Steroid Receptors as Targets for Receptor-Directed Radiotherapy

Geoffrey Greene

Robert Hanson
John Katzenellenbogen
Ralph Weichselbaum

Steroid receptor proteins are widely used as targets for hormone- or hormone ablation-based management of breast and prostate cancers, either alone or in combination with radiotherapy and chemotherapy.  Tamoxifen, a partial estrogen antagonist, is the signature adjuvant therapy for breast cancers that express estrogen receptor alpha (ERa). It has also proved to be effective in a prevention setting for women at increased risk for breast cancer.  Casodex, an androgen antagonist that targets androgen receptor (AR), when combined with LHRH agonists, is an established treatment for primary as well as metastatic prostate cancers, in combination with radiation therapy.  For both cancers, metastatic tumors that respond initially to these therapies almost always progress to an antagonist-resistant state, frequently being stimulated by the antagonist.  Many recurrent, hormone-resistant tumors continue to express ER and/or AR, and these receptors are still potential targets for alternative therapies.  In some cases, more potent antagonists (e.g. Fulvestrant for BC or Enzalutamide for PC), or hormone ablation (e.g. aromatase inhibitors for BC, or Aberaterone for PC) are effective in treating these resistant tumors.  Recent data also suggest that estrogens (BC) and androgens (PC) may be paradoxically effective in patients whose tumors become resistant to antagonists.  Thus, BC/PC progression from hormone dependence to apparent independence is complex, and our understanding of the underlying mechanisms is incomplete, due in part to tumor heterogeneity and evolution to resistant states. 

The primary focus of our research is to exploit ERa/b, AR and progesterone receptor (PR) in progressive BCa and PCa in novel ways that take advantage of their continued presence. We are actively developing and characterizing radiolabeled SRMs (steroid receptor modulators) and steroid analogs that can be used to image and kill tumor cells that express, or are proximal to tumor cells that express, ERa/b, AR or PR.  Receptor-specific ligands labeled with I123, Br76 or I131 are being explored and tested in cell and animal tumor models for their ability to inhibit cell/tumor growth or induce cell death. These same agents are also being exploited for tumor imaging. It is likely that primary and metastatic cancers of the lung and ovary, which express ER, AR and/or PR, will also benefit from ligand-mediated radiotherapy, possibly using a combinatorial approach. These studies involve collaborations with Ralph Weichselbaum, Robert Hanson, at Northeastern University, and John Katzenellenbogen at the University of Illinois.

Receptor-directed cancer therapy is attractive because steroid receptors (SRs) have high affinity and specificity for small molecule ligands that are easily delivered to tumors throughout the body.  Multiple human tumors, especially those of the reproductive tract, express steroid receptors.  In addition, receptor density within tumor cells is high enough to allow targeting.  Furthermore, it is possible to label receptor ligands with an radioisotope that allows imaging, thereby providing a means to assess whether the primary tumor, or more importantly metastases, contain sufficient concentrations of steroid receptors to be candidates for therapy with the same ligand or an analogous ligand. 

With the recent recognition that prostate and breast cancers also express ERb, and that receptor-selective ligands have been developed for both ERa and ERb, it may be possible to selectively target ERb without the potential therapeutic complications resulting from the presence of ERa in reproductive tract tissues where ERa is dominant, especially the uterus.  Conversely, it should also be possible to selectively target ERa, thereby avoiding tissues that predominantly express ERb (e.g. bladder, intestine, lung, ovary, prostate). If this approach proves feasible, it could be extended to other steroid receptor-containing cancers such as those in the ovary (ERb, AR, PR), colon (ERb) and lung (ERa, ERb, PR). Our approach is to test both Auger electron-emitting and beta-emitting isotopes of iodine, with the goal of delivering high linear energy transfer, LET, (123I  - Auger electrons), resulting in short range damage that is effective in micrometastases, as well as longer range radiation (131I – beta decay) that will irradiate adjacent tumor cells that may not contain these receptors. 123I also emits a 159 keV gamma that can be used for imaging (SPECT) to determine the location of metastases in animal models and humans.  In addition, 76Br can be used as a short-lived (t1/2 = 16 hr) isotope for PET imaging and 77Br (t1/2 = 57 hr) as a potential therapeutic radioisotope (Auger emitter). We will also explore the possible use of 211At, an alpha particle emitter, for therapeutic purposes. All of these isotopes can be introduced into receptor-selective steroid analogs at the 17a-position of the D ring, using the same chemistry.

The basis for this therapy approach is that radiolabeled ligand-SR complexes localize to DNA response elements associated with target genes.  Because SRs are intimately associated with cellular DNA, Auger electron cascades involved in nuclides that decay by electron capture give rise to high radiation density within a very small range, typically limited to the cell nucleus.  For decay with a 13 hr half-life [123I], on average about 12 electrons are deposited in this volume.  The major advantage of this approach is that, unlike the use of antiestrogens or aromatase inhibitors, which are currently the standard treatment for breast cancers, receptor-expressing tumor cells can be unresponsive to traditional therapies, which is common for metastatic disease.  This approach only requires that tumor cells express the appropriate SRs that are able to bind and deliver radiolabeled steroid to chromatin/DNA binding sites in the nucleus.