Prostate cancer's growth and progression is largely driven by hormones (for example, testosterone) that are naturally present in the blood.
Aimi ng to reduce the hormone levels in the blood, surgical and chemical castration methods have been a standard of care for prostate cancer for over 70 years. Although castration is initially very effective, dramatically reducing tumor size, castration resistant prostate cancer inevitably develops. At this stage, the tumor continues to grow and spread despite reduced hormone levels. Often the mechanism by which prostate cancer becomes castration resistant is to over produce the receptor targets to which the hormones bind, thereby continuing to generate a growth signal. Once prostate cancer becomes castration resistant, the second tier of treatment is to try to delay growth by inhibiting these receptors. Such an approach potentially affords lengthened survival, but is not curative. In this proposal, we plan to develop a new type of therapy for castration resistant prostate cancer that turns this mechanism of resistance into a therapeutic advantage. The more a prostate cancer cell over produces its hormone receptors, the more sensitive it should be to the killing effects of our proposed therapy. Specifically, we do this by producing a molecule that emits a very special type of radiation. This molecule is similar to one of the hormones used by the tumor in that it binds to the over produced receptor and then travels to the cell nucleus where it binds to the DNA. The radioactive element that we incorporate into the molecule is special in that, unlike other forms of radiation, this radiation hs an extremely limited range of lethality. It is somewhat like a shot-gun, very lethal when it is cloe to critical molecules like DNA, but virtually harmless when it is elsewhere in the cell or in the blood. Radiation of this type is routinely injected into patients without harmful effect because these molecules do not bind to DNA. The main objective of this proposal is to develop this therapeutic molecule to bind selectively and lethally only to the DNA within prostate cancer cells. As a secondary objective in this proposal, we plan to produce a molecule that acts identically to the therapeutic molecule but uses a non-therapeutic isotope that can be used to make three-dimensional images of the tumor. These images can be used to select the patients that are most likely to be successfully treated by this therapy.
An estimated 27,540 men will die of prostate cancer in 2015 (1) and virtually all of these will have progressed to a castration resistant form of the disease (CRPC) after an initial successful response to anti-androgen therapy (2). One third of these tumors will develop resistance mediated by overexpression of the androgen receptor (AR) (3-6); amplifying each cell's sensitivity to androgen such that even the extremely low levels present in castrate patients is sufficient to stimulate cell growth. We propose to turn this mechanism of resistance into a therapeutic advantage using an exquisitely targeted form of radiotherapy that is as yet untried in the treatment of prostate cancer.
