to other treatment groups. In image A, doses used were 40mg/kg free DTX, 170mg/kg Nab-PTX and 170mg/kg Cellax-DTX which may be different for other images. Image from Ernsting et al. JCR 2015;206:122-130.