American Association for Cancer Research
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Supplemental Figure 3 from Necuparanib, A Multitargeting Heparan Sulfate Mimetic, Targets Tumor and Stromal Compartments in Pancreatic Cancer

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journal contribution
posted on 2023-04-03, 16:01 authored by Amanda MacDonald, Michelle Priess, Jennifer Curran, Jamey Guess, Victor Farutin, Ilse Oosterom, Chia Lin Chu, Edward Cochran, Lynn Zhang, Kristen Getchell, Martijn Lolkema, Birgit C. Schultes, Silva Krause

Supplemental Figure 3 shows MMP1 and MMP7 protein levels were unchanged in the plasma of patients.

Funding

Dutch Cancer Foundation

Momenta Pharmaceuticals

History

ARTICLE ABSTRACT

Pancreatic cancer has an abysmal 5-year survival rate of 8%, making it a deadly disease with a need for novel therapies. Here we describe a multitargeting heparin-based mimetic, necuparanib, and its antitumor activity in both in vitro and in vivo models of pancreatic cancer. Necuparanib reduced tumor cell proliferation and invasion in a three-dimensional (3D) culture model; in vivo, it extended survival and reduced metastasis. Furthermore, proteomic analysis demonstrated that necuparanib altered the expression levels of multiple proteins involved in cancer-driving pathways including organ development, angiogenesis, proliferation, genomic stability, cellular energetics, and invasion and metastasis. One protein family known to be involved in invasion and metastasis and altered by necuparanib treatment was the matrix metalloprotease (MMP) family. Necuparanib reduced metalloproteinase 1 (MMP1) and increased tissue inhibitor of metalloproteinase 3 (TIMP3) protein levels and was found to increase RNA expression of TIMP3. MMP enzymatic activity was also found to be reduced in the 3D model. Finally, we confirmed necuparanib's in vivo activity by analyzing plasma samples of patients enrolled in a phase I/II study in patients with metastatic pancreatic cancer; treatment with necuparanib plus standard of care significantly increased TIMP3 plasma protein levels. Together, these results demonstrate necuparanib acts as a broad multitargeting therapeutic with in vitro and in vivo anti-invasive and antimetastatic activity.