Novel Prostate cancer therapy based on m-aconitase inhibition

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ABSTRACT Treatment options for patients with early-stage prostate cancer include mostly watchful waiting, radical prostatectomy or radiation therapy, whereas for patients with advanced disease hormone therapy followed by chemotherapy/radiotherapy are the preferred options. However, all of these options suffer from very serious side effects. While early-stage cancers can be addressed with radical prostatectomy, this is not the case for advanced cancers at hormone refractory and/or metastatic stages. Approaches with lesser side effects and more effectiveness are needed, especially for the latter scenarios. Our proposed approach takes advantage of the innate property of the prostate gland, which is accumulation of enormously high levels of citrate and zinc by the prostate glandular epithelial cells. Zinc serves as an inhibitor of m-aconitase, the enzyme, which controls the first reaction for the entry of citrate into the Krebs cycle. The Krebs cycle in these cells is truncated, and synthesized citrate accumulates for secretion into prostatic fluid. However, in prostate cancer cells the ability to accumulate zinc is lost due to downregulation of zinc transporter. This deficiency leads to normalization of m-aconitase activity and oxidation of citrate via a functional Krebs cycle resulting in 38 ATP/glucose compared to 14 ATP/glucose produced from the aerobic oxidation of glucose in normal prostate cells. Thus, the malignant cells become energy-efficient in contrast to the energy-inefficient, specialized citrate-producing prostate epithelial cell and change their phenotype to a “citrate-oxidizing”. In this study we propose to inhibit m-aconitase with the goal to reverse the “citrate-oxidizing” phenotype in prostate cancer. This will be done by delivering zinc to tumors in vivo using prostate specific membrane antigen (PSMA)-targeted image-guided liposomes loaded with zinc. We expect that inhibition of m-aconitase by zinc will cause a dramatic decrease in energy production by cancer cells, which will ultimately lead to energy deprivation and cell death. Since monitoring the delivery of Zn-containing liposomes will provide us with opportunity to alter formulation in the course of investigation and adjust treatment regimen, the proposed liposomes will contain imaging reporters for magnetic resonance and optical imaging. We propose to synthesize and test Zn-containing PSMA-specific image-guided liposomes first in vitro and then in pilot studies in vivo in non-metastatic and metastatic mouse models of prostate cancer. The latter is of high significance since it is the advanced stage that causes high mortality in prostate cancer patients.