Enhancing tumor uptake of chemotherapeutics by novel heparin-derived compounds

DESCRIPTION (provided by applicant): Many cancer patients reportedly have a hypercoagulable state with recurrent thrombosis due to the impact of cancer cells and chemotherapy or radiotherapy on the coagulation cascade. Studies have demonstrated that heparin or its derivatives, low molecular weight heparins (LMWHs), interfere with various processes involved in tumor growth and metastasis. These include fibrin formation; binding of heparin to angiogenic growth factors; modulation of tissue factor via the enhanced endothelial tissue factor pathway inhibitor (TFPI) release; and inhibition of various matrix-degrading enzymes. Clinical trials have suggested a clinically relevant effect of LMWH, as compared to standard heparin, on the survival of cancer patients with deep vein thrombosis. We hypothesize that tumor-associated thrombosis and fibrin generation provide a significant microenvironment for tumor survival and in creating a barrier to the penetration of natural killer cells and chemo- or radiotherapies resulting in chemo- resistance. In this proposal we will investigate the efficacy of TF-associated strategies in reducing tumor-associated fibrin deposition and thereby augmenting the uptake of chemotherapeutic agents into the tumor. Specifically, we will test two groups of agents: 1) a commercially available LMWH, Tinzaparin, to provide proof-of-concept and 2) two oxidized ultra-LMWHs with limited-to-no systemic anticoagulant effects but rather intravascular anticoagulant and antithrombotic effects through the release of TFPI and with limited effects on hemostasis. The studies proposed in this Phase I application will test the following: (1) whether LMWHs function by increasing uptake of chemotherapeutic agents using noninvasive PET imaging, 2) if LMWHs given in conjunction with the chemotherapeutic agent Paclitaxel would limit tumor proliferation and/or angiogenesis, and 3) if LMWHs given in conjunction with Paclitaxel work to limit the amount of fibrin production in the tumor interstitium, thereby reducing a barrier to drug uptake. Ultimately, the goal of such studies would be improved uptake of chemotherapy (non-invasive imaging) using novel heparin-derived compounds, and subsequent improved outlook in terms of tumor growth, tumor markers, and apoptosis markers. Protocols utilizing adjuvant therapy with novel heparin-derived compounds could lead to improved tumor chemotherapy uptake, efficacy, and safety.