Based on the extent of disease, hormonal status, and absence or presence of detectable metastases on an imaging study, rising levels of prostate-specific antigen (PSA) after radiation therapy or surgery with no detectable metastases, and clinical metastases in the non-castrate or castrate state, the different clinical states of the disease are defined. Most men that ultimately die of prostate cancer die from metastatic castrate-resistant disease. However, of the approximately 30,000 men that die of prostate cancer per year, the vast majority of these men originally presented with localized prostate carcinoma which failed local therapy such as radiation and/or radical prostatectomy and progress along the pathway as shown below. Importantly, these men at the time of initial diagnosis represent potentially curable patients. Valiant efforts to improve cure rates have focused on interventions when patients have failed local therapy and progressed to metastatic disease (majority of men) or present with de novo metastatic disease (minority of men).
In spite of the success of surgery and radiation therapy, prostate cancer is still the second leading cause of cancer deaths in men. We propose that focusing more on men in the curable stage of their disease, but with difficult to treat localized prostate cancer, will make the most impact. Our failures with radiation are primarily due to the lack of biomarkers that can be efficiently targeted to kill or cooperate with radiation when men are in the curable localized stage of their disease. In our quest to understand the altered state of cancer cells, we have identified a gene (DDX3) that is essential for the maintenance of many high-grade tumors including those of prostate cancer.
Intriguingly, in the cohort of prostate tumor samples we stained for DDX3, it appears that 35% have increased expression of DDX3. The significance of this finding is that we have rationally designed a drug (referred to as RK-33) that abrogates the function of DDX3 resulting in selective death of only cancer cells and not that of normal cells. Importantly, RK-33 in combination with radiation produces a synergistic cell death effect on cancer cells. As radiation is one the mainstay treatment for prostate cancer, including locally advanced disease, we are confident that the use of DDX3 as a biomarker to select for RK-33 treatment in combination with radiation, will not only significantly reduce the tumor burden but also reduce many side effects experienced by current conventional therapy. Moreover, as RK-33 showed no toxicity in mice experiments (even at 100 times the amount required to kill prostate cancer cells in vitro), we can expedite the use of RK-33 into the clinical setting, with the intent of providing the much needed relief for these patients.
Written by: Phuoc T. Tran and Venu Raman
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