Docosahexaenoic Acid Loaded Low-density Lipoproteins: A Novel Biologic Intervention for Hepatocellular Carcinoma.

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PROJECT SUMMARY/ ABSTRACT Hepatocellular carcinoma (HCC) is ranked as the second most common cause of cancer-related death globally. Transarterial chemoembolization (TACE) remains the only first-line treatment for unresectable intermediate- stage HCC, despite the fact that this stage is comprised of a heterogeneous group of patients with a wide range of liver function, variable tumor number and size. In clinical practice only 50-60% of patients with intermediated HCC benefit from TACE, thus repeated rounds of TACE therapy are performed to achieve maximum tumor recession. The critical factors that impact the effectiveness of TACE therapy are the worsening of liver function and tumor recurrence. The former arises from progressive off-target embolic ischemic injury to the liver, while the latter results from hypoxia-induced angiogenesis, epithelial-to-mesenchymal transition (EMT) and tumor growth triggered by TACE. These processes inevitably dominate the course of this disease resulting in poor long term survival, with a 5-year survival rates <12%. Novel therapies against HCC are urgently needed as the incidence of HCC is steadily increasing in the United States. In recent years the natural omega-3 fatty acid, docosahexaenoic acid (DHA) has been shown to possess promising anticancer properties and its consumption has been implicated in reducing the risk of HCC. The effects of dietary DHA on established solid tumors is nominal. To address this issue, our lab has engineered a novel low-density lipoprotein (LDL) based biologic that is reconstituted with unesterified DHA (herein referred to as LDL-DHA). Therapeutically, we have shown in a syngeneic rat model of HCC, that transarterial delivery of LDL-DHA is able to induce extensive necrosis (>80%) of HCC tumors and impede the tumor growth (3 fold) without injury to surrounding normal liver. Moreover, repeated intra-arterial LDL-DHA treatments was shown to provide sustained regression of HCCs. Furthermore, the uptake of LDL-DHA in the normal liver was shown to be not only safe but potentially hepatoprotective. In addition, recent preliminary data from our group has documented that LDL-DHA is able to downregulate HIF-1α and EMT signaling in HCC cells, thus inhibiting tumor angiogenic/regrowth activity. The goal of the present proposal is to evaluate the utility image-guided locoregional LDL-DHA therapy for intermediate-stage HCC. To address this goal we will examine the following specific aims: 1) evaluate the safety of intra-arterial LDL-DHA delivery in rat models of cirrhosis; and 2) compare the therapeutic efficacy of LDL-DHA versus conventional TACE methods to provide sustained tumor control in a patient derived-xenograft rat model of HCC. We expect that the combined work of these Aims will validate the safety of LDL-DHA treatment in preserving liver function in settings of cirrhosis and demonstrate the efficacy of this therapy to provide sustained tumor eradication over TACE. The LDL-DHA treatment strategy will be significant because it offers a new method of effectively treating HCC while preserving liver function. Ultimately it is our endeavor to bring this technology to the clinic, where it is anticipated to provide safe and efficacious approach to managing of unresectable HCC.