Necuparanib, A Multitargeting Heparan Sulfate Mimetic, Targets Tumor and Stromal Compartments in Pancreatic Cancer.

Amanda Macdonald,Jennifer Curran,Chia Lin Chu,Kristen Getchell,Lynn Zhang,Silva Krause,Birgit C Schultes,Edward Cochran,Martijn Lolkema,Michelle Priess,Ilse Oosterom,Victor Farutin,Jamey Guess

doi:10.1158/1535-7163.mct-18-0417

Amanda Macdonald, Jennifer Curran + Show 11 more

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https://doi.org/10.1158/1535-7163.mct-18-0417

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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.

Highlights

Pancreatic cancer is a devastating disease with a high unmet need for effective therapies
To confirm whether our findings of altered matrix metalloprotease (MMP) protein levels with necuparanib treatment could be observed in patients, we examined plasma from patients treated with necuparanib
We demonstrated that necuparanib's multitargeting abilities reduced tumor growth, mediated tumor–stromal interactions, and altered multiple cellular processes in in vitro and in vivo models of pancreatic cancer

Summary

Introduction

Pancreatic cancer is a devastating disease with a high unmet need for effective therapies. Over 80% of patients with pancreatic cancer have advanced metastatic disease at diagnosis, which has few therapies and low survival rates [3,4,5]. As projections suggest that the incidence of pancreatic cancer will increase in the decade, the need for novel therapies will increase [6]. The intrinsic resistance of pancreatic tumors to treatment is the biggest challenge for novel drug development. Resistance is driven by stromal components, which can constitute up to 90% of a pancreatic tumor and are hypothesized to create both biological and physical impediments to treatment [7, 8]. The extracellular matrix (ECM) becomes dysregulated, promoting tumor transformation and metastasis and promoting stromal dysregulation, increasing

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