The combination of androgen ablation (hormone therapy) along with early detection and surgery has made prostate cancer highly treatable at the initial stage. However, this cancer remains the second leading cause of cancer death among American men. Recently, we demonstrated that PI3K p110beta isoform, a major cellular signaling molecule, is critical for prostate cancer progression in cell culture model and mouse xenograft model. In addition, p110beta-specific inhibitor TGX-221 significantly suppressed tumor growth of prostate cancer xenografts in our preliminary studies. Therefore, with the help of novel nanocarrier that targets prostate specific membrane antigen (PSMA) present in all clinical prostate cancers, cancer cell specific delivery of TGX-221 will be a potent therapy for late-stage prostate cancer patients.
Our hypothesis is PSMA-targeted nanocarrier delivery of the PI3K-p110beta inhibitor TGX-221 will eliminate prostate cancer cells that are dependent on p110beta for proliferation and survival. This hypothesis has been based on our recent publications and preliminary data, as well as previous reports from other groups. The rational is that its successful completion would lead to a novel therapy for prostate cancer. The objective of the proposed study is to establish that a nanocarrier-approach for targeted p110beta-specific inhibition in prostate cancer cells. This cancer cell-targeted nanocarrier approach will be effective in blocking xenograft tumor growth with few or no side-effects, which fits into our long term goal of developing novel therapeutic strategies for prostate cancer treatment.
Ideally, a functionalized nanocarrier targeting prostate cancer cells for clinical use should have high tissue/cell selectivity, molecular target specificity and long blood stream circulating time to increase the efficiency of delivered therapeutic molecules. The nanocarrier should not have a broad range of tissue distribution to avoid systemic side effects. Therefore, in this proposal, we plan to develop such a nanocarrier with components that are biocompatible, biodegradable and FDA-approved.
This project was supported by a grant from the Department of Defense Prostate Cancer Research Program (PC080275).
Rapid biochemical recurrence with distal metastasis are often found in high-risk prostate cancers include locally advanced such as positive surgical margin and high grade like Gleason sum score > 8 tumors. Although prostate specific antigen (PSA) screening has led to earlier diagnosis of the disease, it has failed to save many lives because the death rate did not change significantly. One plausible reason is that prostate cancer cells migrate to extra-prostatic surrounding tissue and that micro-metastasis already exists even in clinically high-risk cancers.
Collapsin response mediator protein-4 (CRMP4, also termed as dihydropyrimidinase-like 3, DPYSL3) belongs to the CRMP family of cytosolic phosphoproteins, which are involved in semaphorin/collapsin-induced cellular events. So far, five members of the CRMP gene family (CRMP1-5) have been cloned and they have 50-70% sequence homology. Recent studies indicated that CRMP1 is an invasion suppressor in human glioma and lung cancer cells, and its reduced expression correlates with poor clinical outcomes in non-small cell lung cancer. CRMP-2 and CRMP-5 were found to be extensively expressed in colorectal cancers and high-grade lung neuro-endocrine carcinomas, respectively.
In our preliminary studies, we identified CRMP4 as a metastasis suppressor in prostate cancers, since its expression is inversely associated with lymph node metastasis and its over-expression in prostate cancer cells not only suppressed cell motility/invasion in vitro but also strongly inhibited tumor metastasis in animal xenograft model. Thus it is feasibly to suppress tumor metastasis by enhancing CRMP4 expression in high-risk prostate cancers.
Recent emerging evidence shows that small double-stranded RNAs (saRNA) targeting gene promoters are potent in inducing prolonged gene activation at the transcriptional level. Several reports have demonstrated the potential usage of double-stranded RNAs targeting tumor suppressor genes in inhibiting tumor cell growth in vitro and in vivo. The objective of this proposal is to develop and validate double-stranded activating RNAs targeting CRMP4 promoter for suppressing metastasis of prostate cancer. The rationale is based on our recent publication and preliminary studies, as well as previous reports from other groups. It is conceivable that distal metastatic tumor begin with a micro-metastatic cell that can be targeted to prevent the development of metastatic disease. If micro-metastatic cells are taken off the table, then most of prostate cancers will be manageable and severe side effects due to extensive therapies can be avoided. We believe that its successful completion of this project would lead to a novel preventive therapy for prostate cancers.
This project was supported by a grant from the KUMC Masonic Foundation.