Allelic loss and loss of function of tumor suppressor genes (TSGs) are the most frequent geneticabnormalities in lung cancer. Replacement of TSG function alone is therapeutic and often leads to lungcancer cells undergoing apoptosis or cell cycle arrest in vitro. Currently it appears that such 'replacementtherapy' must be done with genes rather than small-molecule mimics of TSGs. We recently demonstratedthat restoration of function of 3p21.3 TSG FUS1, a proapoptotic protein, with the use of systemicnanoparticle delivery successfully cured mice with large human lung cancer orthotopic xenografts. In aphase I clinical trial systemic nanoparticle therapy delivered the FUS1 TSG to distant sites in stage IV nonsmallcell lung cancer (NSCLC) patients after intravenous injection. The FUS1 gene is inactivated in primarytumors due to 3p21.3 allele haploinsufficiency and defective post-translational modification of the remaininggene product. Enforced expression of the wild-type FUS1 in 3p21.3-deficient NSCLC cells significantlysuppressed tumor cell growth by induction of apoptosis, functioning as a TSG in vitro and in vivo. However,FUS1 overexpression in human bronchial epithelial cells and other normal cells does not affect their viability.We also observed that exogenous expression of wild-type FUS1 protein in NSCLC and SCLC cells deficientin FUS1 had inhibitory effects on several oncogenic protein tyrosine kinases (PTKs), including EGFR,PDGFR, c-abl, and c-kit in NSCLC and small cell lung cancer cell lines. Associated with this PTK inhibition,there was a markedly enhanced cell response to the clinically available tyrosine kinase inhibitors (TKIs)imatinib and gefitinib. Thus, combined treatment with FUS1 and TKIs led to a significant growth inhibitoryeffect on lung cancer cells that were resistant to TKIs given alone. We hypothesize that treatment with theFUS1 gene delivered by nanoparticles combined with TKI therapy will have additive or supra-additivegrowth inhibitory and pro-apoptotic effects on lung cancer cells overcoming TKI-induced or intrinsicresistance. Our long-term goal is to develop personalized, pathway-targeted treatments which are moreeffective and less toxic than current treatments.
The specific aims i n this proposed study are 1) to determinewhether FUS1-induced apoptosis and growth arrest are potentiated in various lung cancer cells /n vitro andin vivo in tumor xenograft models by TKIs that are currently being used in the clinic, 2) to identify sensitivityand resistance phenotypes associated with FUS1 expression and molecular signatures associated withthese phenotypes in human lung cancer cell lines and tumor specimens and validate candidate signaturemolecules in a larger population of lung cancer cell lines, tumor xenografts, and clinical specimens from lungcancer patients, and 3) to conduct a Phase l/ll clinical trial combining Fl/S7-nanoparticles and erlotinib instage IV lung cancer patients who have progressed following treatment with platinum-containing regimens.
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