The clinical reality for patients with the triple-negative breast cancer (TNBC) subtype is grim because of a lack of response to targeted therapies against the estrogen receptor (ER) or human epidermal growth factor receptor 2 (HER2). Furthermore, TNBC presents with increased rates of metastasis, relapse, and mortality. Common sites of metastasis for TNBC include the lung, bone, liver, pleura, and the brain. Of particular interest is breast cancer brain metastasis (BCBM) because it accounts for about 15% of metastatic disease observed in breast cancer patients but have poor median survival times that are only between 4 to 6 months. Brain metastasis is an even more common feature in TNBC patients, with incidence rates that reach up to 20-50%. At the present time only palliative options are available for patients with BCBM, primarily because of challenges in determining the molecular basis of brain metastatic lesion development. In our preliminary research, we have taken the initial steps of identifying the scientific underpinnings of BCBM. Our preliminary data indicate that the long non-coding RNA (lncRNA) Lnc-BM shows predictive potential for brain metastatic development in breast cancer patients. Also, our preclinical models demonstrate that elevated Lnc-BM expression levels resulted in increased breast cancer cell metastasis to the brain, while Lnc-BM knockdown drastically inhibited the incidence of brain metastasis. The central hypothesis of the proposal is that Lnc-BM-triggered activation of the JAK2/STAT3 pathway promotes breast cancer brain metastasis, which could be attenuated in vivo by nanoparticle-delivery of siRNAs. The hypothesis will be addressed in accordance to the following specific aims.
In Specific Aim 1, we will demonstrate the functional role of Lnc-BM and the JAK2/STAT3 pathway in promoting breast cancer brain metastasis.
In Specific Aim 2, we will demonstrate the underlying mechanisms that promote Lnc-BM-dependent JAK2 hyperactivation.
In Specific Aim 3, we will determine whether targeting Lnc-BM using NP-delivered siRNAs can effectively inhibit the development of brain metastatic lesions in xenograft models. By using mouse models, the proposal will assess the biological significance of Lnc-BM by delivering anti- Lnc-BM siRNAs across the blood brain barrier (BBB) using nanoparticles and by evaluating its ability to diminish Lnc-BM levels in vivo as well as the extent of brain metastatic lesions. If further developed, Lnc-BM may prove useful in early identification of breast cancer patients who are at increased risk for developing brain metastatic lesions. Although additional studies will be required to validate the degree of Lnc-BM involvement in brain metastatic potential in TNBC patients, a prognostic screening marker would improve early detection and perhaps even prevention.
Each year more than 40,000 American mortalities can be attributed to breast cancer alone, with particularly frightening prognosis for patients that develop breast cancer brain metastasis (BCBM), which have proved difficult to treat because of the brain's impermeable protective layer called the blood brain barrier (BBB). A growing body of evidence suggests that nanoparticles can be used to effectively transport a therapeutic agent across the largely impermeable BBB, without concern for immunogenicity or toxicity. Additionally, preliminary data show that a specific long non-coding RNA (lncRNA), Lnc-BM (lncRNA for brain metastasis), is expressed in most brain metastatic tissues and is predictive of metastasis to the brain; thus, this proposal will identify the molecular mechanisms that are crucial to BCBM, especially in relation to Lnc-BM and the JAK2/STAT3 pathway, and subsequently demonstrate the biological consequence of using nanoparticle delivery of siRNAs against Lnc- BM in mouse models, with specific interest in the inhibition of brain metastatic lesion development.
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