Selective Targeting of Breast Cancer with Radioiodide
| Institution: | Stanford University | ||
| Investigator(s): |
Irene Wapnir , M.D. -
|
||
| Award Cycle: | 2001 (Cycle VII) | Grant #: 7WB-0137 | Award: $315,200 |
| Award Type: | STEP Award | ||
| Research Priorities | |||
| Innovative Treatments>Gene therapy and other treatments: new frontiers | |||
Initial Award Abstract (2001)
Few anti-cancer agents can actually target cells selectively. Thus, current therapies, which poison the entire body in order to treat a small tumor, cause much suffering and usually fail to eradicate the disease. We have developed a novel approach to directly treat breast cancer. Our interest evolved from our recent discovery that the mammary gland harbors an iodide transporter protein capable of delivering radioactive iodide (Nature Medicine, 6:871-8, 2000). This was surprising, because iodide accumulation is primarily associated with the thyroid gland. We found that during lactation the breast concentrates iodide in milk so that, adequate amounts of this dietary element are available to the infant. Since radioiodide is currently used to successfully treat thyroid cancer, we are optimistic that our experiments will directly lead to translational applications in breast cancer. In treating thyroid cancer the patients are evaluated by an iodide tracer scan and receive treatment if their cancer cells can concentrate iodide. Then, treatment consists of taking a capsule by mouth. From a clinical standpoint the side-effects are minimal- these include salivation or gastric irritation and last only a few days. Clearly, there is a pressing need to explore more effective treatments with such low toxicity profiles in breast cancer. In this project we will determine whether it is possible to activate the iodide-concentrating capacity of human breast cancers after they have been implanted into immune-deficient mice. This is in ideal model system to explore the future clinical application of using radioiodide to treat breast cancer. It is our hypothesis that the iodide transporter of the breast, which is normally functional during lactation, can be activated and experimental human tumors will be selectively destroyed by radioactive iodide. We will also perform experiments to validate this approach without damaging the thyroid gland. The iodide concentrating capacity of these experimental tumors will be modulated with a derivative of vitamin A (retinoic acid) and/or hormones associated with pregnancy and lactation (oxytocin and prolactin). Thyroid hormone supplements will be provided to the mice to purposefully decrease or obliterate the ability of the thyroid gland to absorb any iodide. Thus, we predict that radioactive iodide treatment will be significantly directed to breast cancer cells. Results from this research will be useful in the formulation of a clinical treatment trial. Creating an experimental mouse model carrying a human breast cancer that accumulates iodide is an important step for testing the feasibility and efficiency of this approach. Unlike other anti-cancer modalities, we envision that radioiodide therapy would be selectively given to patients whose cancers concentrate iodide. Because of the extensive clinical experience in using radioactive iodine to treat thyroid cancer, we think that this novel approach promises to be safe and well tolerated.
Final Report (2004)
Background: Initial studies pioneered by our group identified an iodide-carrier protein, called NIS (sodium/iodide symporter), in milk-producing breast cells and in approximately 70% of human breast cancers. Iodide transport has been primarily linked to the thyroid gland where it is integrated into the production of thyroid hormones. Radioiodides can be used to visualize iodide-transporting tissues or to destroy them with a radioactive form of iodide (131I). Discovering the presence of the same protein in breast tissues generated great enthusiasm, because of the possibility of translating the success of 131I therapy in thyroid cancer to breast cancer. The likelihood that NIS could be used to selectively target and destroy breast cancer cells without targeting the thyroid was enhanced by our observations that lactation-associated hormones (estrogen, prolactin and oxytocin) governed NIS production and activity in the non-pregnant breast cell. In contrast, thyroid NIS is regulated by thyroid stimulating hormone and iodide accumulation can be blocked with thyroid hormones. Aims: We set out to study the factors that could activate the iodide-concentrating capacity of human breast cancers using immune-deficient mice as an experimental model. The experiments tested the effects of (i) lactational hormones plus hydrocortisone, (ii) and a vitamin A derivative, retinoic acid on tumors that lacked NIS expression or iodide-accumulation. Animals were exposed to short courses of various combinations of these agents over several weeks and then given tracer amounts of radioactive iodide. Mice were analyzed on a nuclear scanner to determine to location of iodide accumulation, and then sacrificed. Radioactivity counts were tabulated and tissue studies were performed to indicate the presence of NIS. Results were compared to similar (positive control) experiments in mice carrying tumors derived from breast cancer cells that had the NIS gene’s DNA introduced onto the cells. Progress: This CBCRP funding allowed us to develop a very useful model to study NIS-mediated iodide transport. We were able to demonstrate in tumors that express NIS, iodide accumulation was detectable-- even 24 hours after injection. Breast cancer cells that lacked NIS can be stimulated to produce NIS by retinoids and lactational hormones, although the amount of NIS was reduced. Importantly, NIS expression was associated with increased iodide-concentration. In addition, we showed that thyroid uptake of iodide could be dramatically reduced without affecting breast cancer cell accumulation. Finally, that tumor size was either reduced or tumors destroyed after treatment doses of radioactive iodide were given. Future direction and impact: These experiments allowed us to establish an experimental platform (animal model) prior to more clinically-directed studies. We gained important insights into understanding what factors are likely to influence NIS production and activity in breast cancer. Our results are “proof of principle” that the iodide-carrier NIS protein can be exploited for the selective targeting and destruction of breast cancers. In summary, we believe that it will be possible to harness the iodide-concentrating capacity of NIS positive breast cancers for an innovative therapeutic approach. Furthermore, it may also be possible to either modulate or activate this mechanism in breast cancer cells that lack NIS. Because of prior clinical work in treating thyroid cancers, radioactive iodide could be, (i) less toxic, (ii) individually tailored, and (iii) easy to administer to breast cancer patients. It could provide many women with an alternative strategy to combat this deadly disease.
Symposium Abstract (2003)
The Na+/I-symporter [NIS] mediates transport of I-in thyrocytes, gastric mucosa, salivary gland and lactating mammary cells. Over 70% of invasive breast cancers, like thyroid cancers, express NIS although the degree of functional activity in the former remains largely undefined. In lactocytes, NIS is regulated by suckling and lactational hormones (LH). Retinoic acid (RA) upregulates NIS in MCF-7 cells, an non-I-transporting, estrogen-dependent human breast cancer cell line. In these experiments, functional expression of NIS was evaluated in MCF-7 xenografts treated in vivo with LH and RA. Methods : MCF-7 cells (1-2 x 106) were implanted subcutaneously along with an estrogen pellet in the dorsum of four week-old nude mice. 125I biodistribution was studied in 15 control mice and compared to tumoral I-accumulation in mice implanted with NIS-transfected (t-MCF) cells. Experimental mice carrying MCF-7 tumors were treated with RA (300 mg/Kg) by gastric gavage, LH [estrogen (E)1 mg, prolactin (P)(10 IU), oxytocin (O)(1 IU), hydrocortisone(H) (0.15mg); daily x 4 or, prolonged high dose E 100 mg] in 50mL i.p., or or combinations of RA and LH. Thyroid hormone (T4) was administered in drinking water in several experiments. Mice were injected with 50 uCi 125I i.v., scintigraphically imaged and sacrificed at different time points over 24 hrs. Tissue/organ radioactivity was assessed by scintillation counter and expressed as %-injected-dose-per-gram of tissue (%ID/gm). Results : Maximal I- uptake in non-I--transporting organs is observed at 2 hrs, decreasing gradually thereafter. Thyroid well counts peak at 12 hours (1221%ID/gm) and wash out slowly. Thyroid hormone administration results in about a 10-fold decrease in thyroid uptake. NIS-expressing tumors demonstrate up to 18% ID/g at 10 hrs. RA therapy alone in non-transfected tumors results in higher tumor well counts at ~2 hrs. RA in combination with EO or EPO did not increase tumor uptakes. However, high dose E (100 mg) + H + O had a stimula-tory effect in non-transfected tumors, showing peak I- uptake at 9hrs (N=12, 1.7 % ID/gm). The addition of RA to this combination appeared to dampen rather than enhance uptake (N=6, 1.3 %ID/gm). Plasma membrane NIS immunoreactivity was seen in about 15 to 20% of cells in NIS-transfected tumors. In RA and EHO treated mice, NIS protein was identified predominantly as intracellular immunopositivity. Conclusion : Prolonged accumulation rather than progressive wash-out of 125I is observed in MCF-7 xenografts treated with high E, H and O. The feasibility of radioablative therapy will depend on percentage tumor uptake and tracer residence time.
Bioluminescent monitoring of NIS-mediated 131-I ablative effects in MCF-7 xenografts
Periodical:Molecular Imaging
Index Medicus: Mol Imaging
Authors: Ghosh M, Gambhir SS, De A, Nowels K, Goris M, and Wapnir I
| Yr: 2006 | Vol: 5 | Nbr: 2 | Abs: | Pg:76-84 |
