Louisiana Biomedical Research Network

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Combinatorial treatment of miRNAs and novel palatinate against lung cancer

Gene therapy carries the strongest potential for the realization of the "personalized treatment". Uniquely, each gene therapy application stems from and depends on the expression of key genes or driver mutations present in the cancer. Its application spans from downregulation of specific genes to activation of tumor suppressor pathways for inhibition of tumor growth, chemoresistance and metastasis. Unfortunately, no clinically actionable gene therapy approaches have emerged so far and the need for research on this field is ever direr. Similarly, in lung cancer (LC), the leading cause of cancer deaths worldwide, gene therapy can have a significant impact in controlling tumor growth. With non-small-cell lung cancer accounting for >85% of all lung cancer cases, our clinical approach is commonly limited to identical therapies among different patients, primarily the use of platinum based drugs, such as cisplatin. Despite significant efforts for early detection and treatment, we practically disregard the biological background of the disease. microRNAs (miR) are looked upon as a novel class of biologicals to synergistically complement the chemotherapy, as they can simultaneously affect multiple pathways involved in cancer progression and metastasis. miR-34a, a downstream target of TP53, is capable of restoring the tumor suppressor function of an otherwise highly mutated and non-functional TP53 protein. Interestingly, TP53 aberrations have been detected in >50% of cancer patients. Furthermore, miR-30a downregulation is associated with establishment of the metastatic niche and promotion of metastasis. These two miRNAs are often downregulated in the majority of lung cancer tissues, and their exogenous delivery can prove beneficial. However, nucleic-acid delivery is limited by poor bioavailability, rapid metabolism and low cellular-uptake . We will entrap miR-34a and miR-30a mimics inside a novel tocopherol-PEl-PEG (TPP) nanovector that can encapsulate, protect and deliver multiple loads, i.e. oligonucleotides and active drugs, to the tumor mass in vivo. We will decorate the nanovectors with the tumor cell-targeting peptide, Chlorotoxin, to achieve active targeting and enhance intracellular delivery. Chlorotoxin is known to strongly discriminate between tumor and normal cells, including in lung cancer. The treatment will be combined with a novel lipid-modified platinum compound, CDDP-c8, which demonstrates higher lipophilicity, thus higher encapsulation efficiency in nanocarriers, and more importantly, has superior selective cytotoxicity, compared to cisplatin, against cisplatin-resistant cells of lung cancer.