Approximately, 15-20% of all breast cancers account for triple negative breast cancers (TNBCs) that exhibit aggressive, distinct metastatic pattern and poor prognosis resulting in disproportionate number of breast cancer deaths. Despite, a better chemotherapy response rate in early-stages, >60% of patients with TNBCs develop chemoresistance leading to early relapse and shorter survival. Understanding the mechanisms underlying such resistance is therefore crucial for the development of new, efficacious cancer drugs. Recently, we have discovered that small non-coding RNAs-miRNAs play critical roles in mediating drug sensitivity/resistance in TNBCs. Through high-throughput miRNA inhibitor library screens, we have identified miRNA inhibitors that uniquely sensitize drug resistant TNBCs to paclitaxel. Interestingly, our preliminary sensitizer miRNAs are expressed at significantly lower levels in relapsed metastatic TNBC patient sera compared to sera from their healthy siblings. Furthermore, using liposome- or biocompatible PLGA nanoparticle-based approaches, we show that systemic delivery of candidate miRNA suppresses breast cancer lung metastasis without any hepatotoxicity in preclinical mouse tumor models. These findings led us to hypothesize that tumor-specific miRNAs render selective cell cytotoxicity in a drug-specific manner, that these miRNAs may serve as detection markers for identifying patients those who might benefit most from specific drug treatment, and that these miRNAs may represent novel therapeutic tools for the treatment of the TNBCs. We propose three specific aims to test our hypothesis.
In Aim 1, we will test the hypothesis that candidate miRNA sensitizes cellular response to taxol by targeting microtubule-associated proteins (MAPs).
In Aim 2, we will test the hypothesis that candidate miRNA affects taxol response by targeting DNA damage surveillance pathway.
In Aim 3, we will determine the therapeutic potential of candidate miRNAs in improving the efficacy of taxol for treating therapy resistant TNBC using tumor xenograft mouse model and syngeneic mouse model with intact immune system. We will also test the response of candidate miRNAs and taxol combination therapy using ex-vivo explants from therapy sensitive and therapy resistant TNBC patients. Successful completion of this study will set stage for a new paradigm of treating therapy resistant TNBCs using miRNA therapeutics. Recent miRNA-based clinical trials have begun to establish miRNA therapeutics as a feasible approach for treating diseases in general and cancer in particular. Since miRNAs function through subtle regulation of a large numbers of factors, and can be easily manipulated using synthetic oligos, they represent more attractive targets than the single gene or gene product that is the target of conventional cancer treatments, which are typically prone to drug resistance.
Resistance to chemotherapy drugs results in poor response rates and treatment failure in more than 90% of patients with metastatic breast cancers. Moreover, breast cancer survivors often have debilitating side effects (such as cardiac toxicity) due to toxicity associated with these chemotherapy drugs. Therefore, identification of a safe and potent therapeutic drug/s that sensitize drug resistant breast cancers to chemotherapy drug could lead to more efficient treatment selection at the patient level and an improved response rates at the population level. We have discovered a novel class of molecules 'microRNAs' that not only sensitize drug-resistant breast tumors to chemotherapy drugs but also lower the dose of chemotherapy drugs required to kill tumor cells. Most importantly, microRNAs are naturally made in the body and are safe as our pre-clinical studies in mice showed that these molecules kill tumors effectively without any liver toxicity. In addition, we can measure the levels of these molecules in blood, therefore by comparing their levels in patients and healthy individual as wells as in patients before and after treatment, we can predict the treatment outcomes and tailor the drug and dose effectively for individual patients.
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